Skin Infections Diagnosis and Treatment 1ed 2009

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SKIN INFECTIONS
Diagnosis and Treatment

This is the first textbook linking the two disciplines of dermatology and infectious diseases. As the number of elderly, AIDS,
transplant, and cancer surviving patients continues to rapidly
increase worldwide, all medical personnel need to be able to rapidly recognize and treat infections. The skin is the most easily
accessed and monitored of all organs and is often the first sign
of infection. Knowledge of the integument’s link to infection is a
must for the modern medical nurse, nurse practitioner, medical
student, resident, and practitioner. To accomplish these goals, the
text features authors from around the world who are considered
experts in their various fields. The book is organized into types of

infections, locations in the integument, specific subpopulations
of patients at risk, and regional variations of infections.
John C. Hall, M.D., is an associate staff in dermatology at the
University of Missouri–Kansas City School of Medicine. He is
also on primary staff in the Department of Medicine (subspecialty
dermatology) at St. Luke’s Hospital in Kansas City, Missouri, and
on staff in dermatology at the Kansas City Free Health Clinic.
Brian J. Hall, M.D., is a pathology resident at St. Louis University
School of Medicine.

For Charlotte,
Shelly, Kim, Tony, and Tori

SKIN INFECTIONS
Diagnosis and Treatment

EDITED BY

John C. Hall
University of Missouri–Kansas City School of Medicine

Brian J. Hall
St. Louis University School of Medicine

CAMBRIDGE UNIVERSITY PRESS

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Published in the United States of America by Cambridge University Press, New York
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© Cambridge University Press 2009
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First published in print format 2007

ISBN-13

978-0-511-53380-8

eBook (EBL)

ISBN-13

978-0-521-89729-7

hardback

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accurate or appropriate.

Contents

List of Contributors
Acknowledgments
I N T ROD U C T ION

page vii
xi
1

John C. Hall
T E C H N I Q U E S I N DIAG N O SI N G
DE R M ATOL O G IC M A N I F E S TAT ION S OF
I N F E C T IOU S DI SE ASE S

2

Francisco G. Bravo and Salim Mohanna
P R I N C I P L E S OF M A NAG E M E N T OF
DE R M ATOL O G I C I N F E C T I ON S I N T H E SK I N

PA RT I I L E S S C OM M ON I N F E C T I ON S
4 C U TA N E O U S T U B E RC U L O SI S
Bhushan Kumar and Sunil Dogra
5 L E P RO SY
Arturo P. Saavedra and Samuel L. Moschella
6 AT Y P I C A L M YC OBAC T E R IA
Francesca Prignano, Caterina Fabroni,
and Torello Lotti
7 A RT H ROP OD  B OR N E I N F E C T ION
Dirk M. Elston
8 DE E P F U NG A L I N F E C T ION S
Evandro Ararigbóia Rivitti and
Paulo Ricardo Criado
9 PA R ASI TOL O G Y
Francisco G. Bravo and Salim Mohanna
PA RT I I I I N F E C T ION S I N
SE L E C T E D E C O SYS T E M S
10 I N F E C T I ON S I N T H E DE SE RT
Joseph C. Pierson and David J. DiCaudo
11 I N F E C T I ON I N T H E T ROP I C S
Marcia Ramos-e-Silva, Paula Pereira Araújo,
and Sueli Coelho Carneiro

PA RT I V I N F E C T ION S I N SE L E C T E D
PAT I E N T P OP U L AT I ON S
13 SK I N I N F E C T I ON S I N H I V PAT I E N T S
Joseph S. Susa and Clay J. Cockerell
14 I N F E C T ION S I N ORG A N
T R A N SP L A N T PAT I E N T S

17
23

167

185

195

Daniela Kroshinsky, Jennifer Y. Lin,
and Richard Allen Johnson

8

John C. Hall
PA RT I C OM M ON I N F E C T I ON S
1 C OM M ON BAC T E R IA L I N F E C T ION S
Tammie Ferringer
2 C OM M ON V I R A L I N F E C T I ON S
Alejandra Varela, Anne Marie Tremaine,
Aron Gewirtzman, Anita Satyaprakash,
Natalia Mendoza, Parisa Ravanfar, and
Stephen K. Tyring
3 C OM M ON F U N G A L I N F E C T I ON S
Aditya K. Gupta and Elizabeth A. Cooper

12 AQUAT IC DE R M ATOL O G Y
Domenico Bonamonte and Gianni Angelini

15 C A N C E R PAT I E N T S A N D SK I N I N F E C T I ON S
John C. Hall
16 SK I N I N F E C T I ON S I N P E DIAT R I C PAT I E N T S
Michelle R. Wanna and Jonathan A. Dyer
17 SK I N I N F E C T I ON S I N T H E E L DE R LY
Noah S. Scheinfeld
18 SK I N I N F E C T I ON S I N AT H L E T E S
Brian B. Adams
19 SK I N I N F E C T I ON S I N DIA B E T E S M E L L I T U S
Nawaf Al-Mutairi

206
211
233
238
246

42

59
76
88

92
96

117

135

PA RT V I N F E C T I ON S OF SP E C I F I C
SK I N  AS S O C IAT E D B ODY SI T E S
20 I N F E C T I ON S OF T H E S C A L P
Shannon Harrison, Haydee Knott,
and Wilma F. Bergfeld
21 I N F E C T I ON S OF T H E NA I L U N I T
Gérald E. Piérard, Claudine
Piérard-Franchimont, and Pascale Quatresooz
22 I N F E C T I ON S OF T H E M U C O U S M E M B R A N E S
Julia S. Lehman, Alison J. Bruce, and
Roy S. Rogers, III
PA RT V I SP E C IA L DI SE ASE C AT E G OR I E S
23 I N F E C T I ON S I N SK I N SU RG E RY
Jean-Michel Amici, Anne-Marie Rogues,
and Alain Taïeb
24 V E N E R E A L DI SE ASE S
Travis Vandergriff, Mandy Harting,
and Ted Rosen
25 L I F E  T H R E AT E N I N G SK I N I N F E C T I ON S :
SK I N SIG N S OF I M P ORTA N T BAC T E R IA L
I N F E C T IOU S DI SE ASE S

255

268

275

303

309

322

Lisa A. Drage

150
Index

329
v

Contributors

Brian B. Adams , MD, MPH
Associate Professor of Dermatology
Director of Sports Dermatology Clinic
Chief of Dermatology, VAMC Cincinnati
University of Cincinnati
Cincinnati, OH

Francisco G. Bravo , MD
Associate Professor of Dermatology and Pathology
Facultad de Medicina Alberto Huardo
Instituto de Medicina Tropical Alexander von Humbold
Universidad Peruano Cayetano Heredia
Lima, Peru

Nawa f A l - Mu ta i ri , M D, F RC P C
Associate Professor
Faculty of Medicine
Kuwait University
Safat, Kuwait

Alison J. Bruce , MB C h B
Consultant, Department of Dermatology
Mayo Clinic
Associate Professor of Dermatology
College of Medicine, Mayo Clinic
Rochester, MN

Jean-Michel A mici , MD
Service de Dermatologique
Groupe Hospitalier Saint-Andre
Bordeaux Cedex, France
Gianni Angelini , MD
Professor of Clinical Dermatology
Head of the Dermatology Clinic
Department of Internal Medicine, Immunology
and Infectious Diseases
University of Bari, Italy
Pau l a P e re i r a A r aú j o , M D
Former Post-Graduation Student, Sector of Dermatology
University Hospital, Federal University of Rio de Janeiro
Rio de Janeiro, Brazil
Wilma F. Bergfeld , MD
Head of Dermatology and Pathology
Department of Dermatology
Cleveland Clinic Foundation
Cleveland, OH
Kumar Bhushan , MD
Department of Dermatology, Venereology and Leprology
Postgraduate Institute of Medical Education and Research
Chandigarh, India
D omenico B onamonte , MD
Research Fellow
Department of Internal Medicine, Immunology
and Infectious Diseases
Dermatologic Clinic
University of Bari
Bari, Italy

Sueli C oelho C arneiro , MD, P hD
Dermatologist, Sector of Dermatology
University Hospital, Federal University of Rio de Janeiro
Associate Professor, Sector of Dermatology
University Hospital, State University of Rio de Janeiro
Rio de Janeiro, Brazil
C l ay J. C o c k erel l , M D
Professor of Dermatology and Pathology
University of Texas Southwestern Medical Center
Dallas, TX
E liz abeth A. C o oper , B.E.S c., H.B.S c.
Mediprobe Research, Inc.
London, Ontario, Canada
Pau l o R ic ard o C riad o , M D
Dermatologist, Division of Dermatology
Hospital das Clinicas
School of Medicine
San Paulo University, Brazil
San Paulo, Brazil
Dav i d J. D i C au d o , M D
Associate Professor
Department of Dermatology and Pathology
Mayo Clinic
Scottsdale, AZ
Sunil D o gra , MD, DNB
Assistant Professor
Department of Dermatology, Venereology and Leprology
Postgraduate Institute of Medical Education and Research
Chandigarh, India
vii

viii — List of Contributors

L i s a A . D r ag e , M D
Assistant Professor of Dermatology
Mayo Clinic
Rochester, MN
Jonat ha n A . D y er , M D
Assistant Professor of Dermatology and Child Health
University of Missouri School of Medicine
Columbia, MO
Dirk M. E l ston , MD
Director, Department of Dermatology
Geisinger Medical Center
Danville, PA
C aterina Fabroni , MD
Specialist in Dermatology and Venereology
Department of Dermatological Sciences
Florence University
Florence, Italy
Tammie Ferringer , MD
Associate
Departments of Dermatology and Pathology
Geisinger Medical Center
Danville, PA
Aron Gewirtzman , MD
Center for Clinical Studies
Houston, TX
A d i t ya K . Gu p ta , M D, P h D
Mediprobe Research, Inc.
London, Ontario, Canada
Professor of Dermatology
Sunnybrook Health Sciences Center
University of Toronto
Toronto, Ontario, Canada
Brian J. Hall , MD
Resident
Department of Pathology
St. Louis University School of Medicine
St. Louis, MO
Joh n C . H a l l , M D
Associate Professor of Dermatology
University of Missouri–Kansas City
St. Luke’s Hospital
Kansas City Free Health Clinic
Kansas City, MO
Shannon C. Harrison , MBBS, MMed, FACD
Clinical Research Fellow
Department of Dermatology
Cleveland Clinic Foundation
Cleveland, OH

M an dy H art i n g , M D
Assistant Professor
Department of Dermatology
Baylor College of Medicine
Houston, TX
R ichard Allen Johnson , MD CM
Department of Dermatology
Massachusetts General Hospital
Harvard Medical School
Boston, MA
Haydee Knot t
Department of Dermatology
Cleveland Clinic Health Sciences Center
Cleveland, OH
Daniel a Kroshinsky, MD
Department of Dermatology
Massachusetts General Hospital
Harvard Medical School
Boston, MA
Ju l ia S. L eh man , M D
Resident of Dermatology
Mayo School of Graduate Medical Education
Rochester, MN
Jen n i f er Y. L i n , M D
Dermatologist
Department of Dermatology
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
Torel l o L ot t i , M D
Chairman
Department of Dermatological Sciences
Florence University
Florence, Italy
Natal ia Men d oz a , M D, M S c
Center for Clinical Studies
Houston, TX
Sal i m Mohan na , M D
Clinical Research Associate
Instituto de Medicina Tropical Alexander von Humbold
Universidad Peruano Cayetano Heredia
Lima, Peru

Samu el L . Mosc h el l a , M D
Clinical Professor (Emeritus) of Dermatology
Harvard Medical School
Staff Dermatologist
Lahey Clinic
Burlington, MA

List of Contributors — ix

Gérald E. P iérard , MD, P hD
Professor and Head of the Dermatopathology Department
University Hospital of Liège
Liège, Belgium
C l au dine P iérard-Franchimont, MD, P h D
Associate Professor, Chief of Laboratory
Dermatopathology Department
University Hospital of Liège
Liège, Belgium
Joseph C. P ierson , MD
Dermatopathologist, Anatomic and Clinic Pathologist
Uniformed Services University of Health Sciences
Bethesda, MD
United States Military Academy
West Point
New York, NY
Francesca P rigna no , MD, P h D
Assistant Professor
Department of Dermatological Sciences
Florence University
Florence, Italy
Pas ca le Q uat res o o z , M D, P h D
Master of Conference, Chief of Laboratory
Dermatopathology Department
University Hospital of Liège
Liège, Belgium
M arcia R amos-e-Silva , MD, P hD
Associate Professor and Head, Sector of Dermatology
University Hospital, Federal University of Rio de Janeiro
Rio de Janeiro, Brazil
Pa ris a R ava nfa r, M D, M BA, M S
Dermatology Clinic Research Fellow
Center for Clinical Studies
Houston, TX
Evandro Ararigb Óia R ivit ti , MD
Dermatologist and Chairman of
Department of Dermatology
School of Medicine
San Paulo University, Brazil
San Paulo, Brazil
R oy S . R o g e r s I I I , M D
Professor of Dermatology
Mayo Medical School
Consultant in Dermatology
Mayo Clinic
Rochester, MN
A n n e - M a ri e R o g u e s , M D, P h D
Service d’Hygiene Hospitaliere
Groupe Hospitaliere Pellegrin
Bordeaux, France

Te d R o se n , M D
Professor of Dermatology
Baylor College of Medicine
Chief of Dermatology
Michael E. DeBakey VA Medical Center
Houston, TX
Art u ro P. Saav ed r a , M D, P h D
Instructor in Dermatology
Harvard Medical School
Boston, MA
A n i ta Sat ya pr a kash
Dermatology Clinic Research Fellow
Center for Clinical Studies
Houston, TX
Noah S. S c h ei n f el d , M D, J D
Assistant Clinical Professor
Department of Dermatology
Columbia University
New York, NY
Joseph S. Susa , D O
Assistant Clinical Professor
Department of Dermatology
University of Texas Southwestern Medical Center
Dallas, TX
A l a i n Ta ï e b, M D, P h D
Head
Department of Dermatology and Pediatric Dermatology
University Hospitals of Bordeaux
National Reference Center for Rare Skin Disorders
Bordeaux Cedax, France
A n n e M a ri e Tre m a i n e , M D
Clinical Research Fellow
Center for Clinical Studies
Houston, TX
Stephen K. Tyring , MD, P hD, MBA
Clinical Professor of Dermatology
University of Texas Health Science Center
Houston, TX
Travis Vandergriff , MD
Department of Dermatology
Baylor College of Medicine
Houston, TX
Alejandra Varel a , MD
University of Texas Health Science Center
Houston, TX
Mic h el l e R . Wan na , M D
Resident Physician, Dermatology
University of Missouri School of Medicine
Columbia, MO

Acknowledgments

My wife, Charlotte, gave me all the encouragement anyone
could ask.
The late Richard Q. Crotty, MD, gave me the chance to be a
dermatologist. The late Clarence S. Livingood, MD, taught me to
be true to my science and my patients. The late David Gibson,
MD, and Ken Watson, DO, led my way in dermatopathology.
My office manager, Christa Czysz, has kept me afloat. My nurses,

Brandi DelDebbio and Kelly Hudgens, and my office staff, Kelly
Howell and Jennifer Phillips, have helped in enumerable ways.
A special thanks is due to my son, Brian J. Hall, MD, for
endless hours helping edit and organize this text. The incredible
group of authors in this book will speak for themselves through
these pages. It would be an honor to be half the physician these
dermatologists have proven to be.

xi

INTRODUCTION
John C. Hall

A comprehensive melding of the fields of dermatology and
infectious diseases is long overdue. It is the skin that is often
the first sign of infection and the easiest organ to quickly
access with an educated eye, culture, scraping, and histopathologic evaluation. It is the observation of the skin that can
hold the chance for the earliest diagnosis and thus the most

timely attempts at therapy. This same observation can guide
the clinician through the maze of enumerable, often confusing, and sometimes costly follow-up confirmatory tests. Let us
now, in these pages, take this opportunity the integument has
given us to lead us through the ever-increasingly important
field of infectious diseases.

1

TECHNIQUES IN DIAGNOSING
D E R M AT O L O G I C M A N I F E S TAT I O N S O F
INFECTIOUS DISEASES
Francisco G. Bravo and Salim Mohanna

GETTING THE SAMPLE

A vital step toward making the right diagnosis when dealing
with infectious diseases is ordering the appropriate test. That
implies having a certain idea of the range of possible organisms
involved and directing your workup toward ruling in or out
a specific agent. Of course, there will be cases where a more
blind approach is in order and a large range of diagnostic possibilities should be considered. In those situations, smears and
cultures for bacterial, mycobacterial, and fungal microorganisms are indicated. Also viral diseases should be considered in
specific situations, such as febrile patients with disseminated
maculopapular or vesicular rashes. However, just for practical
purposes, it is better to take a syndromic approach, considering a range of possibilities regarding the etiology of the lesions
and then, selecting the appropriate test. Let us take an example such as a patient with a sporotrichoid pattern of lesions.
If the diagnosis to confirm is sporotrichosis, a fungal culture
will be very sensitive and very specific. Pyogenic bacteria such
as Staphylococcal aureus can also produce such a pattern. In
these cases, a Gram stain and routine culture will be helpful.
But, if the patient likes fishing, swimming, or diving besides
gardening an atypical mycobacterial infection (M. marinum)
also has to be listed in the differential. In such cases, a biopsy,
acid-fast stain, and mycobacterial culture should also be considered, although recognizing this is a difficult diagnosis to
make because of the low sensitivity of each individual test. In
the same line of thought, the same patient just came back from
a trip to the Amazon: leishmaniasis is then another possibility. In leishmaniasis, there is no test with high sensitivity, so a
panel approach is indicated (direct exam, culture, intradermal
reaction, histopathology, and PCR, when available). Nocardia,
another disease capable of giving such a pattern, can only be
detected if the laboratory takes special precautions while culturing. Then, it is better to direct our workup toward a specific
diagnosis. Of course, that also implies having some knowledge
regarding the sensitivity and specificity of each test for a specific etiological agent.
Nobody other than the clinician will know best where to take
the sample from. Unfortunately for regulatory or administrative
reasons, the task is commonly left to a technician.
As a rule, purulent or oozing secretions are considered excellent samples and should be regularly submitted for direct examination with Gram, fungal, and acid-fast staining. Abscesses
should be punctured and the pus submitted under sterile conditions. Taking a biopsy of an abscess is usually not rewarding, but
clinically if there is a thick wall surrounding the cavity, it may
reveal a granulomatous infiltrate when biopsied.
2

Solid lesions, such as those suspicious for granulomatous
diseases, are better studied submitting the tissue for culture; even
then, the appropriate area should be sampled. In mycetoma, for
example, unless the biopsy is taken from areas containing granules, the yield of histology and culture will be very low.
When dealing with dry, scaly lesions, such as in tinea cases,
the scraping is very sensitive. However, in hairy areas (scalp,
beard), getting some hairs may reveal the presence of spores in
the absence of superficial hyphae. This is usually the case when
a tinea barbae has been previously treated blindly with a topical
antifungal. In cases where there is a possibility of tinea incognita,
it is advisable to microscopically examine the proximal portion
of the hairs. When dealing with white onychomycosis, scrape the
surface. If the subungeal area is affected, the detritus under the
nail are most likely to reveal the hypha or spore. Nail clippings
are considered good samples, even suitable for histological study.
The diagnosis of microscopic ectoparasites, such as scabies,
requires taking the sample from the most commonly affected
areas. Blindly scrapping off different areas is not very rewarding. In contrast, scrapping a whole scabies burrow will frequently
reveal the presence of the mites, eggs, or feces.
Moist ulcers can be swabbed and the secretions submitted
for direct examination and culture; dry ulcers can be sampled by
touch preparation. Aspirating the fluid under the border of the
ulceration with a micropipette is useful for leishmania; in leprosy, examining the fluid obtained by slitting the ear lobe under
pressure is an excellent method to visualize the mycobacteria.

TECHNIQUES

Smears
Direct examination of material obtained from lesions is a vital
first step to orient the clinician toward a specific etiology. Gram
and acid-fast stains are now routinely performed by laboratory
technicians, and the techniques themselves are beyond the scope
of this book. However, the results provided are of vital importance. Gram stain is regularly done in urethral secretions to
look for Neisseria gonorrhoeae; its absence in the presence of
neutrophiles is indicative of nongonococcal chlamydial urethritis. Acid-fast staining of smears from leprosy patients may help
establish the bacterial load.
Some tests are more easily done, on a daily basis, at dermatology offices around the world. Examples of such tests are
potassium hydroxide (KOH) preparations and the Tzanck test.
The KOH preparation is usually done using a 5% to 40% concentration. The idea is that the reaction will dissolve most of the
normal host cells, sparing the infectious agent. The condenser of

Diagnostic Techniques in Dermatology — 3

the microscope is lowered, to facilitate observation by light contrast. The test is done on skin scrapings to detect the presence of
hyphae in dermatophytes or candida. Yeast of invasive fungi such
as Blastomyces and Paracoccidioides can also be detected by this
method in purulent secretions. Hairs and nails can also be examined under the microscope in a similar manner. The same preparation can be used to examine scrapings while looking for scabies
mites and Demodex. A variation on the theme is adding colored
stains to facilitate viewing of fungal structures. Using mineral oil
instead of KOH may allow the assessment of viability and motility of ectoparasitic mites. Instead of regular scraping, one can use
adhesive tape to take the sample, a technique especially useful
when dealing with rapidly moving targets, such as the face of a
small child. Surprisingly, a similar technique will allow detection
of large fungal structures, such as the agents of chromoblastomycosis and lobomycosis when the tape is applied on top of the
clinical lesion. This is possible because of the phenomenon of
transepidermal elimination of the microorganisms. Tzanck test
implies the examination of cells at the base of an unroofed blister in suspected cases of Herpes simplex or Herpes Zoster infection. Once air dried, the slide is stained with Wright, Giemsa,
or methylene blue. The goal is to detect multinucleated giant
keratinocytes that are indicative of herpetic infections. A more
sophisticated technique utilizes an immunofluorescent antibody
against the virus, allowing species-specific identification.
Touch preparation of a genital ulcer can be examined under
dark field for the presence of treponemal spirochetes. The same
preparations, if stained as a PAP smear may allow detection of
the presence of multiple intracellular bacteria in cases of granuloma inguinale. Touch preparation of the bottom of a large ulcer
with undermined borders and acid-fast staining will be extremely
useful in detecting large amount of mycobacterium in a Buruli
ulcer (Table T-1).

Culture
The purpose of cultures is isolation of the infectious agent
to comply with one of the Koch postulates. If the diagnosis is
uncertain, samples should be sent for bacterial, fungal, viral and
acid-fast bacterial cultures. Culturing requires special media,
depending on the microorganism suspected (see Table T-2).
One has to keep in mind that certain areas of the body are heavily contaminated, such as the mouth and perianal region. The
skin, by no means an aseptic organ, can be colonized by different
bacteria and fungi. The result of cultures should be interpreted
appropriately, with correlation to the clinical lesion. Some culture
media are designed to facilitate the growth of the microorganism (such as the Thayer-Martin media for gonococcal infection or oxygen depleted systems for anerobes). Others, such as
the Mycosel, will restrict the growth of saprophytic fungi while
allowing the growth of dermatophytes. Most bacteria will grow
in a matter of days; some, such as Brucella, may require weeks in
specially designed media (such as Ruiz Castañeda). Candida will
also grow fast, even on bacterial culture media, in days. Regular
fungi, cultured in Sabouraud’s agar may grow as fast as in 1 week
(Sporothrix), 2 weeks (dermatophytes), or 4 weeks (Histoplasma
and Actinomyces). Mycobacteria may be fast growers (M. fortuitum, M. chelonae, or M. abscessus) or take several weeks (M.
tuberculosis and M. ulcerans), with additional specific temperature requirements.

Table T-1: Selected Microorganism with Special Culture
Requirements
H. influenza

Chocolate agar with factors V and X

N. gonorrhea

Thayer-Martin media

B. pertussis

Bordet-Gengou agar

C. diphtheriae

Tellurite plate, Loffler’s medium,
blood agar

M. tuberculosis

Lowenstein-Jensen agar

Lactose-fermenting enterics

MacConkey’s agar (pink colonies)

Legionella

Buffered charcoal yeast extract agar

F. tularensis

Blood or chocolate cystine agar

Leptospira

Fletcher’s or Stuart’s medium with
rabbit serum

Fungi

Sabouraud’s agar

Table T-2: Special stains
Giemsa

Borrelia, Plasmodium, trypanosomes, Chlamydia,
Leishmania

PAS

Stains glycogen, mucopolysaccharides; good for
fungi

Ziehl-Neelsen

Acid-fast bacteria and Nocardia

India ink

Cryptococcus neoformans

Silver stain

Fungi, PCP, Legionella, Bartonella, Klebsiella
granulomatis

Surprisingly enough, even in the 21st century, some famous
pathogens are still unable to be isolated in culture media.
Treponema pallidum, Mycobacterium leprae, and Loboa Loboi are
three examples. The isolation of virus by culture is not routinely
done (except for herpes simplex and varicella-zoster viruses).
Modern diagnosis relies more on molecular techniques or serologic assays.

Intradermal reactions
Intradermal reactions are widely used to support the diagnosis
of some dermatological and nondermatological diseases. They
are mainly indicated for the detection of type I (immediate
hypersensitivity) and type IV (delayed hypersensitivity) reactions toward exogenous or endogenous antigens. Intradermal
reactions for the diagnosis of infectious diseases are indicated
to detect previous contact with the agent as revealed by delayed
hypersensitivity to the whole organisms or their antigens.
The intradermal reaction is a localized inflammatory reaction with marked proliferation of lymphocytes, monocytes, and
small numbers of neutrophiles, with a tendency toward cellular accumulations arround small vessels. The induration results
from fibrin formation.
The principle of an intradermal reaction is the inoculation
of an antigen into the superficial layer of the dermis through a

4 — Francisco G. Bravo and Salim Mohanna

fine-bore needle with its bevel pointing upward. The quantity
injected may vary from 0.01 to 0.1 mL, but 0.1 mL is universally
used. Although the test could be done at any site, the proximal
part of the flexor aspect of the forearm is conventionally used.
Corticosteroids or immunosuppressive agents should be discontinued before testing for intradermal reactions because they may
inhibit the delayed hypersensitivity reaction. Intradermal reactions for the detection of delayed hypersensitivity are read at 48
hours, although they can be read as early as 12 hours and as late
as 4 days. The size of the induration is more important than erythema when interpreting delayed hypersensitivity reactions.
The tuberculin test (also called PPD [purified protein derivative], Pirquet test, or Mantoux test) is a diagnostic tool used to
detect latent infection or recent infection (as shown by conversion from negative to positive) and as part of the diagnosis of
tuberculous disease. A standard dose of tuberculin is injected
intradermally on the flexor aspect of the forearm and a reading
is taken after 48 hours. The reaction is read by measuring the
diameter of induration in millimeters. The interpretation of the
test result will depend on all relevant clinical circumstances. An
induration measuring more than 10 mm in diameter is considered to be a positive response while that measuring less than 5
mm is considered negative. A positive test indicates past or present infection with M. tuberculosis or vaccination with bacillus
Calmette-Guérin (BCG). An induration of more than 15 mm is
unlikely to be due to BCG vaccination and is strong evidence
in favor of active tuberculosis. In the absence of specific risk
factors for tuberculosis, an induration between 6 and 10 mm is
more likely to be due to previous BCG vaccination or infection
with environmental mycobacteria than to tuberculosis infection.
When there is a higher probability of tuberculosis, such as recent
contact with an infectious case, a high occupational risk or residence in a high prevalence country, an induration of 6 mm or
more is more likely to be due to tuberculosis. Anergy is present in AIDS patients. Other factors that can weaken the reaction include severe tuberculous disease, renal failure, diabetes,
immunosuppressive drugs, and old age. Initial skin tests may
have a booster effect on reactions to subsequent doses. More
sophisticated tests based on interferon production by stimulated cells are also available. Intradermal reactions for atypical
mycobacteria have also been prepared. They include PPD-Y for
Mycobacterium kansasii, Scrofulin for Mycobacterium scrofulaceum, and Burulin for Mycobacterium ulcerans.
The leishmanin test was first done by Montenegro in 1926, in
Brazil. This test (also called the Montenegro test) is indicative of
the delayed hypersensitivity reaction to leishmania, which plays
a major role in disease resolution and wound healing. It usually
becomes positive early in the course of cutaneous or mucocutaneous leishmaniasis (except in diffuse cutaneous leishmaniasis)
and only after recovery from visceral leishmaniasis. It is highly
sensitive for cutaneous leishmaniasis. The test is considered positive when induration is more than 5 mm in diameter after 48 to
72 hours. The test is not species specific. A negative test may be
attributed to an anergic state, decreased cell mediated immunity,
early treatment, or presence of an unusual serotype of leishmania, whereas a positive test favors active disease if the patient is
not a resident of the area. The same positive reaction does not
have the same relevance for natives and current residents.
The lepromin test classifies the stage of leprosy based on the
reaction and differentiates tuberculoid leprosy, (in which there is

a positive delayed reaction at the injection site) from lepromatous
leprosy (in which there is no reaction despite the active infection). The test is not diagnostic since normal uninfected persons
may react. Two types of antigens are available: Mitsuda lepromin,
an autoclaved suspension of tissue (whole bacilli) obtained from
experimentally infected armadillos; and Dharmendra lepromin,
a purified chloroform-ether extracted suspension of M. leprae
(fractionated bacilli with a soluble protein component). The
response after intradermal injection is typically biphasic, with an
early Fernandez reaction (in the form of a tuberculin reaction
with Dharmendra antigen) and a late Mitsuda reaction (in the
form of erythematous, papular nodules with Mitsuda antigen).
Other important tests used for diagnostic aid, or to evaluate the cellular immune response in patients suspected of having
reduced cell-mediated immunity, or in epidemiological studies
include the anthraxin test, the onchocerca skin test, the candidin
test, the coccidioidin or spherulin test, the histoplasmin test, and
the trichophytin test. Finally, there are some tests of historical
importance only, as they are no longer used for diagnostic purposes: Lymphogranuloma venereum (Frei’s test), Chancroid (Ito
Reenstierna test), Bartonellosis (Foshay test) and Scarlet fever
(Dick’s test).

Serology
Some tests are based on the detection of the infectious agent
antigens in serum or by the detection of the circulating antibodies generated by the host. Agglutination tests (latex agglutination
test) are based on the capturing the antibody from a suspected
patient with whole bacteria or antigen absorbed to latex particles.
The presence of circulating antibodies will then be detected by
the agglutination phenomenon. N. meningitidis and Cryptococcus
can be detected by latex agglutination. The complement fixation
(CF) test measures complement-consuming (complement-fixing) antibody in the serum or CSF of the patient. The serum to
be tested is mixed with known quantities of complement plus the
antigen targeted by the antibodies to be measured. The degree
of complement fixation indicates the amount of antibody in
the specimen. CF is used for diagnosis of some viral and fungal
infections, particularly coccidioidomycosis.
Enzyme immunoassays are based on detection of antibody
binding to a substrate linked to an enzyme. They are very sensitive and for that reason, commonly used for screening. They
include the enzyme immunoassay (EIA) and the enzyme-linked
immunosorbent assay (ELISA). ELISA is available for Chlamydia
infections, herpes virus, and human immunodeficiency virus
(HIV). On the other hand, Western blot test detects the specific
antibodies by measuring its union to antigens fixed to a membrane by blotting. It is quite specific and commonly used as a
confirmatory test in tandem with ELISA as the screening test
(i.e. in HIV, HTLV-1, and Borrelia burgdorferi).
Other examples of humoral responses that can be tested
include the treponemal serology test (including VDRL, RPR, and
the most specific FTA-Abs), as well as antibodies against Borrelia,
Legionella, Bartonella, and Leptospira. Also many viral infections,
such as hepatitis A, B and C, Epstein-Barr virus (EBV), dengue,
CMV, coxsackie, and parvovirus can be tested. Rising titers of
four times the normal baseline over a 2-week period are especially useful in viral diseases with occasional skin involvement.
Even parasitic diseases such as enteric amebiasis, cysticercosis,

Diagnostic Techniques in Dermatology — 5

and fasciolasis, as well as toxocariasis and toxoplasmosis can be
studied via serology.

Table T-3: Skin infectious diseases where PCR can be a
useful diagnostic technique

Molecular biology

Bacterial pathogens

The current concept in the use of molecular biology techniques is
based on the detection of DNA and RNA material from specific
organisms, providing an extremely reliable method of diagnosis
with high specificity and sensitivity. The current method can rely
either on the amplification of the material and posterior identification (polymerase chain reaction) or on the direct detection of
the material in tissues (in situ hybridization).
Polymerase chain reaction (PCR) consists of denaturalization of nuclear material (DNA), with posterior addition of complementary primers and synthesis of new chains by adding an
enzyme such as a polymerase. By using repeated cycles of high
and low temperatures one can obtain an amplification of nuclear
material (amplicon) until reaching amounts detectable by gel
eletrophoresis or enzyme assay base using color detection. Real
time PCR is a more sophisticated method, whereas the newly
synthesized amplicons can be detected as they are produced by
using immunofluorescent methods. Ligase-based method (LCR)
amplifies the probe rather than the microorganism’s nuclear
material. Some methods, like transcription-mediated amplification (TMA) and nucleid acid sequence-based amplification
(NASBA), rely on the amplification of RNA material, which is
usually more abundant than DNA. The current application for
those techniques includes several pathogens listed in Table T-3.
For example, both PCR and TMA are FDA approved for the
diagnosis of pulmonary and extrapulmonary tuberculosis. By
this technique, some researchers have been able to demostrate
the presence of bacillus in cutaneous tuberculosis and tuberculids. These findings are, however, not consistent with other similar studies. The variable sensitivity and specificity of the method
may be related to tissue inhibitors or fixation methods. PCR is
also available for the second and third most common mycobacteriosis around the world, which are, Mycobacterium leprae and
Mycobacterium ulcerans. The PCR technique has been very helpful in the study and discovery of new bartonella species as well.
Several viruses are suitable for PCR testing, with some variations in methodology such as the multiplex reverse transcriptase
PCR used in varicella zoster infections. The cause–effect relation
between HHV-8 and Kaposi’s sarcoma has been demostrated by
PCR. The role of different HPV in cutaneous neoplasia, such as
HPV-16 in verrucous carcinoma of the foot and HPV-6 and -11
in anogenital verrucous carcinoma have been possible by this
amplification method. PCR allows not only identification but
also quantification of viral loads in in HIV infections. In some
parasitic diseases such as leishmaniasis, the PCR techniques are
considered quite sensitive and quite specific. The gene targets
include 18S-rRNA, small subunit rRNA, mini-exon gene repeat,
β-tubulin gene, transcriber spacer regions, and microsatellite
DNA of the kinetoplast. The sensitivity is so high that it may
allow detection of as little as half a parasite. Many fungal infections can now be precisely identified, as is the case for mycetomas by Madurella mycetomatis.
Another useful technique now available is in situ hybridization (ISH). It is based on the detection of nucleic acid material
from different microorganisms directly in tissues, even if they are
fixed in formalin. Fluorescent ISH (FISH) is a more sophisticated

Mycobacterium tuberculosis
M. leprae
M. ulcerans
Rickettsia rickettsii
R. prowazekii
Baronella henselae
Spirochetes
Treponema pallidum
Borrelia burgdorferi
Virus
Herpes simplex 1 and Herpes simplex 2
Varicela zoster virus
Human herpesvirus 8
Human papillomavirus
HIV
Hepatitis C virus
Parvovirus B19
Epstein-Barr virus
Parasites
Leishmania infantum
Leishmania braziliensis
Balamuthia mandrillaris
Fungi
Aspergillus fumigatus
Aspergillus versicolor
Aspergillus flavus
Blastomyces dermatitides
Cryptococcus neoformans
Candida albicans
Candida dubliniensis
Coccidioides immitis
Histoplasma capsulatum
Sporothrix schenckii
Madurella mycetomatis
Various dermatophytes
Modified from Sra KK, Torres G, Rady P, Hughes TK, Payne DA,
Tyring SK. Molecular diagnosis of infectious diseases in dermatology.
J Am Acad Dermatol. 2005 Nov;53(5):749–65.

6 — Francisco G. Bravo and Salim Mohanna

Table T-4: Infectious Agents that can be Identified by ISH
Varicella Zoster
Molluscum contagiosum
HIV
HPV
EBV
Hepatitis C virus
HHV-8
Mycobacterium tuberculosis
Mycobacterium leprae
Leishmania spp.
Candida albicans
Cryptococcus neoformans
Modified from Sra KK, Torres G, Rady P, Hughes TK, Payne DA,
Tyring SK. Molecular diagnosis of infectious diseases in dermatology.
J Am Acad Dermatol 2005;53(5):749–765.

method that is used not only to identify infectious agents but
also in gene mapping and chromosome analysis. ISH has been
used to confirm the presence of HPV in epidermodysplasia verruciformis and EBV in hydroa-like lymphomas. Table T-4 details
infectious agents that can be identified by ISH.
The development of DNA microarray technology, also
known as DNA chip technology, will allow testing for multiple
microorganisms or genetic defects, all at once. In this method,
DNA from a clinical sample is first amplified by PCR, converted
to RNA or more DNA, mixed with fluorescent dyes, and then
applied over a plate containing many different oligonucleotides
or cDNA libraries. After the hybridization between sample
material and fixed probes on the plates takes place, stimulation
by laser will light up the hybridized labeled probes. The total
image then obtained will reflect the DNA or RNA contents in
the original sample and compare them to control arrays. This
technique has allowed identification of M. tuberculosis variants with gene mutations conferring resistance to isoniazid and
rifampin. As more of these sophisticated methods become available, our understanding of disease mechanisms and the interactions between humans and pathogens will be complemented by
knowledge about microorganism genetic variations, drug resistance, and disease epidemiology.

Skin biopsy as a diagnostic technique
While dealing with cutaneous infectious diseases the accessibility of skin as a source of sampling makes the biopsy an important diagnostic tool. Like any other method, one can determine
the sensitivity and specificity of the biopsy for diagnostic purposes. Specificity can be very high, as in a case of molluscum
contagiosum or rhinoscleroma, or very low, such as in a grossly
superinfected ulcer, where one can see many bacterial colonies
on the surface. The sensitivity can be very high, in a case of South

American blastomycosis (paracoccidioidomycosis), or very low
in a case of sporotrichosis.
Biopsies can be considered suggestive of, compatible with,
or diagnostic of a specific infectious disease. How we use these
terms, although subjective, may be based on the frequency of specific histological patterns seen associated with a specific agent, or
the findings of the microorganism itself in the histological cuts.
We think the term “suggestive” should be used if the histological
pattern is commonly seen in a condition unsuspected by the clinician. The term “compatible with” should be used if the pattern
seen coincides with one of the entities considered in the differential listed by the clinician, although the microorganism itself is
not seen. The term “diagnostic of ” should imply visualizing the
agent itself, and carries the most certainty. Biopsies also allow
establishing the inflammatory or neoplastic nature of a lesion.
The prevalence of a specific cell in a pattern will also direct
our diagnosis:. For example a plasma cell–rich liquenoid infiltrate with histiocytes will be in favor of a spirochete-induced
disease (either syphilis or borreliosis). Vacuolated histiocytes
accompanied by a lymphoplasmacytic infiltrate are commonly
seen in leishmaniasis, rhinoscleroma, and granuloma inguinale.
Suppurative granulomas are indicative of mycobacteria and deep
fungal infection. A dense perivascular and interstitial, superficial
and deep inflammatory infiltrate rich in eosinophils, with extension into the subcutaneous tissue, is suggestive of a deep larva
migrans or gnathostomiasis.
An important fact obtained from the skin biopsy is the granulomatous nature of an infiltrate. Many chronic infectious diseases are characteristically granulomatous. Granulomas can be
divided into five types: tuberculous, suppurative, foreign body,
palisaded, or sarcoidal. It should be mentioned that tuberculous
granulomas are not exclusively seen in tuberculosis but in several other entities. Caseation necrosis is a more reliable sign of
tuberculosis, but in its absence, other diagnostic possibilities for
tuberculoid granulomas may include leishmaniasis, tuberculoid
leprosy, and sporotrichosis. Even caseation necrosis may not be
that specific as it can be seen in nontuberculous processes such
as rosacea.
Suppurative granulomas, containing neutrophils in the center, are commonly seen in deep fungal infections such as North
American blastomycosis, paracoccidioidomycosis, chromoblastomycosis, and sporotrichosis, as well as in some atypical mycobacterioses. A pseudocarcinomatous hyperplasia may be seen on
top of the granuloma. Stellate necrosis in a granuloma is suggestive of cat scratch disease. Sarcoidal granulomas can be seen
in sarcoidosis but also as a reaction to foreign materials such as
silica and beryllium. Rarely, leprosy and paracoccidioidomycosis
can be quite sarcoidal in appearance.
The diagnosis by histological patterns of the inflammatory
diseases of the skin, as was outlined by Dr. Ackerman, can also
be applied to these infections. There are some patterns that are
quite specific for certain diseases like rhinoscleroma, bartonellosis, lepromatous leprosy, and Buruli ulcer.
In rhinoscleroma there is a diffuse infiltrate that occupies
all of the dermis. The infiltrate is made up of foamy histiocytes,
arranged in mantles. Plasma cells are intermixed in the infiltrates.
Some of these cells accumulate such an amount of immunoglobulin within their cytoplasm that they develop into eosinophilic
globules, so-called Russell bodies. Occasionally, rod-shaped

Diagnostic Techniques in Dermatology — 7

bacteria will be seen within some of the histiocytes. These represent the causal agent, Klebsiella rhinoscleromatis.
The cutaneous lesions of bartonellosis (including verruga
peruana and bacillary angiomatosis) are characterized by a
dome-shaped silhouette. Below a flattened epidermis there is a
capillary vascular proliferation, with a background of histiocytes
intermingled with small neutrophilic abscesses. Occasionally in
cases of bacillary angiomatosis, there is a purple material in the
intercellular space representing aggregates of bartonellas. The
combination of histiocytes, vascular proliferation, and neutrophilic abscesses should be considered suggestive of infection by
this group of bacteria.
Lepromatous leprosy is characterized by a proliferation of
foamy histiocytes at the level of the reticular dermis, either in
a diffuse or linear form, following vascular or neural structures.
Commonly a zone of uninvolved papillary dermis separated
from the epidermis may be seen (which is referred to as the
Grenz Zone). Basophilic globi represent clumps of intracellular
mycobacteria. Buruli ulcer, an infection induced by M. ulcerans,
will produce a pattern of necrotizing panniculitis with a sparse
or absent inflammatory infiltrate, and innumerable acid-fast
bacilli will be present as well. This pattern of bacteria-rich necrotizing panniculitis is not seen in any other mycobacterioses like
tuberculosis or leprosy.
Depending on how easily the causative microorganism can
be seen, skin biopsies can be divided into three categories: biopsies of high, medium, and low sensitivity.
The first category is those biopsies that have a high diagnostic sensitivity. They are diagnostic when the causal agent is seen
either in routine (H&E) or slides stained for microorganisms.
Examples in this category include molluscum contagiosum,
K. rhinoescleromatis, and deep fungal agents such as P. braziliensis (South American blastomycosis), L. loboi (lobomycosis),
C. neoformans, C. immitis, B. dermatitides, H. capsulatum, and
the agents of chromoblastomycosis. Easily detectable as well are
the sulphur grains of actinomycosis, eumycetomas, and actinomycetomas. The acid-fast stain allows the detection of innumerable bacilli in lepromatous leprosy and Buruli ulcer. PAS
and Gomori stains typically reveal large amounts of hyphae in
mucormycosis or in immunosuppresed patients with invasive
aspergillosis.
The second category includes entities with biopsies of
medium diagnostic sensitivity. In such cases the infectious agent
is not always visible in the routine cuts. Agents occasionally seen
in skin biopsies include leishmaniasis, free living amebas, bartonellas in cases of bacillary angiomatosis (with Warthin-Starry
stain), and dermatophytes. In leishmaniasis the number of visible parasites is related to the different evolutionary stages and the
degree of immunity developed by the host. In early lesions the
Leishmania spp. are seen intracellulary inside macrophages close
to the epidermis. In cases of poor immune response (the so-called

diffuse cutaneous leishmaniasis), the parasites are observed in
great numbers as intracellular forms. In long-standing cases, the
infiltrate is made of lymphocytes and plasma cells, and the possibility of finding parasites is small. If present, they are scarce,
and they can easily be confused with fragments of plasma cells.
So, in leishmania cases the specificity of the biopsy diminishes
as a method of diagnosis. It is better to take a panel approach,
including intradermal leishmanin tests, direct examination and
culture, and where available, PCR studies. In syphilis cases, an
inmunoperoxidase stain is now available that can facilitate the
identification of treponemes in tissue cuts.
The last category is of those biopsies with very little diagnostic sensitivity, where the microorganism is particularly difficult to visualize, even with special stains. This includes parasites
causing cutaneous larvae migrans, gnathostomiasis, fungi such
as Sporotrichum, and bacteria such as the bartonellas of verruga
peruana. Also difficult to see are M. tuberculosis, M. marinum,
and the M. leprae in cases of tuberculoid leprosy. In sporotrichosis, diagnosis is based on culture isolation, which is by far the
method of greatest sensitivity. In tuberculosis, the direct examination and culture also have a low sensitivity. Commonly, just
a tuberculous granulomatous inflammation is seen. It is in this
group of diseases that PCR technology appears very promising.
Special stains such as rodamine or immunoperoxidases such as
anti-BCG may allow better detection.
In summary, the biopsy of skin is of variable utility from a
diagnostic point of view. The diagnosis can be suggested by a
specific pattern, but absolute certainty is only obtained when
the causal agent can be seen. The clinician should consider these
limitations. Rather than depending only on special stains, the
pathologist should familiarize himself or herself with the histological pattern of the disease, as well as with the frequency the
causal organisms are seen in routine cuts. The new techniques
of immunoperoxidase and PCR will indeed play a role in those
entities where routine H&E-stained biopsies have the lowest
sensitivity.

SUGGESTED READINGS

Nagar R, Pande S, Khopkar U. Intradermal tests in dermatology-I:
tests for infectious diseases. Indian J Dermatol Venereol Leprol
2006;72(6):461–465.
Nelson K. Tuberculin testing to detect latent tuberculosis in developing countries. Epidemiology 2007;18(3):348–349.
Sadeghian G, Momeni A, Siadat AH, Usefi P. Evaluation of leishmanin
skin test and its relationship with the clinical form and duration of
cutaneous leishmaniasis. Dermatol Online J 2006;12(7):3.
Sra KK, Torres G, Rady P, Hughes TK, Payne DA, Tyring SK. Molecular
diagnosis of infectious diseases in dermatology. J Am Acad
Dermatol 2005;53(5):749–765.

PRINCIPLES OF MANAGEMENT OF
D E R M AT O L O G I C I N F E C T I O N S I N
THE SKIN
John C. Hall

As with all of medicine, correct therapy depends on a correct
diagnosis, which is established through clinical and laboratory
(see chapter on techniques in diagnosing manifestations of infections) observations.
The progress of an infection can be more carefully monitored
in the skin than in any other organ due to ease of clinical observation. The four primary signs of acute infection are color, warmth,
tenderness (and/or pain) and swelling. Additional signs include
induration, erosion or ulceration, vesiculation, pustulation, linear
streaking along lymphatics, lymphadenopathy, asymmetry, vasculitic appearance, necrosis, and progression. This progression can be
visually monitored and marking the edge with an indelible marker
can help demonstrate the spread or regression of the edge of the
infection. These clinical signs can all be less apparent in the growing
population of immunocompromised patients who do not mount
the typical immune response. On the contrary, immunocompromised patients may have worse clinical signs that appear at a faster
rate than those seen in nonimmunocompromised individuals.
Probably the best example of the importance of these principles
in all of medicine is illustrated in the case of necrotizing fasciitis,
the sine qua non of importance for the skin and infectious diseases.
Each chapter will have a brief history about the disease or diseases
covered at the beginning as well as a reminder of potential pitfalls
and myths at the end. The pitfalls and myths section will help to
serve as a summary of where it is easy to go wrong clinically and
where you want to go right. Necrotizing fasciitis will be used as a
brief sample of how each chapter will be laid out in the book.

H I STORY

Necrotizing fasciitis is thought to be first named and described in
detail by Joseph Jones, who was a historian and leading medical
officer in the Confederate army during the Civil War of the United
States. He kept copious records of hundreds of patients seen during the civil war including many injured soldiers at Andersonville
prison in Georgia, which was ill equipped in resources and physical room to keep the overabundance of captured Union troops
who often died of malnutrition, disease, and starvation. The original designation for this illness was “hospital gangrene.” Fournier,
a respected French dermatologist was credited with describing a
group of patients with this form of cellulitis in the groin, mainly
in men, 1883 and hence the designation “Fournier’s gangrene.”
In 1924, Meleny (“Meleney’s ulcer”) recognized that this condition rapidly became a fatal systemic disease. Wilson coined the
term “necrotizing fasciitis” in 1952. Five cases were reported in
Gloucestershire, England, between June 1 and June 30, 1994 and
two of theses cases were seen in patients who had an operation
8

in the same operating theater. This led to the idea that it was a
highly contagious “flesh-eating” bacterial infection. No other
such cluster of patients has ever been reported, however.
CLINICAL DIAGNOSIS

The commonest predisposing condition is diabetes (seen in 40 to
50%), especially when associated with dialysis. Other associated
underlying diseases are traumatic wounds, AIDS, metastatic
cancer (with or without chemotherapy), varicella (especially in
children which is sometimes called varicella gangrenosum), postoperatively and rarely post delivery. The abdomen, perineum,
and extremities are the commonest areas affected.
Fever is present in at least two-thirds of patients with hypotension and in at least a third of cases. Altered sensorium is present
in approximately one-fourth of patients and crepitus in 10%.
Pain and anesthesia have both been reported at the site of erythema, which rapidly becomes edematous and bluish. Gangrene
develops within 5 days or less and may or may not be covered
with a bulla. Mortality can range from 25% to 50%, especially if
treatment is delayed. An unexplained association with the oral
use of nonsteroidal anti-inflammatory agents has been reported
in some cases.
L A B O R AT O RY D IA G N O S I S

A several fold increase in creatinine phosphokinase can be helpful in differentiating necrotizing fasciitis from erysipelas or other
more benign types of cellulitis. Culture most often shows group A
β-hemolytic streptococci (including strains causing toxic shock)
when there is a single agent present. Klebsiella is probably the
second most common. Community-acquired methicillin-resistant Staphylococcus aureus has also been reported as a pathogen.
There is a trend toward more polymicrobic infections. Necrotic
tissue for culture may be helpful in determining the causative
bacteria, but awaiting this report can be fatal for the patient.
T R E AT M E N T

Poor prognosis is associated with increased age (especially greater
than 60 years old), female gender, delay of first debridement, extent
of infection, increased creatinine, increased lactate, anemia, thrombocytopenia, and extent of other organ system involvement.
Early extensive surgical debridement is mandatory (magnetic resonance imaging may help tell the extent of debridement necessary) and may have to be repeated multiple times.

Principles of Management of Infections in the Skin — 9

Immediate intravenous broad-spectrum antibiotic therapy with
adequate coverage for streptococci, staphylococci, as well as
gram-negative organisms is also important. This can be modified
when cultures are obtained. Hyperbaric oxygenation and highdose intravenous IgG immunoglobulin have been advocated as
being beneficial by some authors.

P I T FA L L S A N D M Y T H S

This skin infection illustrates the importance of early decision
making based on clinical data. Laboratory data may be confirmatory but may be acquired too late to save the patient’s life.
Overtreatment of a less serious infection is preferable to undertreatment of necrotizing fasciitis. The difficult patient is the one
with a paucity of symptoms, (i.e. patients exhibiting no pain and
little generalized toxicity). Do not assume that a relatively asymptomatic patient is not gravely ill and will stay symptom free for very
long. Hospitalization is quite helpful since significant changes in
the patient’s condition can occur over hours. This disease is usually more extensive than first suspected (see Fig. Principles.1).
Do not let cultures that do not show streptococci or are polymicrobic dissuade you from the diagnosis. When reviewing the
medical literature remember that multiple names may have been
used for the same condition. “Progressive ischemic gangrene” is
one example.
Clinical judgment and close observation are of no small
importance. Remember that in any skin infection the great
advantage is that the skin can be easily seen and followed as no
other organ. Use your skill of careful surveillance.
While awaiting laboratory confirmation of a clinical diagnosis
there are a subgroup of patients (such as those discussed already
with necrotizing fasciitis) that are so ill that empiric therapy
needs to be started before actual identification of the offending
organism is established (see Table Principles.1).
With infections in dermatology, unlike many other specialties, there is often an opportunity to use topical instead of oral,
intramuscular, subcutaneous, or intravenous therapy. The advantages of topical versus systemic treatment of cutaneous infections
is discussed in Table Principles.2. Combination therapy in serious disease is often the best choice.

Table Principles.1 Conditions Where Empiric Therapy Is
Needed
Blueberry muffin baby with generalized papules, pustules, or purpura
at birth (always cover for herpes simplex virus until diagnosis is
confirmed) and consider the TORCH (toxoplasmosis, others {HIV,
syphilis, varicella}, rubella, cytomegalovirus, herpes simplex)
complex
Necrotizing Fasciitis (always cover for streptococci)
Cellulitis (always cover for staphylococcus and β-hemolytic
streptococci since a positive culture is often difficult and may only be
obtainable from a blood culture if patient is septic)
Cutaneous necrosis (cover for staphylococcus, β-hemolytic
streptococci and if indicated by history for vibrio vulnificus infection
or if indicated by clinical setting for sepsis and immunocompromise,
pseudomonas, candidiasis, or aspergillosis)
Vasculitis (cover for Rocky Mountain spotted fever and
meningococcus)
Staphylococcal scalded skin syndrome (cover for staphylococci
including methicillin-resistant staphylococci, which may now be
community acquired and streptococci)
Atypical mycobacteria (histopathology and culture may be falsely
negative, so may have to treat based on clinical impression alone)

Table Principles.2 Topical vs Systemic Therapy for Skin
Infections
Topical Therapy
Pro

Systemic Therapy

1. Less systemic side effects

1. More efficacious, faster

2. No access site needed

2. Treats concomitant
disease in other
organs

3. Gastrointestinal absorption
not essential

3. Can monitor blood
levels

4. No gastrointestinal symptoms
5. Less chance of sensitization
6. Healing benefit of a base as
well as an anti-infectious
agent
Con

1. Topical therapy may obscure
disease progression

1. Serious allergic
reaction more likely

2. Contact sensitization can
occur

2. May need access site

3. Less efficacious, slower

3. May be much more
expensive

4. Systemic absorption can still
result in systemic side effects

4. May not be available
5. Absorption of oral
drugs may be erratic

Figure Principles.1 Necrotizing fasciitis on the scalp of an elderly
man with MRI showing extension well into the neck and shoulders.
Culture was positive for β-hemolytic streptococci. The patient survived in large part due to repeated aggressive surgeries.

6. Drug interactions
are an important
consideration

10 — John C. Hall

Table Principles.3 General Guidelines for Topical Therapy of Skin Infections
1. Ointments’ (hydrophobic) bases repel water and tend to hold the product on the skin longer and increase penetration. Ointments also
protect the skin better and facilitate re-epitheliazation.
2. If a skin condition is weeping or oozing then an initial period of 2 to 5 days may be needed when the exudate is debrided chemically or
surgically or the wound is dried with water, saline, Aveeno (oatmeal), or Domeboro compresses. A cream (hydrophilic base) may be used if
more drying is felt to be indicated.
3. A thick adherent eschar may need surgical debridement to allow healing and treatment of the underlying infection.
4. Incision and drainage may be as important or more important (as shown in the recent outbreak of MRSA skin infections) than any topical or
even systemic therapy.
5. Restoration of the epidermal barrier (such as in eczema) is necessary to prevent the need for continual therapy.
6. Signs of increased heat, spreading redness, regional lymphadenopathy, fever, and increased tenderness may indicate that systemic therapy
needs to be added to topical therapy.
7. Allergic contact dermatitis due most commonly to antibiotics, antifungals, antiyeast, preservatives, and adhesives in tape and other
surgical dressings needs to be considered in the differential diagnosis of any worsening skin infection. Clues to this include itching,
blistering, and sudden increased redness without fever or regional lymphadenopathy. Unless accurately diagnosed, the condition will
continue to worsen.
8. Systemic absorption of the drug is always a consideration. This is especially a concern when the epidermal barrier is compromised, in
intertriginous areas where absorption is increased, large areas are treated, and in infants where the body surface area is increased, when large
areas compared to the body mass.

Table Principles.4 Topical Therapy for Skin Infections
Antibacterial

Bacitracin
Neosporin cream and ointment contains polymyxin B, Neomycin, bacitracin; neomycin
allergy 1%
Polysporin cream and ointment contains polymyxin B and bacitracin; can use if
neomycin allergy
Centany (Bactroban) cream and ointment contains mupirocin, and is effective against
MRSA in addition to the same coverage as polysporin and neosporin. Resistance by
some staphylococci is reported
Silver-containing compounds used in chronic ulcers, burn patients, and patients with
toxic epidermal necrolysis
0.5 % silver nitrate solution poured over dressing
Silvadene Cream (cannot use if sulfa allergy is present)
Aquacel Ag Hydrofiber
Acticoat Absorbent Fiber
Silvercel
Contreet Foam
Polymem Silver Foam
Urgotal S. Ag
Silvasorb Hydrogel
Iodine-containing products
Betadine solution, surgical scrub, hand cleanser, and ointment
Tincture of iodine
Lugol’s solution
Altabax (retapamulin) ointment
Gentamicin cream and ointment

Principles of Management of Infections in the Skin — 11

Antibacterial
Antifungal

Bacitracin
Imidazoles effective against yeast and dermatophytes
Micatin (Monistat) cream contains miconazole
Lotrimin cream contains clotrimazole
Lotrisone lotion contains clotrimazole and betamethasone
Spectazole cream contains intraconazole
Oxistat cream contains oxiconazole
Nizoril cream, shampoo, lotion contains ketoconazole
Ertaczo contains sertaconazole
Ciclopirox effective against yeast and dermatophytes
Loprox gel, lotion and shampoo and Penlac nail lacquer
Whitfield’s ointment (6% salicylic acid, 12% benzoic acid) is also antiyeast and
antibacterial

Antiyeast

See above
Nystatin cream, ointment, oral suspension contains nystatin
Mycolog II cream and ointment contains nystatin and triamcinolone

Antiviral

Denavir contains penciclovir for herpes simplex
Zovirax contains acyclovir for herpes simplex
Aldara contains imiquimod for warts (esp. genital warts), molluscum contagiosum

Antiparasitic

Thiabendazole for cutaneous larva migrans
Aldara (imiquimod) for leishmaniasis
Permethrin for lice and scabies
Malathione for lice
Gammabenzene hexachloride for lice and scabies but permethrin has largely replaced
this medication since it is less toxic
Results (50% isopropyl myristate) for lice

Nonspecific (helps all infections by changing pH
and acting as a drying agent)

Domeboro compresses (dilute in water with packets or tablets)
Vinegar compresses (mainly for pseudomonas or gram-negative infections) can use
equal parts white vinegar and water
Bleach compresses (mainly recurrent Staphylococcus aureus infections) can use 1 tbsp in
1 pint of water or one cup to a full tub of water as a soak

Topical therapy has some general guidelines, which helps
when trying to select the correct topical agent (see Table
Principles.3)
A formulary for the most commonly used topical agents is
listed in Table Principles.4. When dealing with infected ulcers
and wounds, chemical or surgical debridement is an important
fundamental part of therapy.
Infectious diseases of the skin may be transmitted by insect
vectors, and it is important, therefore, to discuss repellants of
these pests (Table Principles.5). Prevention of these potentially
hazardous envenomations is the best treatment. Bees, wasps,
hornets, and yellow jackets are not repelled by insect repellants.
They can become secondarily infected with streptococci and

staphylococci. There is no proven effective repellant for ticks,
and tsetse flies also do not respond to insect repellants. Insect
bed netting should have 1.5 mm openings or less for mosquitoes.
If coated with permethrin there is more protection. Finer mesh
is needed for sandflies.
No discussion of dermatology and infection would be complete without mentioning the importance of cutaneous transmission of infections. Universal precautions in the hospital or
outpatient setting are a mandatory part of any attempt to control the spread of disease. Antiseptic liquids that can be applied
without water are very easily accessed in both the hospital and
outpatient clinics and have become a mainstay of decreasing skin
transmission of infectious diseases.

12 — John C. Hall

Table Principles.5 Insect Repellants for Mosquitoes and
Sandflies
DEET (N,N-diethylmetatoluamide)

Effective against mosquitoes, especially at
higher concentrations above 20%

Example is Bite Blocker for Kids
Vitamin B1

Waterproof and safe

20 to 30% used as directed is safe

Mosquitoes, gnats, no see-ums, ticks may be
repelled

Effective when applied to clothes

Composite Repellants

May damage some plastics
Avoid repetitive use to large areas of skin
especially in children
Picaridin (KBR 2033)

Don’t Bite Me for Kids Patch

Available in a longer-acting formula
(Ultrathon-lasts 8 hours)

Example is Sawyer Gold Repellant
(Contains DEET 17% and MGK 2645)

Callicarpenal (derived from
Beauty Berry shrub)

Available in Europe, Asia, Australia and Latin

Appears to be safe and effective for
mosquitoes, ticks, fireants
Not yet available for commercial use

America for years
New 7% variant available in United States
No odor, will not damage plastic
Not a dermal sensitizer
Good repellent for mosquitoes flies, no seeums, fleas
No toxicity

Table Principles.6 Skin Diseases Associated with Increased
Infection
Eczema

Decrease in immunity especially to
staphylococcus.

According to WHO best repellant for
preventing malaria
Reapply after several hours
Permethrin (Permanone)

Psoriasis

Interruption of epidermal barrier. Not as well
documented as in eczema.

Burns

Second- or third-degree causes loss of epidermal
barrier, especially Pseudomonas aeruginosa.

Toxic Epidermal
Necrolysis

Loss of epidermal barrier and sepsis is the usual
cause of death frequently acquired through the
skin.

Epidermolysis Bullosa

Especially in the more severe recessive form of
the disease.

Hailey-Hailey Disease

Control of yeast and bacterial infection is an
important

(Chronic Benign
Familial Pemphigus)

part of therapy. Loss of epidermal barrier in
intertriginous macerated areas.

Pemphigus Vulgaris

Loss of epidermal barrier. Sepsis is usual cause of

Apply to clothing only
0.5% permethrin spray is applied to clothing
and may last up to 6 weeks
Examples of sprays are Repel and Sawyer
Permethrin Tick Repellant
The best way to apply is to spray on clothes
outside and let it dry (it is inactivated in 15
minutes on the skin)
Potent dermal sensitizer
May help repel and kill ticks,

Oil of Lemon Eucalyptus

Not approved in children under 3 y/o
Active ingredient should be oil of lemon
eucalyptus (PMD) and not the essential or
pure oil of lemon eucalyptus

death, often entering through the skin
Wiskott-Aldrich
Syndrome

Decreased immunity

Repels mosquitoes, flies, gnats
Safe but odiferous

Interdigital tinea pedis

Especially in diabetics this can be a nidis
for tinea, candida and ultimately staph and strep

Examples are Repel Eucalyptus Oil (6 hour
Protection), Cutter Lemon Eucalyptus Spray
Cintronella

and can lead to a limb threatening infection.
Related to local factors of warmth and wetness
and increased

As a candle possibly some benefit
No evidence of topical application benefit

Precipitated Sulfur

Interruption of epidermal barrier.

susceptibility in a diabetic patient.

Shake powder in socks or shoes
Effective for most insects, possibly even ticks,
but has a “rotten egg” odor

Catnip Oil (nepatalactone)

Probably ineffective

Soybean Oil

Repels, mosquitoes, gnats, no see-ums, ticks

Chronic leg ulcers

(ischemic ulcers) or venous (stasis ulcers)
and no epidermal barrier.
Puncture wounds

Be sure tetanus vaccinations up to date.
Copious irrigation.

Safe even in children
Relatively sweat and waterproof

Decreased circulation either arterial

Animal bites

Augmentin is probable drug of choice.

Principles of Management of Infections in the Skin — 13

Table Principles.7 Noninfectious Skin Diseases that Mimic
Infection

Disease

Infections Mimicked

Disease

Infections Mimicked

Dermatitis herpetiformis

Scabies

Pyoderma gangrenosum

Furuncle or carbuncle early

Herald patch of Pityriasis
rosea

Tinea corporis

Granuloma annulare

Tinea corporis

Insect bites

Hot tub folliculitis (Pseudomonas)

Verrucous carcinoma

Verrucae

Oral lichen planus

Candidiasis (Thrush)

Psoriasis of the nails

Onychomycosis

Bowen’s disease in the
groin

Tinea cruris (especially if unilateral)

Infected ulcer or granulomatous infection late.
Eosinophilic fasciitis

Cellulitis

Sclerosing panniculitis

Cellulitis

Thrombophlebitis

Cellulitis with lymphangitis

Steroid folliculitis

Staphylococcous Folliculitis

Eosinophilic pustular
folliculitis

Staphylococcous Folliculitis

Angioedema

Erysipelas
Cellulitis

Extramammary Paget’s in
the groin

Tinea cruris (especially if unilateral)

Relapsing polychondritis
Pityriasis rosea

Secondary syphilis

Dyshidrotic eczema

Vesicular tinea pedis

Acute generalized
eruptitve pustular drug
eruption

Staphylococcous folliculitis

Pilonidal cyst

Abscess

Morbilliform drug reaction

Viral exanthem

Pustular psoriasis

Staphylococcous folliculitis

Panniculitis

Cellulitis

Inflammatory breast
cancer

Cellulitis

Parasitophobia

Scabies

Fiberglass dermatitis

Scabies

Subcutaneous emphysema

Cellulitis

Psoriasis

Crusted or Norwegian scabies

Nummular eczema

Impetigo

Factitial dermatitis

Contact dermatitis

Cellulitis

Fixed drug eruption

Herpes simplex

Almost any infection in which culture and
histopathology are repeatedly negative for
organisms and especially if the course is
atypical

Guttate psoriasis

Secondary syphilis

Hidradinitis suppurativa

Carbuncles, furuncles
Granuloma inguinale
Abscesses

Dissecting cellulitis of the
scalp

Abscesses

Pustular acne

Staphylococcal folliculitis

Cystic acne

Abscesses

Lethal midline granuloma
(lymphoma)

Granulomatous infections such as deep fungi
or mucormycosis

Stewart-Treves syndrome

Cellulitis

Vasculitis

Cellulitis

Squamous cell cancer

Granulomatous infections such as deep fungi,
mycobacteria, mycetoma or leishmaniasis,
verrucae

Actinic keratosis

Verrucae

Seborrheic keratosis

Verrucae

Ruptured sebaceous cyst

Abscess

Brown recluse spider bite

Cellulitis, necrotizing fasciitis

Sweet’s syndrome

Cellulitis

Well’s syndrome

Cellulitis

Lymphoma

Granulomatous infection
Cellulitis
Nodular scabies

In the general population, infection is more apt to be acquired
through skin that has had epidermal barrier damage. The opportunity to treat these infections early is apt to make the overall
burden of disease much less. The commonest examples of these
are listed in Table Principles.6.
Just as infections can mimic a multitude of noninfectious
skin conditions, noninfectious skin conditions can also mimic
infection. Some of those most common of these pseudoinfections of the skin are listed in the following Table Principles.7.

SUGGESTED READINGS

Elliott DC, et al. Necrotizing soft tissue infections. Risk factors for mortality and strategies for management. Ann Surg.
1996;224(5):672–683.
Liu YM et al. Microbiology and factors affecting mortality in necrotizing fasciitis. J Microbiol Immunol Infect (2005);38(6):430–435.
Misago N, et al. Necrotizing Fasciitis due to group A streptococci: a clinicopathological study of six patients. J Dermatol.
1996;23(12):876–882.
Vulgia JD, et al. Necrotizing fasciitis 24 cases in children with varicella.
Renal Fail, 1995;17(4):438–447.

PA R T I : C O M M O N I N F E C T I O N S

1

COMMON BACTERIAL INFECTIONS
Tammie Ferringer

INTRODUCTION

Uncomplicated skin and skin structure infections (uSSSIs) are
frequent causes of office visits. The most common bacterial uSSSIs include impetigo, ecthyma, folliculitis, furuncles, carbuncles,
abscesses, erysipelas, and cellulitis.

is a confluence of furuncles with multiple sinus tracts. The posterior neck is a typical location. Occasionally these more complex
lesions are associated with fever, malaise, and lymphadenopathy.
Chronic staphylococcal carriage, diabetes, and obesity are predisposing factors. Similar to furuncles and carbuncles, abscesses
are tender, fluctuant nodules (Fig. 1.3) with surrounding erythema. Abscesses are usually not associated with a follicle.

Folliculitis
Follicular pustules, often with a rim of erythema, characterize folliculitis (Fig. 1.1). Bacterial is one cause, but physical and chemical
irritations are also etiologic factors. Predisposing factors include
shaving, occlusion, oily topicals, staphylococcal carriage, and
friction. Children and young adults are most commonly affected,
but folliculitis can occur at any age. Areas of involvement include
the face, scalp, beard, axillae, buttocks, and legs.
Hot-tub folliculitis is a variant associated with the use of
contaminated hot tubs, whirlpools, and heated swimming pools.
This characteristically pruritic folliculitis commonly develops on
the trunk 1 to 4 days after exposure.

Cellulitis
Cellulitis is also a nonfollicular infection but typically lacks the
purulence of abscesses. Spreading erythema, edema, and warmth

Furuncles/Carbuncles/Abscesses
Folliculitis, furuncles, and carbuncles represent a continuum of
follicular infection. Furuncles or “boils” (Fig. 1.2) are similar to
folliculitis, however,the suppurative infiltrate extends beyond the
follicle into the dermis and subcutaneous fat. These lesions are
fluctuant and tender but typically do not have systemic symptoms. These nodules eventually rupture and discharge pus. The
most commonly involved areas are those prone to friction,
including the breasts, axillae, buttocks, and thighs. A carbuncle

Figure 1.1. Follicular papules and pustules of folliculitis.

Figure 1.2. Tender erythematous furuncles.
17

18 — Tammie Ferringer

Figure 1.3. Fluctuant nodule consistent with abscess.

Figure 1.5. Sharply defined erythematous raised border of erysipelas.

Figure 1.4. Erythema of cellulitis.

Figure 1.6. Vesicles, pustules, and honey colored crust of impetigo.

characterize cellulitis (Fig. 1.4). The infection involves the deep
dermis and subcutaneous tissue and may be associated with mild
systemic symptoms including fever and chills. The body area
involved varies with age. For children the head and neck are most
commonly affected, while in adults the lower extremities are more
commonly affected. The breach in skin integrity, which serves as
the portal of entry for infection, can be clinically subtle. An underlying dermatosis, macerated interdigital tinea, trauma, surgical
incisions, and foreign bodies can all allow entry. Chronic lymphedema, venous insufficiency, diabetes, alcoholism, malignancy,
IV drug abuse, and immunosuppression are predisposing factors.

the characteristic honey colored crusts (Fig. 1.6). The central
face and extremities are the most common areas involved. Skin
trauma and a diminished cutaneous barrier from preexisting
dermatoses, like eczema, can predispose to impetigo. Other
predisposing factors include warm, humid environments and
staphylococcal colonization. Although it can affect patients of
any age, impetigo is the most common skin infection in pediatric patients. Fewer than one-third of cases of impetigo are of
the bullous form. This variety occurs mostly in infants and on
normal skin. Bullae larger than 5 mm can be seen.

Ecthyma
Erysipelas
Erysipelas is a superficial variant of cellulitis that reveals erythema, warmth, tenderness, and peripheral extension. Unlike
cellulitis, there is a sharply defined, raised border (Fig. 1.5), and
blisters, pustules, and focal hemorrhagic necrosis may be identified. Regional adenopathy, occasionally lymphangitis, and systemic symptoms are often present. The face and legs are the most
common sites involved.

Impetigo
Impetigo is a contagious, superficial skin infection. Vesicles
and pustules develop on an erythematous base and evolve into

Ecthyma is a deeper version of impetigo. The lower extremities
are most often affected. This disease is characterized by thick,
adherent crusts over ulcers (Fig. 1.7) with an indurated border
that often heals with scars.
H I STORY

Penicillin was introduced in the early 1940s as a treatment for
infections caused by gram-positive cocci, such as Staphylococcus
aureus. Shortly after, antibiotic resistance became increasingly
obvious. Currently, the majority of staphylococci are resistant to
penicillins due to the production of β-lactamase. Surprisingly, over
the years, Streptococcus pyogenes has still remained susceptible.

Common Bacterial Infections — 19

Table 1.1: Bacterial Infections and Associated Organisms
Infection

Figure 1.7. Thick adherent crust over ulceration that characterizes
ecthyma.

Methicillin was introduced in 1959 to overcome the problem
of resistance, but this was rapidly followed by identification of
methicillin-resistant Staphylococcus aureus (MRSA). Since then,
hospital-associated MRSA (HA-MRSA) has steadily increased.
More recently, community-acquired MRSA (CA-MRSA) came
to national attention after reports of outbreaks in prisons and
athletic teams in 2002. To this day there continues to be an
alarming increase in the incidence of CA-MRSA.

Folliculitis

Staphylococcus aureus
Pseudomonas aeruginosa (Hot-tub
folliculitis)

Furuncles/Carbuncles

S. aureus

Abscess

Polymicrobial reflecting regional flora
S. aureus alone in one-quarter

Erysipelas

Streptococcus pyogenes

Cellulitis

S. aureus
Streptococcus pyogenes

Ecthyma

St. pyogenes
S. aureus

Impetigo

S. aureus
St. pyogenes

Table 1.2: Characteristics of CA-MRSA and HA-MRSA
Characteristic

CA-MRSA

HA-MRSA

Risk factors

Day care attendees,
athletes, prisoners,
soldiers, IV drug
users, homosexual
men, homeless, Native
Americans, Alaska
natives, Pacific
Islanders

Nursing home residents,
hemodialysis patients,
prolonged hospitalization,
indwelling catheters

Resistance

β-lactam resistance

Multidrug resistance

Infection

Folliculits, furuncles,
and abscesses

Pneumonia, catheter-related
urinary or bloodstream
infection, postoperative
infection

EPIDEMIOLOGY

S. aureus and Group A β-hemolytic streptococci (Streptococcus
pyogenes) are the organisms most commonly associated with
uSSSIs. Table 1.1 lists the most common causes of the uncomplicated bacterial skin infections.
S. aureus is the most common cause of bacterial folliculitis.
However, under certain conditions other organisms may be the
cause. For example, hot-tub folliculitis is caused by Pseudomonas
aeruginosa, and patients receiving chronic oral antibiotics for
acne may develop gram-negative folliculitis, most commonly
due to Klebsiella pneumoniae and Enterobacteriaceae.
Like folliculitis, the most common cause of furuncles and
carbuncles is S. aureus. Abscesses, on the other hand, are often
polymicrobial and reflect the regional skin flora. However,
S. aureus is identified alone in about one-fourth of cases.
Erysipelas is caused almost exclusively by Streptococcus
pyogenes. In most immunocompetent adults, cellulitis is due to
S. aureus and St. pyogenes. Certain circumstances are also associated with other infectious etiologies. Gram-negative bacilli may
be causative in neutropenic patients. Cat and dog bites are typically due to Pasteurella species or Capnocytophaga. Periorbital
cellulitis in unimmunized children is due to Haemophilus influenza. Etiologic bacteria may reflect the regional skin flora. For
example, infection of the ear or toe webs may involve gramnegative organisms while infection adjacent to the gastrointestinal or respiratory tract may include anaerobes.
Streptococcus pyogenes, sometimes with secondary S. aureus
infection, is the cause of ecthyma. The majority of cases of impetigo are caused by S. aureus and less commonly St. pyogenes.

Organism

CA-MRSA, community-acquired methicillin-resistant Staphylococcus
aureus; HA-MRSA, hospital-acquired methicillin-resistant
Staphylococcus aureus.

S aureus, phage group II type 71, is the predominant causative
organism of bullous impetigo. The bulla is due to staphylococcal toxins that cause acantholysis of the granular layer similar to
what takes place in staphylococcal scalded skin syndrome.
In addition to possible bacteremia, the primary cutaneous site
of infection can rarely be associated with other significant consequences. Some strains of streptococci have the ability to cause
acute glomerulonephritis and some produce toxins associated with
streptococcal toxic shock syndrome. Treatment of the cutaneous
infection does not seem to alter the risk of glomerulonephritis but
treatment can decrease spread of the nephrotoxic strain. Toxins
produced by some strains of S. aureus can result in staphylococcal
scalded skin syndrome or staphylococcal toxic shock syndrome.
Methicillin-sensitive S. aureus (MSSA) is the most common
form of S. aureus identified in association with superficial skin
infections. However, MRSA has become increasingly frequent.
There are two forms of MRSA, health care associated (HA-MRSA)
and community acquired (CA-MRSA) (Table 1.2). Antibiotic

20 — Tammie Ferringer

resistance is a concern with HA-MRSA while CA-MRSA remains
sensitive to antibiotics including trimethoprim–sulfamethoxazole
and tetracycline. CA-MRSA has increasingly been identified in
association with furuncles and abscesses. CA-MRSA typically
affects the young and healthy, especially those living in crowded
conditions or in close physical contact, and in certain ethnic
groups. Those most commonly affected include athletes, military
personnel, injection drug users, homosexual men, the homeless,
children in day care, prisoners, Pacific islanders, Alaskan natives,
and Native Americans.
The CA-MRSA and HA-MRSA isolates are distinct both epidemiologically and genetically, but there is increasing cross-over
in clinical presentation. Therefore, it is best to refer to these strains
as “community-type strains” and “health care–type strains.”

DIAGNOSIS

USSSIs are typically diagnosed by clinical presentation and treated
empirically. Tissue culture, needle aspiration, and blood culture
have a poor yield in cellulitis and erysipelas. If bullae or an abscess
is present, culture of these areas is more likely to be positive.
The diagnosis of impetigo and ecthyma can be confirmed with
culture and Gram stain of the exudate below the crust. Culture of the
purulent material associated with folliculitis, furuncles, carbuncles,
and abscesses is useful to help tailor the antibiotic therapy.

THERAPY

In some uSSSIs, conservative treatment alone is sufficient but in
other cases oral antibiotics are necessary. Rarely, resistant cases
and complicated skin infections require intravenous antibiotics.
Folliculitis typically resolves spontaneously; however, topical
clindamycin, mupirocin, or benzoyl peroxide can accelerate the
healing. Disposal of razors and treatment of predisposing factors
is required to prevent reinfection. In the case of hot-tub folliculitis, resolution occurs in 1 to 2 weeks with or without treatment.
In the case of persistent infection, oral ciprofloxacin is the treatment of choice. The contaminated water source should be identified and corrected to prevent further outbreaks.
In the case of furuncles, carbuncles, and abscesses, pain is
relieved with drainage, which can be promoted with moist heat
or surgically via incision and drainage. Drainage alone is often
sufficient; however, drainage with systemic antibiotics is recommended when there is surrounding cellulitis, deep extension,
systemic symptoms, gas-containing lesions, lesions on the central
face, and in patients with serious comorbidities such as immunosuppression. Culture at the time of drainage is recommended
to allow susceptibility testing to guide the choice of alternative
antibiotics in the event of a poor response to empiric therapy.
Treatment of localized impetigo includes topical mupirocin with debridement of the infectious crust. However, mupirocin resistance limits use. Retapamulin ointment was recently
approved by the FDA for treatment of impetigo. In nonresponsive or extensive cases of impetigo and in ecthyma, systemic antibiotics are required.
Erysipelas and cellulitis in immunocompetent patients
is treated with oral antibiotics. When possible, elevation of
the affected area is recommended. If infection is recurrent,

Table 1.3: Organism-Directed Therapy
Organism

Treatment

Alternatives

Staphylococcus
aureus (MSSA)

Penicillinaseresistant penicillin

Penicillin/β-lactamase
inhibitor, cephalosporins,
clindamycin,
fluoroquinolones

S. aureus (MRSA)

Trimethoprimsulfamethoxazole,
tetracyclines,
fluoroquinolones,
clindamycin

Vancomycin, linezolid,
daptomycin, quinopristin/
dalfopristin, tigecycline,
newer generation
carbapenems, and
teicoplanin

St. pyogenes

Penicillin

Erythromycin,
cephalosporins,
clarithromycin,
azithromycin, clindamycin

MRSA, methicillin-resistant Staphylococcus aureus

predisposing factors such as lymphedema or tinea pedis should
be addressed.
When oral antibiotics are necessary, the initial choice of
empiric oral antibiotics should take into account the most likely
pathogen (including the local prevalence of MRSA) (Table 1.3),
regional drug susceptibilities of these pathogens, as well as patient
allergy, and severity of the infection. Purulent lesions, especially
in recognized risk groups, suggest possible CA-MRSA, and
empiric therapy should be based on this assumption. Therapy is
later tailored by culture results for those who fail to improve on
empiric therapy.
Although penicillin is sufficient for treatment of erysipelas
that is almost exclusively caused by St. pyogenes, most uSSSIs
require coverage of S. aureus. Therefore, empiric treatment of
minor skin and soft tissue infections includes penicillinase-resistant penicillins, penicillin/β-lactamase inhibitor (amoxicillinclavulanic acid), cephalosporins, clindamycin, macrolides, or
fluoroquinolones.
CA-MRSA should be suspected in certain risk groups and
those not responding to standard therapy for MSSA. Most cutaneous infections with CA-MRSA are purulent; therefore, drainage is the most important intervention but oral antibiotics may
be required. Susceptibility is constantly evolving and varies by
geographic region but in general, drugs active against CA-MRSA
include trimethoprim–sulfamethoxazole and tetracyclines.
Tetracyclines should be avoided in children below 8 years of age
and during pregnancy. The fluoroquinolones are alternatives but
resistance is emerging. Rifampin can be used in conjunction with
other antibiotics but not alone because of rapid development of
resistance. Clindamycin has been used successfully; however,
inducible resistance can emerge during therapy. Erythromycin–
clindamycin double-disc diffusion testing is required to check
for inducible resistance prior to use of clindamycin.
Vancomycin is reserved for severe systemic infections with
multiresistant MRSA strains. Newer agents for MRSA include
linezolid, daptomycin, quinopristin–dalfopristin, tigecycline,
newer generation carbapenems, and teicoplanin. Many of
these drugs require intravenous administration and are usually
reserved for treatment of HA-MRSA, which is typically resistant

Common Bacterial Infections — 21

to multiple antibiotics. Susceptibility patterns are constantly
evolving, and unfortunately, MRSA strains with resistance to
some of these newer antibiotics have already been identified.
Signs of more serious infection include pain out of proportion to clinical findings, extensive necrosis, violaceous to
necrotic bullae, anesthesia, rapid progression, or crepitus. If
these findings or systemic toxicity (hypotension, tachycardia) is
identified, blood culture, complete blood count with differential,
hospitalization, and surgical and/or infectious disease consultation should be considered.
Cutaneous and nasal S. aureus colonization serves as a reservoir for reinfection. Based on 2001–2002 National Health and
Nutrition Examination Survey (NHANES) data, reported by
Graham et al., the prevalence of colonization of S. aureus and
MRSA in the noninstitutionalized US population was 31.6% and
0.84%, respectively. These numbers are on the rise, and in 2003
CA-MRSA colonization was identified in 1.3% of all adults and
in 2.5% of all children.
Conditions predisposing to S. aureus colonization include intravenous drug use, diabetes, hemodialysis, and skin disorders that
impair the cutaneous barrier such as atopic dermatitis. CA-MRSA
is associated with crowded conditions and close physical contact.
Unlike treatment of infection, lasting eradication of colonization is difficult to achieve. Attempts at elimination of colonization, in the absence of personal or close contact infection, are
not recommended. Various decolonization strategies have been
reported but convincing evidence is lacking and has resulted in
antibiotic resistance and adverse events from systemic therapy.
However, for those with recurrent infection, eradication is an
important part of treatment.
Oral antibiotics achieve poor levels on the skin surface requiring topical agents such as chlorhexidine, triclosan, benzoyl peroxide
wash, or Dakin’s solution to address skin colonization. However, triclosan resistance has been identified in MSSA and MRSA isolates.
Topical mupirocin twice a day for the first 5 days each month
is often used to treat nasal carriage but resistance is emerging.
Intranasal fusidic acid is an alternative but resistance has similarly been reported. Few systemic antibiotics attain adequate levels in nasal secretions; however, oral clindamycin and rifampin
have been used. Failure is not uncommon. Use of rifampin in
combination with other antimicrobials may decrease resistance.
Other measures are important in preventing reinfection in
the presence of colonization. Laundering of clothing, towels, and
linens, in addition to keeping separate towels and washcloths,
is required. Predisposing conditions such as eczema should be
treated. Just as hand washing in hospitals reduces spread of infection, decontamination of fomites, such as athletic equipment, is
helpful in community-acquired outbreaks.

P I T FA L L S A N D M Y T H S

Folliculitis is not always due to a bacterial infection. Other
causes include an acneiform process, a fungal, or a viral infection. Culture of associated pustules may be required for confirmation. Similarly, not all abscesses are infectious and culture
and/or biopsy can help differentiate from ruptured cysts and
hidradenitits suppurativa.
Erysipelas may resemble contact dermatitis, angioedema,
or the butterfly rash of lupus; however, fever and pain are not

typical of the later disorders. Ear involvement can be confused
with relapsing polychondritis. However, the noncartilaginous
earlobe is characteristically spared in relapsing polychondritis.
Lower extremity cellulitis may be confused with stasis dermatitis, panniculitis (especially lipodermatosclerosis), deep
venous thrombosis, and superficial thrombophlebitis. Cellulitis
is rarely bilateral, unlike stasis dermatitis. However, both conditions can coexist, as stasis dermatitis predisposes to cellulitis. If a
palpable cord is not present, duplex ultrasound may be required
to identify superficial thrombophlebitis or deep venous thrombosis. Panniculitis is typically associated with induration and
may require biopsy for confirmation.
Impetigo may be confused with perioral dermatitis, seborrheic dermatitis, allergic contact dermatitis, herpes simplex, and tinea. Primary dermatoses can acquire secondary
impetiginization because of the impaired cutaneous barrier. Culture confirms the presence of impetigo or secondary
impetiginization.
One myth associated with bacterial infections is the assumption that all bacterial colonization should be treated, when in
reality, lasting eradication of colonization can be difficult to
attain and is not necessary in the absence of infection.
Another misconception is that MRSA strains are more virulent and require parenteral therapy. However, the spectrum of
disease with MRSA is similar to that of MSSA and particularly
in the case of CA-MRSA, remains susceptible to several antibiotics. Intravenous treatment is only required in severe systemic or
refractory infections.

SUGGESTED READINGS

Bamberger DM, Boyd SE. Management of Staphylococcus aureus infections. Am Fam Physician 2005;72(12):2474–2481.
Barton LL, Friedman AD. Impetigo: a reassessment of etiology and
therapy. Pediatr Dermatol 1987;4(3):185–188.
Berger RS, Seifert MR. Whirlpool folliculitis: a review of its cause,
treatment, and prevention. Cutis 1990;45(2):97–98.
Centers for Disease Control and Prevention (CDC). Outbreaks of
community-associated methicillin-resistant Staphylococcus aureus
skin infections – Los Angeles County, California, 2002–2003.
MMWR Morb Mortal Wkly Rep 2003;52(5):88.
Cunha BA. Methicillin-resistant Staphylococcus aureus: clinical manifestations and antimicrobial therapy. Clin Microbiol Infect 2005;11
Suppl 4:33–42.
Edlich RF, Winters KL, Britt LD, Long WB 3rd. Bacterial diseases of
the skin. J Long Term Eff Med Implants 2005;15(5):499–510.
Elston DM. Community-acquired methicillin-resistant Staphylococcus
aureus. J Am Acad Dermatol 2007;56(1):1–16; quiz 17–20.
Falagas ME, Bliziotis IA, Fragoulis KN. Oral rifampin for eradication
of Staphylococcus aureus carriage from healthy and sick populations: a systematic review of the evidence from comparative trials.
Am J Infect Control 2007;35(2):106–114.
Graham PL 3rd, Lin SX, Larson EL. A U.S. population-based survey of Staphylococcus aureus colonization. Ann Intern Med 2006
7;144(5):318–325.
Halem M, Trent J, Green J, Kerdel F. Community-acquired methicillin
resistant Staphylococcus aureus skin infection. Semin Cutan Med
Surg 2006;25(2):68–71.
Kielhofner MA, Brown B, Dall L. Influence of underlying disease process on the utility of cellulitis needle aspirates. Arch Intern Med
1988;148(11):2451–2452.

22 — Tammie Ferringer

Kowalski TJ, Berbari EF, Osmon DR. Epidemiology, treatment,
and prevention of community-acquired methicillin-resistant
Staphylococcus aureus infections. Mayo Clin Proc 2005;80(9):
1201–1207.
Lee MC, Rios AM, Aten MF, Mejias A, Cavuoti D, McCracken GH
Jr, Hardy RD. Management and outcome of children with
skin and soft tissue abscesses caused by community-acquired
methicillin-resistant Staphylococcus aureus. Pediatr Infect Dis J
2004;23(2):123–127.
Loeb M, Main C, Walker-Dilks C, Eady A. Antimicrobial drugs for
treating methicillin-resistant Staphylococcus aureus colonization.
Cochrane Database Syst Rev 2003;(4):CD003340.
Pankuch GA, Lin G, Hoellman DB, Good CE, Jacobs MR, Appelbaum
PC. Activity of retapamulin against Streptococcus pyogenes and
Staphylococcus aureus evaluated by agar dilution, microdilution,

E-test, and disk diffusion methodologies. Antimicrob Agents
Chemother 2006;50(5):1727–1730.
Rayner C, Munckhof WJ. Antibiotics currently used in the treatment of infections caused by Staphylococcus aureus. Intern Med J
2005;35 Suppl 2:S3–16.
Roberts S, Chambers S. Diagnosis and management of Staphylococcus
aureus infections of the skin and soft tissue. Intern Med J 2005;35
Suppl 2:S97–105.
Stevens DL, Bisno AL, Chambers HF, Everett ED, Dellinger P, Goldstein
EJ, Gorbach SL, Hirschmann JV, Kaplan EL, Montoya JG, Wade
JC; Infectious Diseases Society of America. Practice guidelines for
the diagnosis and management of skin and soft-tissue infections.
Clin Infect Dis 200515;41(10):1373–1406.
Yang A, Kerdel FA. Infectious disease update: new anti-microbials.
Semin Cutan Med Surg 2006;25(2):94–99.

2

COMMON VIRAL INFECTIONS
Alejandra Varela, Anne Marie Tremaine, Aron Gewirtzman, Anita Satyaprakash,
Natalia Mendoza, Parisa Ravanfar, and Stephen K. Tyring

H I STORY

Viral diseases may produce mucocutaneous manifestations
either as a result of viral replication in the epidermis or secondary to viral replication elsewhere in the body. Most primary
epidermal viral infections result from three groups of viruses:
human papillomaviruses (HPV), herpesviruses, and poxviruses. Secondary lesions are produced by virus families such as
retroviruses, paramyxoviruses, togaviruses, parvoviruses, and
picornaviruses.

DNA VIRUSES

1. Poxviruses: replicate in the cytoplasm
a. Molluscipox: molluscum
b. Orthopox: vaccinia, smallpox, cowpox
c. Parapox: Orf, milker’s nodules
2. Papillomaviruses: replicate in the nucleus
3. Herpesviruses: replicate in the nucleus
4. Hepadnavirus: replicate in the nucleus
5. Adenoviruses: replicate in the nucleus

POX VIRUSES

Molluscipox (Molluscum Contagiosum)
There are two main subtypes of molluscipox: Molluscum
Contagiosum virus (MCV) I and MCV II. Both can be seen
in genital and nongenital areas. MCV I is more prevalent than
MCV II except in HIV infection. Incubation of the virus ranges
from 1 week to months.
Molluscum bodies have large numbers of maturing virons.
These virions are sealed off by collagen and lipid-rich sac-like
structures that protect the virus from host defenses. Free virus
cores can be found in all layers of the epidermis. Histologically,
viral particles in infected keratinocytes and eosinophils can be
observed. These are known as Henderson–Paterson bodies (molluscum bodies).

Treatment

Curettage, liquid nitrogen, cantharidin, lactic acid, CO2, imiquimod, and trichloroacetic acid can be used. Cidofovir is used in
immunocompromised patients.

Orthopox
1.
2.
3.
4.

Smallpox
Vaccinia
Monkeypox
Cowpox

Smallpox
Smallpox is caused by the variola virus. Variola minor is also
known as alastrim. Progressive vaccinia can be related to immunosuppression, malignancy, radiation therapy, or AIDS infection. Histologically, smallpox demonstrates balloon and reticular
degeneration with hemorrhagic inclusion bodies and polymorphonuclear cells.
Clinical Manifestations

Incubation lasts for 12 to 13 days. Fever, malaise, backache, and
exanthema appear after 2 to 4 days. The lesions evolve from
macules to papules to vesicles to pustules. There are four clinical
types of smallpox: ordinary, modified (by previous vaccination),
flat, and hemorrhagic. The latter two have the highest mortality
rate, they are 30% fatal.
The lesions are discrete, firm, deep-seated papules that are
vesiculated and umbilicated. Crusts will form later. All lesions
are in the same stage. Corneal ulceration, laryngeal lesions,
encephalitis, and hemorrhage are all possible complications.
Variola major can also cause fatal complications such as death
secondary to pulmonary edema or heart failure. Patients with
immunosuppression, malignancy, radiation therapy, or AIDS
are at higher risk for progressive vaccinia.
Treatment

No antiviral treatment exists for smallpox. Cidofovir has been
suggested to combat the infection.

Clinical Manifestations

This virus is found mainly in the pediatric age-group and is
characterized by dome-shaped umbilicated papules. Children
often acquire the virus by close contact. The virus can also be
transmitted sexually, resulting in genital papules. In immunocompromised patients, especially patients with HIV infection,
thousands of papules can be present.

Vaccination

The smallpox vaccine provides a high level of immunity for
3 to 5 years, with decreasing immunity thereafter. The vaccine, however, has risks associated with its administration.
Postvaccination encephalitis and progressive vaccinia can
occur.
23

24 — Alejandra Varela, et al.

Vaccinia
Vaccinia is a laboratory virus used to vaccinate against smallpox
and monkeypox. The infection occurs primarily in laboratory
workers.
Clinical Manifestations

Papules appear in 2 to 3 days, followed by an umbilicated
Jennerian vesicle. A scab ensues and results in a pitted scar. The
formation of a pustule at day 7 confirms successful vaccination.
Generalized vaccinia can occur secondary to viremia. It typically occurs 6 to 9 days after vaccination. Eczema vaccinatum
can develop, and this occurs more commonly in immunocompromised patients or patients with a nonintact skin barrier.
Treatment

The suggested treatment is Cidofovir.
Monkeypox
This virus occasionally infects humans, predominantly residents
of western and central Africa. Populations at risk can receive
protection from vaccination with the vaccinia virus.
Cowpox
Cowpox historically infected cows, but is more commonly found
in cats. The animals are generally infected at sites of injury –
especially at the teats. The virus can infect humans and is transmitted by touch from animals to humans.

Over a 36-day period, the lesions advance through six clinical
stages. Each stage lasts for 6 days.
1. Papular stage: lesions are red and elevated.
2. Target stage: nodule with a red center, white ring, and red
halo.
3. Acute stage: weeping surface.
4. Regenerative stage: thin, dry crust with black dots.
5. Papillomatous stage: small papillomas over the surface of the
lesion.
6. Regressive stage: thick crusts heal with scarring.
Diagnosis

History and physical examination, confirmed by cell culture,
fluorescent antibody, complement fixation, electron microscopy,
or histology.
Treatment

Infection spontaneously remits. Direct local care should be
aimed at avoiding secondary infection.
Milker’s Nodules (Paravaccinia)
Paravaccinia, or milker’s nodules, are endemic to cattle. Human
disease is contracted through direct transmission (handling of
infected cow teats) or through fomites. The virus is 150 × 300
nm and brick shaped. Histologically, the lesions are similar to
those of orf.
Clinical Manifestations

Clinical Manifestations

Symptoms of infection of cowpox are localized, pustular lesions
generally found on the hands. Lymphadenopathy and fever may
also occur.

Parapox
1. Orf
2. Paravaccinia (milker’s nodules)
Orf (Ecthyma Contagiosum, Scabby Mouth)
This virus is endemic among sheep, goats, and oxen. Transmission
occurs from animals or fomites (especially barn doors and
troughs). Sheep farmers and veterinarians are mainly affected.
Lesions heal in approximately a month.
The virus is large and ovoid and measures 250 × 160 nm with
surface tubules. It is resistant to drying and lipid solvents, such as
ether and chloroform. Incubation period is 4 to 7 days.
Histologically, vacuolization of cells in the upper third of the
stratum spinosum is observed with multilocular vesicles, acanthosis, and eosinophilic inclusion bodies in the cytoplasm and
nucleus of infected cells. A mixed infiltrate with loss of epidermis over the central part of the lesion is also seen. During the
acute stage of this infection, necrosis with massive infiltration of
mononuclear cells can be seen.
Clinical Manifestations

Typically nodules are seen around the mouth and nose of animals. Patients present with lymphadenopathy, malaise, fever, and
painful lesions (usually on the fingers).

A solitary nodule develops on the finger, which increases slowly
in size over a period of 1 to 2 weeks. The nodules are painless and
bluish red in color. The lesions typically heal without scarring
and patients are often afebrile.
Diagnosis

History and physical examination, confirmed by cell culture,
fluorescent antibody, complement fixation, electron microscopy,
or histology.
Treatment

Most lesions spontaneously heal within 5 to 7 weeks. Direct
local care is aimed at avoiding secondary infection.

H U M A N PA P I L L O M AV I R U S

Three categories are used to clinically describe human papillomavirus (HPV):
1. Anogenital/mucosal
2. Nongenital cutaneous
3. Epidermodysplasia verruciformis (EV)

Diseases and Associated HPV Subtypes
Nongenital Cutaneous Diseases (See Table 2.1)
HPV infects the stratified squamous epithelium. The various HPV
strains display predilections for specific body sites. They can infect
and cause both cutaneous and mucosal disease. HPV gains access

Common Viral Infections — 25

Table 2.1: Nongenital Cutaneous Diseases
Disease

HPV Type

Common warts (verrucae vulgaris)

1, 2, 4, 26, 27, 29, 41, 57, 65

Plantar warts (myrmecia)

1, 2, 4, 63

Flat warts (verrucae plana)

3, 10, 27, 28, 38, 41, 49

Butcher’s warts (common warts of
people who handle meat, poultry,
and fish)

7

Mosaic warts

2, 27, 57

Subungual squamous cell carcinoma

16

Epidermodysplasia verruciformis
(benign)

2, 3, 10, 12, 15, 19, 36, 46,
47, 50

Epidermodysplasia verruciformis
(malignant or benign)

5, 8, 9, 10, 14, 17, 20, 21, 22,
23, 24, 25, 37, 38

Figure 2.1. Verruca vulgaris.
Treatment

to keratinocytes, and thus establishes an infection. The viral gene
expression influences the proliferation and maturation of the
keratinocyte, which results in the growth of a benign tumor. The
virus is transmitted by person to person contact. HPV infection
is often self-limited and a large portion of the world’s population
has at some point been infected with the virus.
P A L M O P L A N T A R WA R T S

HPV-1 is the most common type responsible for palmoplantar warts. The lesions may be located anywhere on the palms
and/or soles, especially on the fingertips and tips of the toes.
Palmoplantar warts may have a number of clinical presentations.
They start as minute punctate depressions that coalesce into
large, thin, endophytic confluent plaques called mosaic warts.
If they coalesce as thick confluent plaques, they are known as
myrmecia warts. The borders are sharply demarcated, with a surrounding border of thick callus.
Histologically, the warts display acanthosis, papillomatosis
and hyperkeratosis. Myrmecia warts show prominent cytoplasmic, eosinophilic inclusion bodies surrounding the vacuolated
nuclei of koilocytes.
Treatment

Available treatments include salicylic acid, 20% trichloroacetic
acid, cryotherapy, CO2 laser, cantharidin, bleomycin, and combination therapy using electrodessication, cryodestruction or
surgery and imiquimod.
C O M M O N WA R T S  V E R R U C A V U L G A R I S 

HPV-2 is the most common HPV type associated with common warts, followed by HPV-4, -26, -27, -65, -78. The clinical
manifestations include single or grouped scaly, rough papules or
nodules especially on the hands (see Fig. 2.1). A close examination would reveal “black dots” which are thrombosed capillaries
within the warts. Common warts are very frequent in children
and young adults. The lesions tend to koebnerize.
Histologically, common warts are characterized by marked
acanthosis associated with hyperkeratosis, elongated rete ridges,
prominent koilocytes and stacks of parakeratotic cells and basophilic keratohyaline granules. Dilatation and thrombosed capillaries are evident at the dermis.

Treatment includes salicylic acid, 50% trichloroacetic acid, cantharidin, cryotherapy with liquid nitrogen, electrodessication, and
combination therapy with cryotherapy or surgery and imiquimod.
F L A T WA R T S  V E R R U C A E P L A N A 

Flat warts are most often caused by HPV-3 and HPV-10, and
less frequently by HPV-27, -28, and -49. Flat warts are characterized by grouped, minimally raised, flat-topped, skin colored
papules measuring 2–4 mm in diameter. They occur most commonly on the face, hands, beard area, and legs of women. The
lesions tend to occur along a line of cutaneous trauma. The koebner phenomenon is also seen with these lesions.
Histologically, flat warts show hyperkeratosis and acanthosis. No papillomatosis is seen. Koilocytes are prominent and the
stratum corneum has a “basket-weave” appearance.
Treatment

Treatment involves retinoic acid 0.05% applied daily, which
causes desquamation. Mild irritation may occur.
Epidermodysplasia verruciformis
Epidermodysplasia is a very rare genetic chronic disease with
autosomal recessive inheritance. It manifests in childhood and
is characterized by a unique susceptibility to cutaneous infection
by a group of phylogenetically related human papillomavirus
(HPV) types, including HPV-5, -8, -9, -12, -14, -15, -17, -19, -25,
-36, -38, -47 and -50. Mutations in the EVER1 and EVER2 genes
(epidermodysplasia verruciformis susceptibility locus 1 (EV1))
on chromosome 17q25, which encode for membrane proteins in
the endoplasmic reticulum, are responsible for the condition.
Clinical manifestations of epidermodysplasia include
polymorphic lesions, pityriasis versicolor-like macules, flat wartlike papules and red brown plaques that can undergo malignant
transformation. Actinic keratoses start early in life, typically
around 30 years of age and 50% will develop squamous cell or
bowenoid carcinomas, mainly on sun-exposed areas, in the fourth
or fifth decade of life. The HPV types associated with malignant
transformation are HPV-5, HPV-8, as well as HPV-14d.
Diagnosis of this disease is clinical and is usually confirmed
by biopsy. The histology demonstrates stratum corneum with a
basket weave appearance, uneven keratohyaline granules, large,

26 — Alejandra Varela, et al.

Table 2.2: Anogenital Disease
Disease

HPV Type

Condyloma acuminata

6, 11, 30, 42, 43, 44, 45, 51, 52, 54

Bowenoid papulosis

16, 18, 34, 39, 42, 45

Bowen disease

16, 18, 31, 34

Giant condylomata

6, 11

coarse granules in the epidermis, koilocytes, and gray cytoplasm.
Dysplasia and actinic keratoses may be evident.
Treatment

There is no effective treatment for this condition. For localized malignancies, surgery is the best treatment option; however,
for the persistent nonmalignant lesions, surgery is impractical
due to the extensive nature of the disease. Counseling is the most
important preventive measure; patients with epidermodysplasia
must protect the skin from exposure to ultraviolet radiation.
Other therapies, such as long-term oral isotretinoin, have
been used to decrease the number of benign lesions, and slow
the appearance of premalignant and malignant lesions. Retinoids
have an endogenous antiproliferative effect through their control
of epithelial cell differentiation. Imiquimod has also been used and
has been shown to be effective on the face and body. Additionally,
it is a good adjuvant for systemic interferon therapy.
B U T C H E R ’ S WA R T S

Butcher’s warts are seen in people who frequently handle raw
meat. Their morphology is similar to that of common warts, with
a higher prevalence of hyperproliferative cauliflower-like lesions.
Most commonly, they are seen on the hands.
Histologically, Butcher’s warts demonstrate verrucae, prominent acanthosis, papillomatosis, hyperkeratosis, parakeratosis,
and elongated rete ridges. Dermal vessels are prominent, as are
koilocytotic cells.
Treatment

Treatment includes salicylic acid, 50% trichloroacetic acid, cantharidin, cryotherapy with liquid nitrogen, electrodessication, and
combination therapy with cryotherapy or surgery and imiquimod.
Anogenital Disease (See Table 2.2)
B O W E N O I D PA P U L O S I S

Bowenoid papulosis is a focal epidermal hyperplasia and dysplasia induced by HPV infection. Most commonly, it is caused
by HPV-16, HPV-18, and HPV-33. It occurs in young, sexually
active adults and manifests as papules/plaques on the genitalia.
Histologically, the lesions are characterized by full thickness
dysplasia with dysplastic keratinocytes. A circumscribed epidermal proliferation composed of pleomorphic cells with clumped
nuclei and abnormal mitoses can be observed.
Treatment

Treatment includes cryotherapy, laser excision, topical retinoids, 5-fluorouracil 5% solution, and imiquimod 5% cream.
C O N DY L O M A AC U M I NAT U M

Condyloma acuminatum (genital warts) are typically caused
by HPV-6 and HPV-11. Less commonly, HPV-16, -18, -21, -22,

Figure 2.2. Condyloma accuminatum.

and -55 cause the infection. Genital warts are spread through
sexual contact. An estimated 500,000 to 1 million new cases of
genital condyloma are diagnosed each year.
Histologically, parakeratosis is observed in the mucosa.
Papillomatosis, acanthosis, elongated rete ridges, koilocytes,
and occasional mitotic figures are also characteristic of the
lesions.
Clinical manifestations

Most patients seek care when they notice lumps on the
vulva, labia, vaginal introitus, perianal area, or periclitoral
area. The lesions are exophytic and cauliflower-like and are
found near moist surfaces (see Fig. 2.2). These lesions are
generally not painful, but can be associated with pruritus and
bleeding.
Cervical cancer can develop from infection with HPV. About
70% of cervical cancers are thought to develop from infection
with HPV-16 and HPV-18.
Treatment

Treatment includes trichloroacetic acid, cantharidin, cryotherapy with liquid nitrogen, electrodessication, and combination therapy with cryotherapy or surgery and imiquimod.
Preventative Therapies

Gardasil® is a recombinant quadrivalent vaccine prepared
from the highly purified virus-like particles of the major capsid
protein of HPV-6, -11, -16, and -18. It is indicated in girls and
women ages 9 to 26 years for the prevention of cervical cancer
and condyloma acuminatum.
VERRUCOUS CARCINOMA

HPV infection is thought to cause or facilitate the development
of verrucous carcinoma. Verrucous carcinoma (VC) presents as a
verrucous, exophytic, or endophytic mass that typically develops
at sites of chronic irritation or inflammation. The tumor enlarges
slowly and may penetrate deeply into the skin, fascia, or bone.
The different types of VC based on the site of occurrence are
the following:
Epithelioma cuniculatum: Also known as palmoplantar VC,
epithelioma cuniculatum commonly involves the skin overlying the first metatarsal. It manifests as a plaque on the sole of

Common Viral Infections — 27

Table 2.3: Nongenital Mucosal Disease
Disease

HPV Type

Oral focal epithelial hyperplasia (Heck’s disease)

13, 32

Oral carcinoma

16, 18

Oral leukoplakia

16, 18

the foot with ulceration. It commonly drains a foul-smelling
discharge and can cause pain, bleeding, and difficulty walking.
Palmoplantar VC is associated with HPV-2 and HPV-16.
Giant condyloma of Buschke and Lowenstein: This slow-growing,
locally destructive verrucous lesion typically occurs on the glans
penis (mainly in uncircumcised men), but may appear elsewhere
in the anogenital region. HPV-6 and HPV-11 have been linked
to these tumors.
Oral florid papillomatosis: The early lesions of oral VC appear as
white, translucent patches on an erythematous base. They may
develop in areas of leukoplakia, lichen planus, chronic lupus erythematous, cheilitis, or candidiasis. More fully developed lesions
may coalesce and extend over large areas of the oral mucosa.
Ulceration, fistulation, and local invasion into bones and soft tissue can occur.

orofacial and 10% are genital. Infection is transmitted by close
personal contact.
Viral properties

HSV-1 is neurovirulent. It has the capacity to invade and replicate in the nervous system. Latency is another property of this
viral infection. The virus is established and maintained as a latent
infection in the nerve cell ganglia. The trigeminal ganglia are
most commonly involved in HSV-1 infection. Reactivation of
the virus is induced by a variety of stimuli: fever, trauma, emotional stress, sunlight, and menstruation.
The primary infection is subclinical 90% of the time and
manifests as gingivostomatitis 10% of time. Forty percent of
clinically apparent infections recur three to four times per year.
Clinical Manifestations
G I N G I VA L S T O M A T I T I S

Gingival stomatitis has an abrupt onset. It occurs in children
aged 6 months to 5 years who present with high fever (102°F to
104°F), anorexia, and listlessness. Gingivitis is the most striking
feature of clinical presentation. Vesicular lesions develop on the
oral mucosa, tongue, and lips. These lesions later rupture and
coalesce, leaving ulcerated plaques. Regional lymphadenopathy,
acute herpetic pharyngotonsillitis, pharyngitis, and tonsillitis
can also occur. The acute disease lasts for 5 to 7 days and viral
shedding may continue for up to 3 weeks.
HERPES L ABIALIS

Treatment

Treatment includes cryosurgery, curretage and electrodessication, excision with conventional margins, Mohs surgery, and
radiation therapy.
Nongenital Mucosal Disease (See Table 2.3)
ORAL FO CAL HYPERPL ASIA HECK DISEASE

Oral focal hyperplasia is characterized by focal epithelial
hyperplasia of the lower labial mucosa. Multiple, flat-topped or
dome-shaped pink-white papules are observed ranging from 1 to
5 mm. Some lesions coalesce to form plaques.
Histologically, the lesions demonstrate a hyperplastic mucosa
with a thin parakeratotic stratum corneum. Acanthosis, blunting,
and anastamosis of rete ridges are commonly observed. The epidermal cells demonstrate pallor as a result of intracellular edema.

Treatments for HPV
Treatments for the multiple presentations of HPV have been
discussed in the above sections. For a comprehensive review of
HPV therapies, see Table 2.4.

Herpes labialis is the most common manifestation of recurrent
HSV-1. A prodrome of pain, burning, and tingling often occurs
at the site of infection. Erythematous papules rapidly develop
into tiny, thin-walled intraepidermal vesicles that become pustular and ulcerate (see Fig. 2.3). Maximum viral shedding occurs in
the first 24 hours of acute illness, but may last for 5 days.
Diagnosis

Histologically, acantholysis, intraepidermal vesicles, balloon and
reticular degeneration, intranuclear eosinophilic inclusion bodies, and multinucleated keratinocytes are observed.
L A B O R AT O RY C O N F I R M AT O RY S T U D I E S :

– Viral culture.
– Polymerase chain reaction (PCR) techniques are useful in
diagnosis.
– Immunofluorescent staining of tissue culture cells or of smear
cells can quickly identify HSV and can distinguish between
types 1 and 2.
– Antibody testing.
– Tzanck smear demonstrating multinucleated giant cells.
Treatment

See HSV-2 below.
HUMAN HERPES VIRUSES
 S E E TA B L E 2 . 5 

Human Herpesvirus 1: Herpes Simplex Virus 1
Herpes simplex 1 (HSV-1) virus belongs to the family
Herpesviridae. Humans are the only natural reservoir and there
are no vectors associated with transmission. In the US, eighty
percent of adults are infected with HSV-1. Worldwide, 85%
of adults are infected. Ninety percent of HSV-1 infections are

Human Herpesvirus 2: Herpes Simplex Virus 2
Herpes simplex 2 (HSV-2) is the cause of 70% of primary genital herpes cases (see Fig. 2.4). Greater than 95% of recurrent
genital herpes infections are caused by HSV-2. The infection is
asymptomatic in approximately 75% of patients. Women are 45%
more likely to have the infection than men. Ninety percent of
asymptomatic females and males actively shed the virus at some

Table 2.4: Treatments for HPV
Treatment
Category
Topical agents

Specific Treatment

Benefits and Drawbacks and Uses

Salicylic acid

Over the Counter
Removes Surface keratin
Cure rates from 70%–80% are reported

Cantharidin

Dried extract of blister beetle
Causes epidermal necrosis and blistering
Treatment may require weekly repetition

Dinitrochlorobenzene
(DNCB)

Powerful sensitizing agent
Induces an allergic contact dermatitis
Causes local inflammation and an immune response
Cure rates from 65%–90% Reported mutagen

Dibutyl squaric acid

Contact sensitizer
Unlike DNCB, it is not a mutagen and therefore may be a safer alternative

Trichloroacetic
acid

Caustic compound
Causes immediate superficial tissue necrosis
Concentration up to 80%
May require weekly applications

Podophyllotoxin

Derived from the roots of the Indian podophyllum plant
Binds to tubulin and prevents microtubule assembly
Genital warts: apply twice daily for three consecutive days per week for up to 4 weeks

Fluorouracil (5FU)

Used primarily to treat actinic keratosis
Antimetabolite: fluorinated pyrimidine
Active form inhibits DNA synthesis by inhibiting the normal production of thymidine
Effective in treating warts but very inflammatory and tetratogenic

Imiquimod 5%
cream

Topical cream approved for treating genital warts; used for other HPV infections
Anogenital warts: treat at night, three times per week
Common warts: treat nightly under occlusion
Palmoplantar warts: treat nightly under occlusion, alternate with a keratinolytic
Potent stimulator of proinflammatory cytokine release
Works best as part of combination therapy for nonanogenital warts

Cidofovir

Nucleotide analogue of deoxycytidine monophosphate
Used for refractory condyloma acuminata
Cidofovir gel must be applied once or twice daily
Must be compounded and it is expensive

Tretinoin

Disrupts epidermal growth and differentiation, thereby reducing the bulk of the wart

Systemic
agents

Cimetidine

Type 2 histamine receptor antagonist
Immunomodulatory effects
Results have varied
Oral, 25 to 40 ng/kg three times daily for three months

Intralesional
injections

Bleomycin

Cytotoxic polypeptide that inhibits DNA synthesis in cells and viruses
Side effects of bleomycin include pain with injection, local urticaria, Raynaud phenomenon, and
possible tissue necrosis
If used periungually, bleomycin may cause nail dystrophy or loss

Interferon-α

Naturally occurring cytokine with antiviral, anticancer, and immunomodulatory effects
Intralesional administration is more effective than systemic administration and is associated with
mild flu-like symptoms
Treatments may be required for several weeks to months before beneficial results are seen
Useful for warts that are resistant to standard treatments

Cryosurgery

Liquid nitrogen (–196°C) is the most effective method

Lasers

Carbon dioxide lasers
Procedure can be painful and leave scarring
Risk of nosocomial infection also exists in health care workers because HPV can be isolated in the
plume

Electrodesiccation
and curettage

May be more effective than cryosurgery
Painful
More likely to scar
HPV can be isolated from the plume

Surgical Excision

Avoid using except in extremely large lesions because of the risks of scarring and recurrence

Surgical care

28

Common Viral Infections — 29

Table 2.5: Human Herpes Viruses
Herpes Type

Associated Diseases

HHV-1

Herpes simplex 1 (HSV-1): herpes labialis > herpes genitalis

HHV-2

Herpes simplex 2 (HSV-2): herpes genitalis > herpes labialis

HHV-3

Varicella-zoster virus (VZV): chickenpox/ herpes zoster

HHV-4

Epstein-Barr virus (EBV): mononucleosis, Gianotti–Crosti, Burkitt’s lymphoma, oral hairy leukoplakia

HHV-5

Cytomegalovirus (CMV): retinitis in AIDS patients

HHV-6

Roseola infantum (exanthema subitum)

HHV-7

Possibly pityriasis rosea

HHV-8

Kaposi’s sarcoma

property of this infection. The virus is established and maintained
as a latent infection in the nerve cell ganglia. Reactivation of the
virus is induced by a variety of stimuli, such as fever, trauma,
emotional stress, sunlight, and menstruation.
Clinical Manifestations

The infection is spread by sexual contact. The incubation period
is 3 to 7 days. Viral shedding lasts for about 12 days. Primary
HSV systematic complaints occur in greater than 70% of cases.
These include fever, dysuria, malaise, and lymphadenopathy.
Treatment

Figure 2.3. Herpes labialis.

Acyclovir:
– First episode: 200 mg five times daily or 400 mg three times a
day for 10 days.
– Recurrent outbreaks: 200 mg PO five times daily or 400 mg
three times a day for 5 days.
– Chronic suppressive therapy: 400 mg twice daily or 200 mg
three to five times daily
Valacyclovir:
– First episode: 1 gram twice daily for 10 days
– Recurrent outbreaks: 500 mg twice daily for 3 days or 2 grams
twice daily for 1 day
– Chronic suppressive therapy: 500 mg to 1 gram daily
Famciclovir:
– First episode: 250 mg three times daily for 10 days
– Single-day therapy: 1000 mg twice daily for 1 day or 1500 mg
once for herpes labialis
– Recurrent outbreaks: 125 mg twice daily for 5 days or 1500 mg
once for herpes labialis
– Chronic suppressive therapy: 250 mg twice daily

Figure 2.4. Primary genital herpes.

point in time. Eighty percent of transmission occurs secondary
to asymptomatic shedding.
Viral properties

Like HSV-1, HSV-2 is also neurovirulent. It has the capacity to
invade and replicate in the nervous system. Latency is another

Herpes Simplex Virus in Immunosuppressed
Patients
In patients with HIV, 95% are co-infected with HSV-1, HSV-2,
or both. Fifty-two percent of HIV infections among people
who have HSV-2 can be associated with infection with the herpes virus. Recurrent HSV episodes may last as long as 30 days,
much longer when compared to immunocompetent hosts. Some

30 — Alejandra Varela, et al.

Table 2.6: Various Herpes Presentations
Disease

Presentation

Herpetic whitlow

– HSV of the fingers of the hand occurs near the cuticle or at other sites associated with trauma
– HSV-2 causes the infection more often than HSV-1

Herpes gladiatorum

– Caused by direct skin to skin contact among wrestlers
– Manifests as scattered cutaneous HSV-1 lesions (>HSV-2)

Herpetic keratoconjunctivitis

– Recurrent erosions of the conjunctiva and cornea that can lead to blindness

Lumbosacral herpes simplex virus

– Infection is typically asymptomatic

Herpes associated EM

– Consistent with delayed type hypersensitivity reactions
– Targetoid lesions are not always limited to palms and soles

Eczema herpeticum

– Widespread HSV infection in patients with skin disorders such as atopic dermatitis, Darier’s
disease, pemphigus, or Sezary syndrome

HSV encephalitis

– Most common cause of sporadic encephalitis
– Sudden onset of fever, headache, confusion, and temporal lobe signs
– 70% mortality if not treated

Ramsay Hunt

– Usually caused by VZV or HSV-1
– Infection of the facial nerve
– Symptoms on the affected side typically include facial weakness and a painful herpes-type skin
eruption on the pinna of the ear
– Frequently, vestibulocochlear disturbances
– Recovery of facial movement occurs in about 50% of treated patients

manifestations of HSV in immunosuppressed hosts include the
following:
Chronic ulcerative HSV: These are persistent ulcers and erosions
that begin on the face or in the perineal area.
Generalized acute mucocutaneous HSV: Characterized by dissemination and fever after localized vesicular eruption.
Systemic HSV: Follows oral or genital lesions. Areas of necrosis
are found in the liver, adrenals, and pancreas.
Treatment

In patients with HIV, 5% to 8% are resistant to acyclovir. Acyclovirresistant HSV in HIV patients can be treated with 1% cidofovir
(compounded) or foscarnet. Foscarnet reversibly inhibits viral
DNA polymerase and does not require thymidine kinase. Side
effects of foscarnet include penile ulcers and nephrotoxicity.

Various Herpes Presentations (See Table 2.6 )
Congential Herpes Simplex Virus
Congential herpes simplex virus occurs in 1/3,500 births. The
majority of these cases (up to 90%) are caused by perinatal transmission, in which the newborn contracts herpes while passing
through the birth canal during delivery. In rare cases (5%–8%),
herpes can be acquired in utero. Postnatal transmission is uncommon. Risk of transmission is 50% if the mother has a primary
infection and 3% to 5% if the mother had recurrent disease. Birth
canal transmission can manifest as lesions on the scalp and face,
encephalitis, hepatoadrenal necrosis, pneumonia, and even death.
If lesions appear on an infant during the first 10 days of life,
mortality is 20%. If transmission occurs during the first 8 weeks
of pregnancy, severe defects can result. Without treatment, the

mortality rate of the disease is 65% in transplacental disease, 80%
if the patient is infected with HSV-2, and 10% if the patient is
infected with HSV-1.
Treatment

In infected females who are pregnant, treatment should be administered from week 36 until delivery. Options include valacyclovir
1 g daily, famciclovir 250 mg twice daily, or acyclovir 400 mg three
times daily (due to increased metabolism in pregnant women).
Human herpes virus 3: Varicella-zoster Virus
Varicella-zoster virus manifests clinically as chickenpox and herpes zoster.
CHICKENPOX

Chickenpox is transmitted to others from the skin and
respiratory tract. The incubation period is about 2 weeks. Lowgrade fever precedes skin manifestations by 1 to 2 days. Lesions
begin on the face and appear as “dewdrops on a rose petal” (see
Fig. 2.5). They progress to the scalp and trunk while relatively
sparing the extremities. The characteristic lesion begins as a red
macule that evolves through various stages: papule to vesicle to
pustule and finally, to a pruritic crust. Varicella’s hallmark is the
simultaneous presence of different stages of the rash.
VZV remains dormant in the sensory nerve roots after primary infection.
In utero infections:
C O N G E N I T A L VA R I C E L L A S Y N D R O M E

Congenital varicella syndrome occurs in 2% of children born
to women who develop varicella during the first trimester of pregnancy. This syndrome manifests as intrauterine growth retardation,
microcephaly, cortical atrophy, limb hypoplasia, microphthalmia,
cataracts, chorioretinitis, and cutaneous scarring.

Common Viral Infections — 31

school more quickly and reduces morbidity. Symptomatic care
is the mainstay of treatment. Be cautious to avoid aspirin to prevent Reye’s syndrome.
A D U LT S

Adults who develop varicella are most effectively treated if one
of the following medications is started within the first 24 to 72
hours after the development of vesicles:
Acyclovir: 800 mg five times daily for 7 days
Valacyclovir: 1 g three times daily for 7 days
Famciclovir: 500 mg three times daily for 7 days
Prophylaxis
VA R I C E L L A VA C C I N E

Figure 2.5. Primary VZV.

Give two doses 4 to 8 weeks apart for all children older than
12 months. Seroconversion typically occurs in 78% of adults and
adolescents after the first dose and in 99% after the second dose.
HERPES ZOSTER SHINGLES

Owing to the reactivation of latent VZV in the sensory ganglion,
there is a 20% incidence of herpes zoster in those who have been
infected. There is a 66% incidence in patients who are older than
50 years of age.
The rash is preceded by a prodrome that is characterized
by fever, malaise, headache, and localized pain in the involved
dermatome. It manifests in a unilateral dermatomal distribution
with erythema, vesicles, pustules, and crusting (see Fig. 2.6).
The rash is contagious until all of the lesions develop crusts.
Potential complications of herpes zoster are found in Table 2.7.
Diagnosis

Nonspecific tests:
– Tzanck smear: multinucleated giant cells, nuclear molding
– Histology: intraepidermal vesicle, ballooning degeneration,
reticular degeneration, inclusion bodies, margination of
chromatin, vascular involvement
Figure 2.6. Herpes zoster.

I N FA N T I L E Z O S T E R

Infantile zoster manifests within the first year of life. The cause
is maternal varicella infection after the 20th week of pregnancy.
Infantile zoster typically involves the thoracic dermatomes.
N E O N A T A L VA R I C E L L A

Neonatal varicella can be a serious illness, depending on the
timing of maternal infection and delivery of the newborn. If the
mother develops varicella within 5 days before and up to 2 days
after delivery, the infant is exposed to the secondary viremia of
the mother. Mortality is 30% if prophylaxis or treatment with
varicella-zoster immune globulin and/or acyclovir is not administered. Onset of varicella more than 5 days antepartum provides
the mother sufficient time to develop and pass on protective
antibodies to the fetus.
Treatment
CHILDREN

Children with varicella can be treated with acyclovir 20 mg/kg
given orally four times daily for 5 to 7 days. Healthy children
may not need acyclovir; however, it allows them to return to

Specific tests:
– Viral culture
– PCR
Treatment of herpes zoster

Acyclovir: 800 mg five times daily for 7 days or
Valacyclovir: 1 g three times daily for 7 days or
Famciclovir: 500 mg three times daily for 7 days
Pain and pruritus: analgesics, oral antipruritics, calamine
lotion, cool compresses
Treatment of postherpetic neuralgia

– Non-narcotic or narcotic analgesic
– Capsaicin cream
– Topical lidocaine gel or patch
– Tricyclic antidepressants: amitryptiline, maprotiline, or desipramine
– Anticonvulsants: carbamazepine, gabapentin, pregabalin
– Sympathetic nerve blockade
– Steroids: methylprednisolone
– Transcutaneous electrical stimulation
– Acupuncture

32 — Alejandra Varela, et al.

Table 2.7: Complications of herpes zoster
Disease

Presentation and Associated Symptoms

Hutchinson’s sign

– Zoster on the tip of nose
– Could result in herpetic keratitis

Zoster sine herpete

– Segmental pain without lesions

Ophthalmic zoster

– Ocular disease occurs in 20%–70% of
patients who develop ophthalmic zoster
– Cicatricial lid retraction, ptosis, keratitis,
scleritis, uveitis, secondary glaucoma,
oculomotor palsies, chorioretinitis, optic
neuritis, panophthalmitis

CNS zoster

– Has asymptomatic cerebrospinal fluid
changes

Primary varicella
pneumonia

– Has a higher incidence in adults and
immunocompromised patients

Bacterial super
infections

– Usually due to Staphylococcus aureus

Clinical Manifestations (See Table 2.8)

Table 2.8: Clinical Manifestations of EBV
Disease

Presentation and Associated Symptoms

Mononucleosis

– Triad: fever, sore throat,
lymphadenopathy
– Maculopapular rash present in
3%–15% of patients
– 80% of patients develop a rash if
they are treated with amoxicillin or
ampicillin
Treatment:
– Supportive care
– Antipyretics, analgesics,
topical steroids for cutaneous
manifestations
– Prednisone for complications
such as hemolytic anemia,
thrombocytopenia, or
lymphadenopathy that
compromises the airway

Oral hairy leukoplakia

– Usually associated with HIV
patients
– Secondary nonmalignant
hyperplasia of epithelial cells
– Accentuated vertical folds laterally
on the tongue
– Mucosa appears white and thick:
does not scrape off
– Pathology: papillomatosis
– Treatment: acyclovir 400 mg five
times daily

Kikuchi’s syndrome

– Hyperimmune reaction to an
infectious agent causing regional
lymph node enlargement

Mucocutaneous lymphoma

– B-cell lymphoma

Burkitt’s lymphoma

– High grade B-cell lymphoma
– EBV genome can be detected in
tumor cells

Nasopharyngeal carcinoma

– Malignant tumor of the squamous
epithelium of the nasopharynx
– Patients have high levels of
antibodies to EBV antigens

Gianotti–Crosti (infantile
papular acrodermatitis)

– Symmetric lichenoid papules that
spare the trunk
– Also associated with hepatitis B,
adenovirus, and CMV

Acute cerebellar ataxia – Unsteady gait 11 to 20 days following rash
Guillian-Barré
syndrome

– Acute idiopathic polyneuritis

Meningoencephalitis

– Encephalitis with headache, fever,
photophobia, nausea, vomiting, and
nerve palsies

Motor paralysis

– Extension from sensory ganglion to
anterior horn
– Occurs within the first 2–3 weeks

Ramsay Hunt

– Facial palsy secondary to herpes-zoster
infection of facial (VII) and auditory
(VIII) nerves
– Affects external ear, tympanic
membrane
– Causes tinnitus, vertigo, deafness,
otalgia, and loss of taste

Postherpetic neuralgia – Defined as pain greater than one month
after vesicles
– Occurs in 10%–15% of patients
– Resolves in 50% of patients by 3 months,
75% by 1 year
– Occurs in 60% of patients over the age
of 60

Prophylaxis
VA R I C E L L A  Z O S T E R VA C C I N E

This vaccine is given to increase the immunity in patients
who have a history of primary VZV in order to prevent
zoster. It is recommended in individuals 60 years of age
and older.
Human Herpes Virus 4: Epstein-Barr Virus
This double-stranded DNA virus infects mainly B lymphocytes. After acute infection occurs, EBV persists throughout the
patient’s lifetime as a latent infection.

Diagnosis of EBV

In patients with EBV, leukocytosis, lymphocytosis, and elevated
liver function tests may be observed. Other laboratory tests that
can be used in diagnosing EBV include the heterophile antibody
test, the monospot test, and EBV serology.

Common Viral Infections — 33
Treatment

Most EBV infections are self-limited and the treatment is symptomatic care.
Human Herpes Virus 5: Cytomegalovirus
Human herpes virus 5, or cytomegalovirus (CMV), is an enveloped dsDNA virus in which a latent infection occurs in the host
after infection, and may reactivate during a period of immunosuppression.
The primary infection is usually asymptomatic. Maculopapular rashes and ulcers may develop, as well fever. Enlargement
of the lymph nodes and spleen is also observed.
Complications of CMV include CMV pneumonia (in 19% of
cases), mononucleosis-like syndrome after treatment with ampicillin or amoxicillin, Guillain-Barré syndrome, and Gianotti–
Crosti syndrome. Bone marrow transplant patients that develop
CMV have an 85% mortality rate secondary to CMV pneumonia.
Patients who have received a solid organ transplant and develop
CMV have a four times fold increase in mortality.

patients present in no apparent distress despite the abrupt onset
of high fever (102.2°F –105.8°F). Other clinical signs of infection
include a bulging anterior fontanelle, tonsillar and pharyngeal
inflammation, tympanic injection, and lymph node enlargement. Fever drops on the fourth day, coinciding with the onset
of a rash with characteristic 2 to 5 mm pink macules that begins
on the trunk and may spread to the neck and upper and lower
extremities. Seizures may occur during the febrile phase of the
illness. Other complications include upper respiratory infection, adenopathy, intussusception, thrombocytic purpura, and
mononucleosis.
HIV and HHV-6

HHV-6 has a tropism for CD4+ cells. It increases upregulation
of CD4 expression, which is needed by the gp120 unit of HIV to
infect cells.
Bone marrow transplant patients and HHV-6

Idiopathic bone marrow suppression occurs secondary to
HHV-6 infection.

Congenital CMV

CMV is the most common congenital infection. Current estimates suggest that 30,000 to 40,000 infants are born with congenital CMV every year in the United States alone. The likelihood
of congenital infection and the extent of disease in the newborn
depend on maternal immune status. If primary maternal infection
occurs during pregnancy, the average rate of transmission is 40%.
Most of these infants have cytomegalic inclusion disease at birth.
If primary infection occurs during the first trimester, intrauterine growth retardation, retinitis, and optic nerve malformations
can manifest. If primary infection occurs after the first trimester,
hepatitis, pneumonia, purpura, and disseminated intravascular
coagulation (DIC) may occur. With recurrent maternal disease,
the risk of transmission to the fetus is lower, ranging from 0.5% to
1.5%. Most of these infants appear normal at birth, but may have
subtle growth retardation as compared to noninfected infants.
HIV and CMV

Retinitis is the most common symptom.

Diagnosis

Diagnosis is based on serology.
Treatment

Symptomatic care is the treatment of choice. Some case reports
describe foscarnet and ganciclovir to be successful, but dosages
are not known.
Human Herpes Virus 7
HHV-7 has significant homology with HHV-6. No clinical disease has been definitely linked to HHV-7, although the literature
describes a questionable relationship to pityriasis rosea. Eightyfive percent of adults are seropositive for HHV-7, and most
infections occur during the first 5 years of life. It is transmitted
through the saliva.
Diagnosis

HHV-7 is diagnosed through serology.

Diagnosis

Vasculitis is apparent histologically. “Owl’s eyes” inclusions or
basophilic intranuclear inclusions are observed. Laboratory
studies include viral culture and shell vial assay.

Treatment

Treatment

Kaposi’s sarcoma (KS) is a spindle cell tumor thought to be
derived from endothelial cell lineage. The condition carries a
variable course that ranges from minimal mucocutaneous disease to extensive organ involvement (see Table 2.9).
Histologically, typical findings include proliferations of spindle cells, prominent slit-like vascular spaces, and extravasated
red blood cells.

Medical care consists of good nutritional support, vigorous supportive care for end-organ syndromes, and specific antiviral
therapy. Ganciclovir is the drug of choice for CMV disease.
Foscarnet treats CMV that is resistant to ganciclovir. Cidofovir is
used for refractory CMV retinitis. Valganciclovir and fomivirsen
may also be used to treat CMV disease.
Human Herpes Virus 6: Roseola Infantum
This enveloped DNA virus is spread mainly by oropharyngeal
secretions. It is the most common childhood exanthem.
Clinical Manifestations

Typically, the infection occurs in children aged 6 months to 2
years. The incubation period is 5 to 15 days. The virus is spread
during the febrile and viremic phase of the illness. Generally,

Treatment is symptomatic.
Human Herpes Virus 8: Kaposi’s Sarcoma

Clinical Manifestations

Lesions can include the skin, oral mucosa, lymph nodes, and
visceral organs. Most patients present with cutaneous disease
only.
C U TA N E O U S L E S I O N S

Cutaneous lesions can occur at any location, but are most commonly concentrated on the lower extremities and in the head

34 — Alejandra Varela, et al.

Table 2.9: Clinical Courses of Kaposi’s Sarcoma (KS)
Type of KS

Clinical Course

Epidemic AIDS-related KS

– Occurs in patients with advanced
HIV infection
– Most common presentation of KS
– Visceral involvement is common
– Most clinically aggressive form
of KS

Immunocompromised KS

– Occurs in patients receiving
immunosuppressive therapy,
namely organ transplantation
patients
– Visceral involvement is common
– Develops about 30 months
following transplantation

Classic KS

– Typically occurs in elderly men
of Mediterranean and Eastern
European descent
– Carries a protracted and
indolent course
– Common complications:
venous stasis and lymphedema
– Visceral involvement is
uncommon

Endemic African KS

– Occurs in HIV-seronegative
persons in Africa
– May carry an indolent or
aggressive course

Figure 2.7. Parvo B19.

injury. Herpes simiae has a high mortality rate, as death occurs
secondary to encephalitis.
Treatment

Treatment is with nucleoside analogues, namely intravenous
acyclovir.
PA R V O V I R U S E S

and neck regions. Nearly all lesions are palpable and nonpruritic.
They range in size from several millimeters to several centimeters in diameter. The lesions may be macular, papular, nodular,
or plaque-like with colors varying from brown to pink to red or
violaceous. In dark-skinned individuals, KS lesions can be difficult to distinguish. The lesions may be discrete or confluent,
and characteristically, they appear in a linear, symmetric distribution, following Langer lines.
Tumor-associated lymphedema may occur, especially in
cases with facial or lower extremity involvement. This is thought
to be secondary to the obstruction of lymph channels.
Diagnosis

A punch biopsy of the skin or an endoscopic, pleural, or transbronchial biopsy is necessary to establish a definitive histologic
diagnosis.
Treatment

Treatment includes antiretroviral therapy, excision of solitary
KS lesions, radiation, topical retinoids, intralesional vinblastine,
interferon α, and chemotherapy.
Herpes Virus B: Herpes Simiae
Herpes virus B is transmitted to humans through primates of the
Macaca species from a bite, scratch, or open wound. The infection is neurotropic, remaining latent in the ganglia. In humans,
initial local erythema occurs with vesicular eruption at the site of

Parvovirus B19: “Slapped Cheeks,” Fifth Disease,
Erythema Infectiosum
Parvovirus B19 is the only member of the Parvoviridae family
known to cause disease in humans. This single-stranded DNA
virus has a tropism for rapidly dividing erythrocyte precursors.
Worldwide, B19 infection is very common. Seropositivity rates
are 5% to 10% among young children in the United States, and
increases to 50% by age 15 and 60% by age 30.
Clinical Manifestations

Twenty percent of B19 infections are asymptomatic. Common
symptoms include a mild prodromal illness of fever, malaise, headache, myalgias, nausea, and rhinorrhea. This occurs
about 2 days before the onset of a rash. A bright red rash
appears on the cheeks; thus the characteristic “slapped cheek”
appearance (see Fig. 2.7). This is often followed by a diffuse
erythematous eruption with a lacy marble-like appearance
that shows up on the trunk and lower extremities. The eruption can last 5 to 9 days and can recur for weeks to months
with triggers such as sunlight, exercise, temperature change,
bathing, and emotional stress. Arthalgias or arthritis occur in
10% of children.
Alternatively, parvovirus B19 infection can manifest with a
purpuric rash, erythema multiforme, or pruritus of the soles and
feet. The infection may also cause a papular-pruritic “gloves and
socks” syndrome that manifests as an erythematous exanthem of
the hands and feet with a distinct margin at the wrist and ankle
joints. Pain and edema also occur.

Common Viral Infections — 35

Complications (See Table 2.10)

S K I N M A N I F E S TAT I O N S

Urticaria and vasculitis may occur secondary to perivascular
depositions of immune globulin complexes.

Table 2.10: Complications of Parvovirus B19

Associated conditions

Complication

Presentation

Aplastic crisis

– Occurs in patients with
hemoglobinopathies, hemolytic anemias,
decreased duration of erythrocyte
survival

Transient hypocomplementemia associated with urticaria

Chronic anemia

– Occurs in immunocompromised patients

Erythema nodosum

Symmetric
postinfectious arthritis

–
–
–
–

Lichen planus

Hydrops fetalis

Affects small joints of hands and feet
More common in women
May persist for weeks to years
May mimic rheumatoid arthritis

– Occurs when maternal infection occurs
before 20 weeks of gestations

Diagnosis

Parvovirus serology (IgM and IgG) can be determined. A complete blood count may demonstrate a low reticulocyte count.

Polyarteritis nodosa
Globulinemia

Leukocytoclastic vasculitis
Gianotti–Crosti
Diagnosis

For active hepatitis B: high levels of the enzymes ALT and AST;
HBsAg and HBeAg identified in the serum; HBcAb
For chronic inactive hepatitis: HBsAg, HBcAb of IgG type, and
HBeAb identified in the serum
For chronic active hepatitis B: Mild to moderate elevation of the
aminotransferases

Treatment

Treatment

Treatment is symptomatic. Red blood cell transfusions may be
necessary for aplastic anemia.

Interferon-α, lamivudine, adefovir dipivoxil, and telbivudine.
Prophylaxis is recommended with the hepatitis B vaccine.

H E PA D N AV I R U S E S

RNA VIRUSES

Hepatitis B

For a brief overview of the RNA viruses, see Table 2.11.

Hepatitis B is a disease of the liver caused by the hepatitis B virus.
This partially double-stranded circular DNA virus encodes four
overlapping reading frames that are as follows:

Picornaviruses

– S for the surface or envelope gene encoding the pre-S1, pre-S2,
and S protein
– C for the core gene, encoding the core nucleocapsid protein
and the E antigen
– X for the X gene encoding the X protein
– P for the polymerase gene, which encodes a large protein
promoting priming, RNA-dependent and DNA-dependent
polymerase and RNase H activities.
The infection is transmitted through exposure to bodily fluids containing the virus. This includes sexual contact, perinatal
exposure, blood transfusions, and the reuse of contaminated needles and syringes. Incubation lasts for approximately 75 days.
Clinical Manifestations
PRODROMAL OR PREICTERIC PHASE

An illness similar to serum sickness develops. In 20% to 30% of
patients, arthropathy, proteinuria, and hematuria also develop.
ICTERIC PHASE

Jaundice occurs about 10 days after the appearance of constitutional symptoms and can last for 1 to 3 months. Nausea, vomiting, and pruritus are also associated with this phase.

Enteroviruses
H A N D , F O O T, A N D M O U T H D I S E A S E

This illness is caused by Coxsackie A16 virus and Enterovirus
71 as well as other viruses. The infection is spread by oral–oral
transmission, as well as oral–fecal transmission and is highly
contagious.
Histologically, intraepidermal blisters, neutrophils, monocytes, necrotic roofs, and intracellular edema are apparent. An
edematous dermis as well as intracytoplasmic particles in a crystalline array are also observed.
Clinical Manifestations

Incubation is 3 to 6 days, which is followed by a prodromal
exanthem of fever, malaise, and abdominal pain. Oral ulcerative
lesions develop on the hard palate, tongue, and buccal mucosa.
Two to 10 lesions develop over 5 to 10 days, and these lesions are
characterized by vesicles on an erythematous base. Cutaneous
lesions develop as well on the hands, feet, and buttocks. A few
hundred lesions can develop, more commonly on the hands
than on the feet. The lesions are characterized by erythematous
macules with a gray center that run parallel to skin lines.
Diagnosis

Diagnosis is made through cell culture and PCR of blood, stool,
pharyngeal secretions, and vesicles.

36 — Alejandra Varela, et al.

Table 2.11: RNA Viruses
RNA Virus Family

Characteristics

Picornaviruses

– Nonenveloped virions

uvula. The lesions are gray/white and papulovesicular with surrounding erythema. They range from 1 to 2 mm.
Treatment

Self-limited.

– Size ranges from 20 to 25 nm
– Capsids composed of four different proteins
– Genome is single-stranded RNA
– Size ranges from 7500–8500 nucleotides
• Rhinoviruses
• Hepatovirus: Hepatitis A virus
• Enteroviruses
• Poliovirus
• Enterovirus

Hepatitis A virus
Hepatitis A
Hepatitis A belongs to the picornaviruses. It is transmitted
through fecal–oral contact and has an incubation period of 2
to 7 weeks. Worldwide, there are more than 1.4 million cases of
Hepatitis A annually. Fourteen percent of hepatitis cases manifest as transient, discrete, maculopapular, urticarial, or petechial
rashes. Rarely, persistent hepatitis A develops into a globulinemia with a cutaneous vasculitis.

• Coxsackievirus

Treatment

• Echovirus

Supportive care since the infection is mild and self-limited. A
combination vaccine for the prevention of hepatitis A and hepatitis B is recommended for persons at risk for infection.

Togaviruses

– Enveloped
– ssRNA
– Rubella

Flaviviruses

– Enveloped
– ssRNA
– Hepatitis C
– Yellow fever
– Dengue
– West Nile virus

Retroviruses

– ssRNA
– Enveloped
– Contain reverse transcriptase
– HIV

Paramyxoviruses

– Spherical
– Enveloped
– ssRNA
– Measles

Arenaviruses

– Lassa fever
– Argentine hemorrhagic fever

Bunyaviruses

– ssRNA – Enveloped
– Helical symmetry
– Sandfly fever virus
– Hantaan virus

Treatment

The infection resolves spontaneously after about 1 week. Treatment is symptomatic care.
H E R PA N G I N A

This infection is spread via the fecal–oral route. It is caused
by coxsackievirus A 1–10, 16, and 22; by echovirus 6, 9, 11, 16,
17, 22, and 25; and by enterovirus 71.

Paramyxoviruses
Rubeola/Measles
Rubeola, or measles, belongs to the family Paramyxoviridae. It
is a single-stranded RNA virus that initially infects the respiratory epithelium and is transmitted through respiratory droplets. Measles is responsible for more than 50 million infections
and 1 million deaths worldwide annually. It has been called the
greatest killer of children in history. The highest incidence of
morbidity and mortality is observed in developing countries,
but disease still occurs in the United States and other industrialized nations.
Clinical Manifestations

There are four phases to measles infection: incubation, prodrome, enanthem, and exanthem. Measles has an incubation
period of 7 to 14 days. It is communicable just before the start of
the prodromal symptoms until approximately 4 days following
the onset of the exanthem. The prodrome develops on day 0 following incubation and consists of the three Cs: cough, coryza,
and conjunctivis. Fever and photophobia are also common during this period. The prodromal symptoms increase in severity
up to 3 to 4 days before the onset of the morbilliform rash. The
enanthem, Koplik spots, precede the exanthem by about 24
hours. Koplik spots are characterized as red spots on the buccal
mucosa with a gray-white center. The exanthem itself begins on
the fourth or fifth day following the onset of symptoms and is
characterized by nonpruritic red papules that begin on the face
and behind the ears that then spread to the trunk and extremities. The exanthem lasts for about 5 days.
Complications

Clinical Manifestations

The incubation period is 7 to 14 days with a sudden onset of fever,
headache, and back/extremity pain. Lesions occur on mucous
membranes, namely, the soft palate, tonsillar pillars, fauces, and

Complications of measles infection include encephalitis, purpura secondary to thrombocytopenia, otitis media, subacute
sclerosing panencephalitis, and pneumonia secondary to bacterial infection, tuberculosis.

Common Viral Infections — 37
Diagnosis

Treatment

Diagnosis is obtained through serology and histology.

No adequate treatment is available for pregnant women exposed
to rubella. The disease is typically self-limited, and symptomatic
care is the treatment of choice. The main defense against rubella
is immunization (i.e. MMR).

Treatment

The treatment for measles is vitamin A and supportive care.
Prophylaxis

The measles vaccine provides protective titers and is usually
given with the vaccines for mumps and rubella (MMR).

Togaviruses
Rubella: German Measles
This single-stranded RNA virus belongs to the family of togaviruses. It is a mild viral illness that involves the skin, lymph nodes,
and occasionally, the joints.
Histologically, a light perivascular infiltrate of lymphocytes
with mild endothelial swelling may be observed. If petechiae or
purpura are clinically present, extravasation of erythrocytes may
be observed.
Clinical Manifestations

The virus incubates for 2 to 3 weeks and infection is spread by
nasal droplets. It is known as “3-day measles,” and most commonly presents with generalized lymphadenopathy. It involves
all nodes, especially the suboccipital, postauricular, and anterior
and posterior cervical nodes.
The exanthem begins as discrete macules on the face that is
then spread to the neck, trunk, and the extremities. The macules may coalesce on the trunk. The rash lasts for 1 to 3 days,
first leaving the face, and it may be followed by desquamation.
Occasionally, a nonspecific enanthem, known as Forchheimer
spots, can be seen over the soft palate and uvula. The enanthem is
characterized by pinpoint red macules and petechiae, and typically occurs just before or along with the exanthem.
Polyarthalgia and polyarthritis may occur along with the
infection and may persist for longer than 2 weeks. A syndrome of low-grade fever, chronic fatigue, and myalgias rarely
occurs and can persist for months or years after the original
infection.
Congenital Rubella Syndrome

Congenital rubella syndrome can occur in the fetus of a pregnant woman without immunity to the virus. Fifty percent of
pregnancies result in complications if the fetus is infected during the first trimester. Ophthalmologic complications such as
cataracts and retinopathy can result. Cardiac complications
include patent ductus arteriosus and pulmonary stenosis.
Neurological sequelae of sensorineural deafness, meningoencephalitis, and mental retardation with behavior defects can
also occur. Another well-known complication of rubella is a
“blueberry muffin” appearance of the infant. This is due to dermal extramedullary hematopoiesis as well as thrombocytopenia
with purpura and petechiae.
Diagnosis

Diagnosis is obtained from an isolate from the nose, blood urine,
or CSF. However, the diagnosis may also be made on a clinical
basis. If the diagnosis is in doubt, a rising titer of IgM antibody
over a 2-week period indicates a recent infection.

Flaviviruses
Hepatitis C
The World Health Organization estimates that there are 170
million individuals worldwide who are infected with hepatitis C. Medical care costs for treatment of HCV infection in the
United States are thought to exceed $600 million dollars per year.
Hepatitis C is a spherical enveloped, single-stranded RNA virus
belonging to the Flaviviridae family. HCV can produce at least
10 million new particles every day. The natural targets of HCV
are hepatocytes, and possibly B lymphocytes.
Clinical Manifestations

Hepatitis C is acquired through parenteral transmission, e.g.
blood transfusion as well as via drug abuse, tattoos, body piercing and sometimes by sexual intercourse. Incubation period is 6
to 7 weeks.
ACUTE HCV

Thirty percent of patients present with jaundice. Symptoms
are indistinguishable from other types of acute viral hepatitis.
Fluctuating serum aminotransferase levels are characteristic.
CHRONIC HCV

HCV is the most common cause of chronic viral hepatitis.
Cirrhosis occurs in 8% to 46% percent of patients. The following
diseases are associated with chronic hepatitis C infection:
– Immune complexes: skin, kidney (glomerulonephritis)
– Sialadenitis
– Autoimmune thrombocytopenic purpura
– Lymphoma: increased antibodies to HCV in patients with
non–Hodgkin’s B-cell lymphoma
– Mixed cryoglobulinemia
– Porphyria cutanea tarda
– Lichen planus
– Polyarteritis nodosa
– Pruritus
Treatment

Treatment includes pegylated interferon α + ribavirin.

Retroviruses
Human Immunodeficiency Virus
Human immunodeficiency virus (HIV) is a single-stranded
RNA retrovirus that causes acquired immunodeficiency syndrome (AIDS). Infection with HIV occurs by the transfer of
blood, semen, vaginal fluid, pre-ejaculate, or breast milk, as the
virus is shed in these bodily fluids. The majority of transmission
occurs through sexual contact.
Human immunodeficiency virus (HIV) is a Lentivirus, a subgroup of retroviruses. This family of viruses is known for persistent viremia, infection of the nervous system, latency, and weak

38 — Alejandra Varela, et al.

host immune responses. HIV has a high affinity for CD4+ T
lymphocytes and monocytes. The virus binds to CD4+ T cells
and replicates itself by generating a DNA copy by reverse transcriptase. In this way, the virus becomes integrated into the host
DNA, enabling further replication.

Table 2.12: Clinical Manifestations of HIV
Body System

Clinical Manifestation

Constitutional

–
–
–
–
–

Fever
Weight loss
Night sweats
Fatigue/malaise
Lymphadenopathy

Head, ears, eyes,
nose, throat

–
–
–
–

Oral/esophageal candidiasis
Oral hairy leukoplakia
Blurry vision
Floaters

Central Nervous
System

–
–
–
–
–
–

Confusion
Dementia
Focal deficits
Meningismus
Progressive multifocal leukoencephalopathy
CNS lymphoma

Skin

–
–
–
–
–
–
–
–
–
–
–

Gastrointestinal

– Nausea
– Vomiting
– Chronic diarrhea

Genitourinary

– Nephropathy
– Cervical cancer

Hematologic

– Burkitt’s lymphoma
– Diffuse large B-cell lymphoma

Clinical Manifestations:

HIV infection increases the likelihood of a patient to be afflicted
by many different diseases; both infectious and non-infectious
(Table 2.12). Primary HIV infection occurs approximately one
month after HIV exposure and it is characterized by a self-limited collection of symptoms including fever, malaise, headache,
weight loss, gastrointestinal complaints, and sometimes a truncal macular eruption.
HIV infected patients have high rates of infectious conditions
which often cause cutaneous manifestations in addition to systemic disease. Viruses including herpesviruses (HSV, VZV, CMV,
HHV-8), human papilloma virus, and molluscum contagiosum
all cause cutaneous manifestations which have been described
previously within this chapter. Epstein Barr virus is a herpesvirus which causes oral hairy leukoplakia. (Table 2.8) Patients with
oral hairy leukoplakia present with white, stuck on, verrucous
plaques on the tongue which are most often asymptomatic.
Staphylococcus is the most common bacterial agent to cause
infection in HIV patients. The infection my result in furuncles,
carbuncles, abscesses, cellulitis, folliculitis, impetigo, or necrotizing fasciitis. HIV infected patients are also susceptible to both
typical and atypical mycobacterium infections. It is possible for
this immunocompromised subset of patients to have cutaneous
inoculation with TB or to have cutaneous findings associated
with systemic infection. Tuberculous chancre and tuberculosis
verrucosa cutis are the two diseases seen with cutaneous inoculation. Tuberculous chancre is a painless ulceration at the inoculation site and tuberculosis verrucosa cutis is a hyperkeratotic
plaque at the inoculation site. Disseminated Mycobacterium
tuberculosis infection can lead to multiple cutaneous findings including; scrofuloderma, lupus vulgaris, and a metastatic
tuberculous abscess. Bartonella infection may result in bacillary angiomatosis, which is a cutaneous vascular proliferation. It
presents with painful, firm, red nodules that appear very similar
to Kaposi’s sarcoma lesions. Treponema pallidum is the infectious pathogen associated with syphilis. Patients with syphilis
and HIV co-infection may have a faster progression through the
stages of syphilis, which can have a multitude of manifestations
including; nontender genital ulceration (chancre) in primary
syphilis; symmetric eruption on the palms and soles, and condyloma lata in secondary syphilis; and destructive granulomatous
lesions (gummas) in tertiary syphilis.
Fungal infections with Candida, Histoplamosis, Cryptococcus,
and Coccidioidomycosis are common in HIV patients. Infections
with Histoplamosis, Cryptococcus, and Coccidioidomycosis can
lead to diffuse rashes with varied appearances. Candida, the most
common fungal pathogen, causes oral thrush, which presents with
white plaques on the tongue and buccal mucosa that can easily be
scraped off. Intertriginous eruptions can also occur with candida
infection. Histoplamosis infections may lead to mucocutaneous
ulcerations or diffuse erythematous eruptions on the body which
can be macular, papular, pustular, or psoriasiform. Disseminated
skin involvement is rarely seen in HIV patients with systemic
Cryptococcus infections and can present with erythematous

Maculopapular rash
Primary HIV infection
Xerosis
Pruritic papular eruption
Atopic dermatitis
Seborrheic dermatitis
Eosinophilic folliculitis
Psoriasis
Drug rash
Photosensitivity
Infectious
• Bacterial:
 Staphylococcus
 Bartonella (Bacillary angiomatosis)
 Mycobacterium
■ M. tuberculosis
■ Atypical mycobacterium
 Treponema (Syphilis)
• Viral:
 Herpesviruses:
■ Herpes simplex
■ Varicella zoster
■ Cytomegalovirus
■ Epstein-Barr (Oral hairy leukoplakia)
■ HHV-8 (Kaposi’s sarcoma)
 Human papillomavirus (Condyloma
acuminata)
 Molluscum contagiosum
• Parasitic
 Sarcoptes (Scabies)
• Fungal
 Candida
 Dermatophytes
 Cryptococcosis
 Histoplasmosis
– Coccidioides

Common Viral Infections — 39

papules, nodules, pustules, granulomatous, or verrucous lesions.
Patients may also develop ulcerative lesions of the oral mucosa and
tongue. Reactivation of pulmonary Coccidioidmycosis can lead to
disseminated cutaneous eruptions. These patients may have papules, plaques, nodules, and pustules that overtime coalesce and
ulcerate.
Sarcoptes scabiei mite infestation is common in immunocomprimised patients. The female mite burrows under the superficial epidermis leaving distinct linear burrows in the digital webs.
In addition, patients have extremely pruritic papular lesions in
the axilla, groin, and digital webs. Norwegian scabies consists
of hyperkeratotic, scaling, plaques on the scalp, face, back, buttocks, nails, and feet.
There are also several non-infectious dermatologic manifestations of HIV. These skin conditions are common in the general
population but when the disease occurs in HIV infected patients
it is much more severe and often unresponsive to treatment.
Xerotic skin conditions such as acquired ichthyosis (thick fish-like
scales) and atopic dermatitis (erythematous scaling plaques) are
often much more severe and unresponsive to treatment in HIV
infected patients. In general, this patient population has a higher
incidence of xerosis; non-erythematous, dry, scaling, cracking
skin. Psoriasis, characterized by indurated annular, erythematous
plaques with silvery scale, is also more difficult to treat in HIV
patients. Explosive episodes of psoriasis may occur with primary
HIV infection. Seborrheic dermatitis, consisting of greasy, yellow
papules and plaques on the face and scalp, is also more prominent
in this patient population. HIV patients may also have involvement of less common areas of the body including the groin, chest,
back, and axilla. In addition, HIV infected patients are more prone
to photosensitivity reactions compared to the general population.
Pruritic papular eruption (PPE) may occur very early in the
course of HIV infection and is characterized by pruritic, hyperpigmented papules on the extremities and trunk that are often
chronic in nature. The pruritic lesions do not often respond to
anti-pruritic medications.
Eosinophilic folliculitis is an uncommon disease that occurs
late in the course of HIV infection and is characterized by pruritic,
perifollicular papules and sterile pustules on the trunk. Similar to
PPE, anti-pruritic therapy if often unsuccessful.
Adverse drug reactions from HARRT and the antimicrobial
therapy used to treat opportunistic infections is frequently seen
in the HIV patient population. Zidovudine, a nucleoside reverse
transcriptase inhibitor, has been associated with nail dyschromia, brown or blue longitudinal bands that spread down from
the proximal nail plate; skin hyperpigmentation, non-specific
macular rashes, and urticaria. Nevirapine and delavirapine, nonnucleoside reverse transcriptase inhibitors, may cause transient,
pruritic maculopapular eruptions. Protease inhibitors have also
been associated with maculopapular eruptions. Trimethoprimsulfamethoxazole, often used to treat Pneumocystis carinii infection, is associated with a wide spectrum of adverse reactions
including morbilliform eruptions to Stevens-Johnson syndrome
or toxic epidermal necrolysis. Foscarnet, used to treat acyclovirresistant HSV infections, can cause genital ulcerations from the
high concentration of the drug in the urine.

Treatment

Three older, well-established classes of medications exist for the
treatment of HIV; three newer classes are also now available.
Treatment generally consists of a combination of two or three
different medications, as HIV may rapidly develop resistance to
single-drug regimens. Patients may undergo testing at various
stages of treatment to determine the sensitivities of their virus.
All treatments listed below are oral and the adult dosing for
treatment-naïve patients, unless otherwise specified.
Nucleoside Reverse Transcriptase Inhibitors (NRTIs):
– Zidovudine: 200 mg TID
– Lamivudine: 150 mg BID
– Stavudine: 40 mg BID
– Didanosine: 20 mg BID
– Zalcitabine: 0.75 mg TID
– Abacavir: 300 mg BID
– Emtricitabine: 200 mg BID
– Tenofovir: 300 mg QD
Several medications are available that are a combination of
two or more NRTIs:
– Combivir: zidovudine 300 mg + lamivudine 150 mg, BID
– Trizivir: zidovudine 300 mg + abacavir 300 mg + lamivudine
150 mg, BID
– Epzicom: abacavir 600 mg + lamivudine 300 mg, QD
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs):
– Nevirapine: 200 mg for 14 days and then 200 mg BID
– Delavirdine: 400 mg TID in 3 oz of water
– Efavirenz: 600 mg at bedtime
– Etravirine: 200 mg BID
Protease Inhibitors:
– Saquinavir: 1200 mg TID
– Ritonavir: 600 mg BID
– Indinavir: 800 mg every 8 hours
– Lopinavir: 400 mg BID (marketed only in combination with
ritonavir 100 mg) or 800 mg QD (marketed only in combination with ritonavir 200 mg)
– Nelfinavir: 750 mg TID
– Amprenavir: 1200 mg BID
– Fosamprenavir calcium: 700 mg BID
– Atazanavir sulfate: 400 mg QD
– Darunavir: 800 mg QD (must be coadministered with ritonavir
100 mg)
– Tipranavir: 500 mg BID (must be coadministered with ritonavir 200 mg)
– Atazanavir: 300 mg QD (coadministered with ritonavir 100 mg)
or 400 mg QD (without ritonavir)
Fusion Inhibitors:
– Enfurvirtide: 90 mg BID (subcutaneous injection)

Diagnosis

Human immunodeficiency virus (HIV) is diagnosed by ELISA,
Western blot assay, and viral load measured by PCR.

Entry Inhibitors:
– Maraviroc: 300 mg BID

40 — Alejandra Varela, et al.

HIV integrase strand transfer inhibitors:
– Raltegravir: 400 mg BID
Multi-class Combination Products:
– Atripla: efavirenz 600 mg + tenofovir 300 mg + emtricitabine
200 mg, at bedtime
P I T FA L L S A N D M Y T H S

There are many popular misconceptions about viral infections of
the skin. Some of the most popular and egregious beliefs include
that frogs transmit warts, herpes can be transmitted through toilet seats, and if someone has chickenpox they cannot bathe or
wash their hair, otherwise wind will enter their body and cause
rheumatism in their old age. In addition, many members of the
lay public believe that a person must have a lesion of genital herpes in order to transmit the virus to a partner.
These common folktales were cleared up in depth throughout the chapter.
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Garman ME, Tyring SK. The cutaneous manifestations of HIV infection. Dermatol Clin 2002;20:193–208.

Trent JT, Kirsner RS. Cutaneous manifestations of HIV: A primer. Adv
Skin Wound Care 2004;17(3):116–129.
Chaker MB, Cockerell CJ. Conconmitant psoriasis, seborrheic dermatitis, and disseminated cutaneous histoplamosis in a patient
infected with human immunodeficiency virus. J Am Acad
Dermatol 1993;29(2 Pt 2):311–313.
Hazelhurst JA, Vismer HF. Histoplamosis presenting with unusual skin
lesions in acquired immunodeficiency syndrome. Br J Dermatol
1985;113(3):345–8.
Kalter DC, Tschen JA, Klima M. Maculopapular rash in a patient with
acquired immunodeficiency syndrome. Disseminated histoplasmosis in acquired acquired immunodeficiency syndrome. Arch
Dermatol 1985;121(11):1445–1449.
Lindgren AM, Fallon JD, Horan RF. Psoriasiform papules in the
acquired immunodeficiency syndrome. Disseminated histoplamosis and AIDS. Arch Dermatol 1991;127(5):722–726.
Dimino-Emme L, Gurevitch AW. Cutaneous manifestations of disseminated Cryptococcus. J Am Acad Dermatol 1995;32 (5 Pt 2):844–850.
Lynch DP, Naftolin LZ. Oral Cyrptococcus neoformans infection in
AIDS. Oral Surg Med Oral Pathol 1987;64(4):449–53.

3

COMMON FUNGAL INFECTIONS
Aditya K. Gupta and Elizabeth A. Cooper

H I STORY

Fungal organisms have a long history of human infection. The
“tinea” infections have historically been referred to as “ringworm,”
because of the presentation of lesions as circular or oval areas of
clearing within a red, scaly, elevated “ring.” It has only been with
the developments in science and medicine in the industrial age
that the causal agents were recognized as being microscopic fungi.
Taxonomy has only distinguished the dermatophyte organisms
most frequently associated with fungal infection (Trichophyton
sp., Microsporum sp. and Epidermophyton sp.) since 1934.
In 1958 the first effective oral antifungal agent, griseofulvin, was developed. Following the success of griseofulvin, other
oral medications continued to be researched. Ketoconazole was
the next major antifungal agent, released in the United States
in 1981, followed by fluconazole, terbinafine, and itraconazole
within the next decade. These medications are typically classified
as azoles (itraconazole, fluconazole, intraconazole, oxiconazole,
spectozole, sertaconazole, chlotrimazole, miconazole, bifonazole, sulconazole, ketoconazole) or allylamines (terbinafine,
butenafine, naftifine).
Besides the common dermatophyte infections, superficial
fungal infections may also result from the Malassezia species
of yeast. Malassezia was first recognized as a pathogen in 1846;
however, laboratory culture was unsuccessful until 1927, when
the lipid requirement of the species was recognized. Initially only
two species under the genus name Pityrosporum were described,
and only three species were recognized as of 1970. Difficulty in
identification was also complicated by the existence of both yeast
and mycelial forms, and conversion between forms could not
be induced in the laboratory until 1977. Genetic research in the
1990s confirmed that at least seven species of Malassezia existed,
and more have been discovered since.
Though dermatology and dermatophytosis have a long history, it is only the most recent past that has greatly changed and
improved dermatological treatment. The future of these specialties holds great change as biochemistry and genetic research
develop and allow for greater understanding of infectious disease. Currently, molecular testing methods are in development
and may lead to easier and more accurate fungal identification.
Furthermore, molecular research may lead to more targeted
treatments that would increase the efficacy of treatment.

EPIDEMIOLOGY

Fungal organisms may infect any location of the body and infections are named on the basis of the area infected. Examples are
42

as follows: tinea corporis/cruris – trunk/face, including arms
and legs; tinea capitis – scalp; tinea pedis and manuum – feet
and hands; tinea faciei, tinea barbae – face or beard area; tinea
unguium, also known as onychomycosis – nails. Three fungal
genera cause tinea infections: Microsporum, Trichophyton, and
more rarely, Epidermophyton. Species of fungus infecting humans
originate from three main sources: other humans (anthropophilic), animals (zoophilic), or less commonly, soil (geophilic).
Anthropophilic dermatophytes are the most frequent causes of
onychomycosis and other superficial dermatophytoses, and the
most frequently seen agents of infection are Trichophyton rubrum
and Trichophyton mentagrophytes. Trichophyton tonsurans is currently the most frequent cause of tinea capitis in North America.
Microsporum canis is a zoophilic organism frequently picked up
by humans from contact with animals such as dogs and cats. The
major causative species differ geographically and may change in
prevalence over time because of population movements from
immigration or travel.
The dermatophytes colonize keratinized tissue of the stratum corneum; invasion by anthropophilic species usually results
in less inflammation than that of zoophilic or geophilic species.
Entry into the stratum corneum may result from trauma to the
skin or some other breach of the skin barrier. Excessive sweating
and occlusive clothing/footwear aid in providing a warm, moist
environment conducive to tinea infection. The presence of health
problems such as diabetes and immunocompromised status may
also increase the risk of contracting fungal infection.
Autoinoculation can occur, for example, tinea pedis spreading to tinea cruris, tinea capitis to tinea corporis, or onychomycosis to tinea pedis. Infection may also be transmitted between
individuals by direct or indirect contact with scales containing
fungal arthroconidia from infected individuals, such as those
seen in individuals participating in contact sports including
wrestling and rugby. Fomites can also play a significant role
in transmission. Humans and animals may be asymptomatic
pathogen carriers.
Dermatophyte infection in outpatients seen by physicians in
the United States was estimated to result in 21.6 million physician
office visits between 1990 and 1994. Infection frequencies in subjects with dermatophytoses were as follows: tinea corporis – 27.2%;
tinea cruris – 16.9%; tinea pedis – 16.7%; tinea unguium – 15.6%;
tinea of hair and beard – 6.9%; and tinea manuum – 1.0%. Tinea
pedis is estimated to affect 10% of the world population and occurs
most commonly in the web space between the fourth and fifth toes
(Figs. 3.1 and 3.2). Onychomycosis has an estimated prevalence of
6.5% to 12.8% in North America, accounting for up to 50% of all
nail disease. Tinea pedis is frequently found in association with
onychomycosis. Similarly, tinea manuum may accompany tinea

Common Fungal Infections — 43

Figure 3.1. Tinea pedis wth interdigital infection.

Figure 3.3. Tinea capitis.

Figure 3.2. Plantar tinea pedis.

Figure 3.4. Tinea capitis

pedis or onychomycosis, and a two feet-one hand syndrome has
been noted to occur.
Tinea capitis shows great variation in epidemiology compared to the other tineas. Unlike the other tineas and onychomycosis, which is associated with increased age, tinea capitis is
most prevalent in children between 6 months and before puberty
(Fig. 3.3). African-Americans develop tinea capitis at much
higher frequencies than the general US population, though this
is not the case in the other types of tinea (Fig. 3.4). There also
appear to be differences in worldwide distribution of infectious
species: In North America, Trichophyton tonsurans is the predominant cause of tinea capitis infection; In Western Europe,
Microsporum canis and Trichophyton violaceum are the most
common pathogens of tinea capitis; T. tonsurans is dominant in
the Caribbean and South America; M. canis, Trichophyton mentagrophytes, and T. violaceum dominate in the Middle East. The
epidemiology of tinea capitis has shown numerous changes in
North America over the past century, with T. tonsurans replacing
Microsporum audouinii as the predominant organism.
Pityriasis versicolor (PV), also known as tinea versicolor, is
not strictly speaking a “tinea,” as the causative organisms are not
dermatophytes, but Malassezia yeast. Malassezia organisms are a
normal part of human commensal skin flora, found particularly
in sebaceous skin such as the chest, back, and head. Pityriasis

versicolor results when Malassezia organisms are converted
from the yeast phase to a mycelial phase and are able to infect
the stratum corneum, producing the characteristic hypo- or
hyperpigmented lesions that can spread into a given area much
like a dermatophyte infection (Figs. 3.5 and 3.6). The most common Malassezia species contributing to PV lesions are M. globosa
(50%–60%), M. sympodialis (3%–59%), M. furfur and M. slooffiae
(1%–10% each). Pityriasis versicolor (PV) has worldwide distribution, though prevalence is higher in tropical climates compared
to temperate climates (30%–40% versus 1%–4%, respectively).
PV does not typically affect prepubescent children, but is more
frequent in adults where sebaceous gland activity is very high.
Equal prevalence between the sexes has been noted. Predisposing
factors include high temperature and humidity, malnutrition, the
use of oral contraceptives, hyperhidrosis, genetic susceptibility,
increased plasma cortisol levels, and immunodeficiency.
DIAGNOSIS

Presentation of tinea infection is typically as annular erythematous plaques with raised leading edges and scaling (central clearing of the lesion may be noticed). Nodules may remain present
throughout the lesion (Fig. 3.7). Infection is typically associated

44 — Aditya K. Gupta and Elizabeth A. Cooper

Figure 3.5. Tinea versicolor hypopigmentation.

Figure 3.6. Tinea versicolor hyperpigmentation.
Figure 3.7. Tinea corpora of the shin (majocchi granuloma).

with pruritus. Infection may also present as an erythematous
papule or series of vesicles. Significant inflammation may result
from infection with zoophilic organisms such as T. verrucosum
or Microsporum canis and produce large pustular lesions or a
kerion or associated with formation of frank bullae causing tinea
corporis bullosa. Infection may also spread down the hair shaft
into the dermis producing inflammatory papules and pustules.
Typical presentations and variations of the major tinea infections
and pityriasis versicolor are listed in Table 3.1.
Definitive diagnosis of tineas requires confirmation of dermatophyte organisms within the affected tissue. For skin infections, scrapings or swabs can be taken from the leading edge
of a lesion. Nail clippings and subungual debris can similarly
be investigated. Currently, fungal elements are detected using
microscopic examination and laboratory fungal culture methods.
Potassium hydroxide (KOH) is added to the samples to dissociate hyphae from keratinocytes, and the samples are examined by
microscopy. Microscopy can indicate the presence of dermatophytes via the presence of hyphae.However, dermatophyte species cannot be distinguished between each other by microscopy,
therefore cultures are required to confirm the causative species.
Microscopic examination of hairs may help differentiate
types of tinea capitis infection. Ectothrix infection can be distinguished from endothrix infection by the way that arthroconidia

appear as chains on the surface of the hair shaft or as a mosaic
sheath around the hair in ectothrix infections. Inspection under
the Wood’s light (filtered ultraviolet light with a peak of 365 nm)
can aid in diagnosis. Ectothrix infections with M. audouinii, M.
canis and M. ferrugineum show bright green fluorescence under
the Wood’s light. T. schoenleinii shows dull green fluorescence.
T. tonsurans, however, does not fluoresce, and the utility of the
Wood’s lamp for diagnosis is currently limited in countries where
this is the major infecting agent.
As with dermatophyte infections, Malassezia organisms
should be identified in skin scrapings for definitive diagnosis.
They are easily identified by microscopic examination of skin
scrapings that reveal fungal hyphae in a typical “spaghetti and
meatball” pattern. PV lesions fluoresce yellow/green or gold
under the Wood’s light.The examination, however, is positive in
only one-third of all PV cases, and most likely in cases when the
causative organism is M. furfur.

THERAPY

Methods of treatment vary widely, depending on the type and
extent of infection. However, antifungal medications used will

Common Fungal Infections — 45

Table 3.1: Presentation of Common Dermatophyte and
Superficial Fungal Infections
Condition
Tinea pedis

Presentation
Interdigital: scaling, fissuring, maceration,
erosions, hyperhidrosis, pruritus, odor
Moccasin: fine silvery scales with underlying pink
or red skin on soles, heels, sides of feet
Vesicobullous: inflammatory vesicular or bullous
lesions, particularly at in-step

Tinea manuum

Dry, scaly, hyperkeratotic skin particularly of the
palmar area, minimal erythema

Tinea corporis

Annular erythematous plaques with raised leading
edges and scaling, over glabrous skin of trunk;
may be central clearing

Tinea cruris

Annular erythematous plaques with raised leading
edges and scaling, over the pubic area, perineal
and perianal skin, typically not affecting the
scrotum or labia majora

Tinea capitis

Non-Inflammatory: erythematous papules around
the hair shaft spreading out with fine scaling
in noticeable patches and partial or complete
alopecia
Black dot: noticeable black dots where hair
breakage at scalp level occurs, scaling with little
inflammation (particularly with T. tonsurans or
T. violaceum)
Inflammatory: kerion with pustules, loose hair,
discharge of pus
Favic: large yellow crusts on the scalp

Onychomycosis

Distal lateral subungual (DLSO): infection at
the distal end of nail plate; discoloration and
thickening of nail plate, onycholysis, subungual
debris
Superficial white (SWO): White spots or patches
on the surface of the nail plate
Proximal subungual (PSO): infection of the
proximal nail fold, and extending distally, typically
whitish in color
Endonyx: Milky white discoloration of the nail
plate without hyperkeratosis, onycholysis; may
show lamellar splitting of the nail plate (typically
caused by T. soudanense or T. violaceum)

Pityriasis
versicolor

Well-defined, hyperpigmented or hypopigmented
lesions of areas with high concentrations of
sebaceous glands such as scalp, chest, back, upper
arms and face; showing fine scaling in most cases
(caused by Malassezia species)

typically be either an azole agent or allylamine (Table 3.2). For
most tineas, topical therapy applied directly to the affected
areas once or twice daily provides adequate resolution of infection. Topical corticosteroid use is not recommended, as it may
lead to suppression of physical signs of infection, with lack of
symptoms being wrongly associated with clearance of infection,

leading to treatment relapse. Oral therapy may be considered for
patients with larger areas of involvement, where infection presents with unusual severity or persistence, or where oral therapy
may be more convenient than daily topical application. Similarly,
patients who are immunocompromised may be provided with
oral treatment where prompt, thorough resolution of infection
is mandatory. Onychomycosis is an exception as topical medications may not penetrate the nail unit adequately, and most cases
will require oral rather than topical therapy. Similarly, tinea capitis is most frequently and effectively treated with oral medication, though topical products may be used prophylactically or to
prevent relapse of infection.
Cure rates of tinea corporis/cruris/pedis are high, and typically infections resolve with a few weeks of topical therapy. Cure
rates for tinea capitis are also high, but longer periods of oral
therapy are required (approximately 4–6 weeks of treatment,
on average). Cure rates for onychomycosis with oral therapy
are not as high as desirable, and reinfection/relapse is common.
Oral therapy for onychomycosis is usually given for 12 weeks at
a minimum, and extra “booster” therapy may be warranted for
cases where improvement is not seen with initial therapy. Also,
since diseased nails must be grown out and replaced by new, normal nails, it can take upwards of 9 to 12 months before sufficient
efficacy becomes clinically obvious.
Relapse after therapy has been noted with most types of dermatophyte infection. Patients must be encouraged to complete a
full treatment cycle, as infection can be present without visible
symptoms. Microscopic examination and culture are required
to confirm elimination of the pathogen. Infection transmission
from symptom-free carriers like family members and pets may
need to be controlled with adjunct therapies and techniques.
Fomites such as hats and combs must also be treated.

Antifungal Medications
Owing to the numerous types and formulations of topical antifungals, individual discussion of the topical antifungals is not
provided here. Antifungals that also provide antibacterial or
anti-inflammatory activity are particularly useful, as bacterial
superinfection can occur in dermatophytosis, and some dermatophytoses may present with significant inflammation. With
topical agents, most adverse events are skin reactions at the
application site, which are mild and transient. Safety of therapy is
less of a concern for topical medications than oral medications,
as serum absorption tends to be minimal with topical dermatophytosis therapy. Current country-specific prescribing information should be consulted prior to prescribing a topical antifungal
formulation.
Five main systemic agents are available: terbinafine, itraconazole, fluconazole, griseofulvin, and ketoconazole. Dosing and
efficacy vary with indication. The oral antifungal medications
may be associated with some potential for severe hepatic toxicity,
rare serious skin events such as Stevens-Johnson syndrome, and
possible drug-drug interactions due to metabolism through the
cytochrome P450 system (Table 3.3). Current country-specific
prescribing information for any oral antifungal medication
should be consulted prior to providing any medication. Though
oral antifungals are typically not approved for use in children,
pediatric use has been documented widely in the medical literature. It has typically provided safety profiles similar to those

46

*Cream: apply
twice daily x 1–4 wks
*1% Solution: apply
twice daily for 1 wk
Oral: 250 mg/day 2–4
wks

See Table 3.4: Pediatric
Dosing

*Oral: 250
mg/day
Toenail: 12 wks
Fingernail: 6 wks

*1% Solution:
apply twice daily
for 1 wk
Oral: not effective

Tinea
corporis/cruris

Tinea capitis

Onychomycosis

Pityriasis
versicolor
Oral: 200 mg/day
5–7 days

*Oral:
*Continuous therapy:
200 mg/day x 12 wks
‡Pulse therapy: 200 mg
BID for 1 week, followed
by 3 itraconazole-free
weeks
Toenails: 3 pulses
*Fingernails only: 2 pulses

See Table 3.4: Pediatric
Dosing

Oral: 200 mg/
day for 1 week

Oral: 200 mg
BID for 1 week

Itraconazole

2% Shampoo: 5
days
Oral: 300 mg
once weekly for
2 wks

Oral: 150 mg
once weekly
Toenail: 9–15
months
Fingernail: 4–9
months

See Table 3.4:
Pediatric
Dosing

Oral: 150–300
mg once weekly
for 2–4 wks

Oral: 150 mg
once weekly for
2–6 wks

Fluconazole

*2% Cream: apply once daily
for 2 wks
*2% Shampoo: single use
Oral: 200mg/day for 2 weeks,
10 days or 5 days; 400 mg
per week for 2 weeks; 400 mg
per day for 3 days; 3 doses of
400 mg given every 12 hours.

Oral: 200–400
mg/day x 6 months Not
recommended due to
hepatotoxicity risk.

Only effective against
Trichophyton.
2% shampoo used
as adjunct therapy

*2% Cream: apply
once daily for 2
wks
*Oral: 200–400
mg/day for 4 wks

*2% Cream: apply
once daily for 6
wks
*Oral: 200–400
mg/day for >4 wks

Ketoconazole

Not effective

*Microsize 1
g/day
Ultramicrosize
660 or 750 mg/
day X 4–12
months

See Table 3.4:
Pediatric Dosing

*Microsize 500
mg/day
Ultramicrosize
330–375 mg/day
X 2–4 wks

*Microsize 1
g/day
Ultramicrosize
660 or 750
mg/day
X 4–8 wks

Griseofulvin

*Ciclopirox
0.77% cream
*Selenium
sulfide

*Ciclopirox
8% lacquer
once daily
x 48 wks

Selenium sulfide
shampoo 1% as
adjunct therapy

*Ciclopirox 0.77%
cream and gel
twice daily for 4
wks

*Ciclopirox 0.77%
cream and gel
twice daily for 4
wks
Antifungal powder
for prevention

Topicals

* FDA approved indication
† There are no approved treatments specifically for tinea manuum; treatments shown are for tinea pedis which are effective in the treatment of tinea manuum.
‡ Current standard of care used by US dermatologists where itraconazole is prescribed.

*Cream: apply twice
daily x 1–4 wks
*1% Solution: apply
twice daily for 1 wk
Oral: 250 mg/day 2 wks

Tinea pedis/
manuum†

Terbinafine

Table 3.2: Treatment options available for dermatophytoses and pityriasis versicolor.

*Clotrimazole
*Miconazole
*Butenafine
*Econazole
*Oxiconazole

Amorolfine
5% laquer66 –
Not approved
in North
America

Corticosteroid
adjunct therapy
for severe
inflammatory
varieties

*Clotrimazole
*Miconazole
*Butenafine
*Econazole
*Naftifine
*Oxiconazole

*Clotrimazole
*Miconazole
*Butenafine
*Econazole
*Naftifine
*Oxiconazole

Common Fungal Infections — 47

seen in adults. Oral suspensions are available for many of the oral
antifungals, providing easier dosing for children.
Oral terbinafine is indicated by the U.S. Food and Drug
Administration (FDA) for the treatment of adults with dermatophyte onychomycosis of the toenails and/or fingernails.
Terbinafine has been safely used in general population, as well as
in children, the elderly, transplant patients, diabetics, and HIV
patients. The more common adverse effects with terbinafine
use are headache, gastrointestinal symptoms, and dermatologic
manifestations (Table 3.3). Less frequently, liver enzyme abnormalities (≥2 times the upper limit of normal), taste disturbances
and visual disturbances have been reported. Serum transaminase
tests (alanine transaminase, ALT, and aspartate transaminase,
AST) are suggested before beginning oral terbinafine to check
for preexisting liver dysfunction/disease. Patients should periodically repeat liver function tests while using terbinafine, and
be monitored for symptoms of liver dysfunction such as persistent nausea, anorexia, fatigue, vomiting, right upper abdominal
pain or jaundice, dark urine, or pale stools. Terbinafine has been
reported infrequently to precipitate or exacerbate cutaneous and
systemic lupus erythematosus, and should be discontinued in
patients showing signs of lupus erythematosus. Furthermore,
physicians should consider monitoring complete blood counts
in patients with known or suspected immunodeficiency who
are administered oral terbinafine for longer than 6 weeks.
Terbinafine is metabolized through the CYP2D6 enzymes, and
thus may interfere with other CYP2D6 drugs. Other drug interactions are possible, and a current country-specific product
monograph should be consulted for complete listing of known
drug interactions, warnings and monitoring requirements prior
to prescribing. Terbinafine is not recommended for patients with
existing liver disease. Terbinafine may be taken in a fasted or fed
state without affecting absorption.
Oral itraconazole is indicated by the FDA for the treatment
of adults with dermatophyte onychomycosis of the toenails and/
or fingernails, and for systemic mycoses such as blastomycosis,
histoplasmosis, and aspergillosis. The most commonly reported
adverse effects are headache, gastrointestinal disorders, and
cutaneous disorders (Table 3.3). Liver function tests should be
considered for any subject before dosing and periodically during dosing. Testing is required for any subject with preexisting hepatic function abnormalities or previous experience of
liver toxicity with other medications. Abnormal liver function
tests were found in 3% of 1845 patients treated with continuous itraconazole compared to 1.9% of 2867 patients treated with
pulse itraconazole (200 mg BID for 1 week out of 4 in a month).
Itraconazole is metabolized through the CYP3A4 pathway and
thus has potential for numerous drug interactions, limiting its
use in some patients. Itraconazole is prohibited in patients showing ventricular dysfunction such as current or past congestive
heart failure. A current country-specific product monograph
should be consulted for complete listing of known drug interactions, warnings, and monitoring requirements before prescribing. Capsules must be taken with a meal or cola beverage to
ensure adequate absorption.
Oral fluconazole is indicated by the FDA for the treatment of
(1) vaginal candidiasis (vaginal yeast infections due to Candida
species), (2) oropharyngeal and esophageal candidiasis, and (3)
cryptococcal meningitis. Fluconazole may also by used as prophylactic therapy to decrease incidence of candidiasis in patients

undergoing bone marrow transplantation who receive cytotoxic
chemotherapy or radiation therapy. Fluconazole has shown
a favorable adverse effects profile, with the most frequently
reported adverse events being nausea (3.7%), headache (1.9%),
skin rash (1.8%), vomiting (1.7%), abdominal pain (1.7%),
and diarrhea (1.5%) as reported in 4048 clinical trial patients
(Table 3.3). When fluconazole and cyclosporine are given concomitantly, careful monitoring of cyclosporine concentration
and serum creatinine concentration is recommended. Similarly,
blood glucose levels should be closely monitored when using oral
hypoglycemics concomitantly with fluconazole, and prothrombin time should be monitored where patients receive coumarintype anticoagulants concomitantly with fluconazole.
Oral griseofulvin is indicated in the United States for the treatment of tinea infections of the skin, hair, and nails. As with other
oral antifungal agents, the use of griseofulvin is not justified for the
treatment of tinea infections that would be expected to respond
satisfactorily to topical antifungals. Griseofulvin is not effective in
the treatment of pityriasis (tinea) versicolor, bacterial infections,
candidiasis (moniliasis), or deep mycotic infections. During prolonged griseofulvin therapy, periodic assessment of renal, hepatic
and hematopoietic functions should be performed (Table 3.3).
Oral ketoconazole is indicated for the treatment of patients
with severe recalcitrant cutaneous dermatophyte infections who
have not responded to topical therapy or oral griseofulvin, or who
are unable to take griseofulvin, as ketoconazole has been associated with a potential for liver damage (Table 3.3). Patients using
oral ketoconazole should be tested for signs of liver dysfunction
before initiating therapy. While on therapy, patients should be
closely monitored for signs of hepatotoxicity, both clinically
and biochemically, using liver function tests including serum
AST, ALT, alkaline phosphatase, gamma-glutamyl-transferase
and bilirubin (e.g., biweekly during first 2 months of therapy;
monthly or bimonthly afterward). Patients should be instructed
to report any symptoms of liver dysfunction such as persistent
nausea, anorexia, fatigue, vomiting, right upper abdominal pain
or jaundice, dark urine, or pale stools.

Tinea Pedis/Manuum
There are no approved treatments specifically for tinea manuum.
Treatments for tinea pedis are effectively used to treat tinea manuum. Topical formulations of terbinafine, butenafine, miconazole, econazole, ketoconazole, clotrimazole, and ciclopirox are
FDA-approved for tinea pedis/manuum (Table 3.2). Topical formulations may be used for milder, limited presentations. Many
topical agents (e.g., miconazole nitrate 1%, ciclopirox olamine
1%, naftifine hydrochloride 1%, sulconazole nitrate 1%) provide antibacterial activity and may be preferred where bacterial
superinfection is suspected. Formulations allowing once-daily
application rather than twice daily (e.g. naftifine 1% cream,
bifonazole 1%, ketoconazole cream 2%) may aid patient compliance and subsequent efficacy.
Chronic infection may warrant the use of oral antifungals,
particularly if previous topical regimens have failed. Off-label
use of oral itraconazole, terbinafine, or fluconazole may be practical where the tinea involvement is extensive and application of
a topical is not feasible. Studies have shown that oral terbinafine
and itraconazole may be the most effective treatments, and a
higher cure rate has been shown with topical allylamines than

48

Allylamine Available as tablet
Inhibits squalene epoxidase =
ergosterol deficiency (fungistatic)
and accumulation of squalene
(fungicidal) Lipophilic;
Binds strongly (>99%) and
nonspecifically to plasma proteins
Extensively metabolized in liver

Reported to inhibit CYP2D6 in
vitro: use with caution in patients
with concomitant 2D6 substrates
such as tricyclic antidepressants

None

Monitor CYP2D6-metabolized
drug concentration for increases
(tricyclic antidepressants, selective
serotonin reuptake inhibitors,
beta-blockers and monoamine
oxidase inhibitors type B)
Not recommended for patients
with chronic or active liver disease;
baseline LFTs for all patients
Not recommended for patients
with renal impairment (creatinine
clearance ≤ 50 mL/min)
Discontinue in patients with
clinical signs or symptoms of
lupus erythematosus
Monitor complete blood counts in
patients with known or suspected
immunodeficiencies (terbinafine
used >6 weeks), for decrease in
lymphocyte counts, neutrophil
counts

Chemistry

Metabolism

Contraindications

Cautions

Terbinafine

Imidazole
Available as tablet Inhibition of C14
demethylation of cell membrane sterols
(e.g., lanosterol); fungistatic; fungicidal
at high concentrations 84–99% bound
to plasma proteins
Partially metabolized in liver

May inhibit synthesis of adrenal
steroids, testosterone Potent inhibitor
of CYP3A group – possible drug
interactions
Cisapride Triazolam Terfenadine,
Astemizole

Close monitoring of hepatic function
required; Discontinue in patients
showing signs/ symptoms of liver
disease
Recommended dosage should be
followed closely to avoid depression
of adrenocortical function and serum
testosterone
Patients using oral hypoglycemics
should closely monitor blood sugar;
may need to adjust hypoglycemic
dosing

Induces hepatic enzymespotential for adverse events,
drug interactions

Patients with porphyria or
hepatocellular failure

Use with caution in patients
with penicillin sensitivity
Female patients should
be aware that there is a
possibility of decreased oral
contraceptive efficacy with
griseofulvin use

Potent inhibitor of
CYP2C9, and CYP2C19;
weaker inhibition of
CYP3A group – potential
for drug interactions
Severe liver disease; Use
with caution in patients
sensitive to other azoles
Cisapride Terfenadine

Discontinue in patients
showing signs/symptoms
of liver disease
Use with caution in
patients with potential
proarrhythmic conditions
Monitor patients
developing rashes closely
for signs of exfoliative
skin disorders
Patients using oral
hypoglycemics should
closely monitor blood
sugar; may need to adjust
hypoglycemic dosing

Potential for itraconazole metabolism
alteration where CYP3A4 is altered by other
medications

Patients with evidence of ventricular dysfunction
such as congestive heart failure (CHF) or a
history of CHF; cisapride, midazolam (oral),
triazolam, terfenadine, astemizole, pimozide,
quinidine, dofetilide, Levacetylmethadol
(levamethadyl) HMG CoA-reductase inhibitors:
lovastatin, simvastatin, etc; Ergot alkaloids
metabolized by CYP3A4: dihydroergotamine,
ergometrine (ergonovine), ergotamine, methlerg
ometrine(methylergovovine)
Use is strongly discouraged for patients with
elevated or abnormal liver enzymes or active
liver disease, or who have experienced liver
toxicity with other drugs
Baseline LFTs for all patients; Discontinue
in patients showing signs/symptoms of liver
disease
Use with caution in patients sensitive to other
azoles
Advise patients with risk factors for CHF
(ischemic and valvular disease, significant
pulmonary disease, renal failure or other
edematous disorders) to watch for signs and
symptoms of CHF
Discontinue if signs of neuropathy develop
Patients using oral hypoglycemics should
closely monitor blood sugar; may need to
adjust hypoglycemic dosing
Drug (capsules) should be taken after a full
meal or with an 240 mL cola beverage

Ketoconazole

Spiro-benzo[b]furan
Available as tablet or oral
suspension
Disruption of fungal cell
mitotic spindle, arresting cell
division (fungistatic)
Concentrated in skin, hair,
nails, liver, fat and skeletal
muscles; deposited in keratin
precursor cells, and bound to
new keratin
Oxidative demethylation
principally in liver

Griseofulvin

Bis-triazole
Available as tablet,
oral suspension or IV
formulation
Inhibits fungal lanosterol
14-α demethylase =
ergosterol deficiency
(fungistatic)
More hydrophilic than
other azoles
Protein binding of 11%
to 12%
No significant first-pass
hepatic metabolism

Fluconazole

Triazole Available as capsule, oral solution
or IV formulation Inhibits fungal lanosterol
14-α demethlyase = ergosterol deficiency
(fungistatic) Lipophilic; binds strongly to
plasma proteins (>99%)
Extensively metabolized in the liver
predominantly by CYP3A4

Itraconazole

Table 3.3: Summary of Systemic Antifungal Agent Properties

49

Adverse Events

GI: Diarrhea (5.6%), dyspepsia
(4.3%), nausea (2.6%), abdominal
pain (2.4%), flatulence (2.2%),
taste disturbance (2.8%)
Cutaneous: Rash (5.6%),
pruritus (2.8%), urticaria
(1.1%) CNS: Headache (12.9%)
Hepatic/Renal: Liver enzyme
abnormalities (≥2× upper limit
of normal) (3.3%) Other: Visual
disturbance (1.1%) Rare events
based on worldwide experience
with terbinafine tablets:
Idiosyncratic and symptomatic
hepatic injury and cases of liver
failure, some leading to death
or liver transplant; serious skin
reaction (Stevens-Johnson
syndrome, toxic epidermal
necrolysis); changes in ocular
lens and retina; agranulocytosis;
thrombocytopenia, angioedema
and allergic reactions (including
anaphylaxis); transient decreases
in absolute lymphocyte count;
cases of severe neutropenia;
precipitation and exacerbation
of cutaneous and systemic lupus
erythematosus; malaise; fatigue;
vomiting; arthralgia; myalgia;
hair loss

GI: Diarrhea (4%), dyspepsia (4%), flatulence
(4%), abdominal pain (4%), nausea (3%),
appetite increase (2%), constipation (2%),
gastritis (2%), gastroenteritis (2%) Cutaneous:
Rash (4%) CNS: Headache (10%), dizziness
(4%), abnormal dreaming (2%) Hepatic/
Renal: Liver function abnormality (3%), liver
enzyme abnormalities (≥2x upper limit of
normal) (4%), urinary tract infection (3%)
Other: Rhinitis (9%), upper respiratory tract
infection (8%), sinusitis (7%), cystitis (3%),
myalgia (3%), asthenia (2%), fever (2%),
pain (2%), tremor (2%), herpes zoster (2%),
pharyngitis (2%) Post-marketing experiences
(rare): Rare cases of serious hepatotoxicity
including liver failure and death; vomiting;
peripheral edema, congestive heart failure,
pulmonary edema; peripheral neuropathy;
menstrual disorders; reversible increases
in hepatic enzymes, hepatitis, liver failure;
hypokalemia, hypertriglyceridemia; alopecia;
allergic reactions (pruritus, rash, urticaria,
angioedema, anaphylaxis); Stevens-Johnson
syndrome; anaphylactic, anaphylactoid
and allergic reactions; photosensitivity;
neutropenia; congenital abnormality including
skeletal, genitourinary tract, cardiovascular
and ophthalmic malformations as well as
chromosomal and multiple malformations
(causal relation to itraconazole not established)

GI: Nausea (3.7%),
vomiting (1.7%),
abdominal pain
(1.7%), diarrhea (1.5%)
Cutaneous: Skin rash
(1.8%) CNS: Headache
(1.9%) Post-marketing
experiences (rare): Rare
cases of serious hepatic
reactions ranging from
mild transient elevations
in transaminases to
clinical hepatitis,
jaundice, cholestasis, and
fulminant hepatic failure,
including fatalities; rare
cases of anaphylaxis
(including angioedema,
face edema and pruritus);
QT prolongation, torsade
de pointes; seizures;
dizziness; alopecia;
exfoliative skin disorders
including StevensJohnson syndrome
and toxic epidermal
necrolysis; leucopenia,
including neutropenia
and agranulocytosis;
thrombocytopenia;
hypercholesterolemia,
hypertriglyceridemia,
hypokalemia; dyspepsia,
vomiting, and taste
perversion

GI: Epigastric distress;
nausea, vomiting, excessive
thirst; flatulence; diarrhea;
oral thrush Cutaneous:
Hypersensitivity reactions
including rash, and urticaria
CNS: Headache, fatigue,
dizziness, insomnia Postmarketing experiences
(rare): Paresthesia of
hands and feet; mental
confusion; impairment of
performance of routine
activities and psychotic
symptoms with large doses;
GI bleeding; angioedema;
erythema multiform-like
reaction, serum-sickness-like
reaction; photosensitivity;
lupus erythematosus,
lupus-like syndrome or
exacerbation of preexisting
lupus erythematosus;
toxic epidermal necrolysis;
proteinuria, nephrosis;
hepatotoxicity; menstrual
irregularity, amenorrhea;
estrogen-like effects
in children; transient
diminution of hearing;
reversible leucopenia;
elevated concentrations
of porphyrins in feces and
erythrocytes; tachycardia,
flushing when concomitant
with alcohol, and
potentiation of alcohol effects

GI: Nausea and/or vomiting (3–10%);
1% or less of patients: Abdominal pain,
constipation flatulence, GI bleeding,
diarrhea Cutaneous: Pruritus (2%)
Less than 1%: Rash, dermatitis,
purpura, urticaria CNS: Less than
1%: Headache, dizziness, somnolence,
lethargy, asthenia, nervousness,
insomnia, abnormal dreaming,
photophobia, paresthesia Hepatic/
Renal: Transient increases in serum
AST(SGOT), ALT (SGPT) and alkaline
phosphatase Other: Less than 1%:
Arthralgia, fever and chills, dyspnea,
tinnitus, impotence, changes in sweat
patterns, alopecia, signs of increased
intracranial pressure, hemolytic
anemia, thrombocytopenia, leucopenia
Post-marketing experiences (rare):
Hepatotoxicity (hepatocellular,
cholestatic or mixed pattern), typically
reversible, death rarely; Bilateral
gynecomastia with breast tenderness
in some men; Adrenocortical
insufficiency; Transient decrease
in serum cholesterol, alterations in
serum triglyceride concentrations;
Anaphylactic reactions after first
dose; Neuropsychiatric disturbances
including suicidal tendencies, severe
depression; Hypertension in several
subjects receiving 400 mg every
6–8 hours for metastatic prostate
carcinoma; disulfiram reactions
(flushing, rash, peripheral edema,
nausea, headache) when ingesting
alcohol

50 — Aditya K. Gupta and Elizabeth A. Cooper

Table 3.4: Tinea Capitis Dosing in Children*
Regimen

Duration

Weight (kg)
10–20

21–30

31–40

41–50

50+

Terbinafine
(continuous)

5 mg/kg/d

2–4 weeks

62.5 mg QD

125 mg QD

125 mg QD

250 mg QD

250 mg QD

Itraconazole
(continuous)

5 mg/kg/d

2–4 weeks

100 mg QD,
every second day

100 mg QD

100 mg QD/BID
on alternate days

200 mg QD

200 mg QD

Itraconazole
(pulse) ‡

Capsules: 5 mg/
kg/d

1 to 3 pulses

100 mg QD,
every second day

100 mg QD

100 mg QD/BID
on alternate days

200 mg QD

200 mg
BID §

Oral suspension:
3 mg/kg/d

1 to 3 pulses

Fluconazole
(continuous)

Oral suspension:
6 mg/kg/d

20 days

Fluconazole
(pulse) ||

Oral suspension:
6 mg/kg/d

8–12 weeks

Griseofulvin†
(continuous)

Microsize:
20–25 mg/kg/day

6–12 weeks

Ultramicrosize:
10–15 mg/kg/day

6–12 weeks

Oral suspension:
#
15–25 mg/kg/d

6–12 weeks

Griseofulvin†
(continuous)

* Durations of treatment are for Trichophyton tonsurans infection. Longer durations for Microsporum canis infections may be required
† Currently only griseofulvin is approved by the FDA for use in tinea capitis
‡ Itraconazole pulses are given for 1 week, with 3 weeks “off ” before starting the next pulse
§ Itraconazole adult dose 200mg BID (approved for pulse use in fingernail onychomycosis); No standard has been established in clinical trials
for tinea capitis for children >50 kg, and use varies from once-daily as with continuous regimen to twice-daily 200 mg dosing
| | Fluconazole pulses are 1 day on, 6 days off, before beginning next pulse
# Dosing based on Grifulvin V suspension 125 mg/5 mL

with topical azoles. Terbinafine 250 mg/day has been used for
tinea pedis with a duration of 2 to 6 weeks. Itraconazole regimens of 100 mg/day for 30 days or 4 weeks, 400 mg daily for 1
week, and 200 mg/day for 2 to 4 weeks have been reported. The
dose of fluconazole for tinea pedis most frequently reported is
150 mg once weekly administered for 2 to 6 weeks.
Though oral griseofulvin is approved in the United States for
treatment of tinea infections that are not expected to respond satisfactorily to topical antifungals, griseofulvin has lower efficacy
than the newer antifungals, poor keratin adherence, and narrowspectrum activity (dermatophytes only). This may be a limitation
when a superimposed bacterial infection is present. Where griseofulvin dosing is used, the suggested dosage for tinea pedis is 660 or
750 mg daily for 4 to 8 weeks. Similarly, use of ketoconazole tablets
has been discouraged due to the potential for hepatic side effects.
However, ketoconazole dosing of 200 to 400 mg daily for 4 to 8
weeks has been used for the treatment of tinea pedis infection.
Prevention of reinfection is important, and education of the
patient on proper foot hygiene is essential. Patients should avoid
walking barefoot in communal areas such as bathrooms, showers or swimming areas, and ensure that feet are dried thoroughly
after bathing, showering, or swimming. Occlusive footwear
should be avoided, or shoes should be alternated every 2 to 3
days, with frequent sock changes to reduce moisture in the foot

environment. Wicking socks decrease moisture as does powder
in socks.

Tinea Corporis/Cruris/Faciei
Topical therapies approved by the FDA for treatment of tinea corporis/cruris include terbinafine, butenafine, econazole, miconazole, ketoconazole, clotrimazole, and ciclopirox (Table 3.2).
Topical formulations may eradicate smaller areas of infection,
but oral therapy may be required where larger areas are involved
or where infection is chronic/recurrent.
Off-label use of oral antifungals may be practical when the
tinea involvement is extensive and application of a topical is not
feasible. Oral itraconazole, terbinafine, and fluconazole have
been used successfully in the treatment of tinea corporis/cruris,
though none of these agents are currently approved by the FDA
for use in these conditions. Terbinafine 250 mg/day has been
used for tinea corporis/cruris with a regimen generally lasting
2 to 4 weeks. A continuous itraconazole regimen of 200 mg/day
for 1 week is recommended for tinea corporis/cruris. Another
regimen of 100 mg/day for 2 weeks has also been reported to
be effective. The dose of fluconazole suggested for tinea corporis/cruris is 150 to 300 mg once weekly administered for 2 to 4
weeks. These oral agents are preferred over ketoconazole, due to

Common Fungal Infections — 51

the potential for hepatic side effects with ketoconazole use, and
griseofulvin is not recommended as it does not adequately bind
the keratin in the stratum corneum, which reduces its efficacy.
When griseofulvin is used for these indications, the suggested
dosage is 250 mg twice daily until cure is attained. Similarly,
when the decision is made to provide ketoconazole, the suggested dosage is 200 to 400 mg daily for 4 to 8 weeks.
Tinea faciei infections are typically cleared with topical treatment. Topical ciclopirox and terbinafine may provide good antiinflammatory effects as well as antifungal activity. Miconazole or
similar azoles may also be effective. Azoles should be used for 3
to 4 weeks, or at least 1 week after resolution of lesions. Resistant
lesions, cases of extensive disease, or more severe cases of infection may require oral therapy.

Tinea Capitis
Unlike most dermatophytoses, topical monotherapy is not
recommended for tinea capitis. Oral therapy is required to
adequately treat tinea capitis, as the dermatophytes are able to
penetrate the infected hair shaft whereas topical therapies cannot. Topical antifungals such as antifungal shampoos (ketoconazole, selenium sulfide, povidone iodine, zinc pyrithione) can be
used as adjunct therapy with or without oral antifungals to prevent reinfection or to treat asymptomatic carriers (Table 3.2).
Griseofulvin is the only oral antifungal treatment approved
by the FDA. However use of terbinafine, itraconazole and fluconazole for tinea capitis are also reported extensively in the medical
literature. The efficacies and safety profiles of terbinafine, itraconazole and fluconazole are similar to those of griseofulvin, and
may be used when griseofulvin therapy has failed. Itraconazole,
terbinafine, and fluconazole have the advantage of shorter treatment durations when compared to griseofulvin. Dosages are
typically given on a weight-based scale, and infections with
Microsporum may require higher dosing or longer therapy durations than infections with Trichophyton (Table 3.4). Oral suspensions are available for griseofulvin, itraconazole, and fluconazole
to aid pediatric dosing. Terbinafine and griseofulvin tablets can
be crushed, and itraconazole capsules can be opened and added
to a fatty food such as peanut butter.
Griseofulvin suggested dosing is 20 to 25 mg/kg/day using
the microsize formulation, for 6 to 12 weeks (Table 3.4). Where
the ultramicrosize formulation is used, a dose of 10 to 15 mg/kg/
day is suggested, as it is more rapidly absorbed than the microsize form. The oral suspension (microsize griseofulvin) contains
125 mg per 5 mL. Treatment should be continued for 2 weeks
after the resolution of clinical symptoms. Mycological cure rates
are generally high, being in the range of 70% to 100%.
The standard terbinafine dosing regimen for tinea capitis daily dosing is based on weight (less than 20 kg = 62.5 mg;
20–40 kg = 125 mg; greater than 40 kg = 250 mg per day) (Table
3.4). The duration of therapy is generally 4 weeks, though pulse
dosing regimens and shorter durations have also been reported
to be effective. Higher dosages or longer duration of therapy may
be required for M. canis infection. Limited studies suggested
that doses greater than 4.5 mg/kg/day may increase cure rates in
both Trichophyton and Microsporum infections, with duration of
therapy being less important.
Both continuous and pulse regimens of itraconazole have
been used to treat tinea capitis. The continuous regimen is 5 mg/

kg/day for 4 weeks, and the pulse therapy regimen is 5 mg/kg/
day for 1 week a month, given for 2 to 4 months (Table 3.4).
When the oral solution is used, dosages are reduced to 3 mg/kg/
day, whether used as continuous or pulse therapy.
A limited number of studies have shown that therapy with
fluconazole 6 mg/kg/day lasting 2 to 3 weeks can effectively treat
tinea capitis (Table 3.4). A comparative study of 5 mg/kg/day for
4 weeks showed similar efficacy to griseofulvin 6 mg/kg/day for
6 weeks. Once weekly therapy with fluconazole for tinea capitis
has also been found to be effective.
Transmission of infection from patients and from symptomfree carriers has been a concern for clinicians treating tinea capitis.
Adjunct therapies can be provided to the patient and family members to control transmission. Infection frequently may initiate
from contact with animals, and treatment of pets may be required.
Patients and family members should be counseled to avoid sharing
items such as caps, combs and toys. Hats, combs, pillows, blankets,
scissors, etc, may be disinfected with bleach. Most clinicians agree
that infected children do not need to be kept out of school once
treatment is initiated, particularly children in higher grades where
little physical contact between students is expected.

Tinea unguium (Onychomycosis)
Onychomycosis is difficult to cure and has a high rate of recurrence. Fingernails may show higher treatment success rates than
toenails due to faster rates of outgrowth, and suggested dosing
regimens are shorter for fingernail infection than toenail infection. It must also be remembered that nails showing past injury or
abnormal growth patterns may never return to “normal” appearance even though the infection may be completely eradicated.
Also, due to the high rate of recurrence, long-term follow-up is
important, so control of relapse can be undertaken as soon as
possible. It is therefore important that patients are informed that
most cases of onychomycosis require long-term therapy, with
improvements being slow to appear, and in some cases the nail
will not return to a normal appearance.
Ciclopirox nail lacquer 8% solution is a topical therapy
approved for mild to moderate Trichophyton rubrum onychomycosis without lunula involvement (Fig. 3.8). Application is once
daily for 48 weeks, and it is suggested that routine nail debridement be provided in conjunction with lacquer applications. The
mycological cure rate at week 48 was 33% in the pivotal clinical
trials. Its use is not associated with any of the potential adverse
effects that might occur with oral antifungals, for example, hepatotoxicity and cutaneous reactions. However, while it is practical to use ciclopirox nail lacquer in situations where three or
fewer nails are involved with onychomycosis, an oral antifungal
agent should be considered when a greater number of nails are
involved, or if the severity of onychomycosis involves greater
than 60% of the nail plate area (Fig. 3.9). Amorolfine 5% nail
lacquer has not been approved for use in North America, and has
proved to be effective therapy in fingernail and toenail onychomycosis without matrix involvement.
Tinea pedis infection is frequently reported in conjunction
with onychomycosis infection, and topical agents to control
tinea pedis may be given along with onychomycosis treatment
for this reason. Topical therapy may also be useful as an adjunctive therapy with oral medications for more severe presentations
of infection. Topical monotherapy with allylamines or azoles

52 — Aditya K. Gupta and Elizabeth A. Cooper

Figure 3.8. Mild onychomycosis.

Figure 3.9. Severe onychomycosis.

would not be expected to provide effective therapy in any but the
least severe cases of infection. Use of topical azoles or allylamines
as prophylactic therapy has rarely been reported. Limited reports
with miconazole powder did not show successful prophylaxis of
infection.
Terbinafine and itraconazole are the most frequently used
oral medications. Though griseofulvin is approved for tinea
infection of the nails, its affinity for keratin is low and long-term
therapy is required. Efficacy in the treatment of onychomycosis is also low, and the newer azole and allylamine agents have
largely replaced griseofulvin for this indication. Ketoconazole
is not recommended for therapy of onychomycosis due to the
potential for hepatotoxicity (blocking human CYP-dependent
demethylation of ergosterol at higher concentrations) and the
availability of alternative oral treatments. Fluconazole has shown
high efficacy, low relapse rates, and usefulness with yeast co-infection However, there have been few studies on this treatment
method.
The FDA-approved oral therapy regimens for onychomycosis are as follows: terbinafine 250 mg/day for 12 weeks (toenails)
or 6 weeks (fingernails only); itraconazole 200 mg/day for 12
weeks (toenails with or without fingernail involvement); and
itraconazole 200 mg twice daily as pulse therapy (one pulse: 1
week of itraconazole followed by 3 weeks without itraconazole)

using two pulses (fingernails only). Though only a continuous
regimen of itraconazole is FDA-approved for toenail onychomycosis, the current itraconazole standard of care of toenail
onychomycosis is a pulse regimen (one pulse: 1 week of itraconazole followed by 3 weeks without itraconazole; three pulses
given). In countries where fluconazole is approved for the treatment of onychomycosis, the most frequently used schedule is
fluconazole 150 to 300 mg once weekly given until the abnormal-appearing nail has grown out (fingernails: 3–6 months;
toenails: 9–12 months).
Mycological cure rates (KOH negative and culture negative) for terbinafine use in dermatophyte onychomycosis are
estimated at 76% in a meta-analysis of clinical trial data from
the medical literature. By comparison, itraconazole mycological cure rates are 59% (continuous therapy) and 63% (pulse
therapy). Clinical response rates (infection cleared or showing marked improvement) were as follows: terbinafine – 66%,
itraconazole continuous therapy – 70%, and itraconazole pulse
therapy – 70%. The complete cure rate (mycological cure and no
residual nail area affected) in the terbinafine prescribing information is 38% versus 14% for continuous 12-week itraconazole
dosing. For cases of nondermatophyte mold infections, cure
rates may be significantly lower, and such cases are known to be
difficult to cure.
It has been suggested that oral antifungals with differing
mechanisms of action may provide synergistic destruction of
nail fungal infection (i.e., terbinafine/itraconazole combination
therapy). Use of a topical medication (amorolfine, ciclopirox
nail lacquer, etc.) in combination with an oral antifungal may
improve the efficacy and cost-benefit rates for severe onychomycosis treatment. These combination methods require further
study to determine efficacy, and are not currently accepted treatment methods.
It may also be beneficial to combine oral therapy with routine nail debridement, particularly where the nail is thickened, or
where the infection presents as a dermatophytoma, spike or lateral infection. Caution must be taken not to damage the underlying skin during debridement, particularly in subjects who are
vulnerable to severe lower limb complications, such as diabetics
or individuals with reduced lower limb profusion.
Nail avulsion by surgical or chemical means is one of the
traditional options available to manage onychomycosis, as this
eliminates most of the fungi and frees the underlying surface
for topical antifungal treatment. Avulsion may be full or partial.
Avulsion has not been examined in large randomized, controlled
trials. There is some potential for permanent nail plate alteration,
and it can be painful for the patient.
As with tinea pedis, proper foot and nail hygiene may help
prevent reinfection. Patients should avoid walking barefoot
in communal areas such as bathrooms, showers or swimming
areas, and ensure that feet are dried thoroughly after bathing,
showering or swimming. Nails should be kept short and clean.
Shoes should fit properly and socks should be made from absorbent material such as cotton.

Pityriasis versicolor
Topical treatment is frequently effective for PV, though systemic
therapy may be desirable when infection is widespread, or when
short-duration oral therapy is preferable to frequent application

Common Fungal Infections — 53

of a topical agent. Topical azoles (ketoconazole, fluconazole,
bifonazole, clotrimazole, miconazole) have demonstrated efficacy in both cream formulation or shampoos. Terbinafine solution, cream, gel or spray has also been effective. Topical ciclopirox
provides both antifungal and anti-inflammatory activity against
Malassezia. Oral therapy with ketoconazole, itraconazole and
fluconazole shows a similarly high efficacy in the medical literature. Oral terbinafine and griseofulvin are not effective for PV.
Treatment does not vary with hyperpigmentation versus hypopigmentation. Pigmentation may not return to normal until well
after infection is mycologically eradicated, particularly when
hypopigmentation is noted.
Ketoconazole and itraconazole may be prescribed prophylactically, as there is a high rate of relapse of PV infection.
Rates as high as 60% to 90% in 2 years post-treatment have been
reported. Prophylactic doses given are as follows: ketoconazole –
single 400 mg dose or 200 mg daily for 3 days once monthly; itraconazole – single 400 mg dose once monthly for 6 months.

P I T FA L L S A N D M Y T H S

A primary pitfall for dermatophytosis treatment is not obtaining mycological confirmation of the infectious agent via fungal
culture on, particularly for onychomycosis. Onychomycosis is
mimicked by many other conditions such as psoriasis or trauma,
and proceeding to oral therapy in these cases without identifying
an infectious agent is inappropriate. Also, standard oral therapies
may be ineffective when the infectious fungi are nondermatophytes. It is not uncommon to require repeat samples to identify
a dermatophyte agent in onychomycosis. For nondermatophyte
infections, multiple samples are required to confirm their status
as the causative agent.
A further pitfall is to assume a negative mycology exam represents a cured infection. Fungal organisms may frequently fail to
present on culture. Where clinical signs of infection remain, and
particularly where microscopy shows fungal organisms present
though culture is negative, there remains a potential for infection
relapse. Repeat sampling may be prudent, and follow-up of the
clinical condition is warranted.
For most tineas, topical corticosteroid monotherapy is not recommended, as it may lead to suppression of the physical signs of
infection, with lack of symptoms sometimes being wrongly associated with clearance of infection, leading to treatment relapse.
It is a myth that children do not get onychomycosis. Though
it is much more frequent in elderly patients, and typically develops over years, there are many reports of children presenting
with classic dermatophyte onychomycosis infections. Children
have also presented with other types of onychomycosis. A suspicion of onychomycosis should not be dismissed due to patient
age. Cultures should be obtained to evaluate the presence of fungal organisms.
Onychomycosis represents a challenge for clinicians, in that
it is difficult to motivate patients to continue with long periods
of follow-up. “Cured” subjects may feel follow-up is a waste of
time, while “non-cured” subjects may feel there is no point in
continuing to try treatments. As the slow growth of the nails
would require years of observation to adequately determine
relapse rates, the potential for relapse has not been adequately
determined through clinical study. However, reports suggest that

the potential for relapse is high. Assessment of cure and relapse is
complicated by the high rate of false negative cultures in mycological assessment. Long-term follow-up is necessary to observe
the clinical appearance of nails, as a clue to whether relapse is
developing when culture remains falsely negative. Follow-up
also provides the only non-invasive method to sample greater
portions of the nail unit. As the nail grows out and portions that
were too deep for sampling earlier now move towards the distal
edge, further opportunities for discovering viable fungi are presented. Patient education on the difficulties of treating onychomycosis is essential at the start of treatment, so that expectations
are clear, and not set too high.

SUGGESTED READINGS

American Society of Health-System Pharmacists, Inc. Miscellaneous
Antifungals – Griseofulvin. In: AHFS Drug Information® 2005.
Bethesda, MD, 2005, pp. 535–537.
American Society of Health-System Pharmacists, Inc. Azoles –
Ketoconazole. In: AHFS Drug Information® 2005. Bethesda, MD,
2005, pp 510–516.
Anaissie EJ, Kontoyiannis DP, Huls C, et al. Safety, plasma concentrations, and efficacy of high-dose fluconazole in invasive mold infections. J Infect Dis 1995;172: 599–602.
Arrese JE, Pierard GE. Treatment failures and relapses in onychomycosis:
a stubborn clinical problem. Dermatology 2003;207(3):255–260.
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PA R T I I : L E S S C O M M O N I N F E C T I O N S

4

C U TA N E O U S T U B E R C U L O S I S
Bhushan Kumar and Sunil Dogra

H I STORY

Tuberculosis (TB) was a disease familiar to the most ancient
civilizations, judging from the inscriptions on Babylonian tablets, which represent the earliest human records. Hippocrates
(460–376 BC) was the first to give an intelligent description of
this disease as “phthisis,” which meant to dry up. Aristotle, a
contemporary of Hippocrates, notes that it was a general belief
among the Greeks of his day that phthisis was contagious. A
similar reference has been made in the Sanskrit works of the
Indo-Aryans, namely the Rigveda (1500 bc), Ayurveda (700 bc),
and in the Laws of Manu (1000 bc). Galen (ad 131–201) considered the disease an ulceration that should be treated by measures
designed to dry the secretion. The Roman acquaintance with TB
is reflected in the writings of Pliny the Elder (ad 23–79), while
John Bunyan called it “The Captain of the Men of Death,” referring to its devastating course and prognosis.
Lupus vulgaris seemed to have been prevalent in Palestine
before and during the time of Christ, and was included in the
conditions termed Tsara’ath in the Old Testament and Gospels.
The origin of the Latin word for wolf, “lupus” is unclear, although
its usage has been established in the Middle Ages. The great
German pathologist, Rudolf Virchow, found that it had appeared
in the writings of the Masters of the Salerno School of Medicine
(circa 10th century). In 1808, Robert Willan, (1757–1812) the
founder of British Dermatology, gave the term lupus to a nodular eruption on the face that progressed to ulceration. In 1887,
William Tilbury (1836–1879) used lupus vulgaris specifically
for skin TB instead of as a term for any destructive cutaneous
condition.
Scrofuloderma was described by the ancient French writers
who called it scrofulous gumma. For many centuries, scrofula,
along with lupus vulgaris and other nonpulmonary manifestations of TB, was considered curable by the touch of a reigning monarch, hence also known as King’s Evil. Rene Laennec’s
(1781–1826) description of his own prosector’s wart in 1826 was
the first published case recognizing the association of cutaneous
disease with mycobacterial infection. The tuberculous etiology
of tuberculosis verrucosa cutis was established jointly by the dermatologist Riehl and the pathologist Paltauf in 1886.
The histopathological characteristics of the disease were
described in detail by Carl Rokintansky (1804–1878) and Rudolf
Virchow (1821–1902). The credit for describing the giant cells

We are thankful to Dr. BD Radotra for providing us the histopathology
photomicrographs and to Drs. JD Wig, V Ramesh, HK Kar, S. Barua, and L
Padmavathy for some of the clinical photographs.

and epithelioid cells in the lupus tissue goes to Forster, who documented these cells in 1855. His findings were later confirmed by
Langhans in 1868. Friedlander in 1873 demonstrated the great
similarity of the histopathology in lupus vulgaris, scrofuloderma,
and TB of other organs. In 1864, Jean Antoine Villemin (1827–
1892) established a significant milestone in the history of the
evolution of the disease by pronouncing that TB was infectious.
Gaspard Laurent Bayle (1774–1816) was the first to discover that
TB could affect the entire body and was not confined to the lungs
only. In 1865, Jonathan Hutchinson (1828–1913) correlated the
incidence of lupus vulgaris with the history of TB in the patient’s
family. Peters and Brock demonstrated the presence of past or
coexisting TB of other organs in relation to cutaneous TB.
Robert Koch (1843–1910) discovered the tubercle bacillus
(1882) and confirmed its role in the causation of TB by satisfying
the conditions first indicated by Henle and later enunciated and
named after Koch, the Koch’s Postulate. Hutchinson (1888) first
used the term “apple-jelly nodule” to describe its peculiar transparency. Scarification, application of caustics, blowing steam
through tubes on to the lesion, freezing with carbon dioxide
snow, cautery, ultraviolet radiation therapy, X-ray treatment, and
vitamin D have all been used in the past, either alone or in combination, to treat lupus vulgaris. Niels Finsen received the Nobel
Prize (1903) for his therapeutic results with UV irradiation in
lupus vulgaris. One of the major medical advances of the 20th
century has been the development of antitubercular therapy.

INTRODUCTION

Tuberculosis (TB), one of the oldest diseases known to mankind, continues to be a significant health problem even as we
have entered the 21st century. Worldwide, it remains the leading
cause of death by an infectious disease. According to the World
Health Organization (WHO), one-third of the world’s population is currently infected with the TB bacillus. Approximately 5%
to 10% of people who are infected with TB bacilli (but who are
not infected with human immunodeficiency virus [HIV]) may
manifest disease during their lifetime. People with HIV and TB
co-infection are much more likely to develop TB. WHO estimates that the largest number of new TB cases in 2005 occurred
in the South-East Asia region, which accounted for 34% of incident cases globally.
Extrapulmonary TB constitutes approximately 10% of all
cases of TB and cutaneous TB makes up only 1.5% of all such
cases. Although cutaneous TB comprises only a small proportion, when the high prevalence of TB is borne in mind, these
numbers become significant. Serious underreporting due to
59

60 — Bhushan Kumar and Sunil Dogra

diagnostic difficulties and categorization cannot be overlooked.
Since 1984, the incidence of extrapulmonary TB has increased at
an even faster rate than that of pulmonary TB and is considered
a diagnostic criterion in the case definition for AIDS. Because
immunocompromised individuals are at increased risk for extrapulmonary TB, dermatologists are renewing their historic role in
the diagnosis of cutaneous lesions of TB.
TB of the skin has a worldwide distribution. While it was
more prevalent in regions with a cold and humid climate in the
past, it now mostly occurs in tropical regions. Cutaneous TB is
still uncommon in industrialized countries despite the rising
incidence of extrapulmonary TB in areas with a high prevalence of HIV infection. In developed countries, cutaneous TB
has typically been observed in patients with immunosuppression
from malnutrition, cancer, prolonged corticosteroid therapy, or
immunosuppressive therapy, whereas in developing countries it
occurs mostly in the generally healthy patients. In India in the
1950s and 1960s, cutaneous TB affected 2% of all dermatology
outpatients and by the 1980s and 1990s, this figure had fallen
to 0.15% to 0.1%. This percentage is even less in developed
countries. In a recent study from the Philippines, no cases of
cutaneous TB were found in 425 patients with pulmonary TB.
In another study of 360 patients with TB from Turkey, the incidence of cutaneous infection was found to be 3.5% and the association was much stronger between cutaneous involvement and
tuberculous lymphadenitis than with pulmonary infection (44%
versus 3%). In a hospital-based study from Tunisia, the estimated
incidence of new cases in the dermatology service was 1.2 % per
year between 1991 and 2000 compared with 1.4 % between 1981
and 1990. Childhood cases constitute 12.8% to 36.3% of the total
patients with cutaneous TB. Childhood TB is a sensitive marker
of ongoing transmission of infection within a community and
represents a reservoir for future disease.

PA T H O G E N E S I S

Tuberculosis involving the skin is caused by Mycobacterium
tuberculosis, Mycobacterium bovis, and under certain conditions, the Bacillus Calmette-Guérin (BCG), an attenuated strain
of M. bovis. Mycobacteria are acid-fast bacilli (AFB), weakly
gram-positive, nonsporulating, and nonmotile rods. The family Mycobacteriaceae consists of only one genus, Mycobacteria,
which includes the obligate human pathogens M. tuberculosis
and the closely related M. bovis, Mycobacterium africanum, and
Mycobacterium microti as well as Mycobacterium leprae and a
number of facultative pathogenic and nonpathogenic species
(the atypical mycobacteria). The AIDS pandemic with its profound and progressive suppression of cellular immune functions
has led to a resurgence of TB and to the appearance or recognition of new mycobacterial pathogens.
Even though mycobacterial diseases are widespread and serious, the organisms are neither very virulent nor very infectious.
Only approximately 5% to 10% of infections with M. tuberculosis actually lead to disease. It is transmitted through inhalation,
ingestion, or inoculation. The development of cutaneous TB is
dictated by the pathogenicity of the infecting organism, the route
of infection (exogenous/endogenous), the patient’s prior sensitization to tuberculous protein, and the nature of the patient’s
cell-mediated immunity (CMI).

The balance between bacterial multiplication and destruction
is determined not only by the properties of the invading organisms but also by the immune response of the host to control such
an infection. After mycobacteria have invaded the host, they may
multiply and lead to progressive disease or their multiplication
can be checked or even completely arrested.
Following infection, T lymphocytes interact with mycobacterial antigens displayed on the surface of antigen-presenting cells
(APC) and release lymphokines, interleukins (ILs), and interferons. These are then responsible for activation and expression of
MHC class II antigens and IL-2 receptors on the T lymphocytes.
There is an accumulation of macrophages and resultant granuloma formation at the infection site. Memory T cells generated
during initial sensitization remain in circulation and in lymphoid
organs for an extended period of time.
Cutaneous TB may evolve either as primary (tuberculous
chancre and acute miliary cutaneous TB) or as secondary infection [lupus vulgaris (LV), tuberculosis verrucosa cutis (TBVC),
scrofuloderma (SF), and tuberculosis cutis orificialis (TBCO)].
Secondary infection TB manifests in a sensitized host. TB from
secondary infection commonly forms a continuous immunopathologic spectrum extending from LV through TBVC, gumma
(s), and SF to TBCO, although there is considerable overlap
between the clinical presentations. Lupus vulgaris and TBVC
represent the “high-immune” pole with active CMI and apparently normal humoral immunity, whereas SF and TBCO represent impaired CMI with a predominantly humoral immune
response (Fig. 4.1).
Infection in a sensitized individual by another strain of M.
tuberculosis results in “reinfection” TB, with LV or TBVC as its
cardinal manifestation. Reactivation of the dormant “persister”
mycobacteria, consequent to lowered CMl, is responsible for
“reactivation” which usually presents as LV or SF but can present
as any of the clinical forms indistinguishable from reinfection
TB. In reinfection, there is a history of either primary infection
or BCG vaccination or both. At times the only evidence of past
infection may be pulmonary scarring and calcification visible on
X-rays. Subsequently, any event that lowers the CMI may reactivate “persisters.” Association of systemic disease with involvement of organs at places distant from cutaneous lesions occurs in
all the clinical forms in varying percentages.
In the true clinical setting, this simple categorization may
not be entirely true because LV and TBVC may also result from
endogenous infection, and SF may result from a continuous
smoldering infection in the lymph nodes acquired in infancy. The
long-standing infection acts as a microvaccination in the patient.
Occurrence of these clinical forms in various combinations
seems to fuzz this rather convenient concept based on immunity
and resultant histology. Inoculation cutaneous TB after tattooing
is quite rare, and is reported mostly from central parts of India,
where local customs and rituals result in several tribal women
opting for this cheap tattoo ornament. It is likely that the shared
tattoo equipment, saliva, or the topical contaminants like soil,
cow dung, etc., applied after the procedure might harbor mycobacteria, resulting in cutaneous TB. Simple social custom of nose
and ear piercing in developing countries like India are also documented routes of spread of tuberculous infection. Infantile ritual
circumcision in the past has been a frequent cause of penile TB
when strict sterilized techniques were not practiced. It is still
occasionally seen in underdeveloped areas. Sexually transmitted

Cutaneous Tuberculosis — 61
Erythema induratum

Tuberculids

Papulonecrotic tuberculid

Host with
good
immunity

Lichen scrofulosorum

Complete healing

Reinoculation, accidental
trauma

Contiguous spread
Lymphatic spread

Tubercle
bacilli

Inoculation: skin,
lungs,
gastrointestinal
tract, lymph nodes

Chancre,
primary TB
complex

Host with
moderate
immunity

Hematogenous
dissemination

Verrucous TB

Lupus vulgaris

Lupus vulgaris

Gumma (subcutaneous abscess)
Erythema nodosum

Tuberculids

Papulonecrotic
tuberculid
Lichen scrofulosorum

Contiguous spread

Autoinoculation
Host with poor
immunity

Scrofuloderma

Erythema induratum

Orificial TB

Lymphatic spread
Acute miliary TB
Hematogenous
dissemination

Figure 4.1. Pathogenesis of cutaneous tuberculosis.

primary Mycobacterium tuberculosis infection of the penis has
been reported in partners of women with endometrial TB.
Inoculation TB (accidental) in laboratories handling pathogenic
strains of tubercle bacilli has also been reported.
The pathologic deviations observed in different types of
cutaneous TB seem to form a spectrum of immunological and
histopathological changes extending from scrofuloderma toward
LV through TBVC. At one end of this spectrum is scrofuloderma,
with a comparatively lower immunity, mild to moderately positive Mantoux test, small to moderate number of lymphocytes in
granulomas in the histopathologic sections, and easy demonstrability of bacilli in tissue sections. Lupus vulgaris, on the other
hand, forms the opposite pole with a high degree of immunity,
moderate to strongly positive Mantoux test, abundant lymphocytes in the granulomas with absent or scant tubercle bacilli,
and absence of any immunologic abnormality. TBVC probably
occupies an intermediate position showing a moderately positive
Mantoux test and ample lymphocytes in granulomas with scant
bacilli. It is likely that TBCO occupy a position on the extreme
left of the spectrum beyond scrofuloderma.

DIAGNOSIS

Diagnosing cutaneous TB is not always easy if we strictly follow Koch’s postulates for any infection. The suggestive clinical

picture, careful history of contact with a TB patient or previous
tuberculous disease, tuberculin test, and histology contribute to
a diagnosis of TB. The definitive diagnosis can only be made by
identification of M. tuberculosis on the smear and the recovery of
organisms on culture, guinea pig inoculation, and their demonstration in the tissue section (Table 4.1).
However, the sensitivity for isolating M. tuberculosis on culture is often low and culture in Lowenstein–Jensen medium may
take up to 6 to 8 weeks or longer. Smear for demonstration of AFB
is particularly helpful in lesions with a high bacillary load such
as disseminated miliary TB, scrofuloderma, and gummatous TB
lesions. Polymerase chain reaction (PCR) can aid in rapid diagnosis but requires expertise, as it is prone to contamination and
false positives. The low yield from PCR and culture may be due
to the low number of viable bacilli within the specimen and/or to
degradation of DNA material. Combination of dot hybridization
with PCR has markedly increased the sensitivity and specificity of
PCR in detecting cutaneous TB. Mantoux test with purified protein derivative (PPD) indicates through the skin the cell-mediated
hypersensitivity to tuberculin. No definite correlation has been
found between Mantoux reactivity and the presence, extent, and
type of cutaneous TB. However, it is still a good indicator of the
presence of infection if strongly positive, especially in an adult. As
the yield from culture and PCR is often low, diagnosis is usually
based on clinical features, histological findings, and retrospective
review of response to treatment. A successful response to treatment

62 — Bhushan Kumar and Sunil Dogra

Table 4.1: Diagnosis of cutaneous tuberculosis
Criteria for the diagnosis of cutaneous tuberculosis
Absolute Criteria
1. Demonstration of AFB in tissue smear/histopathology
2. Positive Culture
3. Positive guinea pig inoculation
4. Positive PCR for M. tuberculosis
Relative Criteria
1. Personal or family history of TB and a morphology compatible
with cutaneous TB
2. Active, visceral tuberculosis
3. Positive tuberculin-purified protein (PPD) derivative reaction
4. Positive serological tests for detection of antibody to
M. tuberculosis antigen
5. Compatible histopathology
6. Response to specific antituberculosis therapy

granulomatous inflammation, variable caseation necrosis, and
the presence of M. tuberculosis demonstrable by special staining, culture, or polymerase chain reaction. In tuberculids, the
pathogenesis is believed to be a hypersensitivity reaction to the
presence of M. tuberculosis or its antigens. The tuberculids, like
true cutaneous TB, also show a spectrum of morphological presentations modified by granulomatous inflammation, variable
necrosis, and vasculitis. While mycobacteria have not always
been demonstrated from tuberculid lesions, most experts believe
M. tuberculosis to be an etiologic factor.
New information has allowed further classification of true
cutaneous TB based on the route of infection and the immune
status of the patient. The system proposed by Tappeiner and
Wolff uses this new approach (Table 4.2). Under this system,
true cutaneous TB is classified as being acquired either exogenously or endogenously. Exogenous infection occurs following
the direct inoculation of the organism into the skin of an individual who is susceptible, either naïve or previously infected or
sensitized with BCG. Endogenous infection denotes the occurrence of disease after variable periods of quiescence in treated or
untreated tuberculosis patients. This endogenous infection can
be in the same site or region or at a distant site/region.

*PCR = polymerase chain reaction

C L I N I C A L F E AT U R E S

over the course of 6 weeks strongly corroborates a clinical possibility of cutaneous TB, especially in resource-poor settings with
lack of sophisticated tests to confirm the diagnosis. However, there
may be critics to this therapeutic response diagnostic approach.
Histological interpretation is often difficult in TB. Differences
in the histopathological appearances depend on the balance
between infection and immunological response. Classical tuberculous histology in the form of tuberculous granuloma is found
in not more than two-third of cases. The fully formed granuloma
consists of a focus of epithelioid cells containing a variable, but
usually sparse number of Langhans’ giant cells and a varying
amount of caseation necrosis in the center. This is surrounded
by a rim of lymphocytes and monocytes. While this tuberculous
granuloma is highly characteristic, it is not pathognomonic and
is not always found. In the remaining, the histological picture
could only be interpreted as chronic inflammation or granulomatous pathology consistent with TB, and the final diagnosis
again depends on the clinical picture, other investigations, and
therapeutic response. Deep fungal infections, syphilis, leprosy,
sarcoidosis, etc. among other diseases can produce an identical
picture difficult to distinguish from the characteristic tuberculous histology.

C L A S S I F I C AT I O N

Numerous attempts have been made to classify cutaneous TB
based on clinical morphology, route of entry of organisms, the
immune status of the host, and so forth, but none of them is
completely satisfactory. The clinical manifestations comprise
a considerable number of skin changes, usually subclassified
into more or less distinct disease forms. True cutaneous TB
skin lesions show a spectrum of morphological presentations
that are the outcome of pathological changes characterized by

Lupus Vulgaris
Lupus vulgaris is an extremely chronic and progressive form of
cutaneous TB occurring in a person with a moderate to high
degree of immunity. Lupus vulgaris is the most common form of
cutaneous TB reported in studies from Africa and India.
Lupus vulgaris originates from TB elsewhere in the body
by hematogenous, lymphatic, or contiguous spread, most often
from cervical adenitis or pulmonary TB, sometimes from an old,
apparently quiescent primary complex. Rarely, it follows primary inoculation TB or is found at the site of BCG vaccination.
The condition is more common in females than in males, and all
age groups are equally affected. The lesions are usually solitary
or few, but two or more sites may be involved simultaneously. In
patients with active pulmonary TB, multiple foci may develop.
Though lupus vulgaris can arise at the site of a primary inoculation, around the ostia of an active lesion of scrofuloderma, or at
the site of a BCG vaccination, it commonly appears in normallooking skin. Following a transient impairment of immunity,
particularly after measles (thus the term lupus postexanthematicus), multiple disseminated lesions of lupus vulgaris may arise
simultaneously in different regions of the body due to hematogenous spread from a latent tuberculous focus. During and following the eruption, a previously positive tuberculin test may
become negative but will usually revert to positive as the general
condition of the patient improves.
The disease shows a predilection for the face and almost
80% of the lesions are seen over the head and neck. On the face
it tends to involve the nose, earlobes, upper lip and frequently
extends to the contiguous mucosal surfaces. Next in frequency
are the arms and legs. Involvement of the trunk is uncommon.
In India the face is affected less often and the buttocks and limbs
more frequently. This has been attributed to the prevailing local
habit of children playing without clothing and defecating in the

Cutaneous Tuberculosis — 63

Table 4.2: Classification of Cutaneous Tuberculosis
Exogenous infection

Nonimmune host
• Primary inoculation tuberculosis
(primary complex)
Immune host
• Tuberculosis verrucosa cutis
• Inoculation tuberculosis (tattoo,
accidental trauma, laboratory
personnel)
• Lupus vulgaris

Endogenous Infection
(spread)

• Lupus vulgaris
• Scrofuloderma
• Metastatic tuberculous abscess
(tuberculous gumma)

Figure 4.2. Lupus vulgaris over face; note scarring and ectropion.

• Acute miliary tuberculosis
• Orificial tuberculosis (including
colostomy opening)
Tuberculids

True tuberculids
• Lichen scrofulosorum
• Papulonecrotic tuberculid
Facultative tuberculids
• Erythema induratum (Bazin)
• Erythema nodosum

Modified from Tappeiner and Wolff.

open and so the possibility of sitting on the dried sputum of
patients with TB.
The characteristic lesion is a plaque, composed of nodules
of an “apple-jelly” color, which extends irregularly in some
areas, while scarring occurs in one edge, causing considerable
tissue destruction over many years. In general, lupus vulgaris
is asymptomatic. The earliest lesion is a small, reddish-brown,
flat plaque of soft consistency, which gives the impression of
being embedded in the skin. The lesion gradually becomes
darker, slightly raised, more infiltrated and, by slow peripheral extension, gyrate or discoid in shape. Slight scaling may
be the only indication of the presence of the lesions. The
lesion extends peripherally, leaving behind an atrophic scar,
on which new lesions may develop (Figs. 4.2–4.4). Pressing
on the lesion with a glass slide may display the characteristic “apple-jelly” color of the nodule/papule, which is often not
appreciated in people with darker skin. The hypertrophic form
displays soft tumorous nodules, and is rather deeply infiltrating (Fig. 4.5). In the ulcerative form, the underlying tissue
becomes necrotic and breaks down (Fig. 4.6 and 4.7). This may
result in marked destruction, particularly if auricular or nasal
cartilage is involved. The vegetative form consists of papular
and nodular forms, and is marked by necrosis and ulceration.
Typical lupus vulgaris plaques do not present diagnostic problems. Sometimes they have to be distinguished from lesions

Figure 4.3. Lupus vulgaris – extensive involvement of the trunk.

of sarcoidosis, lymphocytoma, discoid lupus erythematosus,
tertiary syphilis, leprosy, blastomycosis or other deep mycotic
infections, lupoid leishmaniasis, and chronic vegetating
pyodermas.
In 40% of patients with lupus vulgaris, there is associated tuberculous lymphadenitis, and 10% to 20% have pulmonary TB or TB
of the bones and joints or a focus in another system. In many cases,

64 — Bhushan Kumar and Sunil Dogra

Figure 4.4. Lupus vulgaris – multiple lesions involving the groin and
leg showing central scaring.

lupus vulgaris may be regarded as a symptom of another tuberculous disease running a serious course. The morbidity of lupus vulgaris in patients with pulmonary TB is 4 to 10 times higher than the
rest. Its course is chronic and, without treatment, may extend over
many years or even decades. Complete healing without therapy is
only rarely observed. In developing countries, neglect and lack of
awareness about cutaneous TB is responsible for delayed diagnosis
and complications in long-standing cases in the form of dissemination of the disease, contractures, myiasis, and even malignant
transformation (Fig. 4.8).

Scrofuloderma
Scrofuloderma results from the involvement and breakdown of
the skin overlying a tuberculous focus, usually a lymph gland,
but sometimes an infected bone, joint, subcutaneous gumma,
tuberculous pleural abscess, infected epididymis, or even a lacrimal gland. It occurs most commonly over a lymph node, particularly the cervical lymph nodes. In India, scrofuloderma is a
common presentation in children unlike in Europe where adults
are more often afflicted.
In developing countries, consumption of unpasteurized
milk containing M. bovis is a common source of infection causing scrofuloderma, especially in the cervical region. Bluish red
skin overlying the infected gland or tuberculous focus (cold
abscess) breaks down to form undermined ulcers with a floor

Figure 4.5. Lupus vulgaris (hypertrophic type) involving ear lobule
following ear piercing.

of granulating tissue (Fig. 4.9). Numerous fistulae may intercommunicate beneath ridges of the necrosed/necrosing skin.
The resulting ulcers and sinuses may drain watery, purulent, or
caseous material (Fig. 4.10). Progression and scarring produce
irregular adherent masses, densely fibrous in places and fluctuant or discharging in others. After healing, characteristic puckered scarring marks the site of the infection (Fig. 4.11 and 4.12).
M. avium-intracellulare lymphadenitis and the more benign
Mycobacterium scrofulaceum infection have to be excluded by
bacterial cultures. If there is an underlying tuberculous lymphadenitis or bone and joint disease, the diagnosis usually presents no difficulty. Syphilitic gummas, deep fungal infections,
particularly sporotrichosis, actinomycosis, severe forms of
acne conglobata, and hidradenitis suppurativa may have to be
excluded. Scrofuloderma may heal spontaneously, but this can
take years.

Cutaneous Tuberculosis — 65

Tuberculosis Verrucosa Cutis (Warty Tuberculosis)
This is the verrucous form of reinfection TB that localizes at
the skin sites prone to trauma of a previously infected patient
who usually has a moderate or high degree of immunity. Lesions
arise in many ways: by accidental infection from an extraneous
source – physicians, pathologists and postmortem attendants are
traditionally at risk (thus, “anatomist’s wart,” “prosector’s wart,”
“verruca necrogenica”); autoinoculation in a patient with active
TB; and in children and young adults already infected/BCG vaccinated, who have some degree of immunity.
The lesion starts as a small, symptomless, indurated, warty
papule with a slight inflammatory areola. By gradual extension
a verrucous plaque is formed. Irregular extension at the edges
leads to a serpiginous outline (Fig. 4.13). The center may involute
leaving an atrophic scar, or the whole lesion can form a massive,
infiltrated papillomatous excrescence. It may be purplish, red, or
brown in color with firm consistency but there may be areas of
relative softening. Pus and keratinous material may sometimes be
expressed from these soft areas or from fissures. Lymphadenitis is
rare and may be due to secondary pyococcal infection. This form
of TB needs to be differentiated clinically from common warts,
keratoses, blastomycosis, chromoblastomycosis, actinomycosis,
leishmaniasis, tertiary syphilis, hypertrophic lichen planus, and

Figure 4.6. Lupus vulgaris (ulcerative type) over foot.

Figure 4.7. Lupus vulgaris showing mutilation of the ear.

Figure 4.8. Squamous cell carcinoma developing over lupus vulgaris.

66 — Bhushan Kumar and Sunil Dogra

Figure 4.11. Scrofuloderma – chronic scarring resulting in genital
lymphedema.
Figure 4.9. Cold abscess over trunk (left flank); note healed sinus over
midback.

Figure 4.12. Scrofuloderma – extensive scarring, keloid formation
and webbing of the neck.

Figure 4.10. Scrofuloderma involving inguinal lymph nodes with
ulval edema.

Cutaneous Tuberculosis — 67

Figure 4.13. Tuberculosis verrucosa cutis over foot.

squamous cell carcinoma. Extension is usually extremely slow
and lesions may remain virtually inactive for months or years.
Spontaneous remission has been reported.

Figure 4.14. BCG vaccine-induced lupus vulgaris.

Primary Inoculation Tuberculosis (Tuberculous
Chancre)
A tuberculous chancre is the result of the inoculation of M. tuberculosis into the skin of an individual without natural or artificially
acquired immunity to this organism. The tuberculous chancre and
the affected regional lymph nodes constitute the tuberculous primary complex of the skin. The skin lesion appears 2 to 4 weeks after
inoculation as a small papule, scab, or wound with little tendency
to heal. A painless ulcer develop that may be quite insignificant or
may enlarge to attain a diameter of over 5 cm. It is shallow with
a granular or hemorrhagic base studded with miliary abscesses
or covered by necrotic tissue. The ragged edges are undermined
and of a reddish-blue hue. As the lesions grow older, they become
more indurated, with thick adherent crusts. A slowly progressing,
painless regional lymphadenopathy develops 3 to 8 weeks after the
infection and may rarely be the only clinical symptom. After weeks
or months, cold abscesses may develop that perforate to the surface of the skin and form sinuses. Body temperature may be slightly
raised. Occasionally, lymph node enlargement, abscess formation,
and suppurations may take a more acute course.
Wounds inoculated with tubercle bacilli may heal temporarily but break down later, giving rise to granulating ulcers.
Mucosal infections result in painless ulcers or fungating granulomas. Inoculation TB of the finger may present as painless
paronychia. Inoculations of mycobacteria in puncture wounds
have resulted in subcutaneous abscesses. Clinical differential
diagnoses include tularemia, sporotrichosis, cat-scratch fever,
and M. marinum infections.
Without anti-TB medications, the primary lesion heals with
scarring after several months, and may occasionally evolve into
tuberculosis verrucosa cutis or lupus vulgaris. Scrofuloderma may
evolve if regional lymph nodes break down and cause contiguous extension into the overlying skin. The incidence of post-BCG
cutaneous TB caused by the Bacillus Calmette Guerin is extremely
low in comparison to the great number of vaccinations performed.
Usually the BCG reactions run a milder course than “spontaneous” TB of the skin, and they occur more often after revaccination.
Specific lesions following BCG vaccination include: inoculation
site lupus vulgaris (Fig. 4.14), regional adenitis (which can sometimes be severe), scrofuloderma, and generalized tuberculid-like
eruptions. In addition, there is the occasional occurrence of generalized adenitis, osteitis, and tuberculous foci in distant organs.

Acute Disseminated Miliary Tuberculosis
Disseminated miliary tuberculosis (Tuberculosis cutis miliaris acuta generalisata) of the skin, once a rare form of TB that
occurred mainly in infants in the prechemotherapy era, has now
reemerged among patients infected with HIV. It is an uncommon
form of TB secondary to hematogenous dissemination of tubercle bacilli (classically from a pulmonary or meningeal source)
to multiple organs including the skin. It has also been described
in a few patients with immune dysfunction secondary to malignancy, chemotherapy, or other immunosuppression; post organ
transplant or after treatment of autoimmune disease; and in some
healthy individuals. The initial presentation of this condition is
as a widespread erythematous papular rash. Tiny central vesicles
then develop, and these rupture or dry up a few days later, forming a crust. Healing occurs within 1 to 4 weeks, as a depressed
scar, with a brownish halo. Lesions may appear anywhere on the
body, and usually number between 20 and 50.
Diagnosis is sometimes only made by the biopsy of a skin
lesion showing AFB. The eruption occurs in individuals already
gravely ill, which requires a high index of suspicion for diagnosis
in the early stage. A multitude of maculopapular and purpuric
rashes must be excluded, but the diagnosis is usually substantiated by the evidence of acute miliary disease of the internal
organs. In the untreated or in those with delayed diagnosis, the
prognosis is poor, but a favorable outcome after treatment is
possible. With the increased prevalence of HIV disease and the
accelerated transmission of TB among patients with HIV, more
cases of this once-rare condition are likely to be encountered.

Orificial Tuberculosis
Tuberculous infection of the mucosa or the skin adjoining orifices in a patient with advanced internal TB is now very rare.
It occurs particularly in those with pulmonary, intestinal, or
urogenital disease from where tuberculous bacilli are regularly
shed. In orificial TB of the mouth, the tongue, and particularly
the tip and the lateral margins, are most frequently affected, but
the soft and hard palate are also common sites of involvement.
The lesions are usually mildly symptomatic but can be very painful. In cases with intestinal TB, lesions develop on and around

68 — Bhushan Kumar and Sunil Dogra

the anus, and active genitourinary disease may lead to involvement of vulva and glans penis. A small yellowish or reddish
nodule appears on the mucosa and breaks down to form a circular or irregular ulcer with a typical punched-out appearance,
undermined edges, and soft consistency. Its floor is covered by
pseudomembranous material and often exhibits multiple areas
of yellowish slough and granulation tissue. The surrounding
mucosa is swollen, edematous, and inflamed. Lesions may be
single or multiple and range from being almost asymptomatic to
being extremely painful.
Orificial TB is a symptom of advanced internal disease with a
most unfavorable prognosis. Individuals developing orificial TB
run a downhill course, and as the internal condition progresses,
the orificial lesions enlarge and spread. Chronic ulcers of the
mouth in patients with pulmonary TB should arouse suspicion.
Large numbers of acid-fast organisms can be detected in smears,
and culture confirms the diagnosis. Syphilitic lesions, aphthous
ulcers, and carcinoma have to be excluded.

Tuberculous Gumma
This form of TB is the result of hematogenous dissemination
from a primary focus during periods of bacillemia and lowered
resistance. It usually occurs in undernourished children or in
patients who are severely immunosuppressed. Nontender and
fluctuant subcutaneous abscesses may arise as single or multiple lesions on the trunk, extremities, or head. The underlying
abscesses often invade the overlying skin and it breaks down,
forming ulcerative lesions and sinuses indistinguishable from
scrofuloderma. The extremities are more often affected than the
trunk. Secondary lesions may occur rarely along the draining
lymphatics. This condition may occur with progressive organ TB
but may also occur without any identifiable underlying tuberculous source. Acid-fast stains usually reveal copious amounts of
mycobacteria. Clinical conditions like panniculitis, deep fungal
infections, syphilitic gumma, and hidradenitis suppurativa have
to be excluded by histopathology and culture.

Figure 4.15. Papulonecrotic tuberculids over face.

The term tuberculid is applied to any of a group of eruptions,
which arise in response to an internal focus of TB as evidenced
by strong PPD reactivity and response of lesions to antituberculous therapy (ATT). The lesions are usually symmetrical and disseminated. Such tuberculids may be thought of as belonging to
either one of the two groups: the true tuberculids and the facultative tuberculids. The “true tuberculids” are papulonecrotic tuberculid and lichen scrofulosorum, and are deemed such because
M. tuberculosis is considered to be the only etiological agent. The
“facultative” tuberculids are erythema induratum of Bazin and
erythema nodosum.

new crops of lesions may continue over months or years. The
legs, knees, elbows, hands, and feet are the sites of predilection,
but ears, face, buttocks, and glans penis alone may sometimes be
affected. Young adults are predominantly affected, but papulonecrotic tuberculid has also been seen in infants and young children. As a rule, tubercle bacilli are not seen on tissue examination
and cannot be cultured, but in many cases mycobacterial DNA
has been detected by PCR. Patients usually have strongly positive
Mantoux (tuberculin) test and many have clinical manifestations
of TB. Clinical conditions like vasculitis, pityriasis lichenoides et
varioliformis acuta (PLEVA), and secondary syphilis should be
excluded by histopathology. The lesions respond satisfactorily to
ATT. The rarity of the condition today and the frequent absence
of an obvious focus of TB may deceive the unwary. Biopsy and
tuberculin testing should be carried out in all doubtful cases. A
therapeutic test is usually decisive.

Papulonecrotic tuberculids

Lichen scrofulosorum

The eruption consists of recurring lesions of symmetrical, hard,
dusky-red papules. These soften, ulcerate, and heal with pigmented, mostly atrophic scars, over the course of a few weeks
(Figs. 4.15, 4.16a and 4.16b). Presence of active lesions adjacent
to areas of scarring is considered a diagnostic aid to papulonecrotic tuberculid. The lesions are generally asymptomatic and

Lichen scrofulosorum (LS) was first described by Hebra in
1868. It has been considered a rare immunological manifestation of cutaneous TB. Much of the current information is based
on case reports and small case series. It is mostly observed in
children, though it can also be seen in adolescents and adults.
LS is most frequently associated with concurrent tuberculous

Tuberculids

Cutaneous Tuberculosis — 69
a

b

Figure 4.16. (a & b). Papulonecrotic tuberculids over glans penis.

involvement of lymph nodes, bone, or other organs and exhibits an excellent response to ATT. In a series of 39 cases from
India, 72% of the patients had an associated tubercular focus
elsewhere in the body. Patients presenting primarily with LS
should be thoroughly screened for a possible occult tubercular focus. High incidence of a positive Mantoux test also suggests the presence of a high degree of tissue hypersensitivity
in these patients. It has also been reported following BCG
immunotherapy.
The disease is characterized by eruptions on the trunk of
grouped, closely set, minute lichenoid papules, which are often
perifollicular. These lesions consist of yellow to reddish-brown
papules, 0.5 to 3 mm in diameter, sometimes slightly scaly
and occasionally capped by a minute pustule. They develop in
groups or discoid patches, and involute slowly over a period
of months, without scarring (Fig. 4.17). As these lesions are
subtle and asymptomatic, neither the patient nor the physician
may give it enough importance and thus may miss the diagnosis. A high index of suspicion and awareness about this entity
is needed for diagnosis. Conditions like lichen planus, lichen
nitidus, lichenoid secondary syphilis, and micropapular forms
of sarcoidosis, which resemble LS morphologically, should be
excluded.

Erythema Induratum of Bazin
Originally described by Ernest Bazin in 1861, erythema induratum of Bazin is the tuberculid with an overwhelming female
preponderance. It is characterized by indurated, often ulcerated erythrocyanotic nodules that arise on the calves, especially the posterolateral aspect, of those with heavy legs. The
nodules may at first regress during warm weather but eventually persist and even ulcerate. The ulcers are ragged, irregular,
and shallow, with a bluish edge. Resolution is slow, even with
adequate therapy, since the underlying circulatory dysfunction

Figure 4.17. Lichen scrofulosorum over trunk; note scar of treated
lupus vulgaris over upperback.

is not readily amenable to treatment. Past or active foci of TB
are usually present and the tuberculin test is positive. The term
erythema induratum should perhaps be reserved for cases with

70 — Bhushan Kumar and Sunil Dogra
a

b

Figure 4.18. Lupus vulgaris (a) epidermal hyperplasia with granulomas in the upper dermis (H&E ×40). Lupus
vulgaris (b) higher magnification of the granulomas (H&E ×200).

a proven tuberculous origin though an identical clinical picture
can occur without this association. The peripheral T lymphocytes of patients with erythema induratum show an exaggerated response to PPD.

Erythema Nodosum
Erythema nodosum (EN) is the most frequent cause of acute
panniculitis characterized clinically by erythematous tender
nodules distributed bilaterally over the lower extremities and
histologically by septal inflammation. EN is associated with a
variety of disease processes and results from inflammatory reactions that may be triggered by a multitude of antigenic stimuli
including viral, bacterial, and mycobacterial antigens. In developing countries, where TB is still a major public health problem,
it is a predominant cause of EN. It preferentially affects women
and can occur at any age, with a peak incidence between the second and third decades of life. The individual lesions are 1 to 5
cm in size, tender, do not ulcerate, and spontaneously involute
within a few weeks.
EN has been associated mostly with primary TB. However,
there are reports of its association with secondary or reactivation
extrapulmonary TB as well. EN was considered to be a favorable
finding as it ensured early diagnosis and prompt institution of
appropriate therapy. Since majority of patients with EN show a
strong tuberculin test, these inflammatory nodules are considered to represent a morphologic expression of hypersensitivity to
hematogenous tuberculous antigen. In patients having recurrent/
persistent EN, without any other identifiable cause and a strongly
positive tuberculin reaction, ATT is indicated even in the absence
of other specific signs of infection in an endemic area.

H I S T O PA T H O L O G Y

The microscopic picture of the infectious granuloma due to
Mycobacterium tuberculosis ranges from well demarcated tuberculous granulomas to a diffuse inflammatory infiltrate with
loose granulomas or even nonspecific inflammation. The most
prominent histologic feature in lupus vulgaris is the formation of
typical tubercles, usually in the upper part of dermis with epithelioid and Langhans giant cells. Secondary changes may be superimposed: epidermal thinning and atrophy or acanthosis with

Figure 4.19. TBVC – epithelioid cell granulomas close to the adnexal
structures with a multinucleate giant cell (H&E ×200).

excessive hyperkeratosis or even pseudoepitheliomatous hyperplasia (Fig. 4.18a and 4.18b). Old lesions are composed chiefly of
epithelioid cells and it may at times be impossible to distinguish
it from sarcoidal infiltrates. Lymphocytes are scattered throughout the lesion. The early histopathologic changes in tuberculous
chancre are those of acute neutrophilic inflammation with necrosis. Numerous bacilli are present. After 3 to 6 weeks, the infiltrate
becomes more granulomatous and caseation appears, coinciding with the disappearance of the bacilli. In tuberculosis verrucosa cutis (Fig. 4.19), there is a striking pseudoepitheliomatous
hyperplasia, hyperkeratosis, acanthosis, and papillomatosis with
the dermis showing varying amounts of chronic inflammation
and at times superficial abscess formation. The intense, mixed
infiltrate may show only sparse tuberculous foci. Occasionally
the epidermis may show marked hyperkeratosis and the dermis
may show a varying amount of chronic inflammation. Serial sections may be required to identify a granuloma. Scrofuloderma
reveals massive necrosis and abscess formation in the center
of the lesion on histopathology. However, the periphery of the
abscesses or the margins of the sinuses contain tuberculoid
granulomas and true tubercles, and M. tuberculosis can be more
easily found (Fig. 4.20). Eosinophils may be present in sizeable

Cutaneous Tuberculosis — 71

Figure 4.20. Scrofuloderma – multiple epithelioid cell granulomas in
the deep dermis with Langhans type of giant cells (H&E ×100).

numbers. Rarely biopsy may be nondiagnostic showing only
granulation tissue. As in scrofuloderma, massive necrosis and
abscess formation are found in tuberculous gumma. Acid-fast
stains usually reveal copious amounts of mycobacteria. In orificial TB, there is a heavy nonspecific inflammatory infiltrate and
necrosis, but tubercles with caseation may be found only deep in
the dermis and mycobacteria are easily demonstrable. Lesions
of miliary TB initially reveal necrosis and nonspecific inflammatory infiltrate and small abscesses occasionally with signs of
vasculitis.
Mycobacteria are present both in and around blood vessels. In later stages (if the patient develops immunity), lymphocytic cuffing of the vessels and even classical tubercles may be
observed. Among tuberculids, the most characteristic feature on
histopathology in papulonecrotic tuberculid is a wedge-shaped
necrosis of the upper dermis extending into the epidermis, and
there may be a leukocytoclastic or lymphocytic vasculitis or
granulomatous infiltrate present (Fig. 4.21). In lichen scrofulosorum, superficial tuberculoid granulomas consisting primarily
of epithelioid cells are found usually distributed around hair follicles. Necrosis is infrequent. Mycobacteria are not demonstrable in the sections or on culture. Histopathological features in
erythema induratum are usually nonspecific like those of a nodular vasculitis with areas of tuberculoid granulomas, fat necrosis, and foreign-body giant cell reactions. Erythema nodosum is
a septal panniculitis of the subcutis characterized by a widening
of septa with inflammatory infiltrate and inflammation around
the vessels, but with no evidence of vasculitis (Fig. 4.22a and
4.22b). In the early stages, there is edema and widening of septa
with an inflammatory infiltrate comprised of lymphocytes and
histiocytes. In late stages, granuloma formation with giant cells
may be seen.

SYS T E M I C I N VO LV E M E N T

Figure 4.21. Papulonecrotic tuberculid – epidermal necrosis with
vasculitis and dense infiltrate in the upper dermis (H&E ×100).

a

Systemic organ involvement, which is quite common in all forms
of cutaneous TB, has not received the attention it deserves.
This may precisely be the reason for the very widely differing
protocols recommended for the treatment of cutaneous TB.
Understanding and accepting the significance of endogenous
spread of the disease would automatically imply the presence

b

Figure 4.22. Erythema nodosum (a) subcutaneous tissue showing thickening and dense inflammation of the
septae (H&E ×100). Erythema nodosum (b) entrapped blood vessels with perivascular infiltrate (H&E ×200).

72 — Bhushan Kumar and Sunil Dogra

H I V A N D C U TA N E O U S T U B E R C U L O S I S

Figure 4.23. Scrofuloderma – multiple healed sinuses involving breast

of an active focus of infection somewhere inside (which may or
may not be identifiable with the presently available diagnostic
tools) and the obvious necessity to treat it adequately. Needless
to state that complete treatment of the patients with cutaneous
TB and the focus of infection inside is imperative. Although for
adequate treatment the concept of making all efforts to locate
the focus somewhere in the body is sound, there are only two
studies available, which have investigated for a focus of infection and reported its presence in 18.8% to 22.1% of patients.
The infective focus was found in all variants of the disease but it
was more often seen in patients with scrofuloderma and tubercular gummas. All body organs, namely, lungs, abdomen, and
bones, hosted a focus and rarely even the CNS and heart were
found to be affected. The identification of the focus gains further
significance because the recommended regime of 6 months of
antitubercular therapy may not be sufficient for TB of the CNS,
heart or bone. It would be worthwhile recommending that in
all patients with cutaneous TB, all possible efforts should be
made to identify a focus with relevant investigations for ensuring complete treatment.

TUBERCULOSIS OF THE BREAST

Tuberculosis is rarely localized to the breast. It may be an
isolated disease or may be a part of the disseminated disease
spread hematogenously or by contiguity or through lymphatics
(Fig. 4.23). Coincidental TB of the faucial tonsils of the suckling
infant is suggested as one of the modes of infection. The lesions
occur as an ulcerated plaque or a nodule present unilaterally.
Though the controversy between the entity of granulomatous
mastitis and true TB of the breast is probably only of semantics,
the patient would be better off if treated for a tubercular etiology.
On histology, tuberculoid granulomas with fat necrosis are seen.
Despite a strongly positive Mantoux test, AFBs are not present.
However, the basic principles of diagnosis, that is, a suggestive
history, compatible clinical picture, strongly positive Mantoux
test, presence of TB elsewhere, and poor response to treatment
for conditions mimicking granulomatous pathology should help
in confirming the diagnosis.

Mycobacterium tuberculosis is a common pathogen in persons
infected with HIV. The risk of active TB in people infected with
HIV and M. tuberculosis is 3% to 8% per year, with a lifetime
risk of 50% or more. As many as 50% of AIDS patients may be
infected with AFB at some stage of their disease. The prevalence
of TB in AIDS patients may be 100 times that in the general
population. Several studies have documented a high prevalence
of extrapulmonary disease in HIV-seropositive patients with TB.
However, the skin has remained a relatively unusual site of dissemination. Specific skin lesions of TB in HIV-infected patients
are rare, probably because of the shorter life expectancy of most
HIV-infected patients after reactivation of TB, which allows
insufficient time for TB of the skin or mucous membranes to
develop fully.
Fatal cases can occur in tuberculosis presenting in the skin.
This is especially true with the advent of multidrug resistant
tuberculosis and the increasing occurrence of tuberculosis in
AIDS patients. In most cases, these poor prognostic types are the
multibacillary forms of infection such as miliary TB. Other types
of cutaneous TB reported in HIV-infected patients are tuberculous gumma, tuberculids, cold abscess, and orificial TB.
Cutaneous miliary TB in the setting of HIV infection as well
as other forms of immunosuppression is typically characterized
histologically by a lack of granulomatous response and a high
bacillary load – analogous to lepromatous leprosy. HIV/TB
with low CD4 counts shows less pronounced cellular immune
response to PPD than to M tuberculosis. A negative PPD test,
therefore, does not rule out the diagnosis of TB in patients with
HIV and a low CD4 count.

BCG PROPHYLAXIS

In developing countries, where morbidity and mortality due to
TB are much greater, disease prevention is most desirable. BCG
vaccination against TB, which is relatively safe, inexpensive, and
easy to use in the field, has been used for many years. BCG vaccine was developed from M. bovis in 1908 and first used in 1921.
BCG vaccination does not prevent all tuberculous infections. It
has been used extensively to prevent the more serious forms of
disease caused by M. tuberculosis, such as meningoencephalitis
and miliary TB. There is very extensive worldwide experience
with BCG, and it is generally considered a very safe vaccine with
very rare side effects. The standard dose is 0.1 mL for children and
adults, and 0.05 mL for infants up to 12 months of age. Currently
the intradermal route is preferred. Subcutaneous injection is considered second line, but is also acceptable. Approximately 3 to 4
weeks after vaccination, a 5 to 15 mm erythematous, inflamed,
and infiltrated papule appears. Frequently, a central crust develops, which then falls off, leaving an ulcer that usually heals by the
13th week following vaccination. This crusted ulcer then evolves
into a small, flat scar.
Currently used strains, maintained by many laboratories, are
by no means identical, and this fact may in part explain the very
different protection rates ranging from 0% to 80% found in the
10 major trials of BCG vaccination conducted since the 1930s.
The protective effect of BCG in children is likely to last for at
least 15 years. It is most effective in preventing meningitis and

Cutaneous Tuberculosis — 73

miliary disease. Protection from cutaneous TB may be provided
by the BCG vaccine. This is demonstrated by the fact that patients
with disseminated disease (any systemic organ involvement or
the presence of generalized lymphadenopathy, multiple sites) are
less likely to have been BCG vaccinated than those with localized
disease. One study showed more unvaccinated individuals in a
group with disseminated types of cutaneous TB (80.3%) than
those with localized cutaneous TB (65.5%). A different problem concerns BCG vaccination for TB or leprosy in children in
countries with a high prevalence of AIDS, since attenuated BCG
organisms may become pathogenic, leading to active disease in
children infected with HIV.

T R E AT M E N T

Historically, scarification, application of caustics, blowing steam
through tubes onto the lesion, freezing with carbon dioxide
snow, cautery, ultraviolet radiation therapy, X-ray treatment,
and vitamin D have all been used in the past, either alone or
in combination, to treat cutaneous TB. Volk (1924) highly recommended roentgen therapy, heliotherapy, and tuberculin for
treating scrofuloderma. Presently, except for an additional use of
cryotherapy and electrocautery for destroying small lupus nodules within scarred areas, all the other means of treatment are
obsolete. One of the major medical advances of the 20th century
has been the development of antitubercular therapy. As in TB of
other organs, chemotherapy is the treatment of choice for cutaneous TB.
Essentially, the treatment of TB of the skin is the same as that
of TB in general. Attention to the patient as a whole is an essential part of the proper management of any tuberculous lesion.
This involves a careful search for an underlying focus of disease.
The public health aspect should be taken into consideration
when following these patients. Don’t forget that improvement in
general nutrition can be an important therapeutic intervention.
The optimal treatment for cutaneous TB consists of a multiple
drug regimen for a duration that is long enough to kill all viable
organisms, thus preventing the emergence of resistant strains
and recurrences. Since most patients with cutaneous TB have
systemic disease involvement as well, the treatment of TB of the
skin is the same as that of TB in general. It is inferred that anti-TB
regimens used for pulmonary TB are adequate for treating cutaneous TB. The Centers for Disease Control and Prevention recommends chemotherapy that is split into two phases. The initial
intensive phase, which consists of daily isoniazid, rifampin,
pyrazinamide, and either ethambutol or streptomycin for 8
weeks, is directed at rapidly destroying large numbers of viable
organisms. The maintenance or continuation phase, which consists of isoniazid and rifampin given daily, three times weekly or
twice weekly for 16 weeks, is aimed at eliminating the remaining, persistent organisms. Isoniazid, rifampicin, pyrazinamide
and ethambutol may be as efficacious when given three times
weekly as when given daily. Fully intermittent regimens (directly
observed therapy, DOTS) were used in the two largest TB programs (India and China) with a high level of effectiveness under
program conditions.
Patients with cutaneous TB usually have no demonstrable
AFBs and should be monitored clinically. In all cases of cutaneous TB, there is always a good response observed rather early to

anti-TB treatment. This response is reassuring since there have
been only isolated case reports of multidrug-resistant cutaneous TB. However, the rise in the advent of multidrug resistant
bacilli and the presence of the infection in HIV-positive individuals can pose serious management problems. HIV-infected
patients who strictly adhere to standard treatment regimens
do not have an increased risk of treatment failure or relapse.
Drug interactions, especially between protease inhibitors or
non-nucleoside reverse-transcriptase inhibitors and rifampin,
may result in either toxic blood levels of rifampicin or nontherapeutic blood levels of various other antiretroviral agents.
Intermittent treatment regimens should not be used in HIVinfected patients with CD4+ cell counts less than 100 cells/
µL so as to avoid an unacceptable rate of treatment failure or
relapse.
Surgical excision is sometimes necessary as an adjunct to
chemotherapy, especially in the management of scrofuloderma
and localized lesions of TB verrucosa cutis and lupus vulgaris.
In some cases of LV corrective plastic surgery may be indicated
depending on the degree of mutilation and skin deformity. In
conjunction with ATT, steroids may also have a place in therapy
in a few instances, especially in cases of tuberculids and erythema nodosum.
The treatment of cutaneous TB in most cases is the same as
for pulmonary TB, as lesions in the skin often represent hematogenously or lymphatically dispersed disease from the internal foci
of infection. Along with the increase in the number of patients
who have both AIDS and TB, developing countries are more
likely to face the problem of cutaneous TB including its diagnosis, treatment, and even drug resistance in the future.

P I T FA L L S A N D M Y T H S

Cutaneous TB has not received due importance in the developed
world where it has become a rarity seen only in immigrants and
HIV-infected individuals. The classification system, though useful in understanding the clinical spectrum, does not always help
in ascertaining the endogenous or exogenous mode of spread of
the disease. Morphology of any chronic skin lesion(s) like TB can
mimic any other infections or even malignancy depending upon
the course of the disease, presence of signs of acute inflammation, discharging sinuses, and mutilations caused by the disease.
Spread of the tubercular process by contiguity, through lymphatics and via involvement of regional lymph nodes enlarges the list
of diseases that need to be considered and/or excluded in the
differential (Table 4.3). The difficulty can be more serious in the
presence of a developing malignancy as can happen in a longstanding inflammation and ulceration of the skin due to any
cause.
Diagnosis of cutaneous TB may require more than pure
clinical skills in areas where it is less frequently seen and in HIVpositive patients in whom the course of the disease is altered and
atypical lesions are seen. Demonstration of a classical tubercular
granuloma on histopathology is diagnostic but caseation necrosis is usually sparse or absent. The infiltrate can be nonspecific
in up to one-third of the patients. Demonstration of AFB in
Ziehl-Neelsen–stained tissue smears, histopathological sections,
or their recovery in culture is disappointing in most instances.
The diagnostic value of a positive Mantoux test is ambiguous if

74 — Bhushan Kumar and Sunil Dogra

Table 4.3: Common conditions that mimic
cutaneous tuberculosis
1. Sarcoidosis
2. Tuberculoid leprosy
3. Deep fungal infections
4. Leishmaniasis
5. Syphilis (tertiary stage)
6. Lymphocytoma cutis
7. Discoid lupus erythematosus
8. Blastomycosis like pyoderma
9. Squamous cell carcinoma
10. Verrucous carcinoma
11. Hypertrophic lichen planus
12. Atypical mycobacterial infections

the patient has had BCG vaccination or exposure to the other
environmental mycobacteria. A strongly positive test is significant but the sensitivity decreases with advancing age, early treatment, and conditions that reduce delayed hypersensitivity. Other
than these factors and technical errors (e.g., subdermal injection
of tuberculin), about 5% of patients do not react to ordinary
strength of tuberculin for reasons unknown. Other sophisticated
tools like PCR and detection of mycobacterial DNA are either
not easily available or are also not always reliable.
Lupus vulgaris is the most common variant of cutaneous TB,
accounting for nearly 59% of secondary skin TB cases in India
with an average prevalence of 0.37% among general dermatology patients. It has become so rare in developed countries that
“Lupus,” unqualified, means lupus erythematosus and not lupus
vulgaris.
Typical lupus vulgaris plaques do not present diagnostic
problems; however, they have to be distinguished from lesions of
sarcoidosis, lymphocytoma cutis, discoid lupus erythematosus,
tertiary syphilis, leprosy, blastomycosis or other deep mycotic
infections, lupoid leishmaniasis, and chronic vegetating pyodermas. Criteria helpful in the diagnosis are the softness of the
lesions, a brownish-red color, and a slow evolution of disease.
The apple-jelly nodules revealed by diascopy are highly characteristic, but not pathognomonic. Other diseases with similar
lupoid infiltrates that look like apple-jelly nodules include lupoid
leishmaniasis, sarcoidosis, lupoid rosacea, pseudolymphoma of
the skin, and chronic granulomatous disease. In lupus vulgaris,
a blunt probe easily breaks through the overlying epidermis into
the nodule because of the caseous necrosis present in the lesions.
The nodules of leprosy are firmer and signs of nerve involvement are present. The nodules of sarcoidosis resemble grains of
sand rather than “apple-jelly.” This applies to the feel on probing
rather than to the color, which is instead often grayish. Biopsy
with special stains for organisms and culture are important diagnostic procedures to differentiate from other lupoid or infiltrative conditions. Leprosy and sarcoidosis, however, are still the
chief causes for difficulty in differentiating from cutaneous TB.

Tuberculoid leprosy is differentiated by its neural and perineural
granulomatous inflammation. Scattered, noncaseating, compact
epithelioid cell granulomas sparsely surrounded by lymphocytes
are characteristic of sarcoidosis.
Tertiary syphilis shows more pronounced vascular changes
and a plasma cell infiltrate. Demonstration of causative organisms
in histologic sections or cultures will be diagnostic in leishmaniasis and deep mycoses. Lupus vulgaris may resemble psoriasis
but is more infiltrated, is of a longer duration, and usually has
only a single to few lesions present. Bowen’s disease can closely
resemble cutaneous TB clinically but its chronicity, specific location, and characteristic histology help to differentiate it.
Tuberculosis verrucosa cutis (TBVC) usually affects the
hands and feet and is more scaly and verrucous than lupus vulgaris. Early lesions resemble warts or keratoses. Blastomycosis,
chromomycosis, and actinomycosis may simulate exuberant
forms, and crusted lesions may resemble leishmaniasis. Negative
fungal cultures and the presence of tuberculous foci on histology
are diagnostic aids. Chronic vegetating pyoderma and hyperkeratotic lesions due to other, atypical mycobacteria may be difficult to exclude. Hypertrophic lichen planus is pruritic and more
disseminated and mucosae may be involved. Tertiary syphilis is
generally more aggressive in course unlike indolent TBVC and
has diagnostic serology.
Primary inoculation TB may simulate primary syphilis, tularemia, cat-scratch disease, sporotrichosis, and other
ulceroglandular infectious diseases. Dark-field microscopy can
confirm syphilis. The clinical setting, culture from the lesion,
and specific serology are most useful for distinguishing these
conditions. Any ulcer with little or no tendency to heal and
unilateral regional lymphadenopathy in a child and even an
adult should always arouse suspicion. Acid-fast organisms can
be demonstrated in histologic sections or in smears obtained
from the primary ulcer. They can also be seen by draining
lymph nodes by fine needle aspiration cytology (FNAC) in the
initial stages of the disease but may be difficult to find in older
lesions. Diagnosis is verified by mycobacterial culture. Reaction
to intradermal PPD is negative initially but becomes positive
during the course of the disease.
Miliary TB needs to be differentiated from Letterer-Siwe
syndrome, pityriasis lichenoides et varioliformis acuta (PLEVA),
secondary syphilis, and drug reactions. In syphilis, serology and
biopsy are definitive.
Scrofuloderma: M. avium-intracellulare lymphadenitis and the
more benign M. scrofulaceum infection have to be excluded by
bacterial cultures. If there is an underlying tuberculous lymphadenitis or bone and joint disease, the diagnosis usually presents no difficulty. Syphilitic gummas, deep fungal infections,
particularly sporotrichosis, actinomycosis, severe forms of acne
conglobata, and hidradenitis suppurativa can masquerade this
condition. A confirmation of the clinical diagnosis is achieved by
bacterial culture and supportive histology.
TB gumma: All forms of panniculitis, deep fungal infections,
syphilitic gumma, and hidradenitis suppurativa pose a diagnostic challenge. A confirmation of the clinical diagnosis is obtained
by histopathology, aspiration cytology, and bacterial culture.
TB orificialis: Painful ulcers of the mouth in patients with pulmonary TB should arouse suspicion. Similar ulcers can occur in

Cutaneous Tuberculosis — 75

the perianal region. Large numbers of acid-fast organisms can be
detected in smears, and bacterial culture confirms the diagnosis.
Syphilitic lesions and aphthous ulcers have to be excluded.
Lichen scrofulosorum: Lichen planus, lichen nitidus, lichenoid
secondary syphilis, and micropapular forms of sarcoidosis
should be differentiated. Histology and syphilis serology always
help.
Papulonecrotic tuberculid: The exclusion of PLEVA may present
difficulties. Eruptions in leukocytoclastic necrotizing vasculitis
also have to be distinguished. Prurigo and secondary syphilis
can easily be excluded. The clinical appearance, indolent lesions
with resultant scarring, and histology confirm the diagnosis.
Erythema nodosum: Apart from TB, which is the commonest
cause in developing countries, it is often associated with a variety of disease processes, drugs, and infections. Strongly reactive
Mantoux test helps differentiate it from other etiologies.
We feel that a high index of clinical suspicion is of foremost
importance in the diagnosis of cutaneous TB. This is particularly true for areas where the disease is seen rarely. It remains
a disease of great importance as it can be treated effectively.
Considering all this, it can be suggested that in areas where
TB of the skin is not common, and in the immune compromised patient, a high degree of suspicion should be supplemented with laboratory help in the form of histopathology,
smear and culture for mycobacterium tuberculosis. Mantoux
test (strongly positive test is very helpful), PCR, mycobacterial antigen detection, looking for evidence of TB elsewhere in
the body, and past and family history of TB are other helpful
factors. A therapeutic trial with ATT for not less than 4 weeks

may be indicated if tests are nonconfirmatory and disease is
highly suspected.

SUGGESTED READINGS

Arora SK, Kumar B, Sehgal S. Development of a polymerase chain
reaction dot-blotting system for detecting cutaneous tuberculosis.
Br J Dermatol 2000; 142:72–76.
Barbagallo J, Tager P, Ingleton R, Hirsch RJ, Weinberg JM. Cutaneous
tuberculosis: diagnosis and treatment. Am J Clin Dermatol 2002;
3:319–328.
Chong LY, Lo KK. Cutaneous tuberculosis in Hong Kong: a 10-year
retrospective study. Int J Dermatol 1995; 34:26–29.
Jacinto SS, de Leon PL, Mendoza C. Cutaneous tuberculosis and other
skin diseases in hospitalized, treated pulmonary tuberculosis
patients in the Philippines. Cutis 2003; 72:373–376.
Kivanc-Altunay I, Baysal Z, Ekmekci TR, Koslu A. Incidence of
cutaneous tuberculosis in patients with organ tuberculosis. Int J
Dermatol 2003; 42:197–200.
Kumar B, Muralidhar S. Cutaneous tuberculosis: a twenty-year prospective study. Int J Tuberc Lung Dis. 1999; 3:494–500.
Kumar B, Rai R, Kaur I, et al. Childhood cutaneous tuberculosis: a
study over 25 years from northern India. Int J Dermatol 2001;
40:26–32.
Ramam M, Tejasvi T, Manchanda Y, Sharma S, Mittal R. What is the
appropriate duration of a therapeutic trial in cutaneous tuberculosis? Further observations. Indian J Dermatol Venereol Leprol
2007; 73: 243–246.
Sehgal V. Cutaneous tuberculosis. Dermatol Clin 1994; 12:645–653.
Tappeiner G, Wolff K. Tuberculosis and other mycobacterial infections.
In: Fitzpatrick TB, Eisen AZ, Wolff K, et al., editors. Dermatology
in General Medicine. 5th edition. New York: McGraw Hill, 2004:
2274–2292.

5

LEPROSY
Arturo P. Saavedra and Samuel L. Moschella

INTRODUCTION

Leprosy, or Hansen’s disease, is caused by the acid-fast, rod-like
Mycobaterium leprae. Although effective treatment did not
become available until the 1940s, the organism was discovered by
Gerhard Henrik Armauer Hansen in 1873 and became the first
bacterium known to cause disease in man. Since then, the dramatic, chronic, and debilitating consequences of the disease have
been stigmatizing to those affected. Worldwide, it is still the most
common cause of peripheral neuropathies, and is superseded in
developed countries only by diabetes and alcoholism. Social containment and isolation are not just historical remnants, as those
currently treated continue to face social challenges not only in
the Third World but also in developed societies.

H I STORY

Hansen’s disease has been reported as early as 1400 BC. Evidence
of bone disease has been found in Egyptian mummies. During
the 13th century, it became widespread in Europe, but it is still
endemic in Portugal, Spain, Greece, and Italy.
Despite this fact, the early diagnosis and prevention of leprosy continues to escape health-care providers. In India, the
Vedas included instructions for the prevention of leprosy, yet
today we have been unable to identify cases early before neurologic and dermatologic sequelae ensue. Leprosy is still the
main cause of peripheral neuropathies worldwide. As education programs become more prevalent and basic science evolves
(the entire genome of Lepra is now sequenced), we hope that
historical trends in incidence and disease progression will also
change.

E P I D E M I O L O G Y, M I C R O B I O L O G Y, A N D
TRANSMISSION

According to estimates by the World Health Organization
(WHO), the global registered number of cases of leprosy in 2006
approximated 219,826. Although this figure suggests a general
decrease in prevalence of disease, incidence has been stable (if
not increasing) and several countries such as India, Brazil, and
some central African countries still struggle to contain spread
of disease. In Brazil, 38,410 new cases were detected in 2005
and prevalence was estimated to be approximately 1.5%. In the
United States, the disease is uncommon, but the greatest number of cases have been found in Louisiana, Hawaii, and Texas.
Immigration patterns from endemic communities account for a
76

large number of these cases. Much of the progress achieved so
far has been secondary to the use of multidrug therapy (MDT)
as well as the development of programs aimed at eradicating disease (defined as a prevalence of less than one case of leprosy per
10,000 members in a population). However, given the difficulties
with early detection, compliance with prolonged therapy, and
management of permanent disabilities, leprosy continues to be
a public health problem and many believe that complete eradication is still far into the future, if at all obtainable. Some have
estimated that even after a complete course of antibiotics aimed
to be curative, up to one-third of patients will remain with cutaneous and neurologic disabilities. These data suggest that care of
the patient with Hansen’s disease will transcend “cure” and the
health-care system must be prepared to meet these needs.
Mycobacterium leprae is an obligate intracellular, gram-positive, acid-fast bacterium that is tropic for macrophages, smooth
muscle, and nerve tissue. The organism can survive singly or
be found in aggregates (globi) in infected tissues. It replicates
slowly with a generation time of 13 days and a calculated incubation period of 3 to 5 years. Its genome has now been entirely
sequenced and because of its limited number of genes, interest in
Mycobacterium leprae has increased as a model system in which
to study obligate intracellular parasitism, infection of neurons,
and modulation of the immune response by parasitism. Though
armadillos are the most notable animal reservoir for the organism in the United States, the organism has also been recovered
from chimpanzees and the Mangabey monkey. Though it cannot
be cultured, the mycobacterium may be grown in the footpad of
mice, which has been of particular importance in determining
drug resistance profiles.
The exact mechanisms of transmission are unknown. Close
human contact with prolonged exposure and high-titer inoculums are required for transmission. Nonetheless, conjugal transmission of leprosy is under 8%. In addition, socioeconomic
factors such as poor hygiene, sanitation, close living quarters, and
poor nutrition appear to be risk factors. The disease is observed
twice as often in men as it is in women. The average onset of
disease is between 20 and 30 years of age, and childhood cases
of Hansen’s disease are rarely reported in the absence of another
case in the same home.
Leprosy is acquired through close physical contact, particularly from patients with lepromatous disease. Once on therapy,
patients are not infectious. Respiratory and nasal secretions are
most contagious and account for most transmitted cases; much
less commonly, the organism is acquired from the surface of
the skin. The route of entry is the respiratory tract and there
is no evidence of sexual transmission. Direct inoculation at
sites of cutaneous trauma has been reported. Although animal

Leprosy — 77

reservoirs are not likely an important source of transmission,
the nine-banded armadillo can develop a fully disseminated
M. Leprae infection. Through intravenous inoculation, they
have been the source of in vivo propagation of M. Leprae for
more than 30 years (Fig. 5.1). Though low levels of vitamins A
and E and minerals like calcium and magnesium are seen in
leprosy, diet is not believed to be a risk factor in acquiring the
infection.

PA T H O G E N I C I T Y A N D I M M U N O L O G Y

Perhaps the most fascinating aspect of the disease is that its
clinical expression, pathology, and response to treatment are
determined by the immune response of the affected patient to
mycobacterial antigens. Because bacterial isolates do not vary
widely in virulence, it is unlikely that these clinical differences
are due to infection with different strains of M. Leprae. Patients
with high cellular immunity, low mycobacterial load, and welldeveloped granulomatous responses on pathology are classified
on the “tuberculoid” end of the spectrum. Patients with low cellular immunity against the organism, high mycobacterial loads
and humoral immunity, and poorly formed granulomas with
infiltrates of foamy cells are categorized as having “lepromatous”
leprosy. The majority of patients however, exhibit less “polarized”
responses. Those near the tuberculoid end are termed borderline
tuberculoid (BT), those near the lepromatous end are labeled
borderline lepromatous (BL) and those who exhibit mixed features are termed mid-borderline leprosy (BB). An uncharacteristic clinical and histologic lesion is usually the first expression
of leprosy and is classified as indeterminate leprosy (the WHO’s
single paucibacillary lesion of leprosy).
Interestingly, 95% of people are not susceptible to infection.
In addition, the disease is only rarely found in children, and when
present, there is usually an index case in the home. Whether
these observations are related to the mycobacterium’s long replication time or to the immune milieu of childhood is currently
unknown. Interestingly, there are racial differences in acquiring
infection. For instance, Caucasians have a much higher rate of
acquiring lepromatous leprosy, followed by Asians, Indians, and
African-Americans in that order.
Two major mechanisms of resistance to infection have
been postulated. Innate resistance mediated by monocytes
provides the first layer of protection. Specifically, the promoter
region of PARK2, which has been associated with early-onset
Parkinson’s disease, has been linked to susceptibility to infection by Mycobacterium leprae. The acquired arm of the immune
response, mediated by T lymphocytes and dendritic cells, serves
as a second layer of protection against infection that may also
modulate the expression of disease. HLA-DR2 and DR3, chromosome 10p13, and the transporter associated with antigen processing, (TAP)-2, have been linked to increased risk of acquiring
tuberculoid-type leprosy. On the other hand, HLA-DQ1 has
been associated with lepromatous leprosy. Tumor necrosis factor
A gene (TNF-A), toll-like receptor (TLR)-2, as well as certain
polymorphisms of the vitamin D receptor gene, have also been
associated with an increased risk for infection. Finally, cytokines
such as interleukin IL-12 and IL-18 are linked to resistance to
infection and accordingly are found in high levels in patients
with polar tuberculoid (TT) disease.

Figure 5.1. The nine-banded armadillo can develop disseminated
infection with Mycobaterium Leprae and has become a vector in
which to replicate the organism for research purposes.

It is unclear whether the number and activity of lymphocytes
and dendritic cells determine the phenotype of and susceptibility
to infection. For instance, fewer Langerhans cells are detected in
skin biopsies of both normal and lesional skin of patients with
lepromatous leprosy (LL). On the other hand, the number of
Langerhans cells is higher in patients with TT. In general, tuberculoid lesions are associated with higher levels of Th1 type of
cytokines like IL-2, TNF-α. and IFN-γ, whereas lepromatous
lesions show a Th2-like response and exhibit higher levels of
IL-4 and IFN-γ. Coincident with these findings, Th1-like cytokines are associated with activation of TLR-1 and TLR-2, whereas
Th2-like cytokines appear to prevent activation of these toll-like
receptors.
Overall, impairment in cellular immunity is important for
acquiring the infection. Anergic responses and defects in cellular
immunity appear to be lasting, and evidence suggests that such
defects persist in spite of therapy. Though patients with LL are
anergic to these antigens, this does not imply that they are immunocompromised. As explained by Scollard et. al., these patients
are not at increased risk of other opportunistic infections or of
developing cancer. Interestingly, co-infection with leprosy does
not increase transmissibility or risk of infection with human
immunodeficiency virus (HIV), as is the case with tuberculosis, herpes, and leishmaniasis. Co-infection with leprosy does
not lead to progression or clinical deterioration in HIV/AIDS
(acquired immunodeficiency syndrome).

CLINICAL FINDINGS AND
C L A S S I F I C AT I O N C R I T E R IA

Consistent with its optimal growth temperatures of 27o C to 30o
C, Mycobacterium lepra tends to infect cooler areas of the body
such as the ears and the nose. The skin, peripheral nerves, the
testes, and the anterior chamber of the eye are generally the most
commonly affected sites. In addition, the upper respiratory tract,
lymph nodes, and rarely the viscera (particularly the liver and
spleen) may be affected. Though peripheral sensory nerves are
most commonly affected, autonomic and motor nerves may also

78 — Arturo P. Saavedra and Samuel L. Moschella

become damaged. Usually, temperature sensation is affected first,
followed by light touch, pain, and pressure. In fact, skin lesions
need not be present to make a diagnosis of leprosy. In the absence
of skin lesions, the differential diagnosis elicited in cases that
turn out to be “neuritic” leprosy includes primary amyloidosis,
progressive hypertrophic familial neuropathy, carpal tunnel syndrome, diabetic neuropathy and congenital indifference to pain.
In neuritic leprosy, the ulnar nerve is most commonly affected
and upper motor neuron signs are never elicited. Furthermore,
proximal muscles are not involved, the central nervous system
is spared, reflexes are intact, and coordination examination is
within normal limits. Biopsy is required for diagnosis but electromyography may also be helpful.

Ridley–Jopling Classification
On the basis of the immunologic criteria discussed earlier, clinical classification of leprosy was devised by Ridley and Jopling in
1966. On the basis of the immunological response of the host
to the organism, the disease was categorized into five presentations: polar tuberculoid (TT), borderline tuberculoid (BT),
borderline (BB), borderline lepromatous (BL) and lepromatous
leprosy (LL).
Patients with strong immunity to the organism are diagnosed
with polar tuberculoid (TT) leprosy. As a result, only one or a
few lesions are noted on cutaneous examination. These lesions
can be well-demarcated macules, patches, or plaques with superficial scaling. Fine erythema and hypopigmentation may be
detected (Fig. 5.2). Hypopigmentation is thought to result from
a decrease in the total number of melanocytes in infected skin. A
local xerotic surface accompanies the primary lesion. The morphology may approximate an oval, but geometric configurations
of discrete papules in annular or circinate arrays have also been
reported. The primary lesion may be confused for tinea corporis, psoriasis, gyrate erythema, granuloma annulare, necrobiosis lipoidica, lupus vulgaris, and tuberculosis verrucosa cutis.
The skin may show hair loss and central atrophy at sites noted
to be anesthetic. Peripheral nerve enlargement can be palpated
on examination, usually in only one or two trunks, depending
on the site of infection. Lesions of tuberculoid leprosy may heal
spontaneously.
Borderline tuberculoid (BT) leprosy presents with a greater
number of lesions, which may be hypopigmented, but may also
show erythema and other brownish dyspigmentation patterns
(Fig. 5.3). Macules, patches, and plaques with scale constitute
the primary lesion, but in addition, smaller “satellite” lesions may
be noted in the periphery of a larger lesion. Annular disease is
also common and may be misdiagnosed as granuloma annulare,
erythema multiforme, lupus vulgaris, and tinea circinata. The
disease has often been confused with mycosis fungoides, B-cell
lymphoma, lichen planus, and pityriasis alba. Close inspection
of the primary lesion may show local hair loss, xerosis, and thick
granular margins. Papulonodular lesions and infiltrative plaques
may also develop, with a rough surface and anesthesia. There are
a larger number of asymmetric lesions and the central portions
may show atrophy. There is peripheral nerve involvement and
lesions need not be anesthetic to make the diagnosis (Fig. 5.4).
Screening for peripheral neuropathy is best accomplished with
the use of microfilaments as is currently performed for diabetic
neuropathy. Lesions that resolve spontaneously or during therapy

Figure 5.2. Female patient with polar tuberculoid (TT) disease. Note
that lesions are well demarcated and show focal areas of hypopigmentation and scaling.

Figure 5.3. Female patient with borderline tuberculoid (BT) disease.
Note the arcuate but asymmetrical hypopigmented lesions which are
greater in number when compared to patients with polar tuberculoid
(TT) disease. In addition, there is a claw hand deformity in the right
upper extremity. The patient had evidence of both sensory and motor
deficits on neurologic exam.

Leprosy — 79

Figure 5.4. This patient with borderline tuberculoid (BT) disease
exhibits auricular nerve enlargement, easily seen and palpated on
exam.

may show central clearing within a background of browny erythema. The differential diagnosis may be similar to that listed for
TT, but annular syphilides, sarcoidosis, and leishmaniasis must
be added.
Patients with borderline disease (BB) exhibit more extensive
disease. Many lesions are noted, mostly patches and plaques with
sharp demarcation and edges that slope into surrounding skin.
Plaques tend to be erythematous and are arranged as infiltrated
bands with central areas of anesthesia. “Punched-out” lesions
may be seen. In general, the inner margins of the primary lesion
are easier to discriminate than the outer margin. Disease is asymmetric and peripheral nerve involvement is more widespread.
Neuritis in these cases can be more severe than in other types
of leprosy, as multiple trunks may be damaged asymmetrically
very early in the course of the disease. In general, loss of sweating
precedes sensory nerve damage. As a result, some have advocated the use of sweat function tests in patients with uncertain
neurologic exams. Pilocarpine nitrate and acetylcholine tests are
sometimes used in the diagnosis of leprosy and in the evaluation
of impending sensory nerve damage.
Those patients with lower immunity to the organism tend to
express more disseminated and symmetrical cutaneous and neural
disease. Those with borderline lepromatous (BL) disease present
with several plaques resembling those seen in borderline disease
(BB). Macules, patches, papules, and plaques with a smooth,
shiny erythematous surface are commonly seen. Erythema and
hypopigmentation are common. Primary lesions are more irregularly shaped and bilaterally distributed. Annular lesions can be
seen. Though lesions are infiltrated, they are poorly demarcated
and borders are hard to discriminate and may be slightly anesthetic. The neurologic exam can appear to be within normal limits. Occasionally, tinea versicolor, vitiligo, psoriasis, secondary
syphilis, contact dermatitis, pityriasis rosea, onchocerciasis, and
scleroderma may figure into the differential diagnosis.
Lepromatous (LL) leprosy presents the other “polar” end of
the disease spectrum, when compared to tuberculous (TT) leprosy, and is the most infectious form of the disease. The patient
presents with symmetrically distributed macules, papules,
plaques, and nodules that show hypopigmentation, erythema,

Figure 5.5. Nodules that cause deformities of the nose and ears, as
well as madarosis, can be appreciated in this patient with advanced
lepromatous leprosy (LL).

and a browny dyschromia commonly compared to copper.
Nodules are not subcutaneous and as a result, the skin cannot be moved over them. This may be an important maneuver in establishing a diagnosis. Punched-out papules may be
seen and smaller macules and papules may coalesce into infiltrated plaques. Rare forms of “digitate” morphology have also
been reported. The disease tends to spare the axilla, groin, and
perineum. General xerosis and acquired icthyosis may ensue.
The face may become generally infiltrated, causing leonine-like
faces, with a shiny, smooth texture. Madarosis, or loss of hair in
the lateral aspect of the eyebrows, is commonly seen. Complete
loss of eyelashes has also been reported. The nasal mucosa may
become inflamed and ulcerated and the septum may perforate.
Saddle nose deformities can also result. Recurrent epistaxis is
not an infrequent sign of the disease. In advanced stages, disease
may become nodular, especially in cooler parts of the body and
may cause deformities of the nose, ears, eyelids, joints, and trunk
(Fig. 5.5). The conjunctiva, cornea, and iris are involved and
cataract-like opacities develop. In earlier stages, corneal insensitivity may be a treatable and reversible finding. The viscera
may also become involved, particularly the reticuloendothelial
system. However, glomerulonephritis and secondary amyloid

80 — Arturo P. Saavedra and Samuel L. Moschella

Table 5.1: Comparison between Paucibacillary and
Multibacillary Disease
Category of Disease

Paucibacillary

Multibacillary

Bacillary Index

2 or less

Greater than 2

Number of lesions

5 or less

Greater than 5

Patients affected

TT, BT

BB, BL, LL

TT, polar tuberculoid disease; BT, borderline tuberculoid disease;
BB, borderline leprosy; BL, borderline lepromatous disease; LL,
lepromatous leprosy.

Figure 5.6. Note ulcerations in the fingertips, claw hand deformities,
madarosis, and left-sided facial palsy in this patient with lepromatous
leprosy (LL). This patient had both median and ulnar neuropathies
with both motor and sensory deficits.

have also been reported. At this stage, the differential diagnosis
may include neurofibromatosis, multiple lipomatosis, leukemia
cutis, disseminated fungal and parasitic disease such as anergic
cutaneous leishmaniasis and Kala-Azar, as well as disseminated
xanthomatosis. Usually, there is no sensory nerve involvement in
early stages but symmetric peripheral neuropathies can ensue in
untreated patients. Classic stocking and glove anesthesia develops first but as long nerves become progressively involved, sensory levels may be detected on examination. The facial nerve is
very commonly involved. Muscle atrophy may ensue with time;
claw deformities in hands and feet, foot drop, and the so-called
“papal” hand may also develop (Fig. 5.6).
The term “indeterminate” disease (single paucibacillary
lesion) may be used for those patients presenting with one or
few macules that are hypopigmented and/or mildly erythematous, generally on exposed skin surfaces. There is no anesthesia, but some lesions may show hypoesthesia and hypohidrosis.
Peripheral nerve enlargement is usually not detected. Pathologic
examination reveals a mixed inflammatory infiltrate involving
the neurovascular bundle. This stage is often considered the
very earliest stage of the disease and, most commonly, it leads to
spontaneous resolution.
Histoid leprosy is a special case that deserves mention.
Patients present with multiple papules, nodules, and plaques
interspaced by relatively uninvolved skin. The surface of these
plaques is smooth and shiny, and is sometimes described as
pearly. They may occur at different stages, particularly in disseminated disease, and have been reported to occur near the eye,
in intertrigenous areas, and near fossae of the extremities. The
lesions vary in color from pink to yellow to brown to violaceous
and often exhibit secondary changes such as an excoriated surface. Most patients are thought to be in the lepromatous disease
spectrum, who prematurely interrupted treatment, are drug-resistant (particularly to dapsone), or who are relapsing.

WHO Classification
In addition to using clinical criteria established by the Ridley
and Jopling classification, the WHO introduced the concept

of skin-slit smears as a simplified way of categorizing disease.
A smear is examined under oil for the total number of acid-fast
bacilli recovered. A bacillary index represents a logarithmic
count of organisms seen. For instance, a bacillary index of 2
represents 1 to 10 organisms per high-power field. The WHO
initially classified those patients with a bacillary index of less
than 2 or fewer than five clinical lesions as “paucibacillary” disease. Whereas those patients with an index greater than 2 and
at least six clinical lesions were classified as having multibacillary disease (Table 5.1). In general, patients with TT and BT tend
to be paucibacillary, whereas those with BB, BL, and LL disease
fulfill the criteria for multibacillary disease. However, to prevent
undertreatment, any patient with a positive smear or organisms
on biopsy is currently is said to have “multibacillary” disease,
regardless of the index. Generally, the terms paucibacillary and
multibacillary are more helpful in designing a therapeutic regimen than in establishing clinical classification and prognosis
(see section on treatment). However, patients with multibacillary disease are known to be about 5 to 10 times more infective
than patients with paucibacillary disease.

HYPERSENSITIVITY REACTIONS

Leprosy is a disease that presents with two “clinical faces.” The
first one is a result of a host response to the infective organism.
The other is a hypersensitivity reaction to antigens of the viable
or dead bacillus, the so-called “reactions.” The nature of the reaction depends on the cell-immune status of the patient. Those
patients with BT and BB disease who have a relatively intact cellmediated immunity clinically express a reversal reaction (Type I).
In contrast, those patients with LL and BL are anergic or almost
anergic to M. Leprae and respond with immune-complex disease
and clinically with erythema nodosum leprosum (Type II reaction). These reactions occur in 30% to 50% of all patients with
leprosy as a result of stress, medical illness, pregnancy, injury,
surgery, concurrent infection, vaccination, and multiple drug
therapy. Unfortunately, no laboratory tests are available to specifically diagnose these reactions or to predict who among those
infected will develop them.
Type I reactions are more common in patients with borderline states, particularly borderline lepromatous leprosy
(BL), and occur during the first 6 to 18 months of treatment
but have been reported up to 7 years after initiating therapy.

Leprosy — 81

Figure 5.7. In this patient with BL disease, a reversal Type 1 reaction is exhibited by painful erythematous, edematous, nodular, and
infiltrated nodules. These nodules appeared acutely.

Figure 5.8. Type 1 reaction in a patient with BL disease, presenting with
a new, large erythematous plaque in the setting of general malaise.

Figure 5.9. This patient was treated unsuccessfully with tetracycline for acne vulgaris in the setting of diffuse lepromatous leprosy.
Note that the acute and fleeting nature of the lesions, as well as the
erythematous and deep nodular morphology, suggests the correct
diagnosis of ENL.

Reversal reactions are rarely observed in patients with TT. Type
I reactions belong to the Type IV, cell-mediated, allergic-type
delayed hypersensitivity reactions and appear after an acute
shift toward high cellular immunity. Cytokines such as IL-1,
IL-2, IL-12, IFN-γ, and TNF-α are upregulated, suggesting a
predominant Th1-like response. Most commonly, this type of
reaction occurs as the patient shifts to a higher degree of cellular immunity, termed upgrading. Patients are acutely ill but disease may also develop over days or weeks. Patients present with
edema of the hands, feet, and face as well as tenderness along
nerves and joints. The ulnar, median, facial, greater auricular,
common peroneal, and posterior tibial nerves are most commonly affected. Abscesses have been reported to develop along
nerves. Patients may acutely develop foot drops, facial palsy,
and claw hands. Eye involvement may present as lagopthalmus
with complicating exposure keratitis. The skin lesions become
more erythematous and infiltrated and may ulcerate (termed
Lazarine leprosy). Patients can develop new lesions in the setting of a Type I reaction. If untreated, lesions typically resolve

after 3 to 4 months (Figs. 5.7 and 5.8). Systemic lupus erythematosus and drug reactions often figure into the clinical differential diagnosis.
Type II reactions, termed Erythema nodosum leprosum
(ENL), are characterized by the acute onset of cutaneous and
subcutaneous erythematous nodular lesions that bear no relationship to other lesions that the patient had before this attack
(Fig. 5.9). Some may be very deep seated, may suppurate, and
ulcerate (erythema induratum leprosum). A varicelliform
vesicular and necrotic papular eruption that favors the upper
extremities and face has also been described. Generally, this
reaction is a subtype of Type II humoral lepromatous hypersensitivity reactions and is more common in borderline cases and
in LL disease. Its incidence appears to decrease with increasing age and with decreasing inoculums during primary infection. Rarely, ENL may be the presenting sign of leprosy, and
in these cases, findings consistent with primary infection may
not be seen on physical examination. IFN-γ, TNF-α, and IL-12
are found in high levels in the serum of affected patients. In

82 — Arturo P. Saavedra and Samuel L. Moschella

fact, injection of IFN-γ into a lesion in leprosy has reportedly
lead to the development of ENL. This immune-complex deposition disease leads to a strong polyclonal antibody response
that may be associated with general edema, nerve tenderness,
bone and joint pain, and fever and chills. Neuritic night pain
has also been reported. The associated neuritis can result in
an acute paralysis. In addition, epistaxis, orchitis, proteinuria,
and consequent glomerulonephritis can develop. Stress reactions like those associated with Type I lepra reactions can also
lead to ENL. An important feature of ENL is that it most commonly occurs late in the treatment course. Mild cases of ENL
may spontaneously remit; however, severe cases can be progressive and more apt to recur. Death rarely occurs from renal
insufficiency.
An uncommon third type of reaction is Lucio’s phenomenon, which is usually restricted to Central and South America
and immigrants from those areas. It is usually associated with
high mortality rates. It occurs in a subtype of lepromatous leprosy called primary diffuse lepromatous leprosy, the so-called
“la lepra bonita.” The face is diffusely infiltrated (pseudomyxedematous facies). Madarosis, anhidrosis, and infiltration of the
nasal mucosa with persistent epistaxis and destruction of nasal
cartilage are seen. Diffuse body hair loss is also seen but orchitis
and iritis are not observed. Unlike in ENL, systemic symptoms
such as fever, malaise, chills, joint pain, and nerve tenderness
are rare but anemia and cryoglobulinemia may be observed.
Visceral findings such as hepatosplenomegaly and lymphadenopathy occur. The eruption of Lucio’s phenomenon is characterized by the presence of symmetrical black stellate necrotic
lesions of the extremities (erythema necrotisans). The lesions
may resemble the cutaneous flame figures seen in coagulopathic
states (Fig. 5.10).

L A B O R AT O RY T E S T S

Work up of leprosy is somewhat different than other infectious
diseases because the mycobacterium cannot be cultured. As a
result, clinicopathologic correlation is of utmost importance.
At this time, the role of laboratory tests is adjunctive. Cultures
are taken to exclude other organisms rather than to recover
the mycobacterium. PCR tests are used mostly in experimental analysis, and no true serologic tests exists for routine diagnosis. However, because the diagnosis can be stigmatizing and
requires long periods of treatment with medications that may
not be innocuous, it is important to highlight those tests that
may be useful in establishing the diagnosis or in affecting treatment. In this section, we will review the clinical utility of skinslit smears, the lepromin test, polymerase chain reaction tests, as
well as other investigational assays.
As stated earlier, skin scrapings were initially introduced to
aid in the classification of disease into either paucibacillary or
multibacillary disease. Currently, the role of skin scrapings is
limited as it does not provide high sensitivity or specificity. Skin
smears are only positive in 10% to 50% of cases and are most
helpful when taken from multibacillary patients or from those
with recurrence or clinical relapse. It is more reliable when
used by experienced clinicians and is most helpful in determining drug therapy rather than in making the diagnosis. On the
other hand, a positive index may be obtained in BB, BL, and LL

Figure 5.10. A patient with Lucio’s phenomenon, who portrays
stellate scarring and ulceration, commonly confused with cutaneous
manifestations of hypercoagulation syndromes.

disease. The lack of specificity results from the fact that other
cutaneous mycobacterial infections may have a positive skinslit test.
Though it is not approved by the U.S. Federal Drug
Administration in the United States, the lepromin (Mitsuda)
test has been used worldwide. The test lacks both specificity and
sensitivity. It is not diagnostic of leprosy and it is not required
to make a diagnosis. A suspension of whole autoclaved leprosy
bacilli is injected intradermally and the induration response is
measured 4 weeks later, ideally with the aid of a pathologist
to establish the presence of a granulomatous reaction pattern
on histopathologic evaluation. The lepromin test is negative in
BB, BL, and LL disease. It is most helpful in patients with a
strong cellular immunity to the organism. Therefore, a strong
reaction is observed in TT disease. The intensity of reaction
decreases along the spectrum (i.e. patients with BT may show
a weakly positive result). Results are highly variable in indeterminate leprosy. Though a positive result may be caused by
prior exposure to the mycobacterium, it reflects the presence of
cell-mediated immunity and the ability of patients to eliminate
mycobacterial loads.

Leprosy — 83

Enzyme-linked immunosorbent assays have been developed to test for antibodies against phenolic glycolipid 1
(PGL-1). PGL-1 is the main lipid component of the outer leaflet of the mycobacterial cell wall that affords the test its specificity. It is also responsible for binding laminin 2 and thereby
infecting Schwann cells. Because patients with paucibacillary
disease have strong cellular immunity against the organism but
have poor humoral responses, anti-PGL-1 testing is rarely positive in these patients. However, even when present, humoral
responses to mycobacterial antigens are not robust, stable, or
detectable. Like other tests discussed in this section, PGL-1
ELISA lacks specificity and sensitivity and is a better marker
for the presence of multibacillary disease rather than a way of
making the diagnosis. The test has been used mostly in epidemiological studies and at this time is mostly of interest to the
research community. Similar lipoarabinomannan tests, fluorescent antibody absorption tests (FTA-ABS), and radioimmunoassay techniques are also available but used less frequently than
PGL-1 ELISA.
Mycobacterium leprae cannot be cultured, but it may be
grown in the footpad of the mice to establish sensitivities to
antibiotics. PCR tests that may become increasingly useful
in this regard have been developed. In addition to mutation
analysis, PCR techniques have added greatly to our ability to
detect drug-resistant strains. For instance, missense mutations
in rpoB are associated with resistance to rifampin. Using this
technique, in which microorganisms are detected on Fitestained sections, mycobacterial DNA can be isolated from
skin samples in patients before therapy when the diagnosis
is still questionable. PCR tests are not indicated in patients in
whom no microorganisms could be identified on stains or in
patients who are improving with therapy. Because PCR techniques can detect DNA from both viable and nonviable organisms, it should not be solely used to make a diagnosis of active
infection at this time. Novel techniques that expand 16S rRNA
sequences (which are quickly degraded once the mycobacterium is not viable) may circumvent this problem. Though positive PCR results can also be obtained from other sites such as
nasal mucosa, blood, nerve, and ocular tissue, their use remains
limited to research laboratories of centers that specialize in the
care of patients with Hansen’s disease.
Importantly, no serologic studies are available that identify carriers or that facilitate segregation of patients who are
likely to fail treatment or endure relapse. In addition, though
co-infection with HIV and Mycobacterium leprae does not lead
to progression of either disease, those with leprosy may have a
false negative HIV ELISA test because the mycobacterium may
generate antibodies that cross-react with HIV screening assays.
In addition, patients with LL and BL may have false-positive
VDRL and FTA-ABS. Given the extent of hyperglobulinemias,
false-positive antinuclear antibodies and rheumatoid factor can
also be reported.

PA T H O L O G Y

In general, histopathologic evaluation benefits from a deep
biopsy obtained from the advancing border of a lesion suspicious for leprosy. The atrophic center should not be biopsied. Because the disease exhibits a spectrum of clinical and

histopathologic findings, the most important aspects to evaluate
include (1) the extent of granulomatous inflammation, (2) the
presence or absence of mycobacteria (which usually requires
special stains such as the modified Fite stain due to the fact that
this organism is less acid fast than other mycobacteria), and
(3) the location of granulomas and organisms, whether present diffusely in the dermis or clustered around (and invading)
peripheral nerves. As an obligate intracellular pathogen, M.
Leprae is found in macrophages when it affects the skin and in
Schwann cells when it affects nerve tissue. The extent to which
each of the above three criteria is noted on histopathologic sections helps categorize the disease along the spectrum suggested
by Ridley and Jopling.
Tuberculoid leprosy is characterized by epithelioid granuloma formation, often surrounding nerves and appendages that
may become completely replaced. Dense foci of lymphocytes
may be noted surrounding granulomas as well. Occasionally,
the granulomas may extend superficially to abut the epidermis.
Microorganisms are rarely encountered on Fite-stained sections,
and when observed, they are found near nerves, which may
exhibit caseation. Unlike in lepromatous disease where damage
to the nerve is caused initially by disrupting the perineurium,
in tuberculous disease infiltration of the nerve by microorganisms is generally the rule. When T-cell subtypes are analyzed,
CD4+ cells are found throughout the lesion whereas CD8+ cells
are only present at the periphery of lesions in TT. They are found
at a ratio of 1.9:1 (normal ratio is about 2:1). On the other hand,
in lesions of lepromatous leprosy, the CD4+/CD8+ ratio is 0.6:1
and CD8+ cells are distributed throughout the entire lesion.
Of note, Langerhans cells are not uncommonly seen and infiltrates and lesional skin can be positive for CD1 and langerin.
This finding should not detract the pathologist from making a
diagnosis of leprosy in favor of Langerhans cell histiocytosis. The
level of CD1+ expression is much higher in TT lesions than in
LL lesions.
The histopathology of lepromatous leprosy is on the other end
of the spectrum. A diffuse infiltrate of sheets of foamy histiocytes
and a clear Grenz zone are observed. Abundant microorganisms are seen singly or in large collections called globi. Virchow
cells (Lepra cells) may be seen, which are classically described
as large macrophages with foamy, fatty changes, containing
globi. Lymphocytes can be scant and plasma cells are notable.
Microorganisms cause neural destruction by either disrupting
the perineurium, by their high concentration in Schwann cells,
or by eliciting inflammation and fibrosis.
Patients with borderline disease show histopathology that
is between those seen in tuberculoid and lepromatous disease.
True BB disease is rarely diagnosed histopathologically as most
patients will shift into BT or BL and the biopsy must be interpreted in correlation with clinical findings. In BT, a Grenz zone is
commonly seen within a loosely-formed granuloma surrounded
by lymphocytes. Nerves and the adnexa may be involved but
they are usually not replaced by the inflammatory response.
Acid-fast bacteria can be found. As the disease trends toward BB,
epithelioid granulomas are not commonly rimmed by lymphocytes. Langerhans cells are less common than in BT and acid-fast
bacilli are found in greater numbers. Finally, in BL disease, a diffuse granulomatous response is seen, in which foamy histiocytes
predominate. Lymphocytes are commonly admixed within the
lesion and a well-formed Grenz zone is observed. Perineural

84 — Arturo P. Saavedra and Samuel L. Moschella

infiltration is common and microorganisms are readily observed
on Fite-stained sections.
The findings of indeterminate leprosy include a mild mononuclear cell infiltrate around nerves, vessels, and appendages.
When organisms can be demonstrated on Fite stain, a diagnosis
is easier to make. Without this finding, histopathologic examination can be nonspecific.
In histoid leprosy, a nodular infiltrate of epithelioid and spindled histiocytes is seen surrounded by an atrophic epidermis. A
Grenz zone is observed and microorganisms are readily identifiable, singly or in globi.
Lucio’s phenomenon may show necrotizing vasculopathy associated with a high level of infected endothelial cells.
Leukocytoclastic vasculitis, thrombosis, and resultant epidermal
hemorrhagic infarction are seen in.
Pathology in Type I reactions is nonspecific but may show
perivascular and perineural lymphocytic infiltration. Type 2
reactions show marked edema and a neutrophilic dermal infiltrate, often aggregating in microabscesses and surrounding
the vasculature and adnexa. The subcutaneous tissue is often
involved. Endothelial cell swelling and edema may be observed.
Microorganisms can be identified on stains but they are usually
degenerated.
Neuritic leprosy (no evidence of cutaneous disease) is best
diagnosed by biopsy. In the absence of cutaneous disease, a high
index of clinical suspicion is required to make the diagnosis.
Histopathological examination shows epithelioid granuloma
formation with bacilli present inside nerves in higher concentrations than in other areas. This pathology most closely resembles
the findings in cutaneous TT and BT.

T R E AT M E N T A N D T H E R A P Y

Classification of disease as paucibacillary or multibacillary is
most helpful in establishing treatment protocols for patients.
In general, multidrug treatment is encouraged to prevent
resistance to dapsone. Rifampin is generally employed in all
treatment regimens because of its potent bactericidal action
against the mycobacterium. The treating clinician should
remember that to treat the disease effectively, attention only
to drug therapy is not sufficient. The cost of therapy and availability of medications is important to consider, particularly in
resource-poor settings. More importantly, encouraging adherence to long periods of therapy is perhaps the most important
role of the treating clinician. In those with deformities, physical therapy and a systemic approach to the disease is essential.
Finally, all patients, their friends and family, must be educated
about the infection, its course, and potential social ramifications of the disease. Patients often require support systems
from social workers and clinicians as they face discriminatory
policies.
According to WHO guidelines, paucibacillary disease may
be treated with rifampin 600 mg every month for 6 months in
addition to dapsone 100 mg daily for 6 months. In the United
States, the Public Health Service (PHS) recommends that treatment with both drugs be for an entire year. Patients should be
followed up every 6 months for the first 5 years after treatment
is finished. Though still under clinical investigation, a single
paucibacillary lesion may be treated with one dose of ROM

Table 5.2: Alternative Agents for Use in Leprosy
Rifabutin
Rifapentine*
Moxifloxacin*
Ofloxacin
Perfloxacin
Sparfloxacin
Levofloxacin
Minocycline
Ansamycins
Clarithromycin
Telithromycin
* Represent the most active bactericidal agents

therapy (rifampin 600 mg, ofloxacin 400 mg, and minocycline
100 mg).
Patients with multibacillary disease should be treated with
rifampin 600 mg and clofazimine 300 mg every month in addition to dapsone 100 mg and clofazimine 50 mg every day for 12
months. Unlike the WHO, PHS recommends dapsone 100 mg
daily, rifampin 600 mg daily, and clofazimine 50 mg daily for
2 years. Follow-up every 6 months for a period of 10 years following completion of treatment is encouraged. Table 5.2 shows
alternative drugs with activity against Mycobacterium leprae for
those patients who are allergic to commonly used medications
or otherwise present contraindications to their use. In addition, important side effects to medications are listed in Table 5.3.
Prompt therapy is important in limiting infectivity and spread of
the organism.
Therapy of household contacts and prophylaxis is controversial, but currently, it is not recommended. Dapsone prophylaxis
may lead to resistance or delay in onset of disease, rather than to
prevention. Regular clinical follow-up of household contacts is
encouraged.
Treatment of reversal reactions usually requires some level
of immunosuppression. Mild type I reactions may be treated
with nonsteroidal anti-inflammatory medications (NSAIDs).
Severe cases, those that present with neuritis, potential involvement of the facial nerve, or those that do not respond to conservative therapy, require oral steroids. Dosing should begin
at 1 mg/kg and gradually titrated or tapered as permitted by
symptoms. Though neuritis may respond quickly if it is caused
by compression or edema, once there is nerve trunk damage, symptoms may take much longer to improve. Similarly,
mild cases of ENL may be treated with NSAIDs, colchicine,
pentoxyfilline, and antimalarials. However, unless contraindicated, standard therapy is with thalidomide at doses ranging from 100 to 400 mg/day. Some patients may respond to
an increase in dosage of clofazimine whereas nonresponders
may benefit from oral steroids. The presence of neuritis usually also requires treatment with systemic steroids. Ocular disease is treated with topical steroids and atropine. Opthalmic

Leprosy — 85

Table 5.3: Commonly Used Drugs in Hansen’s Disease: Important Side Effects
Drug

Side Effects

Screening Labs

Dapsone

Hemolytic anemia (mild and dose dependent);
Agranulocytosis (rare)
Hypersensitivity Reaction

CBC (every 6 months); G6PD
(before starting)

Clofazimine

Red/grey discoloration, particularly in lesional
skin; Diarrhea, abdominal pain, intestinal
obstruction at higher doses

Review of systems, abdominal
exam

Rifampin

Transaminitis (address if higher than 2.5×
normal), thrombocytopenia, drug interactions
(steroids, anticoagulants, oral contraceptives)

CBC and platelets, electrolytes,
and liver function tests (every
3 months)

Floroquinolones

Rash, visual disturbance, vasculitis, hematuria,
cartilage erosion

Minocycline

Pigmentation, vestibulitis, transaminitis, lupuslike syndrome

CBC, LFTs

Clarithromycin

Headache, rash, gastrointestinal upset, increased
PT time and BUN

CBC, electrolytes, coagulation
tests

Thalidomide

Teratogenicity and neurotoxicity

CBC and differential, physical
exam, pregnancy test

CBC, complete blood count; LFT, liver function test.

evaluation and referral is strongly suggested. Alternative therapeutic agents that may be helpful in treating ENL are presented in Table 5.4.
Lucio’s phenomenon is best treated with systemic corticosteroids. Unlike ENL it is not responsive to thalidomide. It carries
a high mortality rate and morbidities eventually require wound
care akin to that of a burn victim with admission to intensive
care units.
As mentioned earlier, it is not uncommon for leprosy to
present during pregnancy or early puerperium. Hypersensitivity
reactions, Type I and Type II, relapses, and downgrading of the
disease are more prevalent during pregnancy, especially during
the third trimester, lactation, and the puerperium. The infection
can be treated with dapsone and clofazimine, as well as a monthly
dose of rifampin. Reversal reactions may be treated with clofazimine and steroids, but thalidomide is always contraindicated in
pregnancy.
Though various vaccines have been developed, their efficacy
is poor, particularly among certain populations. Given the relative utility of MDT, less attention has been focused on improving
currently available vaccines. Nonetheless, given their immunologic benefits, particularly in improving bacterial clearance and
inducing a fall in bacillary index among MDT nonresponders,
research on potential vaccines should be pursued particularly
for use in countries such as Brazil and India, where prevalence
continues to be high. Among the vaccines currently investigated
in the field are BCG, mycobacterium ICRC, and mycobacterium W. A vaccine that protects not only against tuberculosis
but also against leprosy could be the answer to the problem of
vaccination.
Importantly, the care of the patient with leprosy must be
multidisciplinary. Given the sequelae of the disease, neurologists,
orthopedic surgeons, otorhinolaryngologists, podiatrists, occupational therapists, rehabilitation specialists, and social workers

Table 5.4: Alternative Agents in the Treatment of ENL
Colchicine
Pentoxifylline
Cyclosporine A
Aziathioprine
Mycophenolate mofetil
Methotrexate
Cyclophosphamide
Etanercept
Adalimumab
Infliximab
Intravenous IgG
Plasmapheresis
ENL, Erythema nodosum leprosum; IgG, immunoglobulin G.

are invaluable adjuncts to the dermatologist, infectious disease
specialist, or the primary practitioner caring for those who are
actively treated or who battle the various disabilities created by
the disease. Even if deformities are not readily visible, care must
be taken to monitor areas such as the feet, hands, and eyes, where
the incidence of insensitivity is high (Fig. 5.11). Cutaneous
ulcers and eye disease may develop as a result of decreased protection from physical and thermal trauma. Importantly, there is
a documented increase in the development of squamous cell carcinoma in chronic foot ulcers. Neuropathy may be responsive in
up to 60% of patients. Early consultation and referral should be

86 — Arturo P. Saavedra and Samuel L. Moschella

Table 5.5: Clinical “Masquerades” in the Diagnosis of
Leprosy
A.

Infectious
Tinea versicolor
Tuberculosis verrucosa cutis
Annular syphilis
Leishmaniasis
Deep fungal infection

B.

Inflammatory Disease
Psoriasis
Gyrate erythema
Granuloma annulare
Necrobiosis lipoidica
Pityriasis alba
Lichen planus
Sarcoid
Contact dermatitis
Leukoderma
Postinflammatory hypopigmentation

C.

Malignancy
Mycosis fungoides

Figure 5.11. This patient with advanced lepromatous leprosy (LL) has
developed foot ulcers at sites of pressure due to developed neuropathies and insensitivity. An increase in the incidence of squamous cell
carcinomas has been documented in these ulcers. At this stage, neurologic changes are often irreversible and require careful follow-up by
the clinical team.

B-cell lymphoma
Leukemia cutis
D.

Metabolic Diseases
Xanthomatosis

E.

Connective Tissue and Autoimmune Disease
Lupus

obtained by those who are not able to perform sensory testing,
surveillance, and follow-up treatment.

Vitiligo
Scleroderma/morphea

P I T FA L L S A N D M Y T H S

Patients with Hansen’s disease have been subject to great
social stigma since the beginning of times. In fact, skin disease described in early literature and the Bible likely represents
papulosquamous diseases rather than leprosy. Yet, to this date,
despite increasing information about susceptibility of hosts,
infectivity, and efficacy of antimicrobial therapy, many patients
suffer from social disparity. Employment discrimination is illegal in the United States, yet many patients fear social isolation
and inability to secure and maintain employment. In addition, because a high index of suspicion must be kept to make
the diagnosis, either clinically or pathologically, many patients
escape the health-care system, misdiagnosed or untreated. As
detailed in Table 5.5, because the differential diagnosis may be
vast, the diagnosis is important to consider, particularly in those
patients from endemic areas.

Because antibody tests and PCR studies are mostly experimental, tests such as the Mitsuda reaction lack specificity, and
skin smears require a well-trained examiner for adequate utility;
laboratory tests are often not helpful in making the diagnosis.
Pathologic examination is paramount, and may also pose challenges when the diagnosis is not considered early. Particularly
in cases of paucibacillary disease, it is necessary to carefully
examine cutaneous nerves, as only few mycobacteria may be
evident even when the index of suspicion is very high. Often,
organisms may not be observed, or only fragments of organisms may be seen, and they are easily confused with nonspecific binding of Fite reactants. Methenamine silver stains may
be helpful in identifying fragmented portions of the bacilli.
Empiric therapy or repeat biopsy may be indicated in these
cases.

Leprosy — 87

Unlike other infectious diseases, the incidence, course, and
prognosis of leprosy do not appear to be affected by co-infection with HIV. Reactivation disease in the setting of immune
reconstitution syndrome in the early treatment of HIV does
not appear to be a concern as has been reported in other disorders like herpetic disease, tuberculosis, leishmaniasis, or
sarcoidosis.
Remember most of the leprosy patients are from “third-world
countries” and have comorbidities, which can be potentially fatal
if activated by immunosuppressive drugs such as corticosteroids
given for reactions and neuritis. Consequently, it behooves the
attending physician to do a PPD, a hepatitis B surface antigen
test, and an immunoassay for strongyloidiasis.
Leprosy is a reportable disease. Early treatment drastically
reduces infectivity and some believe that after the first dose
of antibiotics, transmission is virtually eliminated. Vertical
transmission is below 8% and conjugal transmission also
appears to be in that range. Because early therapy also prevents
the devastating sequelae of the disease, referral to centers that
specialize in the care of Hansen’s disease is recommended.
Particularly in multibacillary disease and in the setting of
reversal reactions, treatment prevents neurologic and cutaneous disability.

CONCLUSIONS

Whether or not the disease is eradicated in the future, Hansen’s
disease continues to affect people across the world. Regardless
of microbiologic cure, treatment of disabilities will continue to
be a public health concern. Because clinical signs of infection
can be subtle, a high index of suspicion must be maintained
in those that present with either neural, cutaneous disease, or
both. As the most common cause of peripheral neuropathies in
developing countries, Hansen’s disease should continue to be on
the agenda of every country, as an increase in availability and
affordability of transportation have facilitated immigration patterns. Importance should not only be placed on treatment and
prevention but also on establishing educational programs that
can mitigate the social difficulties that people with this disease
often face. The battle in reducing incidence will necessitate new

policies in primary health care, which should promote early
detection, adequate treatment, as well as disability prevention,
management, and further research.

SUGGESTED READINGS

Anderson H, Stryjewska B, Boyanton B, et al. Hansen disease in the
United States in the 21st century: A review of the literature. Arch
Path Lab Med 2007;131:982–986.
Britton W, Lockwood D. Leprosy. Lancet 2004;363:1209–1219.
Haimanot R, Melaku, Z. Leprosy. Curr Op Neurol 2000;13:317–322.
www.who.int/lep/leprosy/en/index.html
Jacobs M, George S, Pulimood S, et al. Short-term follow-up of patients
with multibacillary leprosy and HIV infection. Int J Lepr Other
Mycobater Dis 1996;64:392–395.
Mallick SN. Integration of leprosy control with primary health care.
Lepr Rev 2003;74:148–153.
McKee P, Calonje E, Granter, S. Pathology of the Skin, 3rd edition.
Elsevier, London, 2005.
Moschella S. Leprosy: epidemiology and present and possible future
therapeutic approaches. Drugs Fut 2006;31:961–7.
Moschella SL. An update on the diagnosis and treatment of Leprosy. J
Am Acad Dermatol 2004;51:417–426.
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Lepr Rev 2004;75:192–193.
Ramos e Silva M, De Castro M. Mycobacterial Infections. In:
Dermatology, 1st edition. Mosby, London, 2003.
Ridley DS. Skin biopsy in leprosy: Histological interpretation and clinical application. Documenta Geigy, Basle, 1977.
Sabin TD, Swift TR, Jacobson RR. Leprosy. In: Dyck PJ, Thomas PK, eds.
Peripheral neuropathy. Philadelphia: Saunders, 1993;1354–1379.
Sasaki S, Takeshita F, Okuda K, et al., Mycobacterium leprae and leprosy: a compendium. Microbiol Immunol 2001;45:729–736.
Schurr E, Alcais A, Singh M, et al. Mycobacterial infections: PARK2
and PACRG associations in leprosy. Tiss Antig 2007;69:231–233.
Scollard DM, Adams LB, Gillis TP et al. The continuing challenges of
Leprosy. Clin Microbiol Rev 2006;19:338–381.
Utianoski AP, Lockwood, DN. Leprosy: current diagnostic and treatment approaches. Curr Opin Infect Dis 2003;16:421–427.
Yawalkar SJ. Leprosy for medical practitioners and paramedical workers, 5th edition, CIBA-GEIGY, Basle, 1992.

6

AT Y P I C A L M YC O BAC T E R IA
Francesca Prignano, Caterina Fabroni, and Torello Lotti

H I STORY

The nontuberculous mycobacteria are species different from
Mycobacterium tuberculosis. In the past these organisms were
referred to as “atypical” (as they were thought to be unusual M.
tuberculosis strains), as “anonymous,” as “tuberculoid,” or as
“opportunistic,” but actually they are widely known as environmental mycobacteria because their peculiar ability to exist in the
environment.
Their existence has been known since the nineteenth century,
but their role as human pathogens was not seriously considered
until the middle of the twentieth century when a new mycobacterial skin disease called swimming pool or fish tank granulomas, due
to Mycobacterium marinum, was described by Linell and Norden
and Runyon published his classification of the mycobacteria.
Environmental mycobacteria (Table 6.1) are acid-fast mycobacteria, have a wide distribution, and can be found in up to 90%
of biofilms (the slim layer present at the water–solid interfaces)
taken from piped water systems. They are extremely hardy and
thrive in even the most hostile environments; some species such
as the Mycobacterium chelonae or Mycobacterium abscessus group
resist the activity of disinfectants and biocides such as organomercurials, chlorine, and alkaline gluteraldehyde. Pseudo-outbreaks
of mycobacteriosis related to contaminated surgical instruments
have been described all over the world. Mycobacteria, therefore,
can easily affect the skin; in some cases, especially in immunosuppressed patients, they are able to spread toward the pulmonary or lymphoglandular system and even reproduce a systemic
illness. They are characterized by a low pathogenicity, and for
mycobacteria to infect, the tissue has to be damaged or there
must be an immunocompromised host. Clinically, skin lesions
are characterized by nodules or plaques, which at the very beginning remain localized at the inoculation site, or the infection can
spread along the lymphatic vessels toward lymph nodes to reproduce the so-called sporotrichoid syndrome. Histopathology can
be helpful in diagnosis, but the real diagnostic tools are the isolation of the bacteria on a selective media and the PCR technique
(if the first proves not to be sufficient).

C L A S S I F I C AT I O N

For the more than 30 species of nontubercular mycobacteria,
the most available classification criteria is by Runyon, based on
1
the growth
rate, colony morphology on the Loewenstein–Jensen
We wish to thank Prof. Elisa M. Difonzo for providing the pictures used in this
chapter.

88

medium and on the ability to form a pigment spontaneously or
after photoexposition (Table 6.1).
Group 1 includes slowly growing photochromogens such
as M. marinum and Mycobacterium kansasii. Group 2 includes
slowly growing mycobacteria that produce pigment either in
the presence or in absence of light and therefore are called scotochromogens. This group includes Mycobacterium scrofulaceum,
Mycobacterium szulgai, and Mycobacterium gordonae. Group 3
includes the nonchromogens, which are always slow growing;
examples are intracellular Mycobacterium avium, Mycobacterium
malmoense, and Mycobacterium xenopi. Group 4 includes rapidly growing nonchromogens such as Mycobacterium fortuitum,
Mycobacterium chelonae, and Mycobacterium abscessus, which
are also the most pathogenic for human beings. The identification of the different species has been performed in recent years
with molecular methods such as genetic sequencing and PCRbased techniques. In the case of slow-growing mycobacteria,
PCR is used through the direct sequencing of the gene codifying the 16S of ribosomal RNA. In the case of rapidly growing
mycobacteria, identification of species is possible through PCRrestriction fragment length polymorphism analysis of the heat
shock protein 65 (hsp65) gene.

Mycobacterium marinum
Mycobacterium marinum was originally reported after its discovery on saltwater fish in the Philadelphia Aquarium in 1926. The
first human skin infection was reported in 1951 and occurred
in contaminated swimming pools. M. marinum is usually found
on plants, in soil, and on fish in household aquariums, and in
fresh and saltwater worldwide. Its optimal growth temperature is 30°C to 32°C, and it will not grow if the temperature is
≥37°C.
Mycobacterium marinum causes infections that are typically
localized to the skin. Infection only occasionally involves deeper
structures, like the joints and tendons. Disseminated infections
are extremely rare and, if they occur, they occur in immunocompromised individuals only.

Mycobacterium kansasii
This organism is found in fresh water, particularly in temperate regions. It is primarily a pulmonary pathogen and causes a
tuberculosis-like illness with a predilection for middle-aged
or elderly men with chronic obstructive pulmonary disorder.
Cutaneous manifestations vary widely and include erythematous granulomatous plaques, verrucous plaques, and verrucous
nodules with sporotrichoid spread.

Atypical Mycobacteria — 89

Table 6.1: Mycobacteria classification
Group Growth Pigment Growth
Rate

Organism

I

Slow 2–3 Photochromogen
weeks

Mycobacterium kansasii,
Mycobacterium marinum,
Mycobacterium simiae

II

Slow 2–3 Scotochromogen
weeks

Mycobacterium
scrofulaceum,
Mycobacterium szulgai,
Mycobacterium gordonae

III

Slow 2–3 Nonphotochromogen Mycobacterium
weeks
malmoense,
Mycobacterium xenopi,
Mycobacterium
avium–intracellulare

IV

Rapid 3–5 Nonchromogen
days

Mycobacterium fortuitum,
Mycobacterium chelonae,
Mycobacterium abscessus

Taken from Runyon, et al (1959).

Mycobacterium scrofulaceum
This form is widely distributed but most prevalent in the southeastern United States, where it has been isolated from soil, tap
water, raw milk, and pooled oysters. M. scrofulaceum may cause
pulmonary disease but primarily causes local lymphadenitis in
childhood, which can result in fistula formation.

Mycobacterium avium Complex
Mycobacterium avium complex includes Mycobacterium avium
and Mycobacterium intracellulare and is ubiquitous in nature.
Both mycobacteria survive in soil, water, house dust, vegetables,
eggs, and milk. In immunocompromised hosts, these mycobacteria cause widespread, disseminated disease involving the liver,
spleen, gastrointestinal tract, lymph nodes, bone marrow, and
skin. Skin is typically involved in the setting of disseminated
infection. Sporadically, primary cutaneous infections occur after
traumatic inoculation or in association with a contaminated
water source.

Mycobacterium fortuitum Complex
Mycobacterium fortuitum complex includes three species (isolated
in recent years with biomolecular techniques): Mycobacterium
fortuitum, Mycobacterium peregrinum type 1, and Mycobacterium
peregrinum type 2.
Mycobacterium fortuitum is the most important member
of the rapidly growing mycobacteria. The organism is found in
water, dust, soil, marine life, and other animals. The sources of
infection are contaminated surgical instruments or medical solutions, and the infection is a possible complication of surgery and
aesthetic procedures. Clinically Mycobacterium fortuitum complex infection can result in cutaneous or extracutaneous manifestations, including endocarditis, osteomyelitis, mediastinitis,
meningitis, keratitis, and disseminated infection. Skin infections

Figure 6.1. A typical lesion by Mycobacterium marinum shows a typical erythematous plaque with squamous, crusty elements at the center
of the lesion. Courtesy of Prof. M. Elisa Difonzo.

are the most frequent, and the lesions appear after an incubation
period of approximately 4 to 6 weeks and are usually painful,
erythematous nodules at the site of an inoculation. Cellulitis,
furunculosis, ulcers, draining sinus tracts, and abscesses can also
form. Cases of infections have been described after intramuscular injections, biopsy, mesotherapy, and pedicure.

Mycobacterium chelonae–Mycobacterium abscessus
Complex
This group includes M. chelonae, M. abscessus, and Mycobacterium
immunogenum. They are widespread in soil and in water. These
organisms are frequently implicated in pulmonary and systemic
disease, but they can also localize to the skin as primary involvement or spread to the skin after systemic dissemination.

C L I N I C A L P R E S E N TAT I O N

All mycobacteria are characterized by low pathogenicity, and
they can only contaminate affected or traumatized skin. The
most common occasions and locations for infection are fishing,
swimming pools, and aquariums. For quick-growing mycobacteria, medical and aesthetic procedures are the most common
predisposing factors. The incubation period varies from 2 weeks
to 9 months. A small reddish papule normally appears at the
inoculation site. Slowly, the lesion grows and similar lesions can
grow and spread through the lymphatic vessels. In accordance
with the clinical evolution, it is possible to distinguish three different clinical patterns:
1. A unique lesion at the inoculation site (Fig. 6.1)
2. Multiple lesions with a sporotrichoid morphology (Fig. 6.2)
3. Deeper infections with involvement of subcutaneous
structures
The outcome of the lesions is strictly linked to the characteristics of the infecting mycobacterium and to the immunological condition of the host. Cutaneous mycobacteriosis should be

90 — Francesca Prignano, Caterina Fabroni, and Torello Lotti

Figure 6.3. A colony of Mycobacterium marinum with the classic milky
color. Courtesy of Prof. M. Elisa Difonzo.
Figure 6.2. Sporotrichoid syndrome. Courtesy of Prof. M. Elisa
Difonzo.

Table 6.2: Differential Diagnosis
Diagnosis

Discriminative Criteria

Cutaneous leishmaniasis Demonstration of amastigotes in Giemsastained smears from infected skin by
direct microscopy
Subcutaneous mycoses
(Majocchi’s granuloma)

Positive direct microscopic examination
and cultures for Trichophyton rubrum

Cutaneous sporotrichosis Positive direct microscopic examination
for Sporothrix schenckii
Skin tuberculosis

Positive cultures and/or positive PCR for
Mycobacterium tuberculosis

considered in the differential diagnosis of any granulomatous/
nodular dermatosis (see Table 6.2).

DIAGNOSIS

There are three tools to perform a correct diagnosis:
1. The most important is a culture performed on a selective
medium, usually Loewenstein–Jensen agar (Fig. 6.3).
2. Histopathology.
3. Biomolecular techniques, if available.
No single diagnostic criteria by itself is highly specific or sensitive or both. Application of the three together is the best way to
make a definitive diagnosis.

THERAPY

The variability of clinical presentations and the complexity of
laboratory techniques often leads to a delay in the diagnosis of
cutaneous mycobacteriosis. The lack of an antimicrobial susceptibility profile causes most cases to be treated empirically, with

the possibility of therapeutic failure. In addition, many mycobacteria display both in vitro and in vivo drug resistance to antimicrobial agents. Combination treatment is preferred to avoid
the emergence of resistant strains and/or relapse of the disease.
The most often used drugs are tetracycline, antitubercular drugs,
macrolides, quinolones, and trimethoprim–sulfamethoxazole.
M. marinum strains are most often susceptible to quinolones and
doxycycline, clarithromycin, and erythromycin and are resistant
to pyrazinamide and isoniazid.
The treatment of infections due to rapidly growing mycobacteria may be difficult because of multiresistant strains, and
surgery may be the best treatment option.

P I T FA L L S A N D M Y T H S

Cutaneous mycobacteriosis is a challenge for the dermatologist
because the diagnosis requires a high index of suspicion and,
contrary to popular belief, immunocompetent subjects, apparently without risk factors, are frequently affected.
This circumstance is linked to the difficulty of detecting in
the personal history of the patient a dangerous activity or event
that happened weeks or months before the appearance of skin
lesions and to the clinical presentation of skin lesions. M. scrofulaceum lymphadenitis, for example, may be indistinguishable
from M. tuberculosis infection (scrofuloderma), or a M. marinum granulomatous nodular lesion with central ulceration has
to be considered in the differential diagnosis along with other
granulomatous skin infections.
The risk factors linked to these infections are changing.
In the past century a large number of swimming and bathing
related infections were described. Now, the incidence of these
outbreaks has been drastically reduced because of the improvement in the construction and maintenance of these facilities. The
most important chance of infection is mainly related to hobbies
and to medical procedures.
A recent study stressed the capability of environmental
mycobacteria to grow as aggregated “sessile” communities
attached to living and nonliving surfaces (including medical devices), forming a biofilm. A biofilm develops when the
attached cells excrete polymers that facilitate adhesion, matrix
formation, and alteration of the organism’s phenotype with
respect to growth rate and gene transcription. The physical

Atypical Mycobacteria — 91

and genetic profiles of microorganisms within the protected
biofilm community are deeply different from their existence as
unprotected independent cells. The hallmark of biofilm-related
infections is the dramatic resistance to antimicrobials and host
defenses.

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Clin North Am 1959;45:273–290.
Sungkanuparph S, Sathapatayavongs B, Pracharktam R. Infections
with rapidly growing mycobacteria: report of 20 cases. Int J Infect
Dis 2003;7:198–205.

7

ARTHROPODBORNE INFECTION
Dirk M. Elston

INTRODUCTION

Arthropod-borne diseases remain a major cause of death and
morbidity throughout the world. Malaria alone kills thousands
of people every year. Dengue, trypanosomiasis, leishmaniasis,
viral encephalitis, and viral hemorrhagic fevers are important
public health threats. Modern technology affords us some protection from arthropod-borne disease. Window screens and an
indoor life-style results in lower rates of infection in developed
countries. During a recent outbreak of dengue fever along the
US–Mexican border, the incidence of disease was much lower
in Laredo, Texas, than in Nuevo Laredo, Mexico, even though
the vector, Aedes aegypti, was more abundant on the Texas side
of the border. This demonstrates the magnitude of the effect of
screens and indoor living, even when vector-control measures
have failed.
In areas where disease activity is endemic rather than episodic, state health departments administer aggressive mosquito
control programs. Considerable manpower and equipment are
contributed by military reserve units, and recent conflicts have
demonstrated that war disrupts vector control efforts at home
as well as in the zone of conflict. Disruption of the public health
infrastructure in Iraq and Afghanistan as well as the failure to
deliver repellent to our troops contributed to the much publicized cases of leishmaniasis among American troops in Iraq.
Mosquito-borne outbreaks of West Nile fever in the United
States have also gained national attention. Rocky Mountain spotted fever and equine encephalitis remain the most lethal vectorborne diseases in North America, but many other illnesses are
commonly transmitted by mosquitoes, flies, ticks, and fleas.
Mosquitoes transmit West Nile fever, St. Louis encephalitis, and
equine encephalitis. Even malaria has resurfaced as an endemic
infection within the United States. Ticks transmit Lyme disease
(Fig. 7.1), Rocky Mountain spotted fever, babesiosis, ehrlichiosis,
Colorado tick fever, relapsing fever, and tularemia. In the West,
fleas transmit plague and endemic typhus. In the East, house
mouse mites transmit rickettsial pox. Sandflies (Fig. 7.2) in Texas
carry leishmaniasis (Fig. 7.3).
The world is full of bugs. Even if we lived sealed inside our
homes, pets, bats, birds, and rodents carry disease vectors into
the house. Among the homeless, ectoparasite infestation contributes to a high prevalence of infection with Bartonella quintana. It
is important to note that the vector may influence the expression
of disease. Bartonella organisms transmitted by a louse produce

endocarditis, while the same organism causes cat scratch disease
or bacillary angiomatosis when transmitted by a flea.
While some diseases have a single vector, others have multiple possible vectors. Tick bites and handling of infected animals
are the usual mode of transmission for tularemia, but deerfly bites
and bites by horseflies are also responsible for transmission.

H I STORY

Vector-borne diseases are at least as old as mankind. Credible
evidence of bartonellosis has been found in a 4000-year-old
human tooth. Important elements of patient history include

1

Images were produced while the author was a full-time federal employee. They
are in the public domain.

92

Figure 7.1. Erythema chronicum migrans of Lyme disease.

Arthropod-Borne Infection — 93

Table 7.1: Tick-Borne Diseases and Associated Vectors

Figure 7.2. Sandfly.

Disease

Vector

Malaria

Anopheline mosquitoes

Dengue

Aedes mosquitoes

Yellow fever

Aedes mosquitoes

Arboviridae

Culex mosquitoes

Bartonellosis

Fleas, lice, sandflies

Leishmaniasis

Sandflies

American trypanosomiasis
(Fig. 7.4)

Triatome bugs (Fig. 7.5)

African trypanosomiasis

Tsetse flies

Rocky Mountain Spotted
Fever

Dermacentor variabilis Dermacentor
andersoni (Fig. 7.6) Amblyomma
americanum

Human monocytic
ehrlichiosis

Amblyomma americanum (Fig. 7.7)

Human anaplasmosis

Ixodes scapularis (Fig. 7.8)

Lyme disease

Ixodes scapularis

Babesiosis

Ixodes scapularis

Tularemia

Amblyomma americanum
Dermacentor andersoni Dermacentor
variabilis Chrysops deerflies Horseflies

Tick-borne Relapsing Fever

Ornithodoros genus (soft tick)

Tick paralysis

Dermacentor andersoni (wood tick)
Dermacentor variabilis (dog tick)

Plague

Xenopsylla cheopis (Fig. 7.9) and Pulex
irritans (Fig. 7.10)

Typhus

Pediculus humanus

Endemic typhus

Ctenocephalides felis (Fig. 7.11) and
Xenopsylla cheopis

as recommended. The degree of engorgement of a removed tick
or the duration of attachment can be used to estimate the risk of
disease transmission.

EPIDEMIOLOGY

Figure 7.3. Leishmaniasis.

travel and the use of repellents and prophylactic antibiotics. Travelers who follow the Centers for Disease Control and
Prevention (CDC) guidelines for malaria prophylaxis are far less
likely to become infected. Of the 891 reported cases of malaria
among US travelers abroad in 2001, only 180 had followed the
recommended prophylaxis regimen. It is also important to note
if repellents, protective clothing, and mosquito netting were used

Epidemiology of vector-borne illness varies geographically
as well as by season. CDC websites provide detailed risks in
various areas of the country and the world. Table 7.1 lists
some important arthropod-borne diseases and their major
vectors.

DIAGNOSIS

The type of exposure, vector, and disease prevalence may be as
important in establishing a presumptive diagnosis as the subsequent signs and symptoms of disease. Periodic fevers suggest malaria. Headache is common to a wide variety of tick and

94 — Dirk M. Elston

Figure 7.7. Amblyomma americanum.

Figure 7.4. Chagas disease, toxic megacolon.
Image courtesy of Walter Reed Army Medical Center teaching file.

Figure 7.8. Ixodes scapularis.
Figure 7.5. Triatome bug.

Figure 7.9. Xenopsylla cheopis.
Figure 7.6. Dermacentor andersoni.

THERAPY

mosquito-borne diseases. In endemic areas, fever and headache
after a tick bite suggest a diagnosis of Rocky Mountain spotted
fever until proved otherwise. Empiric therapy is appropriate in
this setting, and it is never appropriate to withhold therapy until
a diagnosis is established by laboratory studies.

Once disease has occurred, treatment depends on the disease as
well as the age of the patient and severity of illness. The CDC and
the Infectious Disease Society of America (IDSA) list recommendations for a wide array of arthropod-borne diseases. Most

Arthropod-Borne Infection — 95

Figure 7.10. Pulex irritans.

are now marketed. In general, the propane-powered units are
more versatile and provide better results.
DEET (N,N-diethyl-3-methylbenzamide, previously called
N,N-diethyl-m-toluamide) remains the gold standard against
which other repellents are measured. Extended release products
are preferred. Picaridin is a newer repellent effective against a
broad range of mosquitoes.
Secondary prevention of Lyme disease and rickettsial diseases
is possible in highly endemic areas with the use of prophylactic
doxycycline. However, it should be noted that treatment is only
highly effective when appropriately high doses are started early
in the course of clinical disease, so prophylaxis may not always
be in the best interest of the patient. My practice is to provide
the prescription, but instruct the patient not to fill it unless signs
or symptoms occur. For rickettsial disease, this would include
fever and headache (regardless of the absence of rash). For Lyme
disease, an expanding red ring (erythema migrans) or arthritis
would be reasons for treatment.

P I T FA L L S A N D M Y T H S

Figure 7.11. Ctenocephalides felis.

tick-borne illnesses are best treated with doxycycline. Notable
exceptions include tularemia, where streptomycin remains the
drug of choice, and babesiosis, where drugs such as atovaquone,
azithromycin, clindamycin, and quinine are used. The reader is
advised to consult the guidelines listed for full details.
The best intervention is prevention. Use of mosquito netting, repellents, and malaria prophylaxis are the mainstays of
primary prevention. Prevention of mosquito and sandfly bites
focuses on the use of protective clothing and chemical repellents, as these flying arthropods do not need to crawl over clothing to reach exposed skin. Efforts to reduce the numbers of flies
and mosquitoes are important in areas with endemic disease.
Anopheline mosquitoes that carry malaria bite mostly at night;
therefore, those who must be outside after dark are at greatest
risk. Pyrethroid-impregnated mosquito netting has been shown
to be helpful. As noted earlier, all travelers to malaria-endemic
areas should take the CDC-recommended chemoprophylactic
regimen. The Aedes mosquitoes that carry dengue bite during
the day. In areas where the disease is endemic, repellents and
protective clothing should be worn whenever there is a risk of
exposure. Public health measures, such as control of standing
water, stocking ponds with fish, turtles, and frogs to consume
mosquito larvae, and area sprays play an important role in overall management. Mosquito traps such as the Mosquito Magnet
are effective for small areas such as a backyard. Several such traps

Myth 1: Skin-so-soft is a highly effective repellent. Some years
ago, Skin-so-soft bath oil achieved cult status as a repellent. It
does exert a short-lived repellent effect on some mosquitoes, and
insect wings easily become plastered down to the thick oily film.
It has not, however, performed well in comparison to traditional
repellents such as DEET in controlled trials.
Myth 2: DEET is dangerous in children. Although there are
rare reports of anaphylaxis, toxic encephalopathy, and bullous
dermatitis in both children and adults, DEET products have a
well-established overall safety record. The Academy of Pediatrics
currently recommends sustained release formulations and notes
that there is no evidence of any advantage to concentrations
higher than 30%.
There are two critical points to remember. Rocky Mountain
spotted fever has a high mortality rate if antibiotic treatment is
delayed. In endemic areas, empiric treatment should be started
in any patient who presents with fever and a headache, regardless of the history of tick bite and regardless of the absence of
rash. The second point is that prevention is the best form of
management. Appropriate use of protective clothing, repellents,
mosquito nets, and chemoprophylaxis can reduce the burden of
arthropod-borne disease.

SUGGESTED READINGS

Brown M, Hebert AA. Insect repellents: An overview. J Am Acad
Dermatol 1997;36:243–249.
Carnevale P. Protection of travelers against biting arthropod vectors.
Bull Soc Pathol Exotique 1998;91:474–485.
Coosemans M, Van Gompel A. The principal arthropod vectors of disease. What are the risks of travelers’ to be bitten? To be infected?
Bull Soc Pathol Exotique 1998;91:467–473.
Fradin MS. Mosquitoes and mosquito repellents: a clinician’s guide.
Ann Intern Med. 1998;128:931–940.
Kline DL. Comparison of two American biophysics mosquito traps:
the professional and a new counterflow geometry trap. J Am Mosq
Control Assoc. 1999;15(3):276–282.

8

DEEP FUNGAL INFECTIONS
Evandro Ararigbóia Rivitti and Paulo Ricardo Criado

INTRODUCTION

Fungal diseases affect a considerable number of people worldwide and can cause significant morbidity and mortality. The
number of cases has multiplied with the increase in world travel
and immunosuppression. Generally speaking, fungal infections
can be classified as either superficial or deep. Superficial fungal
infections, including dermatophytes, have an affinity for keratin
and, therefore, are typically limited to either the epidermis or
adnexal structures. Deep fungal infections affect deeper structures, including internal organs.
Cutaneous manifestations of deep fungal infections occur
from primary infection of the skin or from cutaneous dissemination due to a systemic infection.
Deep fungal skin infections are chronic diseases, caused by
various groups of fungi. The clinical spectrum of these infections
can be classified into (i) subcutaneous mycoses and (ii) systemic
mycoses.
Subcutaneous mycoses are due to a large and diverse group of
fungus that produce disease when traumatically introduced into
the skin and subcutaneous tissue. Sporotrichosis, mycetoma,
chromomycosis, and lobomycosis are the most common subcutaneous mycoses.
Systemic mycoses are caused by “true” fungal pathogens
and opportunistic fungi. The “true” fungal pathogens are
agents of histoplasmosis, blastomycosis, coccidioidomycosis,
and paracoccidioidomycosis. The opportunistic deep mycoses
comprise a spectrum of diseases, including zygomycosis,
cryptococcosis, aspergillosis, phaeohyphomycosis, and hyalohyphomycosis.
Dermatologists from all over the world should be able to recognize and diagnose deep mycoses. Many of the deep mycoses,
such as sporotrichosis, commonly occur in the United States,
and others can infect travelers from endemic areas.
In Table 8.1, we summarize the current nomenclature for
most fungi reviewed in this chapter.

Paracoccidioides brasiliensis, the fungus of the South American
blastomycosis. In 1914 the German physician Max Rudolph,
while living in Brazil, described the first six cases of chromomycosis and isolated the fungus in four patients.
Systemic tropical mycoses have been emerging since the
beginning of the deep fungal infections epidemic. The incidence
of these infections is probably even underestimated since most
cases occur in populations with poor access to medical care
and in regions where modern diagnostic methods are unavailable. This scenario is especially applied in third-world countries, which are localized to tropical areas of the planet. In these
areas access to modern therapy for acquired immune deficiency
syndrome (AIDS) (HAART regime) is difficult because of the
elevated financial costs associated. In developed countries, especially in North America, Europe, and a few countries in Asia,
AIDS is sometimes observed in returning travelers, aid workers,
immigrants, and often in organ-transplanted patients who have
been using immunosuppressive therapy. The differential diagnosis of imported systemic tropical mycoses may be especially difficult for uninformed physicians.
In several countries, medical mycology is not taught adequately to medical students (in graduation and in residency
programs). Consequently, there is little awareness of the importance of fungal infections, especially in tropical countries, where
these diseases often show up in medical practice. In addition
sometimes the personal concern with aesthetic dermatology is
favored among medical students and dermatology residents.

Table 8.1: Current Nomenclature of the Fungi and Diseases
Frequently Involved in Deep Fungal Infections
Fungi Molds
Black fungi

Chromoblastomycosis
Mycetoma
Pheohyphomycosis

Non-Black Fungi

Aspergillosis
Hyalohyphomycosis
Mycetoma

Dimorphic Fungi

Blastomycosis
Coccidioidomycosis
Histoplasmosis

Yeasts

Candidiasis
Cryptococcosis

Fungi whose classification
is uncertain

Lobomycosis
Rhinosporidiosis

H I STORY

Tropical medicine was born with Sir Patrick Manson
(1984–1922), the famous Scottish parasitologist who worked
for 24 years in China. While there, he studied superficial mycoses, malaria, and filariasis. In 1908 Lutz (a Brazilian scientist)
described the paracoccidioidomycosis, and Splendore (in 1912)
classified the agent in the Zymonema genus. In 1928, Almeida
and Lacaz, in Brazil, suggested the name Paracoccidioides and
finally the agent then became known around the world as
96

Infection

Deep Fungal Infections — 97

Table 8.2: General Classification of Mycetoma
Actinomycetoma (Bacterium)
• Endogenous Actinomycosis: caused by anaerobic actinomycetes:
Actinomyces israelli, Actinomyces viscous, Actinomyces
odontolyticus, Arachinia propionica
• Exogenous Actinomycosis (Nocardiosis): caused by aerobic
actinomycetes: Genus: Actinomadura, Nocardia and Streptomyces
Eumycetomas (Fungi)
• Maduromycosis: exogenous origin due to several aerobic fungi:
Petrellidium, Acremonium, Madurella, Leptosphera and others

S U B C U TA N E O U S M Y C O S I S

Subcutaneous mycoses consist of a heterogeneous group of infections caused by a broad spectrum of taxonomically diverse fungi.
Fungi gain entrance into the subcutaneous tissue usually following
traumatic implantation, where they remain in localized microenvironmental niches and are often associated with abscess formation.
These mycoses include pheohyphomycosis, hyalohyphomycosis,
chromoblastomycosis, and mycetoma. Subcutaneous mycoses
tend to remain localized and rarely result in systemic infections.

Figure 8.1. Mycetoma. A: eumycetoma (skin with aggregates of
brown fungi of Madurella grisea, constituted by molds with numerous clamidospores – HE, OM 200x); B: actinomycetoma (skin with
grains of Actinomadura madurae – HE 100x); C: eumycetoma in foot;
D: actinomycetoma in foot.

Mycetoma
Mycetoma is a chronic granulomatous infection that is caused
by either a fungus (eumycetoma) or by a bacterium (actinomycetoma). Classification of mycetomas is shown in Table 8.2.
Although mycetoma is not endemic in the United States,
the continual entry of immigrants from areas where the disease
is endemic creates a need for increased awareness and studies
regarding the clinical presentation and treatment of this disease. Mycetoma is more common in individuals who have more
frequent and direct contact with the field environment, such as
farmers, herdsmen, and other field laborers.
The disease is endemic in tropical and subtropical areas. The
majority of cases occur in the “mycetoma belt,” which stretches
between the latitudes of 15° south and 30° north. Within this
belt are countries such as Sudan, Somalia, Senegal, India, Yemen,
Mexico, Venezuela, Colombia, Brazil, and Argentina. Geographic
areas in the mycetoma belt are characterized by short rainy seasons that last for 4 to 6 months with fairly consistent daily temperatures (30°C–37°C) and relative humidities of 60% to 80%.
These rainy seasons are followed by dry seasons of 6 to 8 months
with variable daytime temperatures (45°C–60°C) and relative
humidities of 12% to 18%.
Mycetoma is not contagious and typically remains localized,
involving cutaneous and subcutaneous tissue, fascia, and bone.
All subcutaneous mycoses are caused by fungi or bacteria that
enter the skin via an incisive injury, often a thorn prick or splinter. The incubation period for the disease is variable.
Mycetomas are characterized by abscesses that contain
grains, or large aggregates of fungi or actinomycete filaments
(Fig. 8.1). They enclose cells with modified internal and cell wall
structures and a hard extracellular matrix. Without therapy, this
disease may lead to severe local tissue destruction, requiring surgical amputation. Actinomycetomas can spread more rapidly.

Figure 8.2. Mycetoma: clinical aspects. A: enlargement of the foot and
nodules with draining sinuses; B: involvement of the lower limb; C:
involvement of the buttocks.

Mycetomas start as small, firm, painless subcutaneous
plaques or nodules, usually on the foot or leg (Fig. 8.2), but are
also found on the arms, chest wall, and scalp. The most common etiological agents of mycetoma worldwide are eumycetes,
particularly Madurella mycetomatis (Fig. 8.3), which causes
>70% of the cases in certain regions of Central Africa, including Sudan. The infection involves the skin and the subcutaneous tissues as well as bone. In Central America and Mexico,
mycetomas are more commonly caused by the actinomycetes
Nocardia brasiliensis, Streptomyces somaliensis, Actinomadura
madurae, and A. peletierii. Scalp mycetomas are rare but can
be caused by Streptomyces somaliensis. Mycetomas as a result
of Nocardia are often found on the chest wall and can invade
the lung. In most cases, mycetomas can spread locally, but they
rarely disseminate.

98 — Evandro Ararigbóia Rivitti and Paulo Ricardo Criado

Figure 8.3. Mycetoma and etiologic agents. A: Pseudallescheria
boydii microcultive (septated fungal hyphae with piriform conidia);
B: Madurella mycetomatis macroculture (potato agar at room
temperature).

Eumycotic mycetoma is a localized chronic infection and
is caused by true fungi. The most important fungi are of the
genera Acremonium, Exophiala, Pseudallescheria, Madurella,
Pyrenochaeta, and Leptosphaeria. In the United States, mycetoma is most commonly caused by the fungus Pseudallescheria
boydii (Fig. 8.3). The disease starts as painless, cutaneous papules or nodules that increase in size and spread to the connective
tissue.
Eumycotic mycetoma is characterized by tumefaction, draining sinuses, and the presence of grain (organized, interwoven
mycelial aggregates) formation, usually appearing on the foot.
Mycetoma is typically unilateral, and most often (~70%–80%)
the foot is the primary site of infection, followed by the hands
(~12%), legs, and knee joints.
Ultimate diagnosis is made by visualization of grains, which
can be collected by opening up pustules and expressing the contents or by deep surgical incision. After that the grains are fixed
in a solution of 20% potassium hydroxide, they can be seen on
a glass slide. Usually, fungal hyphae may be seen, and the characteristic colors (black, white, yellow, red or mixed colors) of the
grains are useful in differentiating between the various agents
that cause mycetomas.
Eumycetes that usually have white grains are Acremonium falciforme, Acremonium kiliense, Acremonium recifei, Cylindrocarpon
cyanescens, Cylindrocarpon destructans, Pseudallescheria boydii, Fusarium oxysporum, Fusarium solani, Fusarium moniliforme, Neotestudina rosatii, Polycytella hominis, and Aspergillus

nidulans. Black grains are found in following eumycetes:
Plenodomus avrami, Corynespora cassiicola, Curvularia geniculata, Curvularia lunata, Leptosphaeria senegalensis, Leptosphaeria
thompkinsii, Madurella grisea, Pseudochaetosphaeronema larense,
Pyrenochaeta mackinnoni, Pyrenochaeta romeroi, Madurella
mycetomatis, Exophiala jeanselmei, Phialophora verrucosa.
Aspergillius flavus shows green grains.
MRI can exhibit the extent of involvement. Periosteal thickening, bone lytic lesions, and increased bone density can be seen
on radiographic films.
Management of actinomycetomas can be started with streptomycin (14 mg/kg daily) intramuscularly for 4 weeks. After this
initial four weeks of therapy, dapsone (1.5mg/kg twice daily)
should then be added to the treatment regiment on alternate
days with streptomycin. If this regimen fails, dapsone should
be replaced by trimethoprin/sulfamethoxazole (14mg/kg twice
daily) or rifampicin (15–20mg/kg daily).
Surgery is often performed as a first-line therapy for eumycetes. To be effective, the surgery must be done before the infection has extended to the underlying bone and must be followed
by systemic antifungals. Care must be taken throughout any surgical procedure to avoid contamination and further infection,
with emphasis placed on maintaining the integrity of the capsule.
Aggressive wide excision or amputation should be performed
for early localized lesions. Less aggresive surgery should be performed for extensive disease with bone involvement. Following
completion of surgery, treatment of the wound with iodine is
recommended to eliminate any residual fungi.
Medical treatment of eumycetomas is initiated with ketoconazole (400–800 mg daily) or itraconazole (400 mg daily). Cure
rates with ketoconazole seem to be dose dependent, with some
patients needing treatment for months or years. Use of itraconazole has been associated with good clinical response with a low
recurrence rate. Liver function tests should be monitored. The
following findings are needed for a presumptive cure: disappearance of the subcutaneous mass with healing of the sinuses
and the appearance of normal skin, three consecutive negative
immunoelectrophoresis tests one month apart, restoration of
the normal radiological appearance of bone with remodeling,
absence of hyperreflective echoes and cavities upon ultrasonic
examination, and absence of grains on fine needle aspiration.

Chromomycosis
The synonyms for this disease include chromoblastomycosis,
cladosporiosis, Fonseca’s disease, Pedroso and Lane’s mycosis,
and phaeosporotrichosis. First described by Pedroso and Gomes
in 1920, in Sao Paulo, as “a verrucous dermatitis of infectious
origin” (Fig. 8.4), the disease was later named chromoblastomycosis by Moore and Almeida in 1935. These fungi produce sclerotic
bodies that mostly partition by separation along the septa, and
show brownish spherical formations called fumagoid bodies.
Chromomycosis is a chronic, often debilitating, suppurative, and granulomatous mycosis of the skin and subcutaneous tissues established after inoculative trauma. Chromomycosis
occurs worldwide, but is prevalent in many tropical and subtropical countries, like Brazil, and probably occurs when spores are
implanted from soil or decaying vegetation after minor trauma.
This mycosis is caused by several species of dematiaceus
hyphomycetes: Fonsecaea pedrosoi (Fig. 8.5), Phialophora

Deep Fungal Infections — 99

verrucosa, Cladophialophora carrionii, Fonsecaea compacta,
Rhinocladiella aquaspersa, and Wangiella dermatitidis.
The host defense mechanism in chromomycosis in some
studies demonstrates a predominantly cellular immune response,
with the activation of the macrophages involved in fungus phagocytosis. Although phagocytosis occurs, death of fungal cells is
rarely observed. The ability of Fonsecaea pedrosoi to produce
secreted or wall-associated melanin-like components protects
the organism against destruction by host immune cells.
After inoculation there is an adherence by the fungus to
epithelial cells. The fungus then differentiates into sclerotic
forms (sclerotic bodies, muriform cell, Medlar body). Phaeoid
(dark-colored) hyphae may also be observed in infected tissues.
Sclerotic bodies are dark-brown (melanin produced in the cell
wall), spherical or polyhedral, thick-walled structures which
have horizontal and vertical septa inside. They may be found
singly, in clusters, or within giant cells.
Clinically, chromomycosis is chronic with the development
of nodules, verrucous, cauliflower-like lesions, tumors, plaques,
and scar lesions (Fig. 8.6a & b). Differentiation requires microscopic examination.

The lower limbs are most frequently affected, and upper limb
disease occurs in only 15% of cases (Fig. 8.4). The condition
usually remains confined to the skin and subcutaneous layer,
although lymphatic spread can occur and rare cases of cerebral
involvement have been reported. General health state is not
affected. There is a characteristic odor of secondary fusospiral
organisms. Long-standing cases can also be complicated by lymphedema and, occasionally, squamous cell carcinoma.
Pseudoepitheliomatous hyperplasia, intraepidermal abscesses, and suppurative and granulomatous inflammatory infiltrates
into the dermis are often found. Spherical, dark, or brown bodies
(muriform cell and Medlar bodies) are sometimes present in the
dermis in giant cells.
The major differences between genera are the microscopic
features.

Figure 8.4. Chromomycosis. A: verrucous dermatitis on the foot; B:
verrucous dermatitis on the hand.

Figure 8.6. Chromomycosis. Polymorphous skin manifestations.
A: nodules, verrucous cauliflower-like lesions, and tumors; B: plaques
and scar lesions; C: a lesion in treatment with liquid nitrogen.

•

Fonsecaea type: Conidia are one-celled and arise on swollen dentils that are located at the tips of the conidiophores.
These primary conidia function as sympodial conidiogenous
cells, becoming irregularly swollen at their apices. These in
turn give rise to one-celled, pale brown, secondary conidia

Figure 8.5. Chromomycosis. Fonsecaea pedrosoi cultive. A: macrocultive in potato agar for 21 days at room
temperature; B: microcultive showing Fonsecaea type of conidiogenesis (OM 400x).

100 — Evandro Ararigbóia Rivitti and Paulo Ricardo Criado

•

•

•

on swollen dentils. The secondary conidia often produce
tertiary series of conidia like those formed by the primary
conidia, resulting in a complex conidial head. Long chains of
conidia are not formed in this type of conidiogenesis.
Cladosporium type: Conidiophores give rise to primary
shield-shaped conidia, which then generate long, branching chains of oval, dematiaceous conidia. The conidia have
visible dark hila, which are actually the attachment scars.
This type of conidiogenesis is primarily observed for the
strains belonging to the genus Cladosporium, but may also
be observed in strains of Fonsecaea.
Phialophora type: In this type of conidiogenesis, conidia are
located at the apices of the phialides, which are vase-shaped
and have collarettes. This type of conidiogenesis is primarily
observed for the strains belonging to the genus Phialophora,
but may also very rarely be observed in strains of Fonsecaea.
Rhinocladiella type: Conidiophores are sympodial and have
dentils, which bear one-celled, pale brown conidia. The conidia
may be located at the tips and along the sides of conidiophores.
Formation of secondary conidia is very rare. This type of conidiogenesis is primarily observed for the strains belonging to
the genus Rhinocladiella, but may also be observed in strains
of Fonsecaea.

schenckii. It is found throughout the world as a saprophytic
organism, particularly in temperate and tropical areas. This
mycosis develops mainly through (i) penetration of the
fungus into the dermis after wounds or an abrasion of the
skin from infected materials such as hay, thorns, wood, splinters, barbed wire, gardening tools, flowers, pottery, or contact with cattle and feed; (ii) inhalation of spores through
the respiratory tract; or (iii) insect stings or animals bites.
Sporotrichosis is the most common subcutaneous mycosis in
Latin America.
Most cases of sporotrichosis involve primarily the skin and
neighboring lymphatic channels. Dissemination to other organs
and tissues such as bones and joints occurs in immunocompromised patients (i.e., patients with diabetes, alcoholism, AIDS, or
on corticosteroid therapy).
In most cases, the disease localizes to the upper limbs or the
face. It is exceedingly rare in the trunk (Fig. 8.7).
The clinical spectrum of the sporotrichoses is divided into
the following forms: Cutaneous and Extracutaneous forms. The
Cutaneous form is classified into:
•

The clinical differential diagnosis of the verrucous lesions of
chromomycosis should include verrucous leishmaniasis, verrucous tuberculosis, sporotrichosis, and verrucous carcinoma.
Treatment
For small and localized chromomycosis lesions, extensive excision is the treatment of choice. Other therapies are carbon
dioxide laser, cryotherapy, and heat therapy. Cryotherapy is
performed with two freezing cycles lasting 30 to 60 seconds
(Fig. 8.6c).
A number of systemic therapies have been used, including
ketoconazole, itraconazole, amphotericin, flucytosine, fluconazole, thiabendazole, saperconazole, terbinafine, and potassium
iodide. However, chromomycosis is often resistant to treatment,
especially when the causative organism is Fonsecaea pedrosoi. In
this setting, itraconazole is used at a dose of 200 mg/day associated with flucytosine at a dose of 150 mg/kg/day for several
months. Extensive disease requires treatment with intravenous
amphoterecin B, 25 mg on alternate days (see infusion technique
in Paracoccidioidomycosis) as well as flucytosine at a dose of 150
mg/kg/day, over 2 to 3 months.
Damian et al. reported the use of regional chemotherapy
using the isolated limb infusion (ILI) technique, with melphalan
and actinomycin D. Apart from cytotoxicity-induced desquamation and necrosis, the ILI procedure also produces hyperthermia
of the skin and subcutis, which could contribute to its effectiveness against thermosensitive fungi. Melphalan and actinomycin
D are also likely to have direct cytotoxic effects on the causative fungus, similar to what is observed in vitro and in vivo with
5-fluorouracil therapy.

•

Cutaneous lymphatic form (75%, Fig. 8.8C): This common
presentation usually shows papulonodular lesions, and sometimes ulcerative lesions. It occurs at the site of inoculation
(sporotrichoid chancre). Following this, the disease causes a
lymphangitis cord of nodules or gummatous lesions that can
ulcerate in the configuration of a rosary. Often there is no
regional lymphadenopathy. In adults the initial lesion is most
common on the extremities and in children on the face.
Cutaneous localized forms (20%)
1. Papulonodular form (Fig. 8.8a & b): There are papoulosquamous lesions, crusts, nodular lesions and originating plaques that resemble acne or furuncles. There are no
observed signs of lymphangitis.
2. Ulcerative form: single or multiple ulcers, irregular borders, and variable extension (Fig. 8.9). Sometimes in the
periphery of the lesions there are gummas.

Sporotrichosis
Sporotrichosis is a subacute or chronic subcutaneous mycosis caused by the thermally dimorphic organism Sporothrix

Figure 8.7. Sporotrichosis. A and B: Cutaneous localized form on
children’s faces (Papulo-nodular form); C: cutaneous-lymphatic form
(papulo-nodular, ulcerative lesions and lymphangitis).

Deep Fungal Infections — 101

3.

•

Verrucous form: Generally a single verrucous plaque,
with variable form and extension, showing a central
scar. There are no signs of lymphangitis. Under examination, the lesions show a purulent discharge. This form
is classified under the clinical spectrum of cutaneous
verrucous syndrome (leishmaniasis, sporotrichosis, chromomycosis, and tuberculosis).
Cutaneous disseminated form: Rare, characterized by
nodules or gummas dispersed on extensive areas of the body,
which can ulcerate. It is observed in patients with human
immunodeficiency virus (HIV).

Diagnosis
•

Extracutaneous forms: In rare cases of sporotrichosis there
are lesions in bones, lungs, testis, oronasal mucosa, larynx, and
pharynx. Usually, this form is due to ingestion, inhalation, or is
associated with cutaneous disseminated disease.

•

•

•

Mycological studies:
1. Direct examination: In KOH preparations this fungus
cannot be recognized. Gram stain can demonstrate
gram-positive oval or cigar corpuscles. The better diagnostic technique is fluorescent antibodies, which must be
incubated at 37o C for 12 hours.
2. Culture: The gold standard for diagnosing sporotrichosis is fungal culture (Fig. 8.10). The pus or scrapings are
cultured on Sabouraud dextrose agar and a medium containing cycloheximide. At 30°C growth is usually present
in 3 to 5 days. Microscopically, thin branching hyphae
with pyriform conidia can be seen. This is the mycelia
form. S schenckii is a dimorphic fungus, growing as yeast
at 37°C and mycelium at room temperature. The moldto-yeast form conversion is necessary since other fungi
are morphologically similar. Transferring the fungus
to brain heart infusion agar and incubating at 37°C in
5% to 10 % CO2 produces mold-to-yeast form conversion. In culture, S schenckii appears as a white, smooth,
or verrucous colony with aerial mycelium, which subsequently turns brown, and then black.
Histopathological examination: This can be falsely negative. It can show a granuloma with a central suppurative
reaction and secondary histiocytic epithelioid and plasmocytoid reaction in the periphery of the lesion. In hematoxylin-eosin (H&E) stain, “asteroid bodies” can be observed,
which represent fungal elements surrounded by eosinophilic material.
Intradermal tests: Intradermal skin tests using sporotrichin
as the antigen are useful in epidemiological studies and as an
auxiliary method for detecting atypical forms of the disease.
They can yield false-positive and false-negative results.
Serology: It is possible to use immunodiffusion (ID) and
immunoelectrophoresis tests in the diagnosis of sporotrichosis

Figure 8.8. Sporotrichosis. A: Disease localized on the face;
B: Extensive lesions on trunk.

Figure 8.9. Sporotrichosis. A and B: Ulcerative lesions; C: verrucous
form; D: scars of extensive involvement of the lower limb.

Figure 8.10. Sporothrix schenckii. A: macrocultive in Sabouraud
dextrose agar at room temperature (white, smooth or verrucous
colony with aerial mycelium); B: microscopic features of the yeast
form at 37°C; C: mycelium with conidia on marguerite collection
(microcultive at room temperature).

102 — Evandro Ararigbóia Rivitti and Paulo Ricardo Criado

using a fungal culture filtrate employing sera from patients
with the disseminated cutaneous form. These methods are
mainly used in cases of extracutaneous sporotrichosis or
atypical forms This permits the selection of an adequate
treatment regimen. ELISA test shows 90% sensitivity and
86% overall efficacy when tested against sera obtained from
patients with the lymphocutaneous, fixed cutaneous, disseminated cutaneous or multiple and extracutaneous forms
of sporotrichosis.

central nervous system. Amphotericin B is indicated for treatment of moderate to severe clinical forms in immunosuppressed
individuals and those who did not respond to other drugs.
Amphotericin B is nephrotoxic and cardiotoxic. The drug is
administered intravenously, with a maximum daily dose of 50
mg and a total cumulative dose of 500 to 1000 mg. The duration
of treatment until clinical cure is 6 to 8 weeks, on average, in
immunocompetent patients.

Treatment

Lobomycosis

Potassium iodide (KI) was the first drug successfully used in
the treatment of sporotrichosis and is used for localized cutaneous forms. It is formulated as a saturated solution containing
approximately 20 g potassium iodide in 20 mL distilled water.
Each 10 drops of this solution contains 0.5g of KI. Treatment is
initiated with 5 drops administered twice a day, and the dose is
increased by one drop/dose/day until reaching a total of 4 to 6 g/
day (40–60 drops, twice a day) (Fig. 8.11). If there is gastric intolerance, intravenous sodium iodide in doses of 1 to 2g/day can
be given. KI is not suggested during pregnancy. Adverse effects
include nausea, metallic taste, hypothyroidism, iododerma, and
iodism. Itraconazole is administered orally at a dose of 100 to
400 mg/day. Terbinafine is not formally indicated for the treatment of sporotrichosis but reports have shown therapeutic success. Treatment with fluconazole is cited in the literature, but this
is not a first choice drug. Fluconazole is administered orally at
200 to 400 mg/day and has the advantage of the action on the

Lobomycosis or Jorge Lobo’s disease was described in 1931 by
Jorge Lobo, in Brazil. Lobo suspected that his patient had a modified form of paracoccidioidomycosis, which he called keloidal
blastomycosis. A second human case was reported in 1938, after
which the disease was termed Lobo’s disease. Lobomycosis is a
chronic granulomatous infection of the skin and subcutaneous
tissues caused by the fungus Lacazia loboi.
More than 500 human cases have been reported to date,
although the disease appears to be confined to remote tropical
areas of South and Central America, especially in communities
along rivers. Lobomycosis is rarely reported outside of Latin
America. It occurs in tropical and subtropical areas. The condition has been described in Bolivia, Brazil, Colombia, Costa
Rica, Ecuador, French Guiana, Guyana, Mexico, Panama, Peru,
Suriname, and Venezuela. Brazil and Colombia have the most
cases and they are found along the Amazon basin, especially
among the Caibi Indians.

Figure 8.11. Sporotrichosis (cutaneous-lymphatic form) treated with KI. A, B and C: Before the KI treatment.
D, E, and F: 60 days after KI treatment.

Deep Fungal Infections — 103

Attempts to grow L. loboi on artificial media have been unsuccessful. Successful inoculation of this fungus has been achieved
in a hamster’s cheek pouch (Mesocricetus auratus). L. loboi is
a saprophytic fungus in the soil, on vegetables, and in water. It
is inoculated in humans by trauma. Aquarium employees and
farmers comprise most of the cases. Occupations such as gold
mining, fishing, and hunting also put patients at risk.
L. loboi is abundant in tissue under microscopic examination, and shows globoid or elliptic corpuscles of 6 to 12 μm in
diameter. Numerous yeast-like, round, thick, and birefringent
cell walls are seen (Fig. 8.12, upper left). Chains of yeast cells are
typically formed (Fig. 8.12, medium right). This fungus reproduces by gemmulation.
The initial lesion is a superficial or deep papule that can form
solitary or multiple plaques or nodular lesions (Fig. 8.12 upper
right). It is characterized by the appearance of slowly developing (months, years, or decades), keloid-like (Fig. 8.12, upper
left, down left and right), ulcerated, or verrucous nodular or
plaque-like cutaneous lesions. These lesions occur usually at the
site of local trauma as from a cut, insect bite, animal bite, or ray
sting. Lesions tend to occur on exposed, cooler areas of the body,
and in particular the lower extremities and ears. The disease is
limited to skin and semi-mucosal areas. Other sites reportedly
affected include the forehead, face, chest, scapula, lumbosacral
spine, buttocks, and scrotum. The patient often complains of
pruritus, burning, hypoesthesia, or anesthesia. The disease can

Figure 8.12. Lobomycosis. Upper left: Keloid-like lesion; upper right:
numerous yeast-like, round, thick, and birefringent cell walls of
Lacazia loboi; medium left: chains of yeast cells; down left and down
right: clinical aspects of keloid-like lesions on the ear. The genus
Lacazia was proposed to honor Professor Carlos da Silva Lacaz,
eminent mycologist and university lecturer of the Dermatology
Department, School of Medicine, Sao Paulo University, Brazil.

be complicated by secondary bacterial infection or carcinomatous degeneration.
The organism rarely spreads to the lymphatics.
Diagnosis
•

Histopathological examination shows a granulomatous
infiltrate with Langhans cells and numerous parasites, isolated or in chains. The clinical differential diagnosis includes
anergic leishmaniasis, leprosy, zygomycosis, sarcoidosis, or
benign and malignant neoplasms.

Treatment
Optional treatment of lobomycosis is surgical excision. Full excision of the lesion is required for clinical success. Repeated cryotherapy may also be beneficial. Clofazimine has been effective
in some cases of lobomycosis in doses of 100 to 200 mg/day for
12 to 24 months.

Rhinosporidiosis
Epidemiology
Rhinosporidiosis appears as vegetant lesions of the mucosal surfaces.
Rhinosporidium seeberi has recently been shown to be an aquatic
protist. Phylogenetic analysis of rDNA and rRNA from rhinosporidiosis tissue samples suggests that R. seeberi is the first known
human pathogen from the DRIPs (Dermocystidium, the Rosette
agent, Ichthyophonus, and Psorospermium) class of microbes.
Rhinosporidiosis has been documented in both tropical
and temperate areas worldwide. The infection is usually found
in young males. The mechanism of infection is not known,
but some patients have a history of fresh water exposure. It is
hypothesized that aquatic animals are natural hosts of R. seeberi
and humans become infected when they come into contact with
these animals and their parasites.
Rhinosporidiosis occurs in the Americas, Europe, Africa,
and Asia but is far more common in the tropics. The greatest
prevalence is in southern Índia and Sri Lanka, where the incidence is estimated at 1.4% in the pediatric population. Some
arid countries of the Middle East also show a high incidence of
the disease. South America is the second most common source
of rhinosporidiosis, and the disease is endemic in the northeast
part of Brazil, in a transitional environment between the Amazon
rain forest and some arid areas where the rainfall is highly irregular, known as Caatinga. The incidence of rhinosporidiosis in
this particular Brazilian province is similar to the most affected
areas of India, suggesting that both dry conditions and aquatic
environments are related to the disease.
Rhinosporidiosis occurs in healthy people, and there are no
predisposing factors, besides an exposure to fresh water. Most
infections occur in the nose (Fig. 8.13A), but they can also occur
in the oral mucosa, larynx, conjunctiva, and perianal regions.
Ocular infection is more prevalent in women, while nasal and
nasopharyngeal infections preferentially affect men. The infection causes the development of painless intranasal papules that
evolve into large and hyperplastic polyps studded with flecks. The
surface of the polyp is irregular and red with some white dots, like
small cysts (Fig. 8.13a) that correspond to the sporangia. Visceral
dissemination has been reported but is very uncommon.

104 — Evandro Ararigbóia Rivitti and Paulo Ricardo Criado

Figure 8.13. Rhinosporidiosis. A: irregular polyp and red surface;
B: characteristic thick-walled giant sporangia with multiple spores.

is also found in soil contaminated with chicken feathers or
droppings.
Endemic regions are in the western hemisphere, which
include southern Mexico and some areas in the southeastern
United States. Generally, it is a chronic or acute pulmonary disease. However, depending on the immune status of the host, it can
also occur in disseminated form, especially in the setting of HIV.
Cutaneous lesions of histoplasmosis in HIV-infected patients
may take on a wide variety of patterns, including hemorrhagic,
papular, and ulceronecrotic patterns (Fig. 8.14). The cutaneous
and mucocutaneous manifestations of histoplasmosis are frequently a consequence of the progression of a primary infection
to disseminated histoplasmosis (DH). Rarely, the infection can
appear as a few primary cutaneous lesions with a good prognosis. The acquired immunodeficiency syndrome (AIDS)-related
incidence of DH is 0.5% to 2.7% in nonendemic regions, and up
to 10% in endemic regions. It is important to point out that many
AIDS-related cases present initially as DH.
Diagnosis
•

The differential diagnosis must include pyogenic granuloma,
coccidioidomycosis, and myospherulosis, which is an iatrogenic
condition related to the application of nasal substances.

•

Diagnosis
•

The diagnosis is based on the histopathologic demonstration
of the characteristic thick-walled giant sporangia (Fig. 8.13b).
Sporangia can be seen on direct microscopy or on H&Estained sections and have multiple basophilic spores in a
clear material. The submucosa shows chronic inflammation
and spherical sporangia in different stages of development
and ranging in size from 250 to 300 µm in diameter. When
compared with the spherules of Coccidioides immitis, the
mature sporangia of rhinosporidiosis are larger and do not
have a thick outer wall.

•

Treatment
The best management for rhinosporidiosis is excision because
there is no medical treatment known to be effective. To prevent
the 20% of cases that recur after surgery, the base of the lesion
can be cauterized after excision. Local injection of amphotericin
B may be used as an adjunct treatment to surgery to prevent reinfection and spread of the disease.

•

SYSTEMIC MYC OSIS

Systemic mycoses are those in which the pathogen has disseminated from one organ to another. Frequently, systemic mycoses
originate in the lungs, where the pathogens disseminate by the
hematogenous route. If a vital organ such as the brain is involved,
death may result.

•

Mycological studies: on fungal culture, on Sabouraud agar,
white colonies grow at 30°C. Tuberculate macroconidia can
be visualized on microscopic examination.
Histopathological examination: skin biopsies are a simple
method to diagnose cutaneous histoplasmosis. Owing to the
diverse morphologic presentations of the infecting fungus,
it is particularly helpful to use periodic acid–Schiff (PAS)
stains. Cultures are still the best confirmatory diagnostic test,
but serologic tests are also important, especially when biopsies and culture determinations are negative.
Antigen detection: Detection of antigen in bodily fluids
offers a valuable approach to rapid diagnosis in patients with
progressive disseminated histoplasmosis (PDH) and diffuse
pulmonary histoplasmosis. Antigen is found in the urine of
over 90% of patients with disseminated histoplasmosis and
80% with diffuse pulmonary disease. False-positive results
in other mycoses and nonfungal infections have been rare.
Antigen can also be detected in bronchoalveolar lavage
(BAL) fluid of patients with pulmonary histoplasmosis and
in cerebrospinal fluid (CSF) in those with meningitis.
Antibody response (serology): These tests are useful.
Antibodies measured by ID or complement fixation (CF)
first appear 4 to 8 weeks following exposure and persist for
several years. However, patients who are immunocompromised may not mount an antibody response. For example,
in patients with disseminated histoplasmosis, antibody levels decline slowly in self-limited disease. Several authors
reported that there is no complete recovery from histoplasmosis before a CF titer of 1:8 is reached, despite remission of
the cutaneous lesions.
Polymerase chain reaction: Several molecular biology laboratories offer PCR for diagnosis of histoplasmosis, but the
accuracy of those methods is unclear.

Treatment
Histoplasmosis
Histoplasmosis is a systemic mycosis caused by Histoplasma
capsulatum. It mainly affects the lungs where it is generally
asymptomatic. Histoplasma capsulatum is a saprophyte and

Immunocompromised patients with disseminated histoplasmosis
generally receive IV amphotericin B at a total cumulative dose of
2 g (0.5 to 1 mg/kg/day for 7 days, then 0.8 mg/kg/day). Frequently,
it is necessary to start a concomitant or maintenance treatment,

Deep Fungal Infections — 105

Figure 8.14. Histoplasmosis. A, B, C: hemorrhagic, papular, and ulceronecrotic patterns; D: extensive facial
involvement; E: solitary retroauricular sarcoid lesions.

usually with systemic azolic antifungal drugs. Itraconazole 200 to
300 mg/day or fluconazole 100 to 300 mg/day are considered the
best options. Most cases in immunocompetent patients without
disseminated disease are self-limited and require no treatment.
Blastomycosis (North American Blastomycosis)
Blastomycosis is caused by infection with the dimorphic fungus
Blastomyces dermatitidis. Like histoplasmosis and coccidioidomycosis, this disease occurs most commonly in defined geographic
regions (endemic mycosis). In North America, blastomycosis
usually occurs in the southeastern and south central states that
border the Mississippi and Ohio Rivers, the mid-western states
and Canadian provinces bordering the Great Lakes, and a small
area of New York and Canada adjacent to the St. Lawrence River.
Within these regions of endemicity, several studies have documented the presence of areas of hyperendemicity where the rate
of blastomycosis is unusually high. Point-source outbreaks have
been associated with occupational and recreational activities,
frequently along streams or rivers, which result in exposure to
moist soil enriched with decaying vegetation.
Primary infection initially involves the lungs with hematogenous dissemination to extrapulmonary sites such as the skin
even if the pulmonary nidus is not apparent.
The clinical spectrum of blastomycosis is varied, including
asymptomatic infection, acute or chronic pneumonia, and
disseminated disease. Asymptomatic infection occurs in at least
50% of infected persons. The incubation period is 30 to 45 days.
Acute pulmonary blastomycosis mimics influenza or bacterial pneumonia. Spontaneous cures of symptomatic acute

infections do occur. Most patients diagnosed with blastomycosis have an indolent onset of chronic pneumonia indistinguishable from tuberculosis, other fungal infections, and
cancer.
In rare cases, cutaneous inoculation with B. dermatitidis
can cause a syndrome of cutaneous inoculation blastomycosis.
Criteria for diagnosis have included skin lesions often with focal
lymphadenopathy or lymphangitis, a history of inoculation with
material known or likely to contain the organisms, no evidence
of systemic involvement (before, during, or after presentation),
and recovery of organisms from specimens of skin lesions or
lymph nodes by means of culture or direct smear.
Diagnosis
•

•

•

Definitive diagnosis requires the growth of B. dermatitidis
from a clinical specimen. Visualization of the characteristic
budding yeast form in clinical specimens supports a presumptive diagnosis of blastomycosis and may prompt the
initiation of antifungal therapy. Serological tests are generally not helpful for diagnosing blastomycosis.
Antigen detection: The sensitivity is 93% overall and 89%
in disseminated disease. Sensitivity is somewhat higher in
urine than in serum, and antigen also can be detected with
high sensitivity (~ 80%) in BAL and CSF.
Serology is not useful.

Treatment
Intravenous amphotericin B, in cumulative doses of >1 g, has
been described to result in cure without relapse in 70% to 91%

106 — Evandro Ararigbóia Rivitti and Paulo Ricardo Criado

of cases. Overwhelming pulmonary disease is the most common
cause of death. Increased mortality rates have been associated
with advanced age, chronic obstructive pulmonary disease, and
cancer. Ketoconazole was the first azole shown to be an effective
alternative. Ketoconazole must be used at a dosage of ≥400 mg/
day. Itraconazole is more readily absorbed, has enhanced antimycotic activity, and is better tolerated. Itraconazole dosage is
200 to 400 mg/day.

Coccidioidomycosis
Paracoccidioidomycosis (South American
Blastomycosis)
Paracoccidioidomycosis
(Pbmycosis,
South
American
Blastomycosis, formerly termed Lutz-Splendore-Almeida disease) is a chronic, progressive, and insidious systemic mycosis
caused by Paracoccidioides brasiliensis, a fungus found in the
soil of certain areas of Latin America, from Mexico in the north
to Argentina in the south, but mainly between latitudes 23° to
34°, altitudes between 150 meters and 2,000 meters, and pluviometric indices between 100 and 400 cm/year (see Chapter 10).
Its precise natural history is incompletely understood. In Latin
America, Antilleans and Chile are the only countries where this
disease is not found. Adolpho Lutz first described the disease in a
patient from Sao Paulo, Brazil, and Almeida proposed the name
of the species in 1930. Naturally acquired animal infection has
been demonstrated only in armadillos (Dasiypus novemcinctus).
Bats and saguis (small monkeys from the southeastern forest of
Brazil) are possible natural reservoirs. Dogs, cattle, and horses
also have antibodies against P. brasiliensis. It is possible that the
normal habitat of the fungus is the soil or the plants that grow
in these specific geographic regions, and both animals and men
acquire the pathogen by aspiration. The forms of inoculation in
several tissues are demonstrated in Table 8.3.
Non-autochthonous cases have been reported outside the
endemic areas. All of these patients have either lived in or visited
Latin America at least once. Therefore, Pbmycosis can be considered a traveler’s disease. Unapparent subclinical infection and
minor lung changes are, however, common in affected areas and
in Europeans and Americans who lived in these areas.
This disease has long periods of latency. Some non-autochthonous infections develop over 30 or more years after the patient
left the endemic region.
The constant movement of people from rural to urban areas
and an increase in the average life span will certainly contribute
to a higher frequency of this disease. The association of systemic
Pbmycosis with pulmonary tuberculosis (Tb) is common.

Table 8.3. Paracoccidioides brasiliensis and Forms
of Inoculation in the Host
Organs

Inoculation form

Oro-pharyngeal mucosa

Direct inoculation

Upper respiratory tract and lungs

Inhalation

Bowel mucosa

Ingestion

Skin

Direct inoculation

Pbmycosis is a chronic granulomatous infectious disease.
It is fundamentally a pulmonary and lymph node infection but
may secondarily disseminate to mucocutaneous sites. Primary
infection starts in the lungs after inhalation of fungal propagules,
which then transform into the pathogenic yeast form. Active
paracoccidioidomycosis is estimated to develop in only 2% of
patients.
The P. brasiliensis virulence orthologs are placed in groups,
based either on their functional or on their structural characteristics. These characteristics include metabolism-, cell wall-, and
detoxification-related genes, as well as secreted factors and other
determinants.
P. brasiliensis expresses some molecules that account for its
ability to evade immunity. P. brasiliensis proteases are potentially
associated with the invasion process. However, it is still uncertain whether these proteases help the fungi cause disease. Cellmediated immune response is the main mechanism of defense
against P. brasiliensis infection. The protective cell-mediated
immune response in Pbmycosis is characterized by the production of cytokines (TNF-α, IL-12 and IFN-γ), which are required
for the activation of macrophages. These same macrophages are
the main defensive cells against P. brasiliensis. In the absence of
such cytokines, such as in susceptible hosts, macrophages serve
as a protected environment in which the fungi can undergo
intracellular replication and disseminate from the lungs to other
organs.
P. brasiliensis is a dimorphic fungus, but in humans it presents only in the yeast form and is usually from 2 to 10 μm
in diameter, even though cells up to 30 μm or more are also
common. The principal characteristic in its parasitic state is
the formation of new yeast by evagination of the mother cell
wall, which resembles a helm. The image seen in scanning
electron microscopy is compared to a “grenade.” The fungus
is a eukaryote, with one or more nuclei and nucleoli. At 19º to
28ºC the fungus develops as a mold and produces slow-growing colonies. The microscopic structures show thin septate
hyphae with chlamydospores, which is the same form found
in nature.
Chlamydospores are the infectious form of the fungus. In
cultures at 37ºC, as well as in tissues and exudates, the fungus
appears as an oval-to-round yeast cell that reproduces by multiple buddings (Fig. 8.15). The “pilot wheel” cell is characteristic
(Fig. 8.15d).
Inhalation is considered the most important route of infection. After inhalation, the chlamydospores transform to the yeast
form in the patient’s body. The primary site of infection, which
is often not apparent, is the lung. A benign and transient pulmonary or oral infection occurs in normal individuals. If the host
becomes immunosuppressed, a reactivation occurs in lungs,
skin, mucous membranes, lymphatics, or the CNS. It is not contagious from person to person because at body temperature the
fungus is in the yeast form.
The clinical manifestations of Pbmycosis are polymorphous.
The forms of Pbmycosis are classified into acute/subacute,
chronic, and residual or sequel forms.
ACUTE/SUBACUTE FORM CHILDHOOD/
JUVENILE TYPE

This form represents 3% to 5% of the Pbmycosis cases and
predominates in children and adolescents. The patients have
involvement of the mononuclear phagocytic system, depressed

Deep Fungal Infections — 107

Figure 8.15. Paracoccidioides brasiliensis. A, B and C: fungus appears as an oval-to-round yeast cell that
reproduces by multiple budding; D: yeast form in tissue with multiple budding and characteristic “pilot wheel”
cell (Gomori-Grocott stain); E: mouse testis with numerous P. brasiliensis (Gomori-Grocott stain, OM 100x).

cellular immunity, and increased antibodies. Both sexes are
equally compromised. This form is characterized by rapid evolution, leaving the patient looking for medical attention 4 to
12 weeks after the onset of infection. Respectively, in order of
frequency, the main manifestations include lymphadenopathy,
gastrointestinal symptoms, hepatosplenomegaly, osteoarticular
involvement, and cutaneous lesions. In the subacute form there
is a maintained general state of lymphadenopathy. In the acute
form the patient complains of a deteriorated general state, and
several internal organs are involved, principally the liver, spleen,
and bone marrow, among others.
C H R O N I C F O R M  A D U LT T Y P E 

This form comprises at least 90% of the patients and affects
patients between 30 to 60 years, usually male patients. The
disease progresses slowly, with a silent course for many years.
It is subclassified into mild, moderate, and severe forms. The
pulmonary symptoms are present in 90% of the patients. This
form is called “unifocal” when the Pbmycosis is restricted to one
organ. The lungs can be the only organ affected in at least 25%
of patients. Frequently, Pbmycosis involves many internal organs
simultaneously (multifocal form). The lungs, oral and/or nasal
mucosa, and skin are most frequently involved in this form.
Direct inoculation of the parasite in both skin and oral
mucous membranes is not common, but can explain some cases
of skin and/or mucosal lesions without lung involvement. A
common habit in Brazilian rural areas, the use of twigs to clean
teeth, is the presumptive cause of these lesions. Conspicuous
lesions of Pbmycosis were found in the gingival mucosa of these

patients, and fungus was collected from apical teeth granulomas.
P. brasiliensis was recovered in the amygdales in the absence of
clinical lesions (occult amigdalitis paracoccidioica). The intestinal mucosa can also be a site of direct inoculation after the accidental ingestion of the fungus. The pulmonary route is the most
important one and is the site of inoculation in more than 96% of
all patients with Pbmycosis.
One half of the patients develop subsequent oral lesions,
often with nasal and pharyngeal ulcers. These ulcerations have a
punctate vascular pattern over a granulomatous base, with clinical features of mulberry-like surface, and are known as stomatitis “moriforme” of Aguiar-Pupo (Fig. 8.16). The stomatitis
progresses to ulcerovegetant crusts (Fig. 8.17a & b), which compromise large areas of the oral cavity, pharynx, larynx, and nasal
cavities. Dysphagia and hoarseness due to laryngeal disease and
destruction of vocal cords can ensue. Perioral crusted and granulomatous plaques are common. Gingival involvement may lead
to tooth loss. In the end stages, the epiglottis and uvula are also
destroyed, the hard palate is perforated, and the lips and tongue
may become involved. These oral manifestations are followed
by massive bilateral cervical lymph node enlargement. Other
lymphoid tissue sites, such as axillary, inguinal, and mesenteric
lymph nodes, also can be affected.
The cutaneous lesions of Pbmycosis can vary from crusted
papules to ulcers (Fig. 8.17c & d), nodules, plaques, and verrucous lesions. Centrofacial localization is typical of Pbmycosis,
and most of the lesions occur through dissemination of the oral
and gingival lesions. Most of the skin lesions, however, are the

108 — Evandro Ararigbóia Rivitti and Paulo Ricardo Criado
R E S I D UA L O R S E Q U E L F O R M

This type of disease is from scarring post treatment. Host response
fungi cause a chronic granulomatous inflammatory process with
resultant fibrosis. There is an elevated level of cytokines such as
TNF-α and TGF-β that promote tissue fibrosis, particularly in the
lungs. Pulmonary fibrosis occurs in at least 50% of the patients
with chronic lung disease and can result in chronic obstructive
lung disease.
Patients with Pbmycosis and AIDS generally present in a
form similar to that of the more severe acute forms of Pbmycosis.
Pbmycosis is seen as an opportunistic infection in patients with
AIDS in endemic regions, however, a greater increase in prevalence is expected. It is possible to use trimethoprim–sulfamethoxazole as a prophylaxis for Pneumocystis carinii pneumonia.
It is also effective against P. brasiliensis, which explains in part
the scarcity of reported cases of systemic Pbmycosis.
Figure 8.16. Paracoccidioidomycosis. A, B, C and D: mucocutaneous involvement with the classical mulberry-like surface that are
known as stomatitis “moriforme” of Aguiar-Pupo. Aguiar-Pupo was
an eminent dermatologist, who described this classical mulberry-like
mucosal surface in Pbmycosis. Aguiar-Pupo was university lecturer
of the Dermatology Department, School of Medicine, Sao Paulo
University, Brazil.

Diagnosis
It is established by visualization of P. brasiliensis upon light
microscopic examination, isolation of the fungus by culture from
biological specimens, and clinical appearance. Material scraped
from the mouth can be stained with PAS or placed in 10% potassium hydroxide.
Detection of gp43 glycoprotein and gp70 polysaccharide in
serum has been reported as a sensitive and specific method for
the diagnosis of paracoccidioidomycosis and for monitoring
therapy. The sensitivity and specificity for detection of gp43 and
gp70 are estimated at 98% to 100%. Both antigens could also be
detected in the CSF, BAL, and urine. Detection of a gp87-kDa
antigen has also been reported but would appear to be less useful because of cross-reactions with other fungi and mycobacteria. Polymerase chain reaction with oligonucleotide primers of
the gp43 antigen has recently been used to detect P. brasiliensis
in sputum. However, whether these methods are available for
routine clinical use is unknown.
•

Figure 8.17. Paracoccidioidomycosis. A and B: ulcerovegetant and
crusts lesions; C and D: ulcerated lesions.

result of hematogenic dissemination of the fungus from the
lungs.
The adrenal glands are affected in 48.2% of Pbmycosis
patients submitted to autopsy. Lesions can affect long bones or
cranial bones in a symmetric pattern. The bone lesions are characterized by osteolytic radiological images or bone destruction,
including articulations. Mesenteric lymph node disease may
cause bowel obstruction and symptoms of an acute abdomen.
The involvement of the central nervous system includes a spectrum of meningitis, meningoencephalitis, subacute or chronic
meningoradiculitis or a combination of any of these. Untreated
Pbmycosis can be fatal owing to the possibility of severe pulmonary fibrosis, central nervous system involvement, or adrenal
disease.

•

Serology: Measurement of the antibody response by ID and
CF is useful for diagnosis of Pbmycosis. The ID test is more
specific than CF but is not quantitative. There are recommendations for quantitative results of ID or other diagnostic
tests for Pbmycosis, for better interpretation of the therapeutic response. This is because the antibodies progressively
decrease with clinical control of the disease. Serologic cure is
probable if the titration of antibodies is negative or the dilution stabilizes at 1:2. Some patients at the time of diagnosis
can demonstrate ID titration below 1:4.
Antigenemia enzyme immunoassay (EIA) methods are more
sensitive but less specific than CF, and standardized methods
are not yet available for the clinical testing. Clearance of antibodies with therapy or spontaneously can be measured by CF.

Treatment
Sulfas are first choice for the treatment of Pbmycosis.
Sulfamethoxazole–trimethoprim (SMZ-TMP) is used in initial doses of 800/160 mg, twice a day for 30 days. Subsequently
400/80 mg (SMZ-TMP) is administrated twice daily for an
undetermined time until cicatrization of the lesions, radiological
regression of the lung images, and a relevant decrease of serologic titers.

Deep Fungal Infections — 109

Amphotericin B has elective indication in severe forms of
Pbmycosis and in patients with hepatic disease. Amphotericin
B is administrated intravenously, drop by drop, into 5% dextrose
solution, over 6 hours. In the first infusion, usually it is used in
doses of 0.25 mg/kg, and if it is well tolerated, then subsequently
it can be increased from 0.5 mg/kg to 1.0 mg/kg/daily or on
alternate days. The total cumulative dose depends on the clinical,
serological, and radiological progression. Usually, mucocutaneous Pbmycosis is cured with total doses of 30 mg/kg, but in the
lymphadenopathy form 60 mg/kg of total dose must be given.
Ketoconazole can be used in a dose of 400 mg/day during
30 days, and then subsequently in a dose of 200 mg/day for 12
to 24 months. Itraconazole is better tolerated and has the same
efficacy as ketoconazole. Itraconazole must be used in a dosage
of 200–400 mg/day, especially for nervous system lesions.

Zygomycosis
The class Zygomycetes is divided into two orders, Mucorales and
Entomophthorales. The term mucormycosis is used to describe
infections caused by the fungus Mucorales. Members of the
order Mucorales are the etiological agents of the disease traditionally known as “mucormycosis.” It is a fulminant disease
with high rates of morbidity and mortality that mainly affects
immunocompromised patients, especially ketoacidotic diabetic
patients. However, species of the order Entomophthorales cause
“entomophoromycosis” and they are responsible for the chronic
subcutaneous disease observed in immunocompetent patients in
tropical and subtropical regions.

Mucormycosis
Mucormycosis, the third invasive mycosis in order of importance after candidiasis and aspergillosis, is a disease that may be
caused by several species of different genera, which are listed in
Table 8.1. Fungi belonging to the order Mucorales fall into six
families (i.e., Mucoraceae, Cunninghamellaceae, Mortierellaceae,
Saksenaceae, Syncephalastraceae and Thamnidaceae). The most
important species in order of frequency are Rhizopus arrhizus
(oryzae), Rhizopus microsporus var. Rhizopodiformis, Rhizomucor
pusillus, Cunninghmaella bertholletiae, Apophysomyces elegans,
and Saksenaea vasiformis.
The incidence of mucormycosis is approximately 1.7 cases
per 1000,000 (1.000.000) inhabitants per year, which corresponds to 500 patients per year in the United States. Postmortem
evaluation for the presence of agents responsible for mucormycosis shows that mucormycosis is ten- to 50-fold less frequent
than candidiasis or aspergillosis. It also reveals that mucormycosis appears in one to five cases per 10,000 autopsies. In patients
undergoing allogenic bone marrow transplantation, the incidence may be 2% to 3%.
The main risk factors for the development of mucormycosis
are ketoacidosis (diabetic or other), iatrogenic immunosuppression, especially when associated with neutropenia and graft versus host disease in hematological patients, use of corticosteroids
or deferoxamine, disruption of mucocutaneous barriers by catheters and other devices, and even exposure to bandages contaminated with these fungi.
Mucorales invade deep tissues via inhalation of airborne
spores, percutaneous inoculation, or ingestion. These fungi

colonize a high number of patients but do not necessarily cause
invasion and disease.
Mucormycosis is very infrequent in immunocompetent
patients.
Mucormycosis may occur after traumatic inoculation, especially in those cases where the inoculation is accompanied by
contamination with water and soil. Mortality in these circumstances fluctuates between 38% and 80%.
Mucormycosis manifests most commonly, respectively, in
the sinuses, lungs, skin, brain, and gastrointestinal tract. After
Aspergillus and Candida infections, Mucorales infections are
the third most common fungal infections seen in patients with
hematologic malignancies.
With the exception of rhinocerebral and cutaneous
mucormycosis, the clinical diagnosis of mucormycosis is
difficult, and is often made at a late stage of the disease or
postmortem.
The number of cases of cutaneous and soft tissue mucormycosis has increased during the last few years. This condition can
occur on problem-free skin or follow the rupture of barriers,
(i.e., through surgery, trauma, or burns). Sometimes, the infection begins at catheter insertion sites or even after insect bites. It
has also been described after the use of contaminated dressings
and intramuscular injections.
Most patients with cutaneous mucormycosis have underlying conditions such as diabetes mellitus, solid organ transplants,
or leukemia.
There are three clinical patterns of presentation of mucormycosis infection:
(i) Cutaneous infection: This is rare and characterized by the
development of erythematous and edematous lesions or
papular and nodular lesions, which originate as necrotic
vesicobullous or ulcerated lesions (Fig. 8.18). The fungus
is an exogenous agent inoculated by trauma or it can be
an endogenous agent coming from a visceral focus. The
clinical manifestations range from pustules or vesicles to
wounds with wide necrotic zones. Mucromycoses are characterized by particularly necrotic skin lesions due to the
angiocentric nature of these microorganisms. In their early
stages, lesions may be similar to those present in ecthyma
gangrenosum. In extensive lesions, a cotton-like growth
may be observed over the surface of the tissues, a clinical
sign known as “hairy pus.” Rapid diagnosis of cutaneous
mucormycosis may explain the lower rate of associated
mortality.
(ii) Rhinosinus mucormycosis: The acute infection is dramatic.
At the onset the sinuses or palate are involved with progressive invasion of the orbit or brain tissues. There is invasion
of the nose, orbit, and later, the secondary invasion of the
intracranial structures. This form of infection is involved in
33% to 50% of all cases of mucormycosis. The most frequent
underlying conditions associated are ketoacidotic diabetes
mellitus, and leukemia. Patients that are solid organ or
hematopoietic stem cell recipients and patients with HIV
infection are also more frequently affected.
(iii) Systemic infection: Fatigue and general symptoms are seen,
including weight loss. The infection can disseminate to the
lungs or gastrointestinal system, causing organ-specific
symptoms.

110 — Evandro Ararigbóia Rivitti and Paulo Ricardo Criado

Tests using cultures of clinical samples have limited sensitivity.
Specimens should be cut into small fragments before plating.
The presence of wide, nonseptate hyphae in culture or on slides
should always be interpreted with care, as they may represent colonization. Histopathological testing does not indicate the genus
and species, and should therefore be complemented with culture.
Perineural invasion, angioinvasion, and infarction are common
histologic findings in Mucorales infections. Histological invasion,
particularly of vessels, by wide, nonseptate hyphae branched at
right angles is diagnostic in the appropriate clinical context.

Table 8.4: Different Genera of Mucormycetes and Species
Family

Entomophthoromycosis
For this fungus, the general health state of the patient is not compromised, and it is defined as a chronic disease generally localized tithe subcutaneous tissue or the nasal submucosa.
Usually, the disease consists of two entities, basidiobolomycosis and conidiobolomycosis, which are both capable of
inducing chronic subcutaneous granulomatous infections that
are histopathologically similar but clinically and mycologically
different.
Entomophthorales organisms are aerobic and grow in most
culture media after 2 to 5 days of inoculation and at temperatures of 25°C to 37°C whereas Mucorales organisms typically
show growth at 55°C. Entomophthorales (genera Conidiobolus

Species

Cunninghamellaceae

Cunninghamella

Mortierellaceae

Mortierella

Saksenaceae

Saksenaea

S. vasiformis

Syncephalastraceae

Syncephalastrum

S. racemosum

Mucoraceae

Absidia

A. corymbifera

Apophysomyces

A. elegans

Mucor

M. circinelloides

Treatment
Mucormycosis requires a rapid diagnosis, correction of predisposing factors, surgical resection, debridement, and appropriate
antifungal therapy. Some studies have 50% of cases diagnosed
postmortem. Predisposing factors that could be addressed
include diabetic ketoacidosis, corticosteroids and deferoxamine.
Rapid and complete surgery, if possible, is the best treatment
for mucormycosis. In fact, partial resection of necrotic tissue is
better than none at all, although this is easier in the cutaneous
and rhinocerebral forms than in the visceral forms. Pulmonary
and disseminated disease in neutropenic patients is impossible to operate on in many cases. Surgery combined with the
use of antifungal drugs is always better than antifungal therapy
alone. Current data, although indirect, points to high-dose liposomal amphotericin B as the therapy of choice for this condition. Liposomal amphotericin B is better tolerated and has a
lower toxicity. Itraconazole, despite its in vitro activity against
Mucorales and its success in a few clinical cases, is considered an
inappropriate therapy choice.
Voriconazole is not active in vitro against Mucorales and
fails when used in vivo. Posaconazole and ravuconazole have
good activity in vitro and, in animal models. Posaconazole has
proven to be superior to itraconazole but less effective than
amphotericin B deoxycholate. Recent studies indicate that use of
posaconazole is effective in clinical failures with amphotericin B
and other treatments. Currently, it is the most promising therapeutic alternative to amphotericin B. Some authors consider
that further studies should be done to determine the potential
role of caspofungin in mucormycosis, as there may be a synergy
between caspofungin and amphotericin B lipid complex.
Cytokines such as γ-interferon or granulocyte–macrophage
colony-stimulating factor (GM-CSF) have also been used to treat
mucormycosis (Table 8.4).

Genus

C. bertholletiae

M. hiemalis
M. racemosus
M. ramosissimus
M. rouxianus
Rhizopus

R. pusillus
R. arrhizus

Thamnidaceae

Cokeromyces

C. recurvatus

coronatus and Basidiobolus ranarum) infect primarily immunocompetent individuals and produce chronic, generally indolent,
cutaneous, nasal, or sinus disease.
Basidiobolomycosis is caused by Basidiobolus ranarum and
is also called subcutaneous phycomycosis, subcutaneous zygomycosis, or entomophthoromycosis basidiobolae. This fungus is
usually detected in the intestinal tube of toads, frogs, lizards, and
in the insect class.
Conidiobolomycosis is due to Conidiobolus coronatus and is
also called rhinoentomophthoromycosis, rhinophycomycosis, or
rhinophycomycosis entomophthorae. This agent is found in soil,
often in the presence of decomposing plant matter.
There are three clinical forms: subcutaneous, centrofacial,
and visceral. The agents are soil, saprophytic fungi, organisms
found in animal feces, saprophytes or parasites of insects and
small animals.
(i) The subcutaneous form of infection is caused by
Basidiobolus haptosporus, a soil saprophytic fungus. Through
cutaneous trauma, the parasite is inoculated in the skin and subcutaneous infection occurs. It can involve the adjacent structures,
such as muscles or bones, and disseminate to internal organs by
contiguity or hematogenous dissemination. Basidiobolus ranarum typically causes a chronic infection of the peripheral or subcutaneous tissue, generally on the arms, trunk, and buttocks. It
is usually acquired by traumatic implantation. The disease slowly
evolutes after months or years.
(ii) The centrofacial form of infection, named rhinophycomycosis, is caused by Conidiobolus coronatus. This fungus reaches
the nasal mucosa by inhalation or trauma. This form of entomophthoromycosis occurs in adults and rarely in children. The
clinical manifestations include nasal obstruction, rhinitis, and
epistaxis. On physical examination, there are enanthems of the
mucosa, edema, and polypoid or nodular lesions in the nasal
cavity. The patients develop cutaneous edema and progressive

Deep Fungal Infections — 111

infiltration in the centrofacial region. The infection progresses to
involve the nasopharynx, oropharynx, palate, larynx, and sometimes the blood stream.
(iii) The visceral form is rare, can occur in adults and children, and the symptoms are related to the organ involved. The
visceral form is usually caused by Conidiobolus incongruns that
infects the host via inhalation or trauma.
Because Entomophthorales organisms are ubiquitous and may
be laboratory contaminants, diagnosis should be verified by histological demonstration of organisms in affected tissues. The fungus is difficult to isolate in culture, with an 85% rate of negative
cultures having been reported in several international papers.
Entomophthorales infections are characterized by a mixed
granulomatous inflammatory infiltrate with eosinophils, histiocytes, neutrophils, plasma cells, and giant cells. In addition,
hyphal elements may be surrounded by a dense eosinophilic
sleeve-like material. A polymerase chain reaction (PCR) assay
has recently been developed and may be useful in cases in where
the diagnosis is suspected but histology and culture findings are
negative.
Treatment
Potassium iodide has been the traditional drug employed in the
treatment, although several other drugs, such as amphotericin B,
cotrimoxazole, ketoconazole, itraconazole, and fluconazole have
been successfully tried. A combination of amphotericin B and
terbinafine has been reported. Treatment also includes aggressive surgical debridement and control of underlying risk factors.
Treatment failures with amphotericin B have been reported, and
itraconazole may be preferred as a first-line agent at a dose of
200–400 mg/day.

Cryptococcosis
Cryptococcosis is a fungal infection caused by two varieties of
Cryptococcus neoformans, with five serotypes. According to
some researchers, C. neoformans var. grubii represents strains
of serotype A, var. neoformans represents strains of serotypes D
and AD, and var. gattii represents strains of serotypes B and C.
Based on sequential analysis of intergenic rDNA spaces, Diaz et
al. consider two pathogenic varieties: C. neoformans (serotypes
A, D and AD) and Cryptococcus bacillisporus (serotypes B and
C). The latter corresponds to C. neoformans var. gattii.
Cryptococcus neoformans is a dimorphic fungus, frequently
recovered from pigeon droppings and nesting places, soil, and
dust. Immunosuppressed individuals – such as those with HIV
(most common risk factor) or malignancies, those receiving
immunosuppressive medication after organ transplantation, or
those with connective tissue diseases such as systemic lupus erythematosus – are at an increased risk for developing cryptococcosis after exposure. Interestingly, individuals who work with
pigeons are not at an increased risk for this disease.
Cryptococcosis is the most common systemic mycotic
infection in AIDS patients, affecting 3% to 7% of this population. It occurs in 6% to 13% of patients with AIDS, when their
CD4 lymphocyte count is below 200/mm3. Cryptococcosis at
other sites follows dissemination from the lungs. Cryptococcal
meningitis is the most common condition. Cutaneous involvement and other conditions like endophthalmitis, chorioretinitis

(Fig. 8.19e), conjunctivitis, sinusitis, myocarditis, pericarditis,
endocarditis, gastroduodenitis, hepatitis, cholecystitis, peritonitis, renal abscesses, adrenal involvement, arthritis, osteomyelitis,
lymphadenitis, and breast masses have also been reported.
When the host is immunocompromised, C. neoformans
cells try to escape the defenses of the organism by producing
sialic acid, capsulated polysaccharides, melanin, mannitol, and
phospholipase. In contrast, in immunocompetent hosts, the
mechanisms of pathogenicity have not been carefully clarified.
In cryptococcosis, melanin seems to interfere with the virulence
of the yeast, with great tropism for the central nervous system,
which is rich in catecholamines.
Clinically, cryptococcosis manifests as primary cutaneous
and disseminated systemic disease (Fig. 8.19). Primary cutaneous cryptococcosis occurs through direct infection from an
object contaminated with Cryptococcus. This rare presentation
manifests as a single lesion at the site of infection; it usually clears
without systemic therapy. Cutaneous disease, which affects
10% to 20% of patients, may also appear as a result of disseminated cryptococcosis. The lesions vary greatly in morphology.
Cutaneous cryptococcosis in its generalized forms, especially in
patients with AIDS, presents with multiple lesions, most of them
simulating molluscum contagiosum. Acneiform, nodular or herpetiform lesions, or cellulitis also occur. Cutaneous cryptococcosis is three times more likely to occur in men than in women,
possibly because of the protective effects of estrogen.
Disseminated cryptococcosis begins as an infection in the
respiratory tract that spreads hematogenously from the primary pulmonary site to the skin, prostate, liver, kidneys, bone,
and peritoneum. Disseminated Cryptococcus is more common
in AIDS and renal transplant patients but may occasionally
occur in patients with hematologic malignancies. Cutaneous
signs may be the first indication of infection, sometimes preceding the diagnosis of disseminated cryptococcosis by 2
to 8 months. Recognizing cutaneous lesions is important in
preventing the severe neurologic sequela of cryptococcosis.
Lesions mostly appear on the head and neck, first as painless
papules or pustules, then later develop into nodules that ulcerate and ooze purulent material. Vasculitic lesions presenting

Figure 8.18. Cutaneous mucormycosis. A: ulcerative and destructive
lesion on leg; B: Mucor (microcultive).

112 — Evandro Ararigbóia Rivitti and Paulo Ricardo Criado

Figure 8.19. Cryptococcosis. A, B, C, D: extensive cutaneous lesions in a immunosuppressed patient;
E: chorioretinitis (lesions on retina).

as palpable purpura; eczematous, follicular, or purple papules; nodules; and plaques that resemble Kaposi sarcoma may
appear as well. Secondary osteomyelitis may develop; draining
sinuses may form as a result of subsequent growth to overlying
skin. The mortality of untrearted disseminated cryptococcosis
is 70% to 80%.
Diagnosis
•

•

Direct examination and culture: Skin biopsy reveals plenty
of budding yeast cells with demarcated capsules of 5 to 10
mm in size by India ink preparation (IIP) and Gram staining.
Specimens are inoculated on Sabouraud dextrose agar (SDA)
and incubated at 37°C and room temperature (RT). On SDA,
creamy flat, shiny, moist mucoid colonies grow with smooth
edges. Luxuriant growth on SDA at RT are observed in 2
days.
Antigen detection: Detection of capsular polysaccharide by
latex agglutination (LA) using a variety of U.S. Food and
Drug Administration (FDA)-cleared test kits is a most useful
method for rapid diagnosis of cryptococcal meningitis, and is
positive in about 90% of cases. Antigen also can be detected
in serum, especially in patients with AIDS. Antigenemia may
be seen in patients with pneumonia but then should undergo
prompt evaluation for meningitis or other sites of extrapulmonary dissemination. Antigen may also be detected in BAL
in patients with pneumonia. In most studies, specificity is
above 95%. Causes for false-positive results include rheumatoid factor, antiidiotype antibodies, infection with crossreactive organisms (Trichosporon asahiii, Capnocytophaga

•

canimorsus), contaminated agar, use of disinfectants or soaps
to wash ring slides, and defective test kits.
Antibody response: This plays no meaningful role.

Treatment
Most of the recent information regarding treatment of cryptococcosis has been derived from experience in HIV patients.
The recommended therapy is a 2-week course of amphoterecin
B 0.7 mg/kg/day plus flucytosine 100 mg/kg/day followed by 8
weeks of fluconazole 400 mg/day. Fluconazole at higher doses
(400–800 mg/day), alone or in combination with flucytosine,
has been used successfully. Although it has been suggested
that immunocompromised patients should receive suppressive therapy with low-dose fluconazole (200 mg/day) until
recovery of their host defenses, it is uncertain whether this is
necessary.

Phaeohyphomycosis
Phaeohyphomycosis encompasses distinct mycotic infections
regardless of the site of the lesion, of the pattern of tissue
response, or of the taxonomic classification of the etiologic agents.
Subcutaneous phaeohyphomycosis (Fig. 8.20a & b), improperly
named phaeohyphomycotic cyst, is the most common presentation and also includes cases with dermal involvement. Patients
are usually adults, and some of them are immunologically
compromised with associated underlying diseases or locally compromised because of the application of topical corticosteroids.

Deep Fungal Infections — 113

Figure 8.20. Phaeohyphomycosis and Hyalohyphomycosis. A and
B: subcutaneous phaeohyphomycosis; C: hyalohyphomycosis due to
Fusarium spp. Purpuric lesions on the thigh in a patient with severe
neutropenia secondary to leukemia.

Isolation and identification of the causative organisms is very
important because of variable sensitivity to therapeutic agents.
Because of the increasing number of immunocompromised
patients, the number of fungi causing subcutaneous phaeohyphomycosis has been increasing. Among them, members of the
genera Alternaria, Bipolaris, Curvularia, Exophiala, Phialophora,
and Wangiella are the most common species. Despite the morphological differences among species, the illnesses they produce
have common features. Subcutaneous phaeohyphomycosis has
occurred with equal frequency in tropical, subtropical, and temperate areas.
Subcutaneous phaeohyphomycosis lesions occur often on
exposed body parts and especially on the upper arms. Inoculation
of the agent is considered to be caused by wounds made by contaminated plant materials. The spectrum of clinical presentation
is broad, ranging from well-localized cysts to aggressive infections that invade surrounding tissue. The most common and
typical lesions are subcutaneous cysts or abscesses at the site of
trauma, frequently caused by Exophiala jeanselmei. The primary
lesion occurs as an asymptomatic, small, palpable nodule. The
nodule gradually evolves to become an encapsulated, fluctuant
abscess with a liquefied center. Occasionally, a granulomatous
elevated plaque may also appear. Less frequently, it is manifested
as a verrucous nodule or a diffuse extensive infiltration simulating borderline leprosy.
Cutaneous disease may persist for months or years.
Immunocompromised patients often present with multiple
lesions. Lymph node involvement and dissemination are rare.
However, systemic phaeohyphomycosis may occur from the
subcutaneous infections in immunocompromised patients.

Hyalohyphomycosis
The great increase in the immunosuppressed patient population
has been accompanied by an increasing list of fungal opportunistic infections. The underlying diseases and the intensive

immunosuppressive, antineoplastic, antibiotic, and corticosteroid treatments all contribute.
Ajello and McGinnis proposed the name “hyalohyphomycosis” to accommodate mycotic infections in which the etiologic
agent’s tissue form is septate hyphae with no pigment in the wall
and is characterized by hyaline hyphae in tissue.
Hyalohyphomycosis generally occurs in patients with severe
underlying systemic disorders such as leukemia, lymphoma, systemic lupus erythematosus, or diabetes mellitus. The skin is one
of the most common organs involved, and regional lymph nodes
are also often affected. Occasionally, the etiologic fungi invade
the blood vessels and evoke fungemia.
Dissemination of hyalohyphomycosis occurs more often
than with phaeohyphomycosis. Acremonium spp., Fusarium
spp., Paecilomyces spp., Penicillium spp., Scopulariopsis spp. and
Trichoderma spp. are known to be common causative organisms,
whereas Pseudallescheria boydii is less prevalent. Histologically,
it may be impossible to differentiate between these organisms
based on morphology alone. Definitive identification of the causative organism is needed for effective treatment. In one review
of disseminated Fusarium infections, for example, the skin was
the nidus of infection in 33% of patients. Hematogenous dissemination from primary skin infections generally occurs only
in very neutropenic patients and carries a high risk of mortality
(Fig. 8.20c). In hyalohyphomycosis, thrombotic phenomenon
with local invasion is common, and the majority of organisms
show some sensitivity to amphotericin B.
Species of the genus Fusarium are usually plant saprophytes
and pathogens, known by dermatologists as skin contaminants.
Occasionally, however, these organisms may cause disease in
man. Fusarium species have long been known as rapidly destructive agents in infections of the cornea, burned skin, and subcutaneous lesions following trauma, mainly in immunocompromised
patients. The species is almost always Fusarium solani.
Treatment
It consists of antifungal medications and surgical debridement.
The therapy varies depending on the etiological agent and the
clinical state of the patient. P. boydii is often resistant to amphotericin B. In most cases, miconazole has shown the best in vitro
activity against P. boydii. Hyalohyphomycosis caused by Fusarium
spp. is frequently refractory to antifungal therapy, particularly
in granulocytopenic patients, and restoration of host defense is
essential in order for treatment to be effective. Fusarium dissemination occurs and progresses in spite of amphotericin B therapy.
Nowadays, voriconazole associated with amphoterecin B has
been successful in these cases.
Voriconazole maintains the general properties of the azoles.
However, it has a more pronounced blockage of ergosterol
synthesis in the filamentous fungi, for which it acts as a fungicide. It has a more intense in vitro effect than itraconazole on
Aspergillus species, including A. terreus, which is commonly
resistant to amphotericin B. It is effective against many species
of Fusarium, Paecilomyces, Alternaria, and Bipolaris, as well as
against Scedosporium apiospermum and P. boydii.
Voriconazole is administered orally or intravenously in a
dosage of 6 mg/kg of body weight every 12 hours on the first day
and 4 mg/kg of body weight every 12 hours thereafter. Adults
receive oral doses of 200 mg (in tablet form) every 12 hours

114 — Evandro Ararigbóia Rivitti and Paulo Ricardo Criado

(100 mg every 12 hours for patients weighing less than 40 kg),
which makes it possible to reach a maximum serum concentration of 4 to 6 µg/mL in a state of equilibrium. Absorption does
not depend on gastric acidity, and the bioavailability of the oral
drug is good. Voriconazole reaches levels inhibitory for fungi
in the encephalon and in the cerebrospinal fluid. Because it is
metabolized and excreted by the liver, it is necessary to adjust the
dosage or avoid its use in cases of hepatic insufficiency. In cases
of moderate to severe renal insufficiency, intravenous administration is contraindicated because of the risk of accumulation of
the vehicle cyclodextrin.

OTHER OPPORTUNISTIC DEEP
C U TA N E O U S F U N G A L I N F E C T I O N S

Occasionally, the opportunistic fungi may also cause a variety of
other skin lesions such as subcutaneous nodules, abscesses, and
folliculitis. There are no pathognomonic features of these skin
lesions, and identification of the causative organisms requires tissue biopsy for culture. Primary fungal skin infections may occur
at the cutaneous insertion site of intravenous catheters and at the
sites of contact with arm boards in pediatric patients.
Most reported cases have involved Aspergillus or Rhizopus
spp. The skin lesion is usually a red plaque, which may be studded with pustules or vesicles. A subsequent eschar often develops within the plaque. Hospitalized neutropenic patients are at
a higher risk of primary cutaneous infections by opportunistic
fungi (especially Aspergillus, Mucor, Rhizopus, and Fusarium
spp.). However, these infections are unusual even in this patient
population. Damage to the epidermis facilitates local skin infection that may be caused by a number of factors: intravenous
catheters directly disrupt the skin, tape and occlusive dressings
may cause maceration, prolonged administration of corticosteroids (e.g., for GVHD) may cause cutaneous atrophy and increase
the risk of skin infection, and patients with chronic cutaneous
GVHD experience a greater number of skin infections (as is seen
in other chronic inflammatory dermatoses such as psoriasis and
atopic dermatitis).
Because Aspergillus, Fusarium, and Rhizopus spp., etc. are
common saprophytes, a positive culture alone is not proof of
infection. A skin biopsy specimen that demonstrates tissue invasion is ideal. Repeated cultures that yield only the suspected fungal pathogen are also suggestive. Primary skin infections caused
by opportunistic fungi may act as a nidus for fungemia and subsequent multiorgan involvement. These occurrences have been
documented in all of the primary skin lesions described earlier
(paronychias, infections under adhesive dressings, etc.).
Regionally endemic pathogenic fungi rarely cause primary
skin infections in cancer patients; most are caused by Histoplasma
or Coccidioides spp. These skin infections can act as a nidus for
dissemination in the neutropenic host. In addition, patients who
were immunocompetent at the time of initial skin infection,
and who have residual skin lesions, may experience reactivation
when immunosuppression occurs.
When treating patients with a combination of two or more
antifungal agents, except under certain conditions, care must
be taken to avoid the possibility of antagonism between the
drugs. The combination of amphotericin B and 5-fluorocytosine
presents synergy and is the initial treatment for cryptococcosis

and in certain cases of candidiasis and aspergillosis. The same
effect occurs with fluconazole and 5-fluorocytosine in cryptococcosis and candidiasis. However, the combination of
amphotericin B and azole drugs might result in lower efficacy
than that of amphotericin B in isolated use or, simply, in the
absence of synergism. In general, the combined use of itraconazole or other azoles and amphotericin B is avoided, and,
if possible, the use of amphotericin B in sequence to a therapeutic course of itraconazole or other azoles is also avoided.
Terbinafine, echinocandins, and voriconazole are being investigated in sequence with one another and with traditional
antifungal agents in infections produced in animals, as well as,
experimentally, in patients with severe fungal infections. The
results have varied, and it has not yet been possible to clearly
make other associations with the synergistic effect on the efficacy of antifungal agents.
In Table 8.5, we summarize the antifungal therapies for adults
with disseminated or systemic deep fungal diseases.

P I T FA L L S A N D M Y T H S

Mycotic infections are common and their incidence is increasing. Fungal infections are typically diagnosed by culture, serology, or histopathology. They can be difficult to distinguish from
other infections, particularly tuberculosis, but there are numerous clinical clues that can help suggest the presence of systemic
mycoses. Intradermal tests, serologic tests, and agent isolation
can aid in the confirmation of a fungal infection. Diagnosis of
deep fungal infections is not straightforward. Definitive diagnosis requires the demonstration of fungi in tissue specimens
obtained by biopsy together with a positive culture. Modern
molecular techniques are promising, including PCR that is being
developed to help with rapid diagnosis of deep fungal infections,
since they have higher specificity and sensitivity, particularly
with the use of DNA probes.
There are two medical scenarios that represent a challenge
to definitive diagnosis on deep fungal infections: (i) the presence of the “verrucous cutaneous syndrome,” and/or (ii) the histopathological descriptive diagnosis of pseudoepitheliomatous
and granulomatous dermatitis without an identifiable infectious
agent.
The verrucous cutaneous syndrome is known by the acronym
“LECT,” Leishmaniasis, Esporotricose (Portuguese) (Sporotrichosis, English), Chromomycosis, Tuberculosis, which are infectious diseases that can present like verrucous cutaneous lesions.
The specific intradermal tests, cultures of skin fragments obtained
by biopsies, and serology studies can help in definitive diagnosis.
The presence of pseudoepitheliomatous hyperplasia (PH)
with dermal and/or subcutaneous granuloma is another challenge in the diagnosis of deep fungal disease. PH is a histopathological reaction that is characterized by a downward
proliferation of the epidermis, which may suggest a squamous
cell carcinoma. These lesions show an epithelial hyperplasia
that includes an irregular invasion of the dermis by uneven and
jagged epidermal masses. By strict criteria, this process also
involves the epithelium of adnexal structures after they undergo
squamous metaplasia. PH occurs secondary to a wide range of
stimuli, most notably, a chronic inflammatory process (i.e., deep
fungal diseases).

Deep Fungal Infections — 115

Table 8.5: Summary of Treatment Options in Deep Fungal Diseases
Fungal disease/Clinical form

First-Choice Therapy

Alternative Therapy

PARACOCCIDIOIDOMYCOSIS Lungs, oral
or laryngeal mucosa

Itra (400 mg/day; 6–18 months*) or SMZTMP (2400–480 mg/day or 1600–320 mg/
day; 12–24 months*)

Keto (400 mg/day) Fluco (400 mg/day)

Disseminated, severe cases

Amph B-d (total dose 30–60 mg/kg)
followed by Itra (400 mg/day; 6–12 months)

Itra, Keto, Fluco

CRYPTOCOCCOSIS Pleuropulmonary
localized, in patients without
immunosuppression

Fluco (200–400 mg/day; 3–12 months)

Amph B-d (total dose: 20–35 mg/kg)

Disseminated, meningitis or
immunosuppression

Amph B-d: 0.7–1.0 mg/kg/day plus 5-FC
(100 mg/kg/day: 2 weeks), followed by
Fluco (400–800 mg/day; 10 weeks) followed
by Fluco (200 mg/day; ≥ 6 months)

Amph B-d (total dose: >35 mg/kg) followed
by Fluco (200 mg/day during > 6 months)

COCCIDIOIDOMYCOSIS Pulmonary acute
diffuse

Amph B-d (total dose: 20–35 mg/kg)

Itra, Keto, Fluco

Disseminated

Itra (400 mg/day; ≥ 12 months)

Pulmonary, chronic fibrous-cavitary disease

Itra (400 mg/day; ≥ 12 months)

Keto (400 mg/day); Fluco (400 mg/day);
Amph B-d

HISTOPLASMOSIS Pulmonary, acute, severe
or prolonged disease

Itra (400 mg/day; 6–12 weeks)

Amph B-d (total dose: 20 mg/kg) followed
by Itra (400mg/day; 12 weeks)

Pulmonary chronic; mild disseminated

Itra (400 mg/day; 12–24 months)

Amph B-d (total dose: 20–35 mg/kg)
followed by Itra (400 mg/day; 12–24
months)

Disseminated and severe or
immunosuppressed patients

Amph B-d (total dose: > 35 mg/kg)
followed by Itra (400 mg/day; ≥ 24 months)

Itra (400–600 mg/day)

SPOROTRICHOSIS Cutaneous-lymphatic

Potassium iodide (KI) 4–6 g/day during 2–3
months

Itra (100–400 mg/day)

Pulmonary, disseminated

Amph B-d (total dose 500–1000 mg) or Itra
(400 mg/day; 3–6 months)

Itra (400–600 mg/day; 6–12 months)

ZYGO (MURCOMYCOSIS) Pulmonary,
invasive, disseminated

Amph B-d (total dose > 35 mg/kg)

Amph B-l

PHAEOHYPHOMYCOSIS pulmonary/
systemic (Bipolaris, Exophiala, Exserohilium,
Phialophora, Wangiella ssp, etc)

Amph B-d (total dose > 35 mg/kg) and / or
Vorico 400 mg/day, intravenous

Amph B-l; Itra (400–600 mg/day)

HYALOHYPHOMYCOSIS pulmonary/
systemic (Acremonium, Paecylomices,
Scopulariopsis spp, etc)

Amph B-d (total dose > 35 mg/kg) and / or
Vorico 400 mg/day, intravenous

Amph B-l; Itra (400–600 mg/day)

FUSARIOSIS pulmonary/invasive/
disseminated

Amph B-d (total dose > 30–35 mg/kg) and /
or Vorico 400 mg/day, intravenous

Amph B-l

NEUTROPENIC patients with persistent
fever

Amph B-d or Amph B-l

Itra, Fluco, Vorico or Caspo

SMZ-TMP, sulfamethoxazole–trimethoprim; Amph B, amphotericin B desoxycholate – conventional preparation; Amph B-l,
amphotericin B in lipid formulations: L-Amph, liposomal / Cd-Amph B, coloidal dispersion/Lc Ampho b, lipid complex; Keto,
Ketoconazole; Itra, Itraconazole; Fluco, Fluconazole; Vorico, Voriconazole; Caspo, Caspofungin;* Variable period of treatment,
according to case severity.

Neither histopathology pattern is specific of the mycosis
because deep fungal infections are able to induce a varied spectrum of inflammatory lesions. So it is very important to evaluate the immunological status of the patient, which in many cases
is diminished, because the mycoses are much more frequent

in immunodeficient patients. So for an infection to take place,
there must exist a series of factors that favor it. Examples of
these factors include the immunity of the guest, the virulence,
the amount of fungal cells, and the coexistence of other diseases.
The first response that the organism produces is a suppurative

116 — Evandro Ararigbóia Rivitti and Paulo Ricardo Criado

inflammation by the infiltrates of polymorphonuclear cells.
Later, a response of mononuclear cells and, if it evolves, epithelioid macrophage cells and multinuclear giant cells, can give rise
to a chronic infection and to fibrosis. Nevertheless, all this can
be attenuated if the patient suffers from an immunosuppressive disease or is undergoing immunosuppressive therapy. The
most characteristic histopathology finding is the granuloma
lesion with multinucleated giant cells, stimulated by the cellular
immune response.
The pathologist can observe the fungi with two basic morphologies. The first is with a tubular form or hyphae (multicellular) and the second with an oval form corresponds with the
spores or conidia (unicellular). Also, these forms, may or may
not be pigmented.
The pathologist can identify and diagnose infections by fungi
classified into one of the four groups: dimorphic fungus, classic
pathogens, opportunists, and others.
The ubiquitous dematiaceous fungi can be contaminants
in cultures, making the determination of clinical significance
problematic. A high degree of clinical suspicion as well as correlation with appropriate clinical findings is required when
interpreting culture results. Unfortunately, there are no simple
serological or antigen tests available to detect these fungi in
blood or tissue. PCR is being studied as an aid to the diagnosis
of these fungal infections, but as yet is not widely available or
reliable. However, studies have begun to examine the potential of identifying species within this diverse group of fungi
using PCR of highly conserved regions of ribosomal DNA. The
diagnosis of phaeohyphomycosis currently rests on pathological examination of clinical specimens and careful gross and
microscopic examination of cultures, requiring the expertise of
a mycology reference laboratory. In tissue, they will stain with
the Fontana–Masson stain. Longer than normal staining times
may be required. This can be helpful in distinguishing these
fungi from other species, particularly Aspergillus. In addition,
hyphae typically appear more fragmented in tissue than seen
with Aspergillus, with irregular septate hyphae and beaded,
yeast-like forms.
Deep fungal infections continue to be an important cause
of morbidity and mortality, especially in transplant recipients
and other immunosuppressed patients. The insidious nature and
atypical manifestations of these infections often delay diagnosis
and therapy. In immunosuppressed patients, persistent fever that
does not respond to antibacterial therapy should alert the physician to the possibility of fungal infection.

SUGGESTED READINGS

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Bonifaz A, Cansela R, Novales J, de Oca GM, Navarrete G, Romo J.
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Larone, DH 1995. Medically Important Fungi – A Guide to
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sporotrichosis. An Acad Bras Cienc 2006;78(2):293–308.
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9

PA R A S I T O L O G Y
Francisco G. Bravo and Salim Mohanna

This chapter will cover most of the organisms that directly
or indirectly compromise tissues through human infection.
Although in developed countries they are considered exotic diseases just to be diagnosed in travelers, many of them represent
a major health problem for developing countries around the
world.

H I STORY

Parasites have accompanied mankind since antiquity.
Dracunculiasis is described in the Ebers papyrus from 1500 bc,
and references to this disease are clearly identified in the Bible.
The ancient symbol of medicine, the staff of Asklepios, is believed
by some scholars to also represent the treatment of dracunculaisis which involves slowly extracting the worm by winding it
around a stick. This treatment is still in use to this day. Tenias
were described by the ancient Greeks and are cited by Aristotle
in his History of Animals.
Protozoa have ancient history in human disease annals.
Evidence of Trypanosoma cruzi DNA has been found in mummies from Peru and northern Chile dating from 2000 bc to ad
1400. Old world cutaneous leishmaniasis is described on tablets
in the library of King Ashurbanipal from the 7th century BC. The
famous Arab physician Avicenna already described oriental sore
in the 10th century as Balkh sore. New world leishmaniasis, as
mucocutaneous disease, is clearly represented in ancient Peruvian
pottery from the 5th century. The separation of Old World and
New World Leishmaniasis was a contribution of Gaspar Vianna,
who in 1911 created a new species, Leishmania braziliensis.

P ROTO Z OA

Globalization has changed patterns of protozoal infection with
major implications for world health. The key to the recognition
of protozoal infection is knowledge of epidemiological risk factors such as the parasite’s geographic distribution and the major
modes of clinical presentation.

Leishmaniasis
Leishmaniasis is an infectious process caused by intracellular parasites of the Leishmania genera, belonging to the
Trypanosomatidae family. A particular structure, the kinetoplast,
a unique form of mitochondrial DNA, is characteristic of these
genera. Up to 21 species have been described as pathogenic for
humans. Leishmaniasis is listed among the six most relevant

infectious diseases in the world, with 12 million current cases in
88 countries on five different continents. The disease is transmitted from animal reservoirs, such as dogs and rodents, to humans
by sandflies of the genera Phlebothomus and Lutzomyia; humans
themselves can also be part of the reservoir. Leishmaniasis can
be divided into two broad categories of disease, visceral and
cutaneous. Whereas the visceral forms are mainly seen in India,
Bangladesh, Sudan, Nepal, and Brazil, 90% of cutaneous cases
are seen in Afghanistan, Iran, Saudi Arabia, Syria, Brazil, and
Peru. No predilection for race, sex, or age has been demonstrated, although most cases are seen in adult males between the
ages of 20 and 40 years.
The Leishmania are divided into four groups: tropica, mexicana, braziliensis (viannia), and donovani. The first three are the
cause of cutaneous leishmaniasis whereas Leishmania donovani
is responsible for the visceral forms. The different forms of cutaneous disease are species specific for certain regions in the world.
Cutaneous forms seen in the Middle East are due to Leishmania
tropica, in Central America they are due to Leishmania mexicana, and in South America they are due to Leishmania braziliensis, and Leishmania peruviana. Different names are given to
the disease depending on the geographical location: oriental sore
in Asia, chiclero’s ulcer in Mexico, uta in the Andes, espundia in
the Amazon basin, and pian bois in Northern Brazil. The parasite
exists in two different forms, amastigote and promastigote. The
amastigote, the form commonly seen in human tissue, is nonflagellated, ovoid in shape, and measures 3 to 5 µm in diameter.
Two visible structures can be distinguished on light microscopy,
the nucleus and the kinetoplast. The promastigote is the flagellated form seen in the gut of the sandfly. The conversion from
promastigote to amastigote takes place as the microorganism,
once introduced through the sandfly bite, comes into contact
with human macrophages; this transformation is precipitated by
low ph and lysosomal enzymes.
Regardless of the species involved in the pathogenesis, in
most circumstances the classical elementary lesion for purely
cutaneous leishmaniasis is an ulcer. It is usually round, with
slightly elevated and indurated borders, and with a reddish
base. It is commonly located in areas of the body not covered by
clothing and therefore, exposed to the sandfly bite, such as the
face, neck, and extremities. The lesion itself is painless and tends
to regress spontaneously. Some clinical characteristics based on
geographic distribution are worthy of mention (Table 9.1).
Old World leishmaniasis is caused by Leishmania major,
Leishmania tropica, Leishmania aethiopica, and Leishmania
infantum. Different clinical patterns have been described. The
wet type is associated with L. major and is seen mostly in rural
areas of North Africa as well as in Central and West Asia. It is
117

118 — Francisco G. Bravo and Salim Mohanna

Table 9.1 Leishmaniasis : Geographic Guide and Clinical Manifestations
Complex

Species

Geographic location

Skin lesion

Leishmania tropica

L. tropica

OW: Central and west
Asia, Western India

Cutaneous ulceration, L.
recidivans

Leishmania major

OW:North Africa,
Central and West Asia

Cutaneous ulceration

Leishmania aethiopica

OW: Ethiopia, Kenya

Cutaneous ulceration,
limited MCL, DCL

L. mexicana

NW: Central America

Cutaneous ulceration

Leishmania amazonensis

NW: South America

Cutaneous ulceration,
DCL

Leishmania pifanoi

NW: Venezuela

Cutaneous ulceration,
DCL

L. braziliensis

NW: South and Central
America

Cutaneous ulceration,
MCL

Leishmania peruviana

NW : Peru

Cutaneous ulceration,
more rare MCL

L. panamensis

NW: Central America
and Colombia

Cutaneous ulceration

Leishmania guyanensis

NW: Central America
and Northern Countries
of South America

Cutaneous ulceration,
more rare MCL

L. donovani

OW: India, Kenya, East
Africa

Post kala-azar

Visceral leishmaniasis

Leishmania infantum

OW: Mediterranean
basin, Central and West
Asia

Cutaneous ulceration in
adults

Visceral leishmaniasis in
children

Leishmania chagasi

NW: South America

Papules or nodules

Visceral leishmaniasis

Leishmania mexicana

Leishmania (v)
braziliensis

Leishmania donovani

Internal involvement

Can involve upper airways

OW: Old world; NW: New world; MCL: Mucocutaneous leishmaniasis; DCL: Diffuse cutaneous leishmaniasis

zoonotic, with rodents as the natural reservoir. It has an incubation period of up to 2 months. The lesion is crusty, associated with lymphadenopathy and has a tendency to involute
spontaneously in 2 to 6 months. The dry type, caused by L.
tropica and known as oriental sore, is seen mostly in Central
and West Asia, Western India, Ethiopia, and Kenya. It is urban
anthroponotic, and humans and dogs are the main reservoir.
The incubation period can be as long as 1 year and takes 8 to
12 months to heal. L. infantum, although a cause of visceral
disease in children, is associated with cutaneous disease in
adults. Another type is associated with L. aethiopica. It is seen
in Ethiopia and Kenya, and is usually a single facial ulceration,
and takes up to 5 years to heal. It is known to cause mucosal
involvement by continuity, but never to the extent that is seen
with L. braziliensis infection. Two forms are remarkable for
their chronicity: the lupoid forms seen in the Middle East and
caused by L. tropica and the diffuse cutaneous form described
as lepromatoid or pseudo-lepromatous leishmaniasis caused
by L. aethiopica.
New World leishmaniasis, the type seen in the Americas,
manifests primarily as a skin ulceration. The causal microorganism can belong to two groups: the mexicana group and

the braziliensis (also known as viannia) group. Cases produced by the L. mexicana group predominate in Mexico and
Central America (with a few cases described in the state of
Texas). Cases produced by the L. braziliensis (viannia) group
predominate in South America, from the coastal areas to the
highlands of the Andes, the Amazon forest, and other tropical
river systems. However, the distribution of both groups seems
to overlap, especially in the southern tip of Central America
and the northern regions of South America. The clinical variants include purely cutaneous, mucocutaneous, diffuse, and
visceral leishmaniasis.
The purely cutaneous forms appear 10 to 90 days following
the bite of the vector. The initial papule becomes an ulcer, with
raised borders (Fig. 9.1 and 9.2), although sometimes the lesion
will be a plaque or nodule, even adopting a sarcoidal appearance. Although single lesions predominate, they can be multiple.
They may adopt a sporotrichoid pattern (Fig. 9.3); 10% may have
regional lymphadenopathy. Some lesions will have a verrucous
appearance, similar to tuberculosis verrucosa (Fig. 9.4). The
lesions are distributed in areas exposed to insect bites, including near mucosa. Those locations should be differentiated from
true mucocutaneous lesions, which carry a completely different

Parasitology — 119

Figure 9.1. Cutaneous leishmaniasis, showing the raised borders.

Figure 9.2. Cutaneous leishmaniasis.

Figure 9.3. Cutaneous leishmaniasis, sporotrichoid pattern.

Figure 9.4. Verrucous cutaneous leishmaniasis: can be easily confused
with tuberculosis verrucosa.

prognosis. A classical location for the mexicana complex is on the
ear area, although an identical clinical presentation can be seen
in infection by leishmanias of the braziliensis complex (Fig. 9.5).
Parasites from both groups, mexicana and braziliensis, will produce purely cutaneous lesions. Most of the lesions produced by
the mexicana complex will heal spontaneously and never develop
mucosal involvement. Some species of the braziliensis group,
such as L. (v) peruviana, will follow the same course, whereas
other species such as L. (v) braziliensis and Leishmania (v) panamensis may carry the possibility of progressing to mucocutaneous involvement.
The variety known as mucocutaneous leishmaniasis, which is
caused by several species of the L. braziliensis complex, is characterized by its ability to produce, after a dormant period (months
to years), an ulceration on the mucosa of the nasal septum. This
can progress externally causing infiltration of the nose and upper
lip or mutilating the whole nose and nasolabial area (Fig. 9.6).
It is a consequence of hematogenous dissemination. When the
progression is toward the mucosal side, it may destroy the palate, producing a granulomatous infiltration of the pharynx, the
larynx, and even the upper respiratory airway. In a patient with
the classical presentation of a facial midline destructive lesion
involving the nasal pyramid associated with marked edematous
infiltration of the upper lip, hoarseness will be a sign of laryngeal
involvement.
The diffuse form of leishmaniasis is seen rarely but represents a very particular variant. In the Americas, it is produced
by Leishmania amazonensis of the mexicana group. The patients
seem to lack the capability to react against the microorganism, similar to what is seen in the lepromatous pole of leprosy.
Multiple microorganisms will be seen inside foamy histiocytes.
The clinical expression will consist of multiple large, rarely ulcerated nodules distributed all over the body surface, with nondestructive mucosal involvement.
Visceral disease can be seen in Old World and New World
leishmaniasis. It is caused by leishmanias of the donovani group,
including L. donovani, L. infantum, and L. chagasi. The disease is
systemic, with fever and hepatosplenomegaly as the main manifestations. Involvement of the skin can be seen as papular and

120 — Francisco G. Bravo and Salim Mohanna

Figure 9.5. Cutaneous leishmaniasis caused by Leishmania peruviana,
mimicking chiclero’s ulcer.

Figure 9.6. Mucocutaneous leishmaniasis.

nodular eruptions. The post kala-azar form is very dramatic as the
lesions are quite extensive, ranging from macules to nodules.
In the diagnosis of leishmaniasis it is important to consider
the great similarity of lesions produced by different species of
leishmanias. Thus, the history of either living or traveling to specific geographic areas will be important to establish a most likely
etiological agent. It is quite important to establish the possibility of infection by species with the potential to induce mucocutaneous disease (L. (v) braziliensis and L. (v) panamensis).
This especially applies to patients who acquired the infection
in the Amazonic regions of South America, and in a few countries in Central America. It should be kept in mind that none
of the methods have 100% sensitivity, and it is better to rely on
multiple methods to increase the likeness of a correct diagnosis.
Direct examination, either by smear, or microaspiration is often
used. Staining techniques include Giemsa, H&E, Romnowsky,
and specific immunostaining. Skin biopsy is quite reliable if
multiple organisms are seen (such as in early cases), but not so
helpful when parasites are scarce, especially in old, granulomatous lesions. Where amastigotes can be confused with other
structures, the visualization of the kinetocore seems to be quite
specific. Culturing requires specific medium, such as NNM. The
sensitivity is 40% in mucocutaneous disease but quite high in
visceral disease. Isolation in laboratory animals is cumbersome
but it is an alternative for difficult cases. Intradermal reactions,
such as the Montenegro test are useful, although it requires
some interpretation. Its positivity has diagnostic relevance in

patients not living in endemic areas, but it is not that reliable
in the local residents. Serology testing will include immunofluorescent techniques, direct agglutination, ELISA, latex agglutination, and immunoblotting. The most modern methodology
is based on molecular biology. PCR techniques are considered
quite sensitive and quite specific. The gene targets include 18SrRNA, small subunit rRNA, miniexon gene repeat, β-tubulin
gene, transcriber spacer regions, and microsatellite DNA of the
kinetoplast. PCR testing can detect as little as half a parasite, and
should be the method of choice when available; unfortunately,
that is not the case for most endemic rural areas. In such areas,
sometimes the clinical criterion is enough for a therapeutic trial.
In travelers who are not residents of endemic areas, the diagnosis
should require visualization or isolation of the microorganism or
molecular evidence of infection.
Decision for treatment should be based on the precise definition of the species involved, when identification is possible. Old
World leishmaniasis may get by with no treatment. Treatment,
when indicated, is based on use of antimonial preparations,
either injected around the lesion, or systemic administration by
the IM or IV route. L. major and L. tropica usually respond to
a 10-day course. For Old World leishmaniasis, methods such
as cryotherapy with liquid nitrogen, oral fluconazole, and topical paramomycin are also valid alternatives. One should keep in
mind that spontaneous resolution is quite likely in many cases.
For American leishmaniasis, either cutaneous or mucocutaneous, treatment is always recommended. The choices include

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available antimonial preparations, such as N-methyl-glucamine
and sodium stibogluconate. A dose of 10 to 20 mg per kilogram
should be given daily, IM or IV. The treatment should extend to
10 days for patients with cutaneous leishmaniasis with a low risk
of developing mucocutaneous disease (such as L. mexicana) and
for 20 days for those exposed in high-risk areas for developing
mucocutaneous disease (L. braziliensis group). Active mucocutaneous disease should receive up to 28 days of therapy or receive
an alternative therapy such as amphotericin-B or pentamidine.
The treatment with antimonials is not free of complications,
such as cardiac and renal toxicity. Liposomal amphotericin-B is a
costly, but rather effective treatment for mucocutaneous disease.
Oral miltefosine has shown high cure rates in areas where L. (v)
panamensis is common (Colombia and Guatemala), but not as
effective with infections due to L. (v) braziliensis and L. mexicana
groups.
There is evidence that cure is related to the type of cellular
immune reaction provoked by the microorganism. Those with
a Th1 reaction will do better than those with a Th2 reaction.
Interferon production is also quite important because of its ability to induce parasite destruction by macrophages. Unfortunately,
too much of an immune reaction can be hazardous to the patient,
as is the case in mucocutaneous disease. In this condition, an
excess of cytokines like interferon-γ and TNF-α overwhelms the
production of interleukin (IL)-10. The result of this imbalance is
an extremely destructive inflammatory reaction despite a small
number of microorganisms present in tissue. The other pole
(analogous to the bipolar spectrum of leprosy) is represented
by cases of diffuse cutaneous leishmaniasis, where poor cellular
responses results in abundant parasites.

2 had cutaneous disease. Up until 1981, the Hospital General de
Mexico reported a case of cutaneous amebiasis for every 3,000
dermatology patients.
The most common locations are those implicated in propagation by continuity, that is, the perianal regions, the perineum,
the genitalia, and the groin. The penis can be inoculated during
anal intercourse. Lesions by external inoculation can be located
elsewhere, that is, the abdominal wall. The classical lesion consists of a very painful ulcer that enlarges rapidly, reaching a large
diameter, with interposing normal areas. The ulcers become
wider and deeper, with erythematous borders that then become
violaceous and later necrotic. The shape is round or oval at the
beginning and then becomes irregular. The base is covered by
exudates including pus.
On histology, the characteristic finding is that of an ulcer,
with a mixed infiltrate of lymphocytes, neutrophils, and eosinophils. Areas of necrosis, as well as extravasated erythrocytes,
are commonly observed. Trophozoites are invariably present,
measuring 20 to 50 μm, staining basophilic, with nuclei measuring 4 to 7 μm. Commonly they will show erythrophagocytosis. Granulomas are usually absent. The diagnosis is based on
the finding of the microorganisms on biopsy. Touch preparations and wet drop preparations from the pus may also be used.
Patients should be evaluated for other sites of involvement.
Serology testing may be used for confirmation. Treatment is
based on the use of oral or IV metronidazole, 250 to 750 mg
every 12 to 8 hours for a 10-day period. Alternatives include
the use of diloxanide, tinidazole, emetine hydrochloride, and
pentamidine.

Free-Living Amebas
Enteric Amebiasis
Entamoeba histolytica is best known as a cause of gastrointestinal
disorders, mainly colitis and liver abscesses. However, the possibility of cutaneous disease does exist, either as the only manifestation (the so called primary cutaneous amebiasis) or associated
with involvement of other organs, most frequently the large
bowel and rectum. Cutaneous disease has been reported in different countries around the world, with an important number of
cases seen in Mexico. Life cycle includes two states: cyst, which is
the infective form, and trophozoites. The transmission pathway
is through the orofecal route. Inoculation in humans occurs by
ingestion of amoebic cyst, and their ability to infect the intestinal
mucosa depends on the interaction of lectins on the surface of
the ameba with mucin glycoprotein on the intestinal epithelium.
Invasion of the mucosa is facilitated by the ability of the protozoa
to destroy human defensive cells, such as neutrophiles, T lymphocytes, and macrophages. To do so, the ameba has a system that is
analogous to the human complement pathway, including a pore
formation protein (amebopore). The ameba itself counters with
a mechanism that allows it to elude the host alternative complement system. After invading the colonic mucosa they may reach
the blood stream and subsequently invade other organs, including the liver, lung, pleura, pericardium, and even the brain.
E. histolytica can cause significant cutaneous disease, either
by continuity or by external inoculation with contaminated
hands. Cutaneous amebiasis is most frequently seen in adults.
Both sexes are equally affected. The incidence varies: in a series
of 5,097 patients with invasive disease from South Africa, only

Free-living amebas, also known as amphizoic amebas, are an
important cause of acute and subacute meningoencephalitis.
Species capable of causing central nervous system (CNS) involvement include Naegleria spp., Acanthamoeba spp., Balamuthia
mandrillaris and, most recently, Sappinia diploidea. Until 1990,
Acanthamoeba was the only species known to cause skin disease
along with CNS involvement, especially in immunosuppressed
patients. However, since the initial report by Vivesvara in 1980, a
new species was identified as an important cause of granulomatous meningoencephalitis. First classified under the Leptomyxes
families, later it was renamed B. mandrillaris. What makes this
microorganism so special to dermatology is the occurrence of
a rather typical cutaneous lesion preceding the CNS involvement by months. This finding is very important, because it may
allow an early diagnosis even before neurological involvement.
The prompt diagnosis is essential for treatment of this otherwise
invariably fatal disease.
Until 2003, nearly 100 cases of B. mandrillaris had been
reported worldwide. Many come from the Americas and there are
additional reports from Asia, Australia, and Europe. Cutaneous
involvement is not always reported. The first description of
the classical centrofacial lesion was done by Reed in Australia.
The disease seems to be acquired from contact with contaminated water or soil. As in cases of Naegleria and Acanthamoeba,
swimming in ponds and lakes seems to be a common history.
Surprisingly, the first environmental isolation in relation to a
clinical case was from soil coming from a flower pot in the home
of the affected child.

122 — Francisco G. Bravo and Salim Mohanna

Around half of the cases are seen in patients under the age
of 15. The initial cases were reported in immunocompromised
patients, including those with AIDS, but, recently, most of the
cases from South America, Asia, and Australia occurred in
immunocompetent patients. It is interesting to note that up to
44% of the US cases reported to the Center for Disease Control
and Prevention for Balamuthia testing had Hispanic ethnicity. Up
to 45 cases of free-living ameba infection have been identified at
the Instituto de Medicina Tropical “Alexander von Humboldt,” at
Hospital Nacional Cayetano Heredia, in Lima, Peru. 20 cases have
been confirmed, by immunofluorescense test, as being caused by
Balamuthia by immunofluorescence test.
Acanthamoeba and Balamuthia are very similar in morphology. A distinction can be made on the basis of culture isolation,
differences in the cell wall of the cystic state and lately, on the
basis of PCR analysis of amebic mitochondrial RNA. They both
enter the skin through microabrasions. From there, the infection may be either contained in the skin for a while, or rapidly
disseminate to the CNS either by continuity (nasal skin involvement) or by hematogenous spread. The classical skin lesion in
Balamuthia cases is an asymptomatic plaque, mostly located on
the central face (Fig. 9.7). The lesion may enlarge, giving origin
to smaller satellite lesions, or progressing into a more infiltrative involvement of the whole facial area. One single lesion is
more common than several, and lesions only ulcerate at a very
late state. When the lesion occurs on the extremities the findings
may seem less characteristic, and with a wider differential diagnosis, the diagnosis is likely to be overlooked. Some patients may
develop regional lymphadenopathy. The natural history will go
toward the development of neurological disease. This progression may take from 30 days to 2 years; with an average of 5 to 8
months. Cutaneous involvement precedes the CNS involvement
as a rule. The CNS involvement will manifest initially as fever,
headache, and photophobia. Later, other signs of intracranial
hypertension, such as seizures, lethargy, and focal signs of motor
or sensorial deficit will appear. The patient will enter a comatose
state and die. As opposed to Balamuthia, Acanthamoeba cases
occur more commonly in immunosuppressed patients, many
with AIDS. Lesions tend to be more ulcerated, and the progression toward CNS involvement may be faster.
The histology of the skin lesion in Balamuthia is very consistent. It is characterized by an ill-defined granulomatous
infiltrate with many giant cells, lymphocytes, and plasma cells.
Neutrophils and eosinophils are seen in only one-third of the
cases. One should actively look for the ameba. Scarce trophozoites can be seen in three-fourths of the cases, but their morphology can be easily confused with macrophages. Only the presence
of the amoebic nucleus and nucleolus may allow its differentiation from a human cell. As opposed to E. histolytica, they do not
phagocytize red blood cells.
In Acanthamoeba cases the biopsy usually shows multiple
trophozoites, many situated along vascular structures. The most
specific identification is based on immunofluorescent staining of
the microorganism in skin or brain tissue, as well as immunofluorescence testing of the patient’s serum. Recently, PCR testing
has become available for B. mandrillaris.
The disease will have a fatal outcome unless therapeutic
intervention takes place. The aim is to make early diagnosis
when the disease is only confined to the skin to avoid its spreading to the CNS. Unfortunately, there is no therapeutic regimen

Figure 9.7. Balamuthiasis, plaque on the central face.

showing consistently good results. The cases reported in the
literature as survivors have tried different modalities. Drugs
used in Balamuthia include flucytosine, pentamidine, fluconazole, sulfadiazine, and a macrolide. Four additional unreported
survivor cases from personal experience of one of the authors
(F.B.P.) received amphotericin, albendazole, itraconazole, and
fluconazole, with one of them also getting benefit from the surgical excision of the clinical lesion.
B. mandrillaris should be kept in mind when dealing with
granulomatous lesions, with the morphology of a plaque occurring on the central face or elsewhere. If this infection is suspected,
the pathologist should be alerted to look for the ameba or to use
immunofluorescent testing (Laboratory of Parasitic Disease,
Center for Disease Control and Prevention, Atlanta). Early intervention may give patients a hope for cure in an otherwise fatal
disease. It is possible that at least some of the previous reported
cases of midline lethal granulomas were nothing but free-living
ameba cases where the causing agent was overlooked.

Trypanosomiasis
Only three members of this genus are capable of infecting humans:
Trypanosoma cruzi, the cause of Chagas disease in the Americas;
and Trypanosoma brucei gambiense and Trypanosoma brucei
rhodesiense, the cause of human African trypanosomiasis.
Human African trypanosomiasis, or sleeping sickness,
is transmitted to human hosts by bites of infected tse-tse flies,

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which are found only in Africa. The life cycle starts when the
trypanosomes are ingested during a blood meal by the tse-tse
fly from a human reservoir in the West African trypanosomiasis (T. b. gambiense) or an animal reservoir in the East African
trypanosomiasis (T. b. rhodesiense). The trypanosome multiplies
over a period of 2 to 3 weeks in the fly midgut; then, the parasite
migrates to the salivary gland where they develop into epimastigotes. Humans are infected following a fly bite with inoculation
of trypomastigotes.
A painful and indurated trypanosomal chancre appears in
some patients 5 to 15 days after the inoculation of the parasite
and resolves spontaneously over several weeks. Hematogenous
and lymphatic dissemination is marked by the onset of malaise, headache, intermittent fever, rash, and weight loss.
Lymphadenopathy is more common in West African trypanosomiasis with discrete, movable, rubbery, and nontender nodes.
Cervical nodes are often visible, and enlargement of the nodes of
the posterior cervical triangle (Winterbottom’s sign) is a classic
finding. Transient edema is common and can occur in the face,
hands, feet, and other periarticular areas. Pruritus is frequent,
and an irregular maculopapular rash is often present. This rash
is located on the trunk, shoulders, buttocks, and thighs and consists of annular, blotchy erythematous areas with clear centers,
called trypanids. Eventually, the parasitic invasion reaches the
CNS, causing behavioral and neurological changes. A picture of
progressive indifference and daytime somnolence develops (giving rise to the name sleeping sickness), sometimes alternating
with restlessness and insomnia at night. The final phase includes
stupor and coma, with high mortality. The most striking difference between the West African and East African trypanosomiasis is that the latter illness tends to follow a more acute course.
A definitive diagnosis requires detection of trypanosomes in
blood, lymph nodes, CSF, skin chancre aspirates, or bone marrow. However, empiric treatment with subsequent symptomatic
improvement is the usual confirmatory test in areas where diagnostic studies are not readily available. Treatment depends on
type and stage of disease. Suramin, eflornithine, melarsoprol,
and pentamidine are drugs that have proven efficacy.
American trypanosomiasis, or Chagas disease, is a zoonosis
caused by the protozoan parasite T. cruzi. This parasite is found
in the Americas from the southern United States to southern
Argentina. Humans become involved in the cycle of transmission when infected vectors take up residence in the cracks and
holes of the primitive wood, adobe, and stone houses common
in Latin America. T. cruzi is transmitted among its mammalian
hosts by bloodsucking triatomine insects, often called reduviid
bugs (kissing bugs). The insects become infected by sucking
blood from animals or humans who have circulating trypomastigotes. The ingested organisms multiply in the gut of the triatomines, and infective forms are discharged with the feces at
the time of subsequent blood meals. Transmission to a second
vertebrate host occurs when breaks in the skin, mucous membranes, or conjunctivae become contaminated with bug feces
that contain infective parasites. T. cruzi can also be transmitted
by transfusion organ transplantation and from mother to fetus
during birth.
Acute Chagas disease occurs at least 1 week after invasion
by the parasites. When the organisms enter through a break
in the skin, an indurated area of erythema and swelling (chagoma), accompanied by local lymphadenopathy, may appear. The

Romaña sign, which consists of unilateral painless edema of the
palpebral and periocular tissues, occurs in cases of entry through
the conjunctiva. These initial local signs may be followed by
malaise, fever, anorexia, and edema of the face and lower extremities. Some patients may also develop a rash that clears in several
days. Generalized lymphadenopathy and hepatosplenomegaly
may develop. Severe myocarditis rarely develops. Neurological
signs are not common, but meningoencephalitis occurs occasionally. Chronic Chagas disease becomes apparent years or
even decades after the initial infection. Cardiac involvement is
the most frequent and serious defined manifestation of chronic
Chagas disease (approximately two thirds of cases) and typically
leads to arrhythmias, cardiac failure, thromboembolic phenomena, and sudden death. The digestive forms of the disease lead to
megaesophagus and/or megacolon in approximately one-third
of chronic cases.
The diagnosis of acute Chagas disease requires the detection
of parasites. Microscopic examination of fresh, anticoagulated
blood or of the buffy coat is the simplest way to see the motile
organisms. Chronic Chagas disease is usually diagnosed by the
detection of IgG specific antibodies that bind to T. cruzi antigens.
Treatment for Chagas disease is unsatisfactory, with only two
drugs (nifurtimox and benznidazole) available for this purpose.
Unfortunately, both drugs lack efficacy and often cause severe
side effects.

HELMINTHS

Worm infections in humans and other animals are a significant
contributor to the global burden of illness caused by infectious
diseases in general. This group includes roundworms (nematodes), tapeworms (cestodes), and flukes (trematodes).

Nematodes
This phylum is the second largest phylum in the animal kingdom, with approximately 500,000 species. Members of this phylum are elongated with bilaterally symmetric bodies containing
an intestinal tract and a large body cavity. Nematodes of medical
importance may be broadly classified as either predominantly
intestinal or tissue nematodes (some with lymphatic involvement). They are widely scattered around the world, especially in
the tropics, and infect millions of people.
Filariasis
Filariasis are systemic infections due to different species of
nematodes, all transmitted by mosquito bites, with hematogenous (rather than cutaneous, as in Onchocerciasis) spread of
microfilariae. These parasites reside in lymphatic channels or
lymph nodes, where they may remain viable for more than two
decades. The symptoms are related to chronic inflammation of
the lymphatic system. They commonly occur in tropical areas
of the world. Wuchereria bancrofti and Brugia malayi are more
common in Asia and tropical Africa. Brugia timori exists only on
islands of the Indonesian archipelago. The symptoms are related
to the stage of disease. During the hematogenous spread, microfilarias are abundant in blood, producing temporary migratory
swelling on extremities that are self-limited and recurrent. Acute

124 — Francisco G. Bravo and Salim Mohanna

lymphangitis and lymphadenitis may affect the groin and axillae.
Genital involvement includes acute orchitis, epididymitis, and
funiculitis, which are very painful. They can also be recurrent,
and evolve into fibrosis. Urticaria may be part of the clinical
presentation. Late changes are due to obstruction of lymphatics, giving origin to different forms of elephantiasis, affecting the
extremities and scrotum with massive edema. Diagnosis is made
by the presence of microfilaria in blood smears, and serological testing. Treatment with diethylcarbamazine (DEC), 6 mg/kg
daily for 12 days), remains the treatment of choice for the individual with active lymphatic filariasis, although albendazole (400
mg twice daily for 21 days) has also demonstrated macrofilaricidal efficacy. Ivermectin is also an option.
Loiasis
Caused by the filariae and microfilariae of Loa loa, loiasis is a
disease of humans that results in skin and eye involvement. It
is endemic in sub-Saharan Africa, from West to East equatorial
countries. The vector is a deer and antelope fly (Chrysops spp.).
Serving as intermediate host between human; it is in the fly that
the microfilariae evolve into infective larvae and as such are then
inoculated into the subcutaneous tissue of uninfected humans by
another bite. Larvae mature into adult worms in the subcutaneous tissue, migrating to different parts of the body, where they
will produce new microfilariae that eventually will be taken by
another Chrysops, starting the cycle again. In a year’s time, the
proliferating mass of worms will reach a level capable of inducing symptoms.
The clinical manifestations are related to the migratory
angioedema induced by moving worms. If the disease is present
near joints, it will induce pain or itching. They are often located
in the periorbital area. The lesions may last from days to weeks,
giving the idea of a “fugitive swelling.” At times, the microfilariae
can be seen migrating under the skin or under the conjunctiva,
causing severe conjunctivitis. Urticarial rashes may also develop.
The allergic response induced by the worm may express as
regional lymphedema, peripheral neuritis, or encephalitis, and
eventually compromise the kidney, lungs, and heart.
A definitive diagnosis can be done by extraction of the worm
from a subcutaneous nodule or from conjunctiva. Microfilariae
can be detected in blood peripheral smears or from skin snips.
A tentative diagnosis can be made on the basis of clinical findings with associated eosinophilia, leukocytosis, and increased
levels of IgE. The Mazzotti test consists of the administration of
a test dose of DEC, looking for the induction of intense itching,
secondary to dying microfilariae. The treatment itself is based
on the same drug, DEC, given on a 3-week oral course. One
has to watch for severe meningoencephalitic reactions, which
should be treated with steroids and antihistaminics. Ivermectin
and albendazole are considered alternative therapies, although
not exempt from the allergic reactions. Fatalities are more commonly associated to those allergic reactions due to high-dose
therapy or worm rupture.
Onchocerciasis
Onchocerciasis is a chronic infestation of the skin with Onchocerca
volvulus. This is a microfilarial nematode whose natural hosts are
humans and the vectors are flies from the genus Simulium. The
disease was first described in Africa and later in Central America.

Recently, some reports indicate the disease extends into the
northern countries of South America. The transmission occurs
when flies became infected by biting sick people. After a short
period of maturation the microfilaria moves to the buccal apparatus of the insect and enters the skin of a noninfected human
with the next blood meal. The infective forms become adults
in 6 to 8 months, inside cutaneous nodules called onchocercomas, where they start to produce microfilarias. From then on,
the infection propagates to all the tegumentary system. Worms
move from one nodule to another to mate. Cutaneous involvement includes the characteristic onchocercomas. They tend to
locate on the scalp in Central American patients and on extensor
surfaces in the African patients. Many times the clinical picture
is of itchy dermatosis. Other clinical presentations include acute
and chronic papular forms, the lichenified unilateral form that
Yemenites call sowda, facial erythema, facial lividoid discoloration, facial aging, and prurigo-like eruption on the buttocks and
extremities. Later signs are extensive lichenification, dyschromia
similar to vitiligo, elephantiasis of the extremities, and the scrotum, and the so called “hanging groin.” Ocular involvement is
related to the direct invasion of eye structures by the microfilaria,
causing uveitis, conjunctivitis, keratitis, optical nerve atrophy,
and glaucoma. All this may end up in complete and permanent
loss of vision, hence the name “river blindness,”
Diagnosis is based on the clinical finding of onchocercomas
and other characteristic skin changes. Scabies and papular urticaria induced by insect bites can be confused with the papular
reactions seen in onchocerciasis. The skin snip is a useful confirmatory test, especially when taken from the iliac crest area.
The amount of visualized microfilariae will give an idea of the
parasitic load. A Mazzotti patch test with DEC will also serve
as a diagnostic guide. ELISA and PCR testing are available, and
a rapid format antibody card is being developed. Histological
analysis of skin lesions will allow the identification of adult forms
surrounded byfibrous or calcified tissue. Occasionally microfilaria may be identified in the surrounding tissue. Treatment for
disease consists of the oral administration of ivermectin, which
is extremely effective even as a single-dose therapy to kill the
microfilariae; however, adult forms are resistant. Patient should
receive repeated doses of ivermectin through the years to kill new
microfilariae, thus keeping a low parasitic load. This scheme will
prevent the development of blindness and improve skin symptoms. The role of symbiotic bacteria, Wolbachia, as a requirement
for worm reproduction has given rise to the combined treatment
of ivermectin and doxycycline, which seems very effective in
decreasing the microfilariae mass more rapidly.
Dracunculiasis
Also known as Guinea worm, this parasitic infection is produced
by Dracunculus medinensis, a nematode parasite of humans
since early ages. The disease is prevalent in several countries of
the sub-Saharan African continent. The population affected is
among the most deprived in the world, and follows a dreadful
cycle that repeats year after year during the harvest season affecting the adult labor force as well as children.
The life cycle starts with the elimination of eggs by a female
worm extruding from an infected patient; each female may carry
3 million embryos. The larvae are then ingested by cyclopoid
copepods, where they evolve into an infective organism. Humans

Parasitology — 125

are again exposed to the microorganism while drinking contaminated water containing Cyclops. When the crustaceans reach the
stomach, the larvae are liberated. They then perforate the gastric
mucosa, and after passing through the peritoneum, they finally
locate in the subcutaneous tissues where a maturation process
to male and female worms takes place. After a year, the female is
fertilized and then migrates even more superficially until she can
eliminate her eggs through the skin to reinitiate the cycle. The
female can reach a length of 120 cm.
The disease will manifest itself only when the worms reach
the maturation and fertilization period. The fertilized female will
approach the skin surface while the patient is experimenting systemic symptoms such as nausea, vomiting, diarrhea, syncope, or
dyspnea. The area of emersion will be preceded by pruritus and
then a papule or a nodule will appear. If the area is located near a
joint the process may become quite painful. They will evolve into
a vesiculobullous lesion, associated with a strong burning sensation, and relieved by the immersion of the affected body area
in water. The subsequent ulceration may become superinfected
by pyogenic bacteria. If the worm ruptures inside the tissue it
may cause a clinical picture of cellulites or eventually become
calcified. Commonly affected areas will be the lower extremities,
especially feet, although other areas can be affected as well. The
average number of worms extruded at any given time is usually
less than five, but as many as 20 at a time have been reported. The
patient will become temporarily disabled, and obligated to stay
in bed, which affects the economic situation of the household or
causes failure to attend school in children or adolescents.
The presence of an extruding adult worm is obviously diagnostic. Also, a direct wet preparation from the lesion may reveal
mobile larvae. Treatment consists of slowly extracting the worm
by winding it around a stick, a process that may take several days.
Oral treatments with mebendazole and metronidazole may facilitate the extraction of the worm.

contact with human skin, it will invade the stratum corneum with
the aid of protease secretions, and will then begin its wandering
cycle. Lacking the appropriate enzymatic armamentarium, it will
not be able to go beyond the dermis as would have been the case
in the definitive canine host.
The classical presentation will be a serpiginous lesion with
an advancing edge, located most commonly on the feet, buttocks, hands, and knees. The trunk can also be involved if the
patient was lying on the sand (Fig. 9.8). An itching, tingling,
or burning sensation may be reported. The advancing border
can extend several millimeters each day. Multiple pinpoint
lesions can occur, especially in the gluteal areas. Secondary bacterial infections due to intense scratching are commonly seen
in populations afflicted by poverty. The clinical course extends
over weeks but rarely beyond 3 months. Spontaneous resolution
usually takes place, but symptoms may force the patient to seek
medical advice.
Peripheral eosinophilia can be seen. Although it is a clinical
diagnosis, if a biopsy is taken one should look for the presence
of a superficial and perivascular infiltrate of eosinophils. Rarely
the larva will be seen on histological cuts, and most commonly
at the stratum corneum level. The current therapies include topically applied thiabendazole, as well as the oral use of albendazole and ivermectin. In pregnant patients, cryotherapy may be
another alternative. Differential diagnosis will include other parasites with migratory patterns, such as gnathostomiasis, loiasis,
myasis, fascioliasis. Linear lesions from jellyfish attacks, blister

Cutaneous larva migrans
Cutaneous larva migrans, also known as creeping eruption, is
a disease produced by the third larval state of intestinal nematodes that parasitize dogs, cats, and other mammals. The disease has a wide distribution around the world and is commonly
seen in the Southeastern United States, the Caribbean, Central
and South America, Africa, India, and South East Asia. It is the
most common parasitic disease of the tropics. Although frequently reported as a disease of the affluent tourist, it is highly
prevalent in areas of poverty of the developing world. The most
common species in the Americas is Ancylostoma braziliensis
(hookworm of dogs and cats). A. caninum is found in Australia
and Uncinaria stenocephala in Europe. Cattle hookworm such as
Butostotum phlebotomun can also be a causative agent of cutaneous larva migrans. Strongyloides stercoralis produces a similar
picture although the speed of migration is faster (thus the name
larva currens) and commonly affects a different body area such
as the buttocks. Even free-living soil nematodes such as Pelodera
strongyloides can invade human skin, although with a more polymorphous clinical picture.
The infection is typically acquired while walking barefoot on
sandy beaches frequented by stray dogs and becoming contaminated by their feces. Kids playing in sandboxes are also at risk.
The larva feeds initially on soil bacteria, but as soon as it gets in

Figure 9.8. Cutaneous larva migrans.

126 — Francisco G. Bravo and Salim Mohanna

beetle dermatitis, or phytophotodermatitis can also mimick
these conditions.
The syndrome associated with Strongyloides stercoralis is
known as larva currens. The migratory pattern is much faster
than in regular larva migrans (up to 5 to 10 cm per hour). It is
quite pruritic. Common locations include the buttocks, groin,
and trunk. In the hyperinfection state, the lesions can adopt a
more petechial to purpuric pattern. Thumbprint-shaped hemorrhages can be seen around the umbilicus. Strongyloidiasis may
specifically affect those patients under immunosuppressive regimens, malnourished patients, or patients infected with HTLV-1.
Gnathostomiasis
Described by Owen in 1836, it is a parasitic infection produced
by round worms of the Gnathostoma family. Different species
have been described as causative agents, the most common being
G. spinigerum. Other species include G. turgidum, G. americanum, G. procyonis, G. miyasaki, G. binucleatum, and lately G.
doloresi. The highest incidence is reported in areas where eating raw fish is part of the local gastronomy, either as sashimi or
ceviche. High prevalence areas in Asia include Thailand, Korea,
Japan, and other countries in Southeast Asia. In the Americas, it
has been reported in Mexico (Sinaloa and Acapulco), Ecuador
(Guayaquil), and coastal areas of Peru. In fact, with more and
more frequent intercontinental travel and tourism, gnathostomiasis is a disease that can now be seen throughout world. Series of
cases have been reported in traveler clinics in the United States,
United Kingdom, and France, and other case reports testify to
worldwide distribution of the disease.
The infection is a zoonosis. The life cycle starts in the stomach of cats, where adult worms nest in the gastric mucosa. Other
primary hosts include dogs, tigers, leopards, lions, minks, opossums, raccoons, and otters. Eventually, eggs reach the intestinal
lumen and, carried in feces, they will reach the fresh water of a
river. The egg will evolve into a first larval state and this in turn
will infect the gastric mucosa of minute crustaceans (Cyclops).
Inside this copepode, the larva will mature into a second and
early third larval state. The copepode will then be ingested by
a new temporary host, most commonly a fish. Other potential
species harboring the infective larva may include frogs, snakes,
chicken, or pigs. The worm will invade the gastric mucosa of the
new host to later evolve into a late third larval state to finish as
a cyst in the muscle tissue. This intermediate host will be at the
same time ingested by the final host, the cat, as fishermen will
throw away infected rotten fish in the beaches near a river. Once
the contaminated flesh is ingested and digested, the larvae excyst
into the stomach, penetrate the gastric wall, migrate through
the liver, and travel to the connective tissue and muscles. After 4
weeks, they return to the gastric wall to form the tumor, where
they mature into adults in 6 to 8 months. At 8 to 12 months after
initial ingestion, the worms mate and eggs begin to pass into the
feces of the host to begin a new cycle.
Humans get the infection by eating raw fish in several ways,
classically in the form of sushi or sashimi in Asia, and ceviche (raw fish marinated in lime juice) in the Americas. Other
potential sources of infection are shellfish (such as oysters) and
undercooked meat from animals, such as pork and chicken, that
are fed along with infected fish. Once the infected meat reaches
the human stomach, the larva is liberated and rapidly perforates

the gastric mucosa, 24 to 40 hours after initial ingestion. Some
patients may then report epigastric discomfort. The parasite will
reach the peritoneal space and either migrates through internal
organs, such as the liver, or straight toward the subcutaneous fat.
In the first case, the symptoms may simulate acute gallbladder
disease, so the disease becomes relevant for surgeons in their differential diagnosis for a patient with acute right upper quadrant
pain.
If the larva ends up in the subcutaneous fat, the classical
presentation will be a migratory panniculitis. This event will
take place about 4 weeks after the ingestion of the contaminated
meat. It will consist of the appearance of a deeply seated, illdefined nodule or plaque, located commonly in the abdominal
wall, but potentially anywhere on the body. Sometimes, the area
involved will have a “peau d’orange” appearance (Fig. 9.9).The
lesion is easily confused initially with a deep bacterial abscess.
It will be erroneously treated with antibiotics, and a temporary
involution of the mass will occur. Then, a few days later, a similar
lesion will recur a few centimeters beyond the original location
(Fig. 9.10). These migratory episodes may continue for months
or even years. A minority of cases may even have a more superficial, “larva migrans” type of presentation, either at the beginning of the process or at the end (Fig. 9.11). We have seen cases
where the larva will move to a more superficial location near
the epidermis after treatment with antiparasitic drugs. A more
serious complication is pneumonia, which can result in a pleural or even pericardial effusion, due to its passing through the
mediastinum. Also, there is always the possibility of migration of
the parasite to the eye (which can cause uveitis, iritis, intraocular hemorrhage, increased intraocular pressure, or even retinal
scarring and detachment). Migration to the CNS has also been
reported. It can produce meningitis or meningoencephalitis. In
Thailand, it is the most common parasitic infection of the CNS,
where up to 6% of subarachnoid hemorrhages in adults and 18%
of those in infants and children are due to gnathostomiasis.
The characteristic migratory pattern through the subcutaneous fat, so called “migratory panniculitis” should alert the
physician about the possibility of gnathostomiasis. When associated with peripheral eosinophilia, as high as 50%, the suspicion

Figure 9.9. Gnathostomiasis “peau d’orange” appearance of a lesion at
the time of first visit.

Parasitology — 127

Figure 9.10. Gnathostomiasis: same patient of figure 9 a week later.
Notice how the lesion has migrated from an area covered with a
band-aid to a different site a few centimeters away.

For diagnostic purposes, a history of eating raw fish, the
clinical finding of a migratory panniculitis, and the presence of
an eosinophilic panniculitis with associated dermatitis on biopsy
should be enough criteria to make the diagnosis. A serological
test has been developed in Thailand using immunoblotting of a
24 kDa protein extracted from Gnatostoma infective larva. This
test will detect antibodies from any infection not older than 6
months. While diagnosing a recurrence, one should expect the
migratory pattern to be present. In the differential diagnosis
of migratory diseases one should include superficial and deepseated parasites, such as Ancylostoma species (superficial larva
migrans) and Fasciola hepatica (in cases of right upper quadrant
location). Even though Toxocara presents most commonly as an
acute pneumonia, it can also more rarely produce a migratory
paniculitis. Myiasis can adopt a subcutaneous migratory pattern. A similar picture to gnathostomiasis can be seen in sparganosis. However, sparganosis most commonly will present as
a fixed subcutaneous nodule, although a migratory pattern has
also been reported.
Treatment is albendazole 400 mg to 800 mg for 14 to 21 days,
or single doses of ivermectin 200 µg per kilogram repeated every
two weeks until the clinical findings subside. Both treatments
seem to be equally effective, but neither show 100% efficacy.
Prevention is based on cooking or freezing of the potentially
infected meat. Lemon juice, the classical ingredient in the preparation of ceviche, has no effect in eliminating the larva. Fish species responsible for the transmission of the disease varies from
one area to the other, requiring a joint effort from physicians,
biologists, and health officials to identify sources of infection for
every region affected by the disease. People who like to prepare
sushi at home are considered a high-risk group, as they lack the
experience to select uninfected fish.
Trichinellosis

Figure 9.11. Gnathostomiasis with a superficial (cutaneous larva
migrans pattern) and deep (panniculitis pattern) component.

should be high. Unfortunately, this finding in the peripheral
blood is not always present. A skin biopsy is a very reliable
method for confirming the diagnosis. Expected histological findings include a dense perivascular and interstitial eosinophilic
infiltrate, mainly localized to the subcutaneous fat and dermis.
Flame figures can be seen around collagen bundles in the dermis,
similar to findings associated with eosinophilic cellulitis (Well’s
syndrome). This last entity, however, lacks the migratory course
characteristic of gnathostomiasis. Of note, it is extremely difficult
to see the worm on histology cuts, because the area of infiltration
is large (up to several square cm in size) compared to the size of
the larva, which is about 0.4 mm in diameter and 4mm in length.
However, a curious observer may note that after medical therapy
is given, the large areas may evolve into a small papule. If then
the minute lesion is excised, the whole wandering larva may be
seen on histologic cuts.

Seven species are recognized as causes of infection in humans
(Trichinella spiralis, Trichinella native, Trichinella nelsoni,
Trichinella pseudospiralis, Trichinella britovi, Trichinella murrelli, and Trichinella papuae). Most human infections are due to
T. spiralis, which is found in carnivorous and omnivorous animals (pigs, rats, bears, foxes, dogs, cats, or horses) worldwide.
Trichinellosis or Trichinosis develop after the ingestion of raw or
undercooked meat (most commonly pork) contaminated with
the infective larvae of Trichinella spp.
After the ingestion of infected meat by the host, encysted larvae are freed by acid-pepsin digestion in the stomach and then
pass into the small intestine. Larvae invade the columnar epithelium at the bases of the villi and then develop into adult worms.
After approximately 1 week, female worms release newborn larvae that migrate via the circulation to striated muscle. A cyst wall
develops around the larvae and may eventually calcify. Larvae
may remain viable in muscles for several years.
Clinical symptoms develop from the successive phases of
parasite enteric invasion, larval migration, and muscle encystment. Small intestine invasion occasionally provokes diarrhea,
abdominal pain, constipation, nausea, and vomiting. Symptoms
due to larval migration and muscle invasion are much more
common and usually begin to appear in the second or third week
after infection. The migrating larvae produce a local and systemic
hypersensitivity reaction, with fever and hypereosinophilia.

128 — Francisco G. Bravo and Salim Mohanna

Symmetric periorbital and facial edema may be associated with
hemorrhages in the subconjunctivae, retina, and nail beds (splinter hemorrhages). Some patients present with a rash that may be
maculopapular or petechial. Headache, cough, dyspnea, hoarseness, or dysphagia sometimes also develops. Myositis with myalgias, muscle edema, and weakness are also common. The most
frequently involved muscles include the extraocular muscles, the
biceps, and the muscles of the jaw, neck, lower back, and diaphragm. Other symptoms may include myocarditis, pneumonitis, and encephalitis.
Trichinellosis should be suspected in a patient who develops periorbital edema, myositis, fever, and eosinophilia. Patients
should be questioned thoroughly about recent consumption
of poorly cooked meat, particularly pork or wild-animal meat,
and about illness in other individuals who ate the same meat.
Eosinophilia typically arises 10 days after infection, with total
eosinophil counts of up to 40% to 80% of total white blood cells.
Erythrocyte sedimentation rates are usually within the reference
range. Creatine kinase, lactate dehydrogenase, and IgE levels are
often elevated. A muscle biopsy requires at least 1 g of involved
muscle. At the time of biopsy, initial preparation may be made
by crushing a portion of muscle tissue between two slides and
viewing it directly.
Serology results are not positive until 2 to 3 weeks after infection. They peak around the third month and may persist for years.
Latex agglutination results are usually not positive for more than
1 year after infection. ELISA is 100% sensitive on day 50, with
88% of results remaining positive 2 years after infection.
Current antihelmintic drugs are ineffective against the larvae
in muscle. Mebendazole (200–400 mg PO TID for 7 days) and
albendazole (400 mg/day PO BID for 7–14 days), are active
against enteric stages of the parasite. Jarisch-Herxheimer-like
reactions have been described following the administration of
antihelmintic medications. Fortunately, most lightly infected
patients recover uneventfully with bed rest, antipyretics, and
analgesics. Corticosteroid treatment can help reduce the immunologic response to the larvae and is beneficial for severe
myositis and myocarditis. The most effective measure to eradicate Trichinella species is by adequate cooking to kill the parasite.
Trichinella species can typically be killed by adequate cooking at
140°F (60°C) for 2 minutes. If no trace of pink in fluid or flesh is
found, these temperatures have been reached.
Mansonelliasis
Three species routinely infect humans: Mansonella streptocerca, Mansonella perstans, and Mansonella ozzardi. Diagnosis
of Mansonelliasis depends on demonstrating the microfilariae
in thick or thin films of peripheral blood, skin snips, or biopsy
specimens of skin.
Mansonella streptocerca is found mainly in the tropical forest
of Africa and is transmitted by midges (Culicoides). Patients are
usually asymptomatic but can develop pruritus, papular rashes,
hypopigmented macules (that may be confused with leprosy),
and inguinal adenopathy. DEC (2 mg/kg PO TID for 14–21
days) is effective in killing both microfilariae and adult worms.
Ivermectin at a single dose of 150 μg/kg is also effective.
M. perstans is distributed across the center of Africa and
in northeastern South America, and is transmitted by midges
(Culicoides). Adult worms reside in serous cavities as well as

in the mesentery and the perirenal and retroperitoneal tissues.
Clinical manifestations may include fever, headache, arthralgias, fatigue, pruritus, and transient angioedema (similar to
the Calabar swellings of loiasis). Mebendazole (100 mg PO bid
for 30 days) and albendazole (400 mg PO bid for 10 days) have
been reported to be effective. Ivermectin has no activity against
this species. Allergic reactions have been reported from dying
organisms.
M. ozzardi is restricted to Central and South America
(Argentina, Bolivia, Brazil, Colombia, Ecuador, and Peru), and
certain Caribbean islands. Vectors include midges (Culicoides)
and blackflies (Simulium). Symptoms include fever, headache,
arthralgias, hepatomegaly, adenopathy, papular rashes, and
pruritus. DEC is ineffective with this species. Ivermectin at a
single dose of 6 mg has been shown to be effective in treating
this infection.
Enterobiasis (Pinworms)
This infection is more common in temperate countries than in
the tropics, and humans are the only natural host for Enterobius
vermicularis. In the United States, more than 40 million people
are estimated to be infected with pinworms; schoolchildren
account for a disproportionate number of cases.
The adult worms are approximately 1 cm long and dwell in
the bowel lumen. The female worm migrates to the rectum after
copulation and, if not expelled during defecation, migrates to
the perineum, where on average of 10,000 eggs are released. The
eggs become infective within hours and are transmitted through
humans from hand to mouth passage. Self-infection results from
perianal scratching and transport of infective eggs on the hands
or under the nails to the mouth. Fecal–oral contamination via
toys or clothes is a common method of infestation. Because of
the ease of person-to-person spread, it is common among family
members and institutionalized populations.
Perianal pruritus is the main symptom. The itching, which
is often worse at night as a result of the nocturnal migration of
the female worms, can lead to excoriation and bacterial superinfection. Heavy infections have been claimed to cause abdominal
pain and weight loss. On rare occasions, pinworms invade the
female genital tract, causing pruritus, vulvovaginitis and pelvic
or peritoneal granulomas.
Diagnosis is made by examination of an adhesive cellophane
tape pressed against the perianal region early in the morning.
Serial examinations (3 or more) are advised. All affected individuals should be given a dose of mebendazole (100 mg once)
or albendazole (400 mg once) with the same treatment repeated
after 10 to 14 days. Because asymptomatic infestation of other
members in a household is frequent, it may be reasonable to
treat all household members simultaneously. Families should be
informed that repeat infestations are common.

Cestodes
Members of this phylum are segmented worms. Cestodes, or
tapeworms, can be divided into two major clinical groups. In the
first, humans are the definitive hosts, with the adult tapeworms
living in the gastrointestinal tract. In the second, humans are
intermediate hosts, with larval stage parasites being present in
tissues.

Parasitology — 129

Cysticercosis
The pork tapeworm Taenia solium can cause two distinct forms
of infection. The form that develops depends on whether humans
are infected with adult tapeworms in the intestine or with larval
cysts in tissues (cysticercosis). T. solium exists worldwide but is
common in Latin America, sub-Saharan Africa, China, southern
and Southeast Asia, and Eastern Europe.
Human cysticercosis develops after the ingestion of raw or
undercooked pork meat contaminated with T. solium eggs. After
ingestion of eggs by the intermediate host, the larvae are activated, escape the egg, penetrate the intestinal wall, and are carried to many tissues. The larvae have a predilection for striated
muscle of the neck, tongue, and trunk. Within 60 to 90 days,
the encysted larval stage develops. These cysts can survive for
months to years. Autoinfection may occur if an individual with
an egg-producing tapeworm ingests eggs derived from his or her
own feces.
The clinical spectrum in cysticercosis is variable. Cysts
can be found anywhere in the body but are most commonly
detected in the brain, skeletal muscle, subcutaneous tissue, or
eye. Symptoms depend on the number and location of cysts as
well as on the extent of associated inflammatory responses and
scarring. Neurological manifestations like seizures, hydrocephalus, and signs of increased intracranial pressure are common.
When cysts develop at the base of the brain or in the subarachnoid space, they may cause chronic meningitis, communicating
hydrocephalus, or strokes.
Diagnosis and treatment of cysticercosis depends on the site
of involvement and the symptoms experienced. Cysts outside
the CNS are usually not symptomatic. These eventually calcify,
to be detected incidentally on plain radiographs of the limbs. For
symptomatic cysts outside the CNS, the optimal approach is surgical resection. Medical therapy with praziquantel or albendazole may also be employed. Intestinal T. solium infection is
treated with a single dose of praziquantel (10 mg/kg). However,
praziquantel can evoke an inflammatory response in the CNS if
concomitant cryptic cysticercosis is present.
Echinococcosis
Echinococcosis results when humans serve as intermediate hosts
for cestodes of Echinococcus spp. This infection has two forms:
hydatid or unilocular cyst disease, caused by Echinococcus granulosus or Echinococcus vogeli, and alveolar cyst disease, caused
by Echinococcus multilocularis. E. granulosus is prevalent worldwide. E. multilocularis is found in Alpine, sub-Arctic, or Arctic
regions, including Canada, the United States, central and northern Europe, and Asia. E. vogeli is found only in Central and South
American highlands. Cysts develop in the intermediate hosts
(sheep, cattle, humans, goats, camels, and horses for E. granulosus; and mice and other rodents for E. multilocularis) after the
ingestion of eggs. When a dog ingests beef or lamb containing
cysts, the life cycle is completed. Humans acquire echinococcosis
by ingesting viable eggs with their food. Once in the intestinal
tract, eggs hatch to form oncospheres that penetrate the mucosa
and enter the circulation. Oncospheres then encyst in host viscera, developing over time to form mature larval cysts.
Symptoms are often absent and infection is detected incidentally by imaging studies. The liver (50%–70% of patients) and the
lungs (20%–30% of patients) are the most common sites involved.

Some patients present with abdominal pain or a palpable mass in
the right upper quadrant. Compression of a bile duct or leakage
of cyst fluid into the biliary tree may mimic recurrent cholelithiasis, and biliary obstruction can result in jaundice. Rupture
of a hydatid cyst may produce fever, pruritus, urticaria, eosinophilia, or anaphylactoid reactions. Pulmonary hydatid cysts may
rupture into the bronchial tree or peritoneal cavity and produce
cough, chest pain, or hemoptysis. A dangerous complication of
cyst rupture is dissemination of protoscolices, which can form
additional cysts. Rupture can occur spontaneously or at surgery.
Other complications include involvement of bones, CNS, heart,
and pelvis. Allergic reactions, including urticaria, asthma, and
anaphylaxis are rare.
Diagnosis can be achieved by complementing imaging studies
with specific ELISA and Western blot serology (available through
the Centers for Disease Control and Prevention). Therapy is
based on considerations of the size, location, and manifestations
of cysts and the overall health of the patient. Optimal treatment
of symptomatic cysts is obtained by surgical resection. An intermediate intervention for inoperable cysts is available, known as
the PAIR (percutaneous aspiration, infusion of scolicidal agents,
and reaspiration) procedure. For prophylaxis of secondary peritoneal echinococcosis due to inadvertent spillage of fluid during
PAIR, the administration of albendazole (15 mg/kg daily in two
divided doses) should be initiated at least 4 days before the procedure and continued for at least 4 weeks afterward.
Sparganosis
Sparganosis refers to the disease caused by the sparganum, second larval state of tapeworms of the genus Spirometra (mainly
Spirometra mansonoides), a parasite of fish. The disease is prevalent in Asia, with some cases reported in North America plus
sporadic cases seen in Australia, South America, and Europe.
The definitive hosts are canids and felines, and the cycle includes
larval states inside Cyclops, copepods, and amphibians. Humans
get the infection by three routes: ingestion of contaminated
amphibian meat, fish, or reptiles, drinking of water contaminated with infected Cyclops, and more rarely by the application
of raw meat contaminated with plerocercoid over open wounds
as folk remedies. The infection in humans will result in the
development of a subcutaneous mass, where the plerocercoid
will end up in a developmental form. Masses can be situated
in deep structures or internal organs. The subcutaneous mass
may have a migratory pattern, similar to what is seen in gnathostomiasis, a disease with a similar form of transmission. The
diagnosis will be established by finding the worm in histological
cuts of a subcutaneous mass, or even during surgery for acute
abdominal pain. A more dramatic form with massive infiltration by multiple worms and high mortality rate has been associated with Spirometra proliferum.
Coenurosis
Coenurosis results when humans accidentally ingest coenurus
(larval stage) of the dog tapeworm Taenia multiceps, Taenia serialis, or Taenia crassiceps, usually in contaminated fruits or vegetables. Larvae of these species may be inoculated directly into a
child’s conjunctiva and skin as the child plays on contaminated
ground. This rare infection has been reported in Africa, and in
North and South America. As in cysticercosis, involvement of

130 — Francisco G. Bravo and Salim Mohanna

the CNS, the eye, and subcutaneous tissue is most common.
Surgical excision is the recommended therapy.

Trematodes
Members of this phylum share the classic, thick, oval leaf shape
with variation in sizes. For clinical purposes this phylum could
be divided according to the habitat in the infected host: blood
flukes, hepatic flukes, intestinal flukes, and lung flukes. Human
infection with trematodes occurs in many geographic areas and
can cause considerable morbidity and mortality.
Schistosomiasis
Schistosomiasis or bilharziasis is the disease associated with
infections by the flukes belonging to the genus Schistosoma.
Humans get infected by coming into contact with water infested
by the fluke. The disease is quite prevalent in the sub-Saharan
African countries and Egypt. There are three species clearly associated with human beings: Schistosoma hematobium, Schistosoma
mansoni, and Schistosoma japonicum. Whereas S. hematobium
is associated with urogenital and late cutaneous schistosomiasis, S. mansoni and S. japonicum is associated with gastrointestinal disease. A very important group is the avian Schistosoma
species associated with cercarial dermatitis. Human schistosomiasis is a disease of the fresh water cycle, whereas cercarial dermatitis of the avian type can occur either in fresh or salt water.
The cycle requires that the eggs be eliminated in human urine or
feces in order to reach the water and then infect an intermediate host, such as a snail. The cercariae, the infective larvae, will
be produced inside the snail and then liberated into the water,
where they can infect the human. The disease is acquired in the
first and second decade of life, with a decline of the infection
toward adulthood. The environmental impact of irrigation and
hydroelectric projects will result in the development of new
endemic areas.
The disease manifests itself by the immune response to
invading and migrating larvae as well as to the presence of eggs
in host tissue. Cercarial dermatitis refers to the clinical picture
elucidated by the penetration of cercaria into the skin. In human
schistosomiasis, it is most commonly seen in visitors to endemic
areas rather than in permanent residents. That is not the case for
avian cercarial dermatitis (swimmers itch), where anyone can be
affected. This last form is self-limited, although symptoms will be
similar for human and avian parasites. The clinical findings are
those of an acute pruritic, papular rash at the site of the cercarial
penetration, usually areas exposed to the water. The erythema
and urticarial rash will be accompanied by a prickling sensation.
The symptoms will peak at 2 to 3 days and resolve after 5 to 7
days, leaving post-inflammatory hyperpigmentation.
Acute schistosomiasis will appear 2 to 16 weeks after the cercarial phase. The symptoms will be similar to acute serum sickness,
with fever, aches and pains, headache, fatigue, anorexia, diarrhea,
and nausea (Katayama syndrome). Organomegaly can be seen.
The disease usually lasts 2 to 3 weeks. It is caused by migration of
the juvenile worm in the bloodstream. The worms will then reach
their final destination, the venus plexus in the bladder, genital and
groin areas in the case of Schistosoma hematobium, and mesenteric areas in cases of S. mansoni, and S. japonicum. The chronic
visceral schistosomiasis will then manifest as symptoms related

to the particular organ involved, that is, hematuria, obstructive
uropathy, and hydronephrosis for S. hematobium. Diarrhea and
bloody stools are more characteristic of S. mansoni and S. japonicum infection. Late cutaneous schistosomiasis will be produced
as a reaction to chronic deposition of eggs in the dermis and subcutaneous tissue. It is commonly associated with S. hematobium
infection. The clinical picture will be of clusters of pruritic papules, which then may coalesce into lichenified plaques. Classic
locations include the anogenital areas, periumbilical areas, chest,
and upper back. A zosteriform distribution may also be seen.
Involvement of female genitalia is quite characteristic. Pruritus
may lead to significant self-inflicted injury.
The diagnosis of cercarial dermatitis is based on the clinical
history. It is based on the history of exposure to contaminated
water of endemic areas associated with fever in the case of acute
schistosomiasis, plus the presence of eggs in feces or urine and
a positive serology. For chronic schistosomiasis, the diagnosis is based on the development of atypical pruritic lesions in
patients residing in or traveling to endemic areas of S. hematobium. This last diagnosis can be corroborated by the presence
of eggs in urine or in the biopsy of skin lesions accompanied by
granulomatous reactions. Prevention of cercarial dermatitis is
based on avoiding contact with contaminated water or the use
of DEET as a repellent. Treatment of cercarial dermatitis and
acute schistosomiasis should be directed toward treating the
symptoms. Chronic schistosomiasis can be effectively treated
with a single dose of praziquantel, or artemisine as an alternative treatment.
Fasciolasis
This infection occurs particularly in regions with intensive
sheep or cattle production. Human cases have been reported in
South America (high endemicity in Peru, Ecuador, and Bolivia),
Europe, Africa, Australia, China, and Egypt. The predominant
species is Fasciola hepatica, but in Asia and Africa an overlap
with Fasciola gigantica has been reported.
Infection is acquired by ingestion of contaminated watercress, other aquatic plants, contaminated water, or food washed
with such water. After ingestion, metacercariae excyst and penetrate the intestinal wall, peritoneal cavity, and Glisson capsule
to reach the biliary system, where they mature into adult worms
and deposit their eggs. These eggs are excreted in feces (about 4
months after infection) and then continue the cycle of infection
in specific snails and encyst on aquatic plants.
The early phase of migration is characterized by fever, right
upper quadrant pain, hepatomegaly, eosinophilia, and positive serologic findings. After migration to bile ducts, symptoms
decline or disappear. Larvae sometimes also travel to ectopic
body sites. Subcutaneous fascioliasis presents with painful or
pruritic subcutaneous nodules, although this condition is rare.
Diagnosis of infection is based on a high degree of suspicion, geographic history, and finding of the characteristic ova in
the feces. Eosinophilia occurs in 95% of acute stage infections,
but may wax and wane during the chronic stage of infection.
Magnetic resonance and computed tomography have been useful in detecting migratory tracts. New serologic tests may help in
establishing the diagnosis. The drugs of choice are triclabendazole (10 mg/kg PO once) or praziquantel (25 mg/kg PO TID for
1 day).

Parasitology — 131

Paragonomiasis
Paragonimus westermani is the most common lung fluke in
humans. These species are endemic in Africa, Asia, and Central
and South America. Humans acquire lung fluke infection
when they ingest raw or pickled freshwater crabs or crayfish
with encysted metacercariae. Once the organisms reach the
small intestine, they excyst and penetrate the intestinal wall
into the peritoneal cavity, traveling through the diaphragm to
reach the pleural space and lungs. Mature flukes are found in
the bronchioles, where they can live for 20 years or more. Eggs
are expelled with sputum or swallowed and passed in human
feces. The life cycle is completed in snails and freshwater
crustacea.
Clinical manifestations include abdominal pain, diarrhea,
and urticaria during the acute phase. These initial symptoms
are followed by fever, dyspnea, chest pain, malaise, sweats,
and dry cough followed by a productive cough with brownish sputum or hemoptysis. Chest examination may reveal
signs of pleurisy. Extrapulmonary paragonomiasis can occur
either from the migration of young or mature flukes to various organs or from eggs that enter the circulation and are
carried to different sites. Subcutaneous paragonomiasis presents with migratory swelling or subcutaneous nodules in the
lower abdominal and inguinal region containing immature
flukes. Scrotal paragonomiasis may mimic epididymitis or an
incarcerated hernia.
Paragonomiasis should be suspected in patients with eosinophilia and chest complaints. Diagnosis is confirmed by finding
eggs in sputum, in feces, or pleural fluid. In extrapulmonary
cases, serologic examination may be helpful. The drug of choice
is praziquantel (25 mg/kg PO TID for 2 days).

P I T FA L L S A N D M Y T H S

One important myth in parasitology is to regard cutaneous larva
migrans as a disease relevant only to tourist and leisure travelers.
In fact, cutaneous larva migrans, along with tungiasis and papular urticaria, are extremely common in developing countries,
and should be approached not only as mere medical curiosities
but also as public health problems requiring the attention of local
authorities and international health agencies.
A common misconception regarding American leishmaniasis is failure to recognize the important role that the immune
system has in the pathogenesis of the disease. Most of the tissue
destruction one can see in mucocutaneous leishmaniasis can
be explained on the basis of marked cytokine imbalance seen
in those patients, rather than a direct injury induced by the
protozoa. Cure has been associated with a TH1 response, and
increased production of IL-2 and gamma-interferon. Failure to
cure, on the other hand, has been related to a TH2 response
with excessive production of IL-4 and IL-10. Similarily, while
TNF-α plays an important role in the destruction of the parasite, an excess of this cytokine is very much responsible for the

associated tissue destruction that can be seen in mucocutaneous
disease.
Another common pitfall in the care of leishmaniasis caused
by L. braziliensis is failure to recognize the character of systemic
disease and its potential for dissemination from just pure cutaneous disease. When dealing with cutaneous leishmaniasis of the
New World, physicians are obligated to consider the possibility
for mucocutaneous disease later. If any chance of L. braziliensis
infection does exist, systemic treatment is obligatory. Although
not 100% protective, systemic treatment will decrease the risk of
developing mucocutaneous disease years later.

SUGGESTED READINGS

Textbooks
Canizares O, Harman R. Clinical tropical dermatology, 2nd edition.
Boston, Blackwell Scientific, 1992.
Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett´s
Principles and Practice of Infectious Diseases, 5th edition. Churchill
Livingstone, 2000.
Tyring S, Lupi O, Hengge U. Tropical Dermatology. Philadelphia:
Elsevier, 2006.

Protozoa
Bravo F, Sanchez MR. New and re-emerging cutaneous infectious diseases in Latin America and other geographic areas. Dermatol Clin
2003;21(4):655.
Kichhoff LV. Agents of African Trypanosomiasis (Sleeping Sickness).
In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and
Bennett´s Principles and Practice of Infectious Diseases, 5th edition.
Churchill Livingstone, 2000, 2853–2858.
Kichhoff LV. Trypanosoma Species (American Trypanosomiasis,
Chaga’s Disease): Biology of Trypanosomes. In: Mandell GL,
Bennett JE, Dolin R, editors. Mandell, Douglas and Bennett´s
Principles and Practice of Infectious Diseases, 5th Edition. Churchill
Livingstone, 2000, 2845–51.
Maudlin I. African trypanosomiasis. Ann Trop Med Parasitol
2006;100(8):679–701.
Moncayo A, Ortiz Yanine MI. An update on Chaga’s disease
(human American trypanosomiasis). Ann Trop Med Parasitol
2006;100(8):663–677.
Singh S. New developments in diagnosis of leishmaniasis. Indian J Med
Res 2006;123(3):311–330.

Helminths
Heukelbach J, Mencke N, Feldmeier H. Cutaneous larva migrans and
tungiasis: the challenge to control zoonotic ectoparasitoses associated with poverty. Trop Med Int Health 2002;7(11):907–910.
Keiser J, Utzinger J. Emerging foodborne trematodiasis. Emerg Infect
Dis 2005;11(10):1507–1514.
Pozio E, Gomez Morales MA, Dupouy-Camet J. Clinical aspects, diagnosis and treatment of trichinellosis. Expert Rev Anti Infect Ther
2003;1(3):471–482.

PA R T I I I : I N F E C T I O N S I N S E L E C T E D
ECOSYSTEMS

10

INFECTIONS IN THE DESERT
Joseph C. Pierson* and David J. DiCaudo*

Deserts make up over one-fifth of the earth’s land surface.
These areas have traditionally been defined as regions with
low precipitation, <10 inches (<250 mm) annually. Potential
evapotranspiration, in conjunction with precipitation levels,
may more accurately delineate desert regions as it reflects the
amount of water the atmosphere removes from the earth’s surface. For example, the Tucson, Arizona area, which slightly
exceeds 10 inches of rainfall annually, experiences evaporation
that can be eight times higher than that amount. Nonpolar deserts are typically hot, have low humidity, and are characterized
by extremes of their diurnal temperature range (high during
the daylight, relatively low during the nighttime). The terrain of
these dry regions is often dominated by sand and rocky surfaces
with sparse vegetation.
There are two main infectious diseases of dermatologic
significance that occur primarily in, or adjacent to the arid
desert regions of the globe: Old World cutaneous leishmaniasis and coccidioidomycosis. The former is limited to the
Eastern Hemisphere, while the latter is limited to the Western
Hemisphere. There is a striking absence of either disease occurring naturally in the opposite hemisphere, and they are discussed
separately here.

EASTERN HEMISPHERE: OLD WORLD
C U TA N E O U S L E I S H M A N I A S I S

Leishmaniasis is a protozoal infection transmitted by the bite
of a sandfly. The three main clinical syndromes are cutaneous,
mucocutaneous, and visceral infections. The cutaneous leishmaniasis (CL) presentation is most common, with the World
Health Organization estimating 1.5 million cases each year. CL is
further classified by geography: Old World (eastern hemisphere)
and New World (western hemisphere) subtypes, each transmitted by a different genus of the sandfly vector, which cause
infection by different Leishmania protozoa species with variable behavior. New World (western hemisphere) leishmaniasis
occurs in tropical and subtropical regions. The more common
Old World CL is seen most frequently in desert regions throughout the Middle East, Central and Southwest Asia, and elsewhere
in Asia, Africa, and the Mediterranean regions. It is transmitted
by the Phlebotomus genera sandfly vector. The identified parasites harbored by the Phlebotomus sandfly in Old World CL are
primarily Leishmania major and Leishmania tropica, and less

commonly Leishmania aethiopica and Leishmania infantum in
Ethiopia and the Mediterranean, respectively.
Old World CL is the most important unique skin infection
afflicting those who reside or travel in desert environments of
the eastern hemisphere. Lesions present clinically following an
incubation period of weeks to months. Although CL typically
heals spontaneously, it can cause disfiguring active lesions or
scarring. The diagnosis should be considered in any individual
who presents with chronic persistent skin lesions and a history
of being in an endemic region in the months before presentation. Although commonly referred to as the “Baghdad boil”
over the last century, the city with the highest incidence now
is actually Kabul, Afghanistan. Primary prevention of the disease-transmitting sandfly bite remains the most critical step in
reducing the impact of CL worldwide. No standardized effective
vaccine currently exists. Traditional methods of diagnosis and
treatment have been well described in texts over the past several
decades. However, there are major advances in both diagnostic
techniques and therapeutic options that will be emphasized in
this chapter.

History
Written descriptions typical of Old World CL appeared as early
as the second or third millennium B.C. The Leishmania protozoa were discovered in 1885 by a British investigator, Major
Cunningham from a “Delhi boil.” Definitive proof that the protozoa caused the disease was established by other British physicians, Colonel Leishman and Colonel Donovan in 1903. Old
World CL received significant global interest during World Wars
I and II, when thousands of international soldiers were afflicted
with the disease.
In some cities infection is so common and so inevitable
that normal children are expected to have the disease
soon after they begin playing outdoors, and visitors seldom escape a sore as a souvenir. Since one attack gives
immunity, Oriental sores appearing on an adult person
in Baghdad brands him as a new arrival … Introduction
to Parasitology, 1944
Numerous pseudonyms have been used to describe Old World
CL by both laymen and clinicians alike (Fig. 10.1).

Epidemiology
* Eastern Hemisphere: Old World Cutaneous Leishmaniasis by Joseph C. Pierson
* Western Hemisphere: Coccidioidomycosis and the Skin by David J. DiCaudo

Old World CL occurs predominantly in the eastern hemisphere
in areas highlighted in the map in Figure 10.2. Inhabitants
135

136 — Joseph C. Pierson and David J. DiCaudo

of both rural desert and urban areas are at risk. World Health
Organization data show Kabul, Afghanistan, had 67,500 cases of
the disease in 2003 – amounting to one-third of infected individuals in that country.
There is no racial predilection. Incidence may be higher in
men from occupational exposures, and also perhaps because
they have more uncovered skin than females in endemic regions,

Old World CL Historical Pseudonyms
Oriental sore
Biskra button
Delhi boil
Aleppo boil
Lahore sore
Baghdad boil

Figure. 10.1. Old World cutaneous leishmaniasis pseudonyms.

whose attire is often more concealing due to religious customs.
The disease can afflict patients of any age, although those very
young and very old may be more prone to complications of the
disease due to reduced immunity.

Transmission: Sandfly Vector and Leishmania
Lifecycle
The 2-mm long female Phlebotomus sandfly vector is a poor flyer,
vulnerable to gusts of wind, and moves via a series of short hops
(Fig. 10.3). Because of their small size, the sandflies are capable of passing through standard untreated mosquito netting.
Ecosystems with feces, manure, rodent burrows, and leaf litter
heighten sandfly breeding activity. It is typically most capable
of transmitting leishmaniasis in the warmer nights during the
spring through autumn months.
In Old World CL caused by L. major, transmission is zoonotic (typical of most Leishmania species) via the Phlebotomus
papatasi sandfly. The reservoir hosts for the Leishmania parasite
are mainly rodents and dogs, and also equines, opossum, sloth,
and monkeys. Humans are actually incidental hosts. In L. tropica, transmission is anthroponotic via the Phlebotomus sergenti
sandfly. Humans are the reservoir, and no known animal reservoir exists (Fig. 10.4).
When an infected sandfly bites a human, the leishmaniasis
promastigotes are injected into the skin. Once phagocytized
by mononuclear cells, they become amastigotes, where their

×
× ×
×
××
× ×
× ×× ××
×
× × × × ×
× × × ×
×
× × ×

Lebanon

L. major
L. tropica

Israel

× L. aethiopica
L. infantum

Figure. 10.2. Geographic distribution of Old World cutaneous leishmaniasis.

Jordan

Infections in the Desert — 137

intracellular presence disrupts normal cellular immunity. It
is during the amastigote phase that a subsequent sandfly may
ingest the parasite, which develops into a promastigote form
again within the insect vector. The pathogen can persist locally
in its host following clinical cure, a reflection of the elusive durability of the parasite despite host immune mechanisms.

Prevention
Currently, the three components of prevention of leishmaniasis are (1) suppression of the host (usually rodent or dog)

Figure. 10.3. Phlebotomus sp. sandfly, the vector of the parasite
responsible for Old World cutaneous leishmaniasis.

reservoir, (2) suppression of the sandfly vector, and most
importantly, (3) personal protective measures.
Host suppression can be done systematically where high rates
of Old World CL due to the zoonotic transmission of L. major are
seen. Bulldozing of rodent burrows and euthanizing of infected
dogs can be helpful. Another approach is insecticide treatment
of reservoir hosts, by pumping the agent into rodent burrows or
by using delmethrin-treated dog collars.
The sandfly vector within living areas can be reduced by area
environmental insecticide spraying. This may be beneficial in
urban areas, though it is often impractical or ineffective in rural
areas where dwellings are more dispersed.
The critical personal protective measures include limiting
outdoor activity during nocturnal hours, permethrin-treated
clothing with long-sleeved shirts tucked into trousers, which
in turn, are tucked into socks or boots, the application of topical insecticides, permethrin-treated bed nets, and bedside fans.
The permethrin-treated clothing will maintain efficacy through
numerous washings. Exposed skin applications of diethyltoluamide (DEET) concentrations of 25% to 35% are recommended
for those above 12 years. Sandfly bed nets are a finer mesh
(smaller hole diameter: 18 holes/square in.) than standard mosquito bed nets, which may be warm for the sleeping occupant.
Soaking the bed nets in permethrin should improve their effectiveness. In the absence of appropriate netting material, bedside
fans may protect individuals by the limiting the approach of the
relatively awkward flying vector.
There is no effective prophylactic medication, nor currently licensed effective vaccine. A killed Leishmania promastigote combined with BCG vaccine has been tested. It
should be noted that individuals infected by one species of

Old World CL Transmission
L. major and L. tropica
1- Sandfly bites animal or human and
ingests blood infected with Leishmania
(L. major –zoonotic, animal reservoir, or
L. tropica – anthroponotic, human
reservoir)

4- Cycle continues when
sandfly bites another
animal (L. major zoonotic ) or human (L.
tropica - anthroponotic)
reservoir

2- Sandfly bites human and injects
Leishmania into skin

3- Another sandfly bites human and
ingests blood infected with Leishmania

Figure. 10.4. Old World cutaneous leishmaniasis transmission cycle.

138 — Joseph C. Pierson and David J. DiCaudo

Leishmania are generally immune to reinfection from that
specific species.

Clinical Presentation
The time range from the entry of the Leishmania amastigote
within a human macrophage to the appearance of clinical lesions
can vary from several days to years, but incubation is usually 2 to
12 weeks. Although the widely described lesion is a painless volcano-like ulceration with rolled borders, it can be a polymorphic
“great imitator” disease and clinicians should keep the broad
list of differential diagnoses in mind when evaluating suspected
cases (Fig. 10.5).
The diversity in both incubation period and clinical appearance results from the variable interplay between the virulence
of the infecting protozoa and the host immune response.
Ultimately, uncomplicated cases in immunocompetent hosts
tend to heal with variable degrees of scarring months to over
a year later.
Classically, an individual with a history of endemic region
exposure in the preceding 2 to 12 weeks initially presents with
one or several inflammatory macules, papules, nodules, or
plaques on exposed skin sites. They may recall transient papules typical of arthropod bite reactions weeks or months earlier. Individuals with significant outdoor nocturnal exposures
in endemic regions may experience hundreds of such sandfly
bite reactions. Ulceration, which may become “volcano-like”
with rolled borders, can occur early or later in the progression of the disease process. Crusting, scaling, and concentric
rings of desquamation may be seen. As a bacterial infection

is often initially suspected, there may be a prior history of
failure to respond to systemic antibiotic treatment, although
this may clear any element of secondary bacterial infection.
The lesions typically do not itch or hurt, although pain may
occur if large, overlying joints are subjected to trauma or secondarily infected. Underlying neural involvement can rarely
cause diminished sensation of lesional skin. Orientation along
skin tension lines and lesion grouping are commonly seen.
Satellitosis of smaller papules and nodules, proximal subcutaneous nodules in a lymphangitic sporotrichoid pattern,
and regional adenopathy are seen in a significant minority
of cases. These changes suggest cutaneous dissemination. In
general, patients do not complain of systemic symptoms and
are not febrile. A summary of the clinical findings that should
raise the suspicion of a diagnosis of CL has been described by
Kubba (Fig. 10.6). See Figures 10.7 to 10.11 for representative
cases of CL.
Among the myriad atypical lesions that may be seen in localized cases of Old World CL are psoriasiform, verrucal, zosteriform, erysipeloid, and eczematous presentations. An olecranon
bursitis underlying psoriasiform Old World CL has been seen
in U.S. service members. L. aethiopica may rarely cause a diffuse
Old World CL pattern in Africa in those who fail to mount an
appropriate immune reaction.
Post-kala-azar dermal leishmaniasis is not a primary form of
Old World CL, but rather a phenomenon seen in those recovering from visceral leishmaniasis in Africa and India. Symmetrical
macules, papules, and nodules are seen on the face (which can
cause a leonine facies), and less commonly on the trunk and
extremities.

Old World CL Differential Diagnosis
Arthropod bite
Foreign body reactions
Brown recluse spider bite
Eczema
Psoriasis
Skin cancer (basal cell carcinoma, squamous cell carcinoma)
Pyoderma gangrenosum
Sarcoidosis
Myiasis
Bacterial infections: (cutaneous anthrax, diptheria, tularemia, Staphylococcal and
Streptococcal species)
Treponemal infections: (syphilis, yaws)
Mycobacterial infections:( TB, leprosy, atypical mycobacteria: M. Marinum, others)
Fungal infections: (kerion, blastomycosis, sporotrichosis, paracoccidodomycosis)
Viral infections: (warts)

Figure. 10.5. A partial list of the differential diagnosis of Old World cutaneous leishmaniasis.

Infections in the Desert — 139

Clinical Features That Should Arouse
Suspicion of Old World CL (Kubba)
Exposed site location
Pairing or clustering of lesions
Orientation of the sore along the skin crease
Volcano-like ulcer
Inflammatory satellite papules <2 cm from primary
Proximal subcutaneous nodules
Subcutaneous induration beneath skin lesion

Figure. 10.6. Clinical features that should arouse suspicion of a
diagnosis of Old World cutaneous leishmaniasis.

Figure. 10.8. Linear array of crusted papules corresponding to sites
of earlier sandfly bites in a patient with cutaneous leishmaniasis.
(Courtesy of Dr. Glenn Wortmann).

Figure. 10.10. Multiple crusted papules and plaques of the neck with
accompanying visible regional adenopathy in a patient with cutaneous leishmaniasis. (Courtesy of Dr. Peter Weina).

Figure. 10.7. Volcano-like ulceration of the dorsal hand in a patient
with cutaneous leishmaniasis.

Figure. 10.9. Crusted ulceration of the upper eyelid in a patient with
cutaneous leishmaniasis. (Courtesy of Dr. Peter Weina).

Figure. 10.11. Granulomatous plaque of forearm in a patient
with cutaneous leishmaniasis. A punch biopsy with tissue impression “touch prep” smears would be the procedure of choice for the
cytologic diagnosis of nonulcerative lesions.

140 — Joseph C. Pierson and David J. DiCaudo

Cases of mucocutaneous spread of Old World CL due to L.
major and L. aethiopica are debatable as these could be instances
of direct extension of skin lesions, rather than metastatic spread
of the organism.
Scarring occurs in a centrifugal fashion within months of
reaching maximum lesion size, but this may take nearly 2 years.
The resulting scar is characteristically atrophic and depressed.
However, dyspigmented, violaceous, and hypertrophic scarring can be seen. Permanent scarring that can be disfiguring in
cosmetically significant areas can be psychologically devastating
for patients, while scarring overlying critical joint areas can limit
mobility.
Leishmaniasis recidivans is a late recurrence of the disease
process at the site of a healed lesion, usually within 2 years, but
sometimes more than a decade later. It is usually due to L. tropica
in Old World CL, often appears as psoriasiform or lupus vulgaris-like “apple-jelly” papular or nodular lesions beginning at the
periphery, and is notoriously treatment resistant.
Systemic spread of Old World CL is extremely rare, but
was reported in several US troops following Operation Desert
Storm in 1991 from L. tropica infection. Systemic spread, when
it occurs, is more likely to occur in immunocompromised individuals, such as those infected by human immunodeficiency
virus (HIV).

Dermal Scraping Technique for
Leishmania Tissue Smears
1.
2.

3.
4.

Anesthetize the area with a local agent such as lidocaine 1%
with epinephrine 1:105 (unless the latter is contraindicated).
Obtain 2 to 4 tissue smears by horizontally scraping the base
of the ulceration with a # 10 or #15 blade (this may require
removal of the overlying crusted debris). The dermal tissue is
then thinly applied in a circular fashion to a nickel-sized
(approx. 2 cm) area in the center of the slide.
As the dermal tissue is required for pathologic visualization,
minimize blood, keratin, pus, and crusted debris on slide.
Dermal tissue for ancillary PCR testing can be inserted into a
small container of 70-100% ethanol. Overlying crusted debris
may also be submitted for PCR analysis.

Figure. 10.12. Instructional steps for collection of dermal scrapings
for Leishmania tissue smears.

Collection of Dermal Scrapings for Tissue
Smears and PCR
Minimize blood, keratin, pus, and crusted debris on slides

Diagnostic Procedures
When inflammatory lesions from a patient with exposure in
endemic region promptly resolve with an empiric course of
antibiotics, this generally excludes a diagnosis of Old World CL.
For persistent lesions, laboratory testing of tissue specimens
from suspected cases serves to confirm the diagnosis of CL
and can exclude other disease processes. As early therapeutic
interventions may reduce subsequent disfiguring or restrictive
scarring, a simple diagnostic procedure with high sensitivity and specificity is ideal. Dermal scraping tissue smears and
punch biopsy with tissue impression “touch prep” smears are
widely employed. Both techniques yield specimens on glass
slides. However, the quality of tissue samples submitted with
either procedure can vary with the diligence and experience of
the clinician, and even when optimal, the sensitivity for both
techniques can be a modest 70% to 75%. In addition to sample
quality variability, which is operator dependent, the diligence
and experience of the microscopist can vary and further impact
diagnostic yield.
Dermal scraping of suspected Leishmania lesions for tissue smears may be optimal when the lesion is ulcerative or
the overlying crust is easily removed, yielding the underlying
ulceration. Stepwise instructions and images of the procedure
are shown in Figures 10.12 and 10.13. Dermal scraping tissue
smears may have a better diagnostic yield than punch biopsy
tissue specimens since the latter have a more dense tissue
background.
Punch biopsies are recommended for nonulcerative lesions.
In addition, the advantage of performing a punch biopsy in
leishmaniasis diagnosis is that the specimen can simultaneously
be examined for other diseases in the differential diagnosis. This
is particularly important for atypical lesions, papules, nodules,
and plaques. The punch should be obtained from an active bor-

Figure. 10.13. Sequential photographs of the performance of dermal
scraping collection for tissue smears and PCR. (Courtesy of Dr.
Glenn Wortmann).

der, the excess blood is blotted, and then the cut edge rolled onto
a glass slide creating the tissue impression smear.
Another option for obtaining specimens from papular or
nodular lesions is through needle aspirates. A needle aspirate can
be obtained by injecting preservative-free saline (0.1 mL) into a
lesional border of intact skin, and then aspirating while moving
the needle back and forth under the skin. A slit-skin smear technique for slide preparation is also used in some countries.
Slides obtained by any of the above techniques are stained
with Giemsa and examined under oil immersion. The diagnostic
feature is the finding of the nucleus and rod-shaped kinetoplast of
the amastigote within the vacuoles of macrophages (Fig. 10.14).
Amastigote kinetoplast visualization is critical in differentiation
from Histoplasma capsulatum.
Formal histology of punch biopsy specimens submitted
for H&E sections will reveal inflammation with lymphocytes,

Infections in the Desert — 141

macrophages, and plasma cells in the dermis. Necrotizing granulomas may also be seen. Upper dermis macrophages may reveal
the engulfed amastigotes, which usually stain well with H&E
or Brown-Hopps modified tissue Gram’s stain. The latter stain
accentuates the kinetoplast and produces minimal background
staining and maximum contrast. Oil immersion observation
with a 100x objective is necessary, and multiple tissue sections
may need to be reviewed before identification of the parasite
(Fig. 10.15).
A portion of punch biopsy or needle aspirates can be sent for
microbiologic culture identification. Specimens are inoculated
for cultures on Novy-MacNeal-Nicolle biphasic or Schneider’s
insect media. Culture allows Leishmania speciation via subsequent isoenzyme electrophoresis. This requires specialized

Figure. 10.14. A tissue impression smear illustrating the
characteristics of an amastigote, with thin cell membrane,
cytoplasm, nucleus, and kinetoplast (arrow) (Giemsa stain;
original magnification, _1000). (Courtesy of Mr. Ron Neafie).

laboratories and strong microbiologist skills. The main disadvantage is that results may take several weeks.
Delayed-type hypersensitivity (Montenegro) skin testing
to Leishmania antigens is not available in the United States or
Canada. This intradermal testing is performed as a diagnostic
adjunct in many endemic countries, but is not standardized, and
cannot distinguish between acute and remote infections.
The exciting key diagnostic advance in leishmaniasis is the
use of polymerase chain reaction (PCR)–based amplification
technology, which detects Leishmania nucleic acid sequences.
Tissue collection for PCR testing is very simple, even for the novice, and more importantly, it has the highest sensitivity, and is
highly specific. It will likely become the gold standard wherever
available.
PCR testing is ideally performed from fresh tissue specimens
(such as the tissue debris obtained from dermal scraping – see
Fig. 10.13) merely inserted into 70% to 100% ethanol, but can
also be done on paraffin-embedded tissue. In addition to the
simplicity of specimen collection, results are available within
hours, the sensitivity is >90%, and it is relatively inexpensive.
Kinetoplast, telomere, nuclear DNA, and ribosomal RNA amplification targets have been used.
Delayed-type hypersensitivity (Montenegro) skin testing
to Leishmania antigens is not available in the United States or
Canada. This intradermal testing is performed as a diagnostic
adjunct in many endemic countries, but is not standardized, and
cannot distinguish between acute and remote infections.
Serologic immunodiagnosis is useful only for visceral
leishmaniasis.
Free diagnostic assistance in the United States for civilian
providers is available through the Centers for Disease Control
and Prevention (CDC): phone 770–488–4475, online http://
www.dpd.cdc.gov/dpdx/HTML/DiagnosticProcedures.htm
For U.S. military providers, diagnostic assistance is available
through Walter Reed Army Institute of Research: phone 301–
319–9956, online http://www.pdhealth.mil/leish.asp
Pathology assistance is available through the Armed Forces
Institute of Pathology: online http://www.afip.org/

Treatment

Figure. 10.15. A tissue section cut at 4μm illustrating an
amastigote, with thin cell membrane, cytoplasm, nucleus, and
kinetoplast (arrow) (hematoxylin and eosin stain; original
magnification, _1000). (Courtesy of Mr. Ron Neafie).

The goal of any treatment options used in Old World CL is to
reduce subsequent disfiguring or mobility-limiting scarring.
As CL is a self-resolving process, no treatment is an option.
This is particularly true for patients infected by L. major, whose
lesions are small, few in number, and at concealed locations
such as the trunk and proximal extremities, especially if they
are in the resolution phase. There are several newer physical
modalities and topical and oral therapeutic options that can
be utilized in the majority of patients requiring treatment. In
general, as opposed to New World CL, only a small minority
of Old World CL patients eventually need aggressive systemic
therapy. A suggested algorithm for the treatment of Old World
CL is shown below (Fig. 10.16). Note the lower threshold
for aggressive therapy of Old World CL due to the L. tropica
parasite because of its tendency for therapeutic recalcitrance.
Regardless of the Leishmania specific therapy employed, identification and treatment of secondary bacterial infection plays
an important role.

142 — Joseph C. Pierson and David J. DiCaudo
Old World Cutaneous Leishmaniasis1

L major

If condition meets all criteria:
Single or few lesions
Uncomplicated lesions2
No lymphocutaneous involvement

Lesion size < 1 cm

Lesion size 1-3.5 cm

Observation3 or
Physical modalities4

Observation3 or
Physical modalities4 or
Oral azoles5 or
Topical paromomycin6

Wide arrows indicate
approach if treatment
failure occurs, defined as
lack of complete reepithelialization 2 months
after completing therapy.

Systemic pentavalent
antimonials for 10–20 days

L tropica

If condition meets 1 or more criteria:
Greater than 10 lesions
Lesion size > 3.5 cm
Complicated lesions
Lymphocutaneous involvement
Immunocompromised patients

Systemic pentavalent
antimonials for 10–20 days

Small (<1 cm),
localized,
uncomplicated lesions

Physical modalities4

All others

Systemic pentavalent
antimonials for 20 days

Systemic pentavalent
antimonials for 20 days
Repeat 20 days of systemic
pentavalent antimonials or
20 days of systemic pentavalent
antimonials with topical imiquimod
or
Systemic amphotericin deoxcholate
or
Intralesional injection of pentavalent
antimonials7

1. Secondary bacterial infections should be treated prior to using any physical methods, but this may be done
concurrently with systemic treatments.
2. Lesions are considered “complicated” if they are located on the hands, feet, over joints, or in cosmetically important
areas. Also consider if located above a bursa, sporotrichoid extension with subcutaneous nodules, multiple daughter
modules, or regional adenopathy > 1 cm in size.
3. Depending on patient wishes. L major typically resolves within one year if left untreated.
4. Physical modalities include heat (ThermoMedTM) or cryotherapy (liquid nitrogen) on aneshetized skin. Regimen
used for cryotherapy is two 30-second freeze-thaw cycles. Can be used in pregnancy; use with care in darkly-skinned
individuals (particularly cryotherapy) due to risk of permanent hypopigmentation. Avoid treatment directly over blood
vessels and nerves, implanted metal, or in those with a pacemaker (specifically, ThermoMedTM).
5. Ketoconazole, itraconazole, and fluconazole have all been used.
6. In the U.S., paromomycin capsules can be compounded into a topical formulation.
7. In some circumstances, pentavalent antimonials may be directly injected into skin lesions (although this is currently
not indicated in the U.S. IND protocols).

Figure. 10.16. A treatment algorithm for the treatment of Old World cutaneous leishmaniasis caused by L. major and
L. tropica. (Courtesy of Dr. Naomi Aronson).

The traditional physical modality treatment option of Old
World CL, particularly for smaller lesions, is cryotherapy with
liquid nitrogen. The recommended regimen is two 30-second
freeze–thaw cycles, which can be repeated in 3 weeks. Liquid
nitrogen treatment should be used with particular caution
in dark-skinned patients because of the risk of permanent
hypopigmentation.
A newer physical modality tool is the ThermoMed™ device
(Fig. 10.17). It is a portable, battery-operated United States
Food and Drug Administration (FDA)–approved device that
delivers localized heat via radiofrequency (50°C × 30 seconds).
Although simple to operate, it should only be used by individuals properly trained in its use. Local anesthetic is injected into
the area before treatment. Treatment on the face, over large
blood vessels or nerves, implanted metal, or in patients with
pacemakers should be avoided. A prominent bullous response
is often elicited in the ThermoMed™-treated area (Fig. 10.18).
Topical application of gentamicin antibiotic ointment (an aminoglycoside that may also have some anti-Leishmania activity)

Figure. 10.17. ThermoMedTM device showing prongs of hand piece that
are applied to the Leishmania lesions. (Courtesy of Dr. Naomi Aronson).

Infections in the Desert — 143

for several days following this localized heat therapy may reduce
secondary infection risk.
The results of a controlled study in 2002 suggest that oral
fluconazole 200 mg daily for 6 weeks speeds healing in Old
World CL. Subsequent experience with this agent, and other
azole antifungals, itraconazole, and ketoconazole, has yielded
mixed results. Reports of success with systemic azole antifungal
treatment of Old World CL have been primarily limited to the L.
major species. Liver function screening and monitoring should
be performed if these agents are utilized.
Topical paromomycin (aminosidine) formulations, an
aminoglycoside antibiotic, hold great promise as an option
for uncomplicated cases of Old World CL due to L. major.
When the agent is mixed with methylbenzonium chloride, an
efficacy of 74% was reported in the treatment of CL due to
L. major; however, local discomfort can occur. In the United
States, a paromomycin sulfate 15% with gentamicin sulfate
0.5% formulation (WR279396) has shown positive responses
in healing times and subsequent scar cosmesis in phase II placebo-controlled studies. Owing to its simplicity for both the
patient and the provider, coupled with the absence of blistering and dyspigmentation that may be seen with ThermoMed™
or cryotherapy treatments, if a paromomycin formulation of
equal or better efficacy is eventually FDA approved, it would
be an attractive alternative to the physical modalities described
earlier. Currently in the United States, some pharmacies can
compound paromomycin (15% paromomycin phosphate with
10% urea in white soft paraffin), which can be applied twice
daily for 3 to 4 weeks. Compounding pharmacies in the United
States can be located at http://iacprx.org/referral_service/
index.html
Aggressive systemic treatment of Old World CL is reserved
for specific scenarios as outlined in the algorithm. The standard
for aggressive systemic treatment of Old World CL remains a parenteral pentavalent antimony (PVA) agent. Pentostam (sodium
stibogluconate) is the agent used in the United States. In addition to relatively simple lesions that do not respond to earlier
measures, larger Old World CL lesions (>3.5 cm diameter for L.
major, >1cm for L. tropica), numerous lesions, lymphocutaneous

manifestations, and the presence of disease in an immunocompromised patient all may merit parenteral PVA treatment. Also,
patients with “complicated” lesions of the hands and feet, cosmetically conspicuous involvement of areas such as the face,
involvement overlying joints or bursa, or the presence of multiple satellite “daughter” lesions are appropriate candidates for
PVA treatment.
Pentostam (sodium stibogluconate) is only available in the
United States via an approved investigational new drug (IND)
protocol within the military (Walter Reed Army Medical
Center in Washington D.C., phone 202–782–1663/8691 and
Brooke Army Medical Center, San Antonio, TX, phone 210–
916–5554) or the CDC Parasitic Drug Services section (phone
404–639–3670) free of cost to civilian physicians for parasitologically confirmed cases. The dosage regimen is 20 mg/kg/day
for 10 to 20 days, with an overall efficacy ranging from 45%
to 100%. It is recommended that the outpatient administration
occur via a steel butterfly needle inserted into the antecubital
vein each day to eliminate the risk of device-related infections.
A timeline for the occurrence of side effects with this regimen
is shown in Figure 10.19. Common side effects are reversible
elevations of pancreatic and hepatic enzyme levels, arthralgias,
and myalgias. The musculoskeletal side effects are the most
common reason for early discontinuation of therapy. Although
severe cardiac problems are rare, note that a >0.5-second prolongation of the QT interval is an indication to stop therapy
temporarily.
Other PVA agents are used around the world, including
Glucantime (meglumine antimoniate) in Europe. Although
PVA in the form of Pentostam is only delivered intravenously in
the United States, intramuscular and intralesional protocols are
used in endemic areas. The intralesional route is advantageous
because of reduced side effects and decreased cost, but can be
painful.
Amphotericin B deoxycholate therapy, 0.5 to 1 mg/kg/day
for 14 to 30 days to a cumulative dose of 1 to 2 gm, is reserved
for Old World CL PVA treatment failures. It has a well-documented risk of nephrotoxicity and infusion-related allergic
reactions.

Sodium stibogluconate
(Pentostam®
(Pentostam®):
Timeline for Common Side Effects
Headache, fatigue, anorexia, nausea
Elevated liver function tests
Musculoskeletal symptoms
Elevated amylase & lipase. Cytopenias

Herpes zoster

Clinical pancreatitis
ECG abnormalities
Day0

Figure. 10.18. ThermoMedTM -treated area yielding representative
second-degree burn change.

Day10

Day20

Figure. 10.19. Chronology of common side effects during a 20-day
course of parenteral Pentostam

144 — Joseph C. Pierson and David J. DiCaudo

Miltefosine, an antineoplastic agent, has been used successfully
to treat various forms of leishmaniasis in both hemispheres of the
world. In a 2007 comparative study, oral miltefosine, 2.5 mg/kg/
day for 28 days was as successful in treating Old World CL as a
PVA agent and no patients showed serious side effects.
Published reports of successful treatment of Old World
CL with photodynamic therapy have appeared in recent years.
A 2006 series of five patients who underwent a regimen of
δ-aminolevulinic acid in a water-in-oil emulsion applied to
lesions, followed by irradiation once weekly for a month showed
excellent results with no scarring (Ghaffarifar). Only mild local
inflammatory reactions occurred at the treated areas.
Other oral agents, including allopurinol, dapsone, rifampicin, both oral and intralesionally injected zinc sulfate, and topical
imiquimod have been used to treat Old World CL, either alone
or in combination with a PVA, with variable results.
Regardless of therapeutic intervention (or nonintervention), complete healing and re-epithelialization of lesions with
no recurrence 6 months later is considered a clinical cure of CL.
In 2007, a systematic review of published randomized controlled
trials of Old World CL concluded that studies thus far were highly
variable in quality and methods, and provided weak evidence for
the treatment of Old World CL. It is clear that well-designed,
double-blinded, controlled studies are strongly needed.

experience severe symptoms, coccidioidomycosis is nevertheless
a significant cause of morbidity, since the infection is so widely
prevalent in endemic areas. Occasional deaths do occur, particularly in patients with risk factors.

History
Since the initial description of coccidioidomycosis in 1892, the
skin has provided particularly important clues to the diagnosis.
The first reported case was discovered as the result of striking cutaneous manifestations. The patient, an Argentine soldier, presented
with cutaneous nodules that clinically resembled tumor-stage
mycosis fungoides. Skin biopsy revealed distinctive organisms,
which are now known to be the fungal spherules of Coccidioides.
In the 1930s, the skin provided another clue to a milder expression
of the disease. At that time in the San Joaquin Valley of California,
erythema nodosum was considered an important sign of “Valley
Fever,” a self-limited respiratory illness caused by coccidioidomycosis. Over the past half-century, as the desert Southwest transformed into a popular destination for tourism and for migration,
coccidioidomycosis became an increasingly important disease. In
current times, cutaneous signs continue to be exceedingly useful
clues to the diagnosis of coccidioidomycosis.

Epidemiology
Follow-up
Patients should be followed up for up to 6 to 12 months after
apparent clinical healing. Relapse can occur and is most likely in
the first few months after initial clearing. Patients should monitor
healed sites for evidence of ulceration, scabbing, scaling, induration, new lesions, or increase in scar size. Reactivations often
occur at sites of trauma of even minimal degree, the Koebner
phenomenon (isomorphic response). Because of this, elective
surgery and tattoo placements should be delayed for 12 months.
Reinfection from the same species causing Old World CL is
unlikely for the remainder of the individual’s lifetime, but occurs
in a very small percentage of patients.
A diagnosis of any type of leishmaniasis precludes blood
donation in the United States for the remainder of the patient’s
life as in the following document:
http://www.militar yblood.dod.mil/librar y/policies/
downloads/03–08.pdf

WESTERN HEMISPHERE:
C O C CIDIOID OMYC OSIS AND THE SKIN

Deserts of the New World are the habitat of Coccidioides species,
the fungi that cause coccidioidomycosis. The organisms live in
the soil and produce arthroconidia, which are dispersed by the
wind. Suitable hosts, such humans, dogs, and horses, acquire
pulmonary infection through the inhalation of the air-borne
arthroconidia. The infection is virtually always acquired from an
environmental source; person-to-person transmission does not
occur.
Most cases of coccidioidomycosis are asymptomatic. A
minority of patients develop a febrile, influenza-like respiratory
illness. Extrapulmonary dissemination occurs in <1% percent of
patients. Though only a relatively small percentage of patients

Coccidioides species are found in arid regions of the New World
from the western United States to Argentina. Areas with hot, dry
summers, few winter freezes, low annual rainfall, and alkaline soil
are particularly suitable for growth of the organism within the
soil. Central and southern Arizona and the San Joaquin Valley of
southern California have the highest incidence rates of coccidioidomycosis in the world. In California, the species Coccidioides
immitis is identified as the causative organism. Outside California,
the species Coccidioides posadasii (sometimes designated C. immitis var. posadasii) is responsible for nearly all infections. Both species produce clinically similar signs and symptoms.
In endemic areas, exposure to air-borne dust is a welldocumented risk factor for infection. Clusters of cases have been
associated with archeological excavations and with military exercises. Epidemics have occurred in association with dust storms,
earthquakes, and droughts. Over the past decade, Arizona
has been experiencing an epidemic attributed to a prolonged
drought. From 1996 to 2006, the incidence in Arizona increased
more than four-fold.
Both healthy and immunosuppressed patients are at risk for
coccidioidomycosis. Occasionally, severe infections can develop
even in healthy persons with no risk factors. Risk factors for
severe disease and dissemination include genetic predisposition, immunosuppression, or pregnancy. Filipinos and AfricanAmericans appear to be genetically predisposed to a markedly
increased risk of severe coccidioidomycosis. Immunosuppressed
patients, including acquired immunodeficiency syndrome
(AIDS) patients and transplant recipients, have a particularly
high risk of fulminant disease and dissemination.

Diagnosis
The lungs are the primary site of infection in nearly all cases.
Chest radiographs commonly show pulmonary infiltrates,

Infections in the Desert — 145

Table 10.1: Cutaneous Manifestations of
Coccidioidomycosis
Reactive skin lesions (without organisms)
Erythema nodosum
Acute exanthem
Erythema multiforme-like eruptions
Sweet’s syndrome
Interstitial granulomatous dermatitis
Skin lesions with identifiable organisms
Disseminated cutaneous coccidioidomycosis
Primary cutaneous coccidioidomycosis

lung nodules, hilar lymphadenopathy, and/or pleural effusion.
Excluding the respiratory system, the skin is the most common
organ to demonstrate clues to the diagnosis of coccidioidomycosis. The organisms may be directly identifiable within the skin, or
the skin may display important reactive signs of the pulmonary
infection (Table 10.1).

Acute Exanthem
An acute exanthem commonly occurs very early in the course
of the illness, often within the first 48 hours. In some cases, the
onset even precedes the development of respiratory symptoms.
The generalized eruption may be morbilliform, macular, papular, urticarial, or target-like (Fig. 10.21a & b). The acute exanthem closely resembles an allergic drug reaction, erythema
multiforme, a viral exanthem, or generalized allergic contact
dermatitis. Associated pruritus ranges from being minimal to
severe. An enanthem sometimes accompanies the eruption. Skin
biopsies demonstrate a nonspecific pattern of spongiotic dermatitis or mild interface dermatitis. The exanthem persists for days
or weeks, and then subsides spontaneously. Desquamation of the
palms ensues in some cases. Because the acute exanthem occurs
so early in the course of the illness, the initial Coccidioides serologies may be falsely negative. Serologic testing may be repeated
in 2 weeks, if necessary, to allow time for seroconversion.
Erythema Multiforme-like Eruptions
For many decades, erythema multiforme has been cited as a
common reactive manifestation of coccidioidomycosis; however, review of the literature fails to reveal histopathologic

Erythema Nodosum
Erythema nodosum is one of the most common and characteristic manifestations of coccidioidomycosis. Women are more
likely than men to develop erythema nodosum in association
with the infection. One to three weeks after the onset of the illness, patients present with tender red subcutaneous nodules,
most often involving the legs (Fig. 10.20). Skin biopsies demonstrate a septal granulomatous panniculitis with no evidence of
organisms. Erythema nodosum appears to reflect a strong cellmediated response against the pulmonary infection and thus is
believed to be associated with a generally good prognosis. The
tender nodules resolve spontaneously as the pulmonary symptoms subside.

(A)

(B)

Figure 10.20. Erythema nodosum. Tender red subcutaneous
nodules developed on the legs 1 week after the onset of pulmonary
coccidioidomycosis.

Figure 10.21. A & B. The acute exanthem of coccidioidomycosis. The
eruption began within 48 hours of the first respiratory symptoms.

146 — Joseph C. Pierson and David J. DiCaudo

confirmation of the association. Both the acute exanthem and
Sweet’s syndrome may produce annular or target-like lesions,
which clinically mimic erythema multiforme. Cases previously designated as erythema multiforme may actually have
represented examples of these other two entities. Regardless
of whether true erythema multiforme is associated, erythema
multiforme-like eruptions (with annular or target-like features) remain an important clinical clue to the diagnosis of
coccidioidomycosis.
Sweet’s Syndrome
Sweet’s syndrome (acute febrile neutrophilic dermatosis) is
associated with a variety of underlying systemic disorders. Only
recently has this eruption been recognized as a reactive manifestation of pulmonary coccidioidomycosis. Despite the paucity of reported cases, Sweet’s syndrome is a common reactive
manifestation of the infection in the experience of the author.
Early in the course of the illness, patients present with painful
edematous red papules and plaques, often with pustular features
(Fig. 10.22). Annular and target-like lesions are sometimes evident. Fever and peripheral blood leukocytosis are frequently
associated. Skin biopsies reveal marked subepidermal edema
and dense neutrophilic dermal infiltrates with abundant leukocytoclastic debris. In skin biopsy specimens, no organisms are
identifiable by microscopy or by culture. The cutaneous signs
and symptoms resolve as the pulmonary symptoms improve.
Recognition of underlying coccidioidomycosis is particularly
important, so that patients do not receive inappropriate treatment with immunosuppressive therapies. Though idiopathic
Sweet’s syndrome is frequently treated with systemic corticosteroids, such immunosuppressive therapies are best avoided in
patients with coccidioidomycosis.

Interstitial Granulomatous Dermatitis
An immunologically induced granulomatous dermatitis occurs
in association with a variety of underlying systemic diseases,
such as systemic vasculitides, connective tissue diseases, lymphoproliferative disorders, and infections. In such cases, the
granulomatous inflammation appears to be a reactive phenomenon, occurring in the absence of detectable organisms.
Histopathologically (and sometimes clinically) the eruptions
resemble granuloma annulare or necrobiosis lipoidica. In a
recent case series of five patients, interstitial granulomatous dermatitis was described as a reactive manifestation of pulmonary
coccidioidomycosis. Despite the small number of reported cases,
this eruption appears to be a relatively common manifestation of
coccidioidomycosis in the experience of the author. Early in the
course of the illness, patients develop scattered plaques and coalescing papules on the trunk and extremities (Fig. 10.23a & b). Skin
biopsies reveal interstitial granulomatous dermal infiltrates,

(A)

(B)

Figure 10.22. Sweet’s syndrome associated with
pulmonary coccidioidomycosis. Edematous
plaques accompanied the patient’s respiratory
symptoms on the first day of illness.

Figure 10.23. A & B. Interstitial granulomatous dermatitis associated with pulmonary coccidioidomycosis. A. Scattered smooth red
papules developed on the extremities on the first day of fever in this
elderly man. B. Edematous pink papules on the back. The patient’s
cutaneous eruption was the first sign of illness in this otherwise
asymptomatic woman with coccidioidomycosis.

Infections in the Desert — 147

which resemble granuloma annulare. In contrast to typical
idiopathic granuloma annulare, neutrophils, karyorrhectic
debris, and subepidermal edema may also sometimes be conspicuous. The eruption resolves as the pulmonary symptoms subside.
Reactive granulomatous dermatitis must be distinguished from
disseminated infection by microscopic examination and culture
of skin biopsy specimens.
Disseminated Infection
In nearly all cases, the lungs are the primary site of infection in
coccidioidomycosis. In less than 1% of cases, dissemination to
other organs occurs. The skin is the most common site of dissemination. Other important sites of involvement include the
meninges and bones. Disseminated skin lesions usually arise
within the first few weeks or months of the illness. Most patients
with disseminated infection have fever and appear acutely ill.
Occasionally, however, patients may present with disseminated
skin lesions after an apparently asymptomatic primary lung
infection. In the skin, the clinical appearance of disseminated
lesions is strikingly diverse. Solitary or multiple papules, nodules,

(A)

verrucous plaques, and abscesses may occur (Fig. 10.24a & b).
In the skin, the organisms sometimes establish a chronic nidus
of infection, which persists despite the apparent resolution of
the pulmonary infection. Unusual cases of disseminated coccidioidomycosis may resemble tumor-stage mycosis fungoides,
lepromatous leprosy, or lupus vulgaris.
Skin biopsy confirms the diagnosis. Histopathologic examination frequently reveals pseudoepitheliomatous hyperplasia and
ulceration. A granulomatous and/or suppurative inflammatory
infiltrate fills the dermis. Eosinophils are sometimes numerous.
The organisms are usually evident in standard H&E-stained sections. Special fungal stains, such as methenamine silver stain or
periodic acid-Schiff (PAS) stain, may also assist in revealing the
organisms. In tissue sections, the spherules of Coccidioides sp are
usually readily distinguished from other fungi because of their
large size (10 to 80 microns). Mature spherules of Coccidiodes sp
contain numerous distinctive endospores (Fig. 10.25). In some
cases, immature Coccidioides sp spherules on the smaller end of
the spectrum may be difficult to differentiate from Blastomyces
or Cryptococcus. For such cases, in situ hybridization is available
to differentiate these three different fungi. Culture is also a useful
technique for confirmation of disseminated coccidioidomycosis. Cultured skin biopsy specimens commonly yield growth of
Coccidioides sp in as early as 2 to 5 days.
Primary Cutaneous Coccidioidomycosis
Primary cutaneous coccidioidomycosis is much rarer than disseminated skin lesions. The literature contains only approximately 20 reported cases. Primary cutaneous infection may
occur by direct inoculation into the skin through a splinter
injury, laceration, or other trauma. Multiple cases have occurred
among agricultural workers and laboratory technicians. The
infection typically presents as an ulcer or nodule at the site of
inoculation. In a pattern resembling sporotrichosis, secondary
foci of infection sometimes arise along the distribution of lymphatics. Fever and regional lymphadenopathy may be associated.
The microscopic appearance is identical to that of disseminated

(B)

Figure 10.24. A & B. Disseminated coccidioidomycosis. A. Ulcerated
plaques on the forehead in an otherwise healthy patient with no risk
factors. B. Red-brown nodules and scar-like plaque involving the
axilla in an immunosuppressed patient taking prednisone.

Figure 10.25. Skin biopsy specimen confirming disseminated coccidioidomycosis (hematoxylin-eosin, 400x). Coccidiodes sp spherules
of varying sizes (small arrowheads). The largest spherule (large
arrowhead) contains numerous endospores.

148 — Joseph C. Pierson and David J. DiCaudo

coccidioidomycosis. Clinical correlation is needed to distinguish
a primary cutaneous infection from a disseminated infection.
Serologic testing
Serologic testing is an important tool in establishing the
diagnosis of coccidioidomycosis. Both qualitative and quantitative serologic tests are commonly used. One of the most widely
used qualitative tests, enzyme immunoassay, yields rapid results
with high sensitivity. Because occasional false positives do occur,
positive results are typically confirmed by a more highly specific
quantitative technique, such as complement fixation or quantitative immunodiffusion. The antibody titer offers both diagnostic
and prognostic information. High antibody titers (such as 1:16,
1:32, or greater) are often seen in severe infections, especially
in cases of dissemination. The antibody titer is useful in assessing the course of the disease. Titers typically decrease and disappear within months or a couple years of an acute infection.
Potential pitfalls in the interpretation of serologies are discussed
subsequently.
Therapy
For patients with coccidioidomycosis, the dermatologist’s
primary role is to assist in the identification of diagnostic clues.
Nevertheless, an awareness of current treatments is also relevant
for the practicing dermatologist, especially in endemic areas.
Decisions regarding treatment are based on the severity of the
pulmonary infection, the presence of dissemination, and the
existence of risk factors. In low-risk patients with mild selflimited respiratory symptoms, systemic antifungal therapy is
frequently not necessary. Most patients improve spontaneously.
Patients with severe respiratory illness and those with disseminated infection do routinely require antifungal therapy. Azoles
and/or amphotericin B are the primary medications employed
at this time. Current treatment recommendations are detailed in
the article by Dr. Galgiani and collaborators, referenced here. An
infectious disease specialist or primary care physician typically
manages treatment. Serial antibody titers offer useful information regarding the patient’s response to therapy. With successful
treatment, antibody titers typically diminish and disappear over
a period of months or several years. Efforts are currently underway to develop an effective vaccine.
Pitfalls and Myths
Serologic tests present a potential diagnostic pitfall. In contrast to
serologic tests for many other infectious diseases, IgG antibodies for Coccidioides sp typically suggest an acute infection, rather
than a remote past infection. In acute coccidioidomycosis, it is
common for IgG antibodies to be present, regardless of whether
IgM antibodies are detectable. The IgG antibody titer typically
diminishes as the patient recovers from the infection. Thus, any
titer, even a titer of 1:2, often signifies a true infection. Serologic
testing also presents the potential pitfall of false-negative results
early in the course of the illness. Dermatologists must recognize
that several of the early reactive cutaneous manifestations of coccidioidomycosis may erupt before the development of detectable
antibodies in the serum. If the initial serologies are negative,
repeating the tests in 2 weeks may be helpful in documenting
seroconversion.

Another important potential pitfall is the failure to
consider coccidioidomycosis in nonendemic areas. Many persons from other regions of the country (and from throughout
the world) may be exposed to the organism during a vacation
in the Southwest. After an incubation period of 1 to 3 weeks,
the infected patient may develop symptoms after he or she
has returned home. If the local physician is unfamiliar with
the signs of coccidioidomycosis, the diagnosis may be missed.
Obtaining a travel history is obviously important to consider the
possibility of coccidioidomycosis. Even in a nonendemic area,
dermatologists can play a crucial role in the recognition of this
fascinating infection.

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features of 3 cases and review of the literature. Arch Dermatol
2006;142(6):744–746.
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Infect Dis 2005;41(9):1217–1223.
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Quimby SR, Connolly SM, Winkelmann RK, et al. Clinicopathologic
spectrum of specific cutaneous lesions of disseminated coccidioidomycosis. J Am Acad Dermatol 1992;26(1):79–85.

11

INFECTION IN THE TROPICS
Marcia Ramos-e-Silva, Paula Pereira Araújo, and Sueli Coelho Carneiro

INTRODUCTION

Infectious diseases in the tropics, such as leishmaniasis, sleeping sickness (African trypanosomiasis), malaria, and Chagas’
disease, which generate a devastating impact on humanity, are
frequently referred to as neglected diseases, and affect mainly
poor people.
According to the World Health Organization (WHO), there
are around 530 million people – or almost one-tenth of the world
population – suffering from some of these so-called neglected
diseases. The number of people at risk for infection, however, is
much greater. 40% of the world’s population is at risk of acquiring malaria; 25% of the Latin American population is in danger
of acquiring Chagas’ disease; 55 million Africans are exposed
to sleeping sickness, and leishmaniasis threatens another
350 million people around the world.
Affecting the skin, they are called dermatoses of the tropical and subtropical area, dermatoses of the poor (a term used by
James Marshall), dermatoses of the developing and underdeveloped countries; and also dermatoses of malnutrition, illiteracy,
sun radiation, humidity, and insect bites.
Tropical dermatosis is a difficult term to define, according to
Canizares. Simmons stated that a tropical disease is one that “by
virtue of its etiology, occurs, either exclusively or predominantly,
in a tropical or subtropical region, where though not strictly
endemic, it is either autochthonous or in residence, since it has
been repulsed from other areas by hygienic measures.”
The factors that most influence the development of tropical
dermatoses are climatic, ecological, human, cultural, and socioeconomic factors.
Presently, tropical dermatoses occur mostly in the southern
hemisphere, but are reappearing in the northern hemisphere;
these recent changes in geography and epidemiology are caused
by migration, opening of the international borders, transportation facilities, and also by acquired immunodeficiency syndrome
(AIDS). By depleting the immune system, AIDS also increases
the incidence of several infectious diseases. These changes are
giving rise to a new specialty called Migration Medicine.
In Brazil and in many other countries, tourism has always
been common and lately off-track tourism is increasing, with
foreigners going to areas with very beautiful landscapes. These
tourists can get bitten by different species of mosquitoes and
flies, and also come into contact with contaminated water, soil,
and animals.
The WHO listed, as its prime targets, six diseases that it
considered major threats to the populations living in the tropics: filariasis, leishmaniasis, leprosy, malaria, schistosomiasis,
and trypanosomiasis. Of these, only malaria does not produce
150

cutaneous manifestations Therefore, dermatological knowledge
is very important since early diagnosis and proper treatment can
often be life saving.
The knowledge of these diseases is of utmost importance
because the so-called tropical dermatoses are becoming more
frequent worldwide because of tourism, migration, opening
of international borders, and human immunodeficiency virus
(HIV) infection. For this reason, they can be seen in any part
of the globe and there has been a change in geography and epidemiology of tropical dermatoses. Thus, dermatologists of the
entire world must be alert to and aware of the diseases foreign
visitors can bring back to their countries.
A careful history can often locate the site of a possible infection and may suggest its nature. Viral infections occur in epidemics, more often in school-age children who had a recent contact
with infected persons. Adults should be asked for the history
of previous exposure to infections, occupation, social pursuits
and hobbies, contact with animals, any kind of recent travel,
insect bites, history of intravenous drug misuse, sexual activity,
blood transfusion, and intake of herbal and “natural” medicines.
Superficial mycoses (tinea nigra and piedra) typically occur
more often in young adults in tropical climates. Subcutaneous
mycoses (chromoblastomycosis, mycetoma, sporotrichosis, and
lobomycosis) described in the tropical and subtropical regions
of South America mainly affect young male and rural workers.
Inoculation seems to occur by trauma. Paracoccidioidomycosis
is endemic to Central and South America. Chagas’ disease occurs
in the rural areas of Latin America, being known as a “poverty
disease.” Leishmaniasis is a zoonosis associated primarily with
forest occupations.
In this chapter, we will discuss some of the infections
observed in the tropics, especially those seen in Brazil. There
are infections, such as tuberculosis and leprosy, more frequently
occuring in tropical areas that, because of their great importance,
are discussed in separate chapters or together with other groups
of diseases such as tinea versicolor and candidiasis.

H I STORY

The tropical infections seen in Brazil were enriched by the
research of many Brazilian dermatologists. Several discoveries related to some of these diseases were made in Brazil and
have been aiding the specialty in the world with several original reports, especially in this specific area of the infectious–
contagious and tropical diseases. Alexandre Cerqueira, in
1891, described tinea nigra palmar; Gaspar Viana, in 1911,
discovered Leishmania brasiliensis and was the first to use an

Infection in the Tropics — 151

effective medication, tartar emetic, for leishmaniasis. Together
with Aragão, in 1912, he also discovered the etiologic agent
of granuloma venereum, Calymmatobacterium granulomatis.
Adolpho Lutz in 1908 described paracoccidioidomycosis and
Floriano de Almeida in 1930 identified its etiologic agent as
being the fungus Paracoccidioides brasiliensis. Parreiras Horta
presented the original report on piedra nigra in 1911; and
Olympio da Fonseca Filho and Arêa Leão, in 1928, identified the
fungus Piedraia hortai as being its agent. In 1914 Max Rudolph, a
German researcher living in Brazil, identified the brown to black
color fungus of chromomycosis in the tissues and was also able to
cultivate it in Sabouraud’s agar. Jorge Lobo described the disease,
lobomycosis, which takes his name in Recife in the Northeast of
Brazil, although this disease is restricted to the North of Brazil.
Montenegro’s test, an intradermal test performed for the diagnosis of leishmaniasis, was idealized by João Montenegro in 1926,
while the first mention of polarity of the several clinical forms of
leprosy was made in 1938 by Francisco Rabello. In 1945, Flaviano
Silva presented the first case of anergic leishmaniasis.

VIRUS

In tropical areas, viruses are frequent agents of exanthematic
diseases, particularly in children. Most exanthemas are transient
and harmless but some are potentially very dangerous. Viruses
have an enormous capability of dissemination, because they
present very frequent mutations and are capable of infecting
men as well as animals. Changes to the tropical environment,
such as deforestation and disorderly urbanization, rising population density, with poor health and living standards, result in
direct exposure of humans to viral agents, thus increasing their
frequency significantly.
In many cases, exanthema is the main marker of the disease,
while in others it may appear merely as an incidental clinical
manifestation. In exanthematous disorders the clinical manifestations are varied and depend on the infectious agent. When
seeing a patient with exanthema, the examiner should check for
general physical signs, such as dehydration, evidence of weight
loss, anemia, jaundice, edema, oral temperature, enlargement
of the liver or spleen, and alterations in lymph nodes. A thorough and careful examination of the skin should be carried
out to detect any nodules, rashes, or insect bites. In addition,
the oral mucosa and throat should be inspected for evidence of
enanthema or ulceration, the conjunctiva for petechiae, and the
nails for splinter hemorrhages.

Hemorrhagic Fevers
Hemorrhagic viruses are common in tropical regions of Old
World countries. Tourism, migration, and contamination of animals can all act as reservoirs for the disease. There are also many
important factors for dissemination of these agents to new areas
and continents. The constant human incursions into areas where
there is circulation of viruses and presence of vectors and animal
reservoirs perpetuate the possibility of viral infection dissemination. Among the agents of the so-called hemorrhagic fevers, the
producers of dengue, yellow fever, Lassa fever, South American
hemorrhagic fevers, Ebola, West Nile, and Barmah Forest viruses
are outlined.

Dengue Fever
Dengue is considered as the disease with greatest morbidity and
mortality rate transmitted by arthropods. Epidemics have been
reported in tropical and subtropical regions of Asia, Africa, and
America. The first case of hemorrhagic dengue was described in
Cuba in 1981 and 8 years later, a new case occurred in Venezuela.
Several factors are responsible for the emergence and maintenance of the disease in those regions, mainly population growth
and uncontrolled urbanization, with inadequate basic sanitation
and care with water. Plane travel, migrations, and the deterioration of public health programs also contribute to the dissemination of dengue.
The dengue virus is an arbovirus (arthropod-borne viruses),
of the family Flaviviridae, genus Flavivirus, like the yellow fever
virus, with four distinct serotypes. Flavivirus are capable of
replicating in different organisms, like man and mosquito, with
an enormous capacity to adapt to the environment, allowing the
preservation of these viruses in nature.
The main vector of the disease is the adult female of the Aedes
aegypti mosquitoes, whose feeding habit is predominantly by day
in the surroundings of homes and whose reproduction occurs in
clean water. After biting individuals with viremia, the mosquito is
infected and transmits, by a new bite, the virus to other susceptible
individuals, thus establishing a transmission cycle. The environmental factors that favor this cycle include temperature (15°C–
40°C) and moderate and high latitude and altitude. Conditions of
the host such as immunological status, type of virus (mainly the
serotype), vector, adult female density, feeding frequency, and others are also of fundamental importance in the transmission chain.
Crossover immunity between the different serotypes may last
for a few weeks so that an individual may present with sequential
infections. Re-infection by a different serotype can lead to dengue hemorrhagic fever.
Dengue has a short incubation period, between 5 and 8 days.
After this period, it may present with sudden onset, fever, chills,
frontal headache, retro-orbital pain, arthralgias, anorexia, nausea, and vomiting. The severe and often protracted aching arthralgia has given rise to the pseudonym of “break bone fever.”
Systemic complications include epistaxis, lymphadenopathy, and
hepatomegaly.
The typical cutaneous feature is a transient mild flush-like
macular rash over the nape of the neck and face that will last
up to 5 days. Petechiae or purpura may also be seen. Difficultto-control pruritus may be present. Fever appears usually in up
to 6 days, beginning in the convalescent phase, and may last for
weeks, with asthenia and depression.
The more severe hemorrhagic form of dengue occurs when an
individual who has had a previous episode of dengue fever is reinfected by a second serotype. The clinical presentation is abrupt
with fever, nausea, and vomiting. Petechiae and purpura appear
on the second or third day. Hemoconcentration and thrombocytopenia can lead to digestive hemorrhages, metrorrhagias, gingival hemorrhage, and epistaxis. Hepatomegaly, hematemesis,
and abdominal pain indicate a worse prognosis, with probable
evolution to a shock syndrome. This syndrome appears between
the third and seventh day of the disease with unrest and abdominal pain and evolves to lethargy and circulatory insufficiency,
with hypotension, cyanosis, accelerated pulse, and cold sweats.
Metabolic acidosis and disseminated intravascular coagulation

152 — Marcia Ramos-e-Silva, Paula Pereira Araújo, and Sueli Coelho Carneiro

occur and, in case of lack of therapeutic support, death can occur
in 4 to 6 hours.
In some tropical countries, dengue is an endemic disease. In
northern Brazil, 40% of patients presenting with fever and exanthema can be expected to have positive serology for acute dengue
fever, with other viral exanthematic diseases (measles, rubella, parvovirus, oropouche, and mayaro) accounting for 26%. Dengue is
rarely seen in urban settings where the mosquito vector is unable
to thrive. However, between 2001 and 2002, an urban epidemic of
dengue fever occurred in the city of Rio de Janeiro, and an outbreak
of hemorrhagic dengue fever occurred 2 years later in Nicaragua,
in which 26 cases of hemorrhagic dengue fever were recorded.
The treatment of dengue is nonspecific and essentially symptomatic. Depending on the severity of disease, volume expanders
and oxygen therapy may be necessary. In severe cases of dengue,
hemorrhagic fever mortality can reach 50%.
Person-to-person contamination does not occur. Therefore,
vector control of mosquitoes is the most important prophylactic measure to control spreading of the disease. An efficient
vaccination against dengue is difficult to achieve, since the
four viral serotypes are present in most countries, and a future
infection with another serotype can predispose to hemorrhagic
dengue.

Yellow Fever
It is generally believed that the yellow fever virus was brought
from Africa during the slave traffic, together with its vector. It
is endemic in Equatorial, Central, and South America, and in
Africa. In South America, infection is often related to deforestation and the subsequent encroachment of reclaimed land for
agriculture. Yellow fever is not found in Asia. The disease continues to expand nowadays, including regions thought to be free
of the disease, mainly in Africa. The virus is still present at low
levels of infection in some tropical areas of Africa and America
and may eventually give rise to an epidemic.
Yellow fever is caused by an arbovirus of the Flavivirus family
(Flavus means yellow in Latin) and is maintained in a transmission cycle that involves monkeys and hematophagous mosquitoes. The mosquito vectors are species of Aedes and Haemagogus
that can transmit the disease to humans.
Following inoculation by the hematophagous insect vector,
the virus replicates itself in local lymph nodes with subsequent
hematogenic dissemination and replication in tissues of the lymph,
spleen, bone marrow, kidney, heart, and the gastrointestinal tract,
mainly hepatocytes, leading to an intense jaundice. Severe yellow
fever is further complicated by thrombocytopenia and clotting
disorders. Renal involvement includes renal insufficiency, albuminuria and, in more severe cases, acute tubular necrosis. In the
heart, myocarditis and alterations to the blood flow system can
occur, leading to arrhythmia. For those patients who develop
jaundice, the overall mortality rate is between 20% and 50%.
Yellow fever has a short incubation period between 3 and 6
days. The clinical spectrum of the disease varies greatly from a
self-limiting, mild prodromal illness to fulminant liver necrosis
and death. However, the classical clinical picture begins abruptly
with fever, chills, intense cephalea, lumbar pain, myalgias, nausea,
vomiting, and gingival hemorrhages or epistaxis of mild intensity. A classical finding is bradycardia despite high temperatures
(Faget’s sign). Approximately 3 days later, corresponding to the

end of the virus circulation phase, remission of symptoms occurs.
However, about 24 hours after the clinical improvement, in
severe cases, the fever reappears as do the remaining symptoms
of abdominal pain, intense prostration, and jaundice. Oliguria
and albuminuria may also occur. This phase is due to the presence of circulating antibodies. The onset of liver failure, gastrointestinal bleeding, disseminated intravascular coagulation, and
hepatic encephalopathy indicates a progressive worsening of the
patient’s prognosis. In laboratory analysis, there may be a rise of
hepatic enzymes, leukopenia, thrombocytopenia, albuminuria,
alterations of the coagulogram and electrocardiogram. In severe
cases, the mortality can reach 40% and is usually due to hepatorenal failure. In the remaining cases, convalescence can last up to
2 weeks with intense asthenia.
For the diagnosis, the following should be considered:
clinical findings, the epidemiologic history of recent travel,
immunization, and professional activity exercised. The specific
diagnosis depends on viral isolation in the blood, demonstration of serous viral antigens, or the detection of the RNA of the
virus by PCR during the viremia phase. Serologically, the discovery of positive IgM in the blood collected after 7 to 10 days
from beginning of the manifestations confers 95% sensitivity
for the diagnosis.
There is no antiviral treatment for yellow fever. Case
management is supportive. Therefore, prevention is the key to
control, which is provided through yellow fever vaccinations. The
yellow fever vaccine is highly efficacious and probably provides
lifetime protection in most persons but should nevertheless be
administered every 10 years.

West Nile Virus
West Nile virus (WNV), isolated for the first time in Uganda in
1937, is an RNA virus, of the Flaviviridae family, genus flavivirus,
and is an important etiologic agent of meningoencephalitis. Two
viral strains were identified. Strain I has a ubiquitous distribution
(Africa, India, Europe, Asia, the Middle East, and North America)
and was considered responsible for the more recent encephalitis
epidemics. The strain II viruses were identified only in Sub-Saharan
Africa. Birds are the natural reservoir. The infection is transmitted
to humans by Culex, Ochlerotatus, and Aedes spp. mosquitoes and
occurs during the period of active mosquito feeding.
In 2002, the spreading of WNV in the United States resulted
in the largest arbovirus meningoencephalitis documented in
the western hemisphere. Clinical manifestations include sudden onset of high fever, malaise, anorexia, photophobia, myalgia,
lymphadenopathy, arthralgia, and neurological dysfunction producing an encephalitic manifestation, with multiple and generalized convulsions. The skin eruption is characterized by punctate,
erythematous, maculopapular eruptions, most pronounced on
the extremities.
The diagnosis of WNV infection is established by IgM-capture
enzyme-linked immunosorbent assay (ELISA). Treatment is
similar to that for a meningoencephalitis patient. There is no
specific antiviral therapy.

Barmah Forest Virus
Barmah Forest virus (BFV) is an emerging mosquito-borne
alphavirus. Many mosquito species can act as vectors for the

Infection in the Tropics — 153

disease, such as Ochlerotatus vigilax. BFV has only been described
in Australia.
The infection is characterized by fever, arthralgias, myalgias,
lethargy, anorexia, and rash. The rash is erythematous, maculopapular, vesicular, or purpuric, involving trunk, limbs, and face.
The diagnosis is made by detection of Barmah Forest–specific Ig-M
by enzyme-linked immunosorbent assay (ELISA) method. Most
cases can recover in weeks, but arthralgias, myalgias, and lethargy
may continue for at least 6 months in about 10% of patients.

Marburg and Ebola
The Marburg and Ebola viruses contain RNA differing from their
close relatives, Rhabdoviridae and Paramyxoviridae, and thus
constitute a different family: Filoviridae. Both cause severe hemorrhagic fevers. The natural reservoirs for Marburg and Ebola
viruses remain unknown.
Marburg virus was originally identified after a laboratory
worker became infected following experiments using green
monkeys (Cercopithecus aethiops). Since then, sporadic cases
have been observed in Zimbabwe, South Africa, and Kenya.
The Ebola virus was responsible for two major epidemics, with
an 88% mortality rate, in Zaire and Sudan in 1976. Since then, other
epidemics have occurred in the Congo, Uganda, and other countries in Central Africa. It comprises four subtypes or genotypes:
Zaire, Sudan, Reston, and Ivory Coast. The first two are responsible for several epidemics and serious cases of hemorrhagic fever.
The third is only recognized in monkeys of the Philippines, while
only a single case is known for the Ivory Coast type.
Humans are the only known source of infection. These diseases are easily transmitted by direct contact with body fluids or
even clothes from the index case. Mortality is high.
Marburg and Ebola virus infections have a short incubation
period of approximately 6 days, but can exceed 2 weeks. Clinically,
there is acute onset of high fever, headache, generalized myalgia,
prostration, odinophagia, abdominal pain, nausea, vomiting,
and intense watery diarrhea. Development of a maculopapular
rash, centripetal, without itch, with varied degrees of erythema,
and with desquamation may occur on the fifth to seventh day of
the disease. However, the characteristic clinical finding is hemorrhage, mainly gastrointestinal bleeding and mucocutaneous
and pulmonary hemorrhages. Leukopenia, thrombocytopenia,
proteinuria, and increased levels of hepatic enzymes and amylases are observed.
The serologic diagnosis includes finding of IgM and IgG,
through ELISA and immunofluorescence, with the antibodies
detectable after the first week of the disease. The virus can be isolated in guinea pigs after inoculation of blood from sick patients.
There is no specific treatment. Despite improvements in the
management of circulatory collapse and disseminated intravascular coagulation the mortality figures remain high (50%–80%)
even in treated cases. Strict isolation of cases and quarantine
are essential to curtail any potential epidemic of these deadly
diseases.

Lassa Fever
Lassa fever occurs in West Africa. It is caused by an arenavirus
that is phylogenetically related to the viral agents of Argentinian
and Bolivian hemorrhagic fevers and is transmitted to humans

via the urine of the peridomicile rodent, Mastomys natalensis. The
endemic regions are near forests with low population densities.
Lassa fever may clinically present 7 to 14 days after the infection. The onset may be insidious and the disease may even be
subclinical. There is fever, chills, headache, sore throat, retro-orbital pain, myalgias, severe body pains, conjunctivitis, oral ulcers,
and pharyngitis with tonsillar patches. A generalized petechial
rash and facial edema may also occur. Shock occurs as a result of
hemorrhage due to thrombocytopenia that contributes to a mortality rate of more than 20%. In pregnancy, the infection presents
with greater severity, especially in the last trimester, when mortality is approximately 40%.
Lassa fever can be treated with ribavirin, which may be
employed at any time of the disease and also as postexposure
prophylaxis. Ribavirin is not indicated during pregnancy. Special
care should be taken in the handling of the patients’ blood and
excreta. Prevention of Lassa fever relies on rodent control.

South American Hemorrhagic Fevers (Argentina,
Bolivia, Venezuela, and Brazil):
The South American hemorrhagic fevers are similar in presentation to Lassa fever but present with more overt disease. They
are caused by viruses of the Arenaviridade family. In Argentina,
the virus involved is Junin, while in Bolivia it is Machupo, in
Venezuela the Guanarito, and in Brazil the Sabia virus. The
cycles of these viruses are relatively simple, being maintained
through rodents, where they can be found in blood, urine and
in the throat. There can be maternal–fetal transmission, perpetuating the virus through generations and generations of
rodents. The true mechanism of human infection is not well
established. Possibilities include the ingestion of food and inhalation of materials contaminated with excretes from infected
animals and penetration through the skin or contact with blood
from sick patients. The incubation period varies from 7 to 16
days. Clinically, it begins with fever and progressive indisposition, altered mental state, tremors, and central nervous system
signs. There is marked thrombocytopenia leading to petechiae
and widespread hemorrhage. Exanthema is less common.
Etiologic diagnosis is made through viral isolation or serological findings.
Ribavirin is the treatment of choice. Hyperimmune globulin has also been used. Healthcare workers who have nursed the
patient(s) should also be offered prophylactic ribavirin therapy.
Once recovered from illness, patients should avoid intimate contact
for at least a month because a persistent detectable viremia is present, and there is a risk of disease transmission during this period.
A live attenuated vaccine is available for the Argentinean
hemorrhagic fever that provides some cross-protection against
the Bolivian hemorrhagic fever virus.
SUPERFICIAL MYC OSES

White Piedra
Described the first time in 1865 by Beigel, white piedra is a
rare infection of the hair cuticle, caused by the Trichosporon
beigelii yeast. Its distribution is universal, but with clear preference for tropical and temperate climates, being common in
South America. In Brazil, a high incidence in the North region

154 — Marcia Ramos-e-Silva, Paula Pereira Araújo, and Sueli Coelho Carneiro

is observed. There is no preference for sex or age-group. Poor
hygiene commonly plays a role in the picture. The agent can be
found in soil, air, water, vegetables, as well as on the surface of the
body of animals such as monkeys and horses and as components
of the normal human skin flora and oral mucosa, but the specific
transmission media remains unknown.
Clinically, asymptomatic, easily detachable, softened nodules characterize it, with colorations varying from white to light
brown. It is adherent to the hair shaft, and forms a refractive,
irregular transparent sheath along the hair. Genitals, armpits,
beards, and mustaches are the most involved sites. Infection of
the scalp, eyebrows, and eyelashes is less frequent but can also
occur. The underlying skin may show erythemato-desquamative
lesions, with ill-defined borders, associated with humidity and
pruritus. Wood’s lamp does not reveal fluorescence.
Diagnostic differentiation should be carried out with black
piedra, pediculosis, nodular axillary trichomycosis, and abnormalities of the hair shaft. In the genital area, involvement of the
underlying skin may place dermatophytoses, candidiasis, and
severe erythrasma in the differential diagnosis.
Diagnosis is made through microscopic examination of the
hair, the finding of nodules made of mycelium elements and
arthroconidea perpendicular to the hair surface. Culture of hair
in Sabouraud’s agar reveals growth of a white-yellowish colony,
similar to wax, with a rough to cerebriform relief, comprising hyaline septated hypha, arthroconidia, and blastoconidia.
Treatment of choice is cutting the hair, and in the case of recurrence, use of topical antifungal medication such as ketoconazole,
ciclopirox olamine, and zinc pyrothione, among others.

Black Piedra
Black piedra is also an infection of the hair shaft, but the fungus
Piedraia hortae causes it. Tropical areas have a higher incidence,
mainly in Africa, Asia, and Central America, with soil being the
most probable infection source. Humans, monkeys, and other
primates can be affected, and women have a higher incidence
of black piedra. During growth, the fungus tends to destroy the
cuticle layer and penetrate deeply into the cortical hair region.
Around the shaft, strongly adherent hardened nodules form,
with sizes ranging from a few millimeters to 150 mm, but these
are usually asymptomatic (Fig. 11.1). The scalp, contrary to white
piedra, is the preferred site.

Figure 11.1. Black piedra.

Clinical and direct mycological examination of the hair shaft
with potassium hydroxide at 10% to 15% confirms the diagnosis.
It reveals a mass of brown arthroconidia and ascie, which are
structures of the sexual reproduction phase. Culture of nodules
inoculated in Sabouraud glucose at 2% reveals slow growing, elevated black colonies that are very adherent to the medium, with
a central groove and a flat periphery. The colony is formed by a
net of brownish, branched, and septated hypha with clamidoconidia. Therapy is cutting the hair, along with the use of topical
antifungals.

Tinea Nigra
Tinea nigra or superficial phaeohyphomycosis is a skin infection
caused by the fungus Hortaea werneckii (formerly Exophiala
werneckii), that dwells in soil and leaves. The microorganism
remains confined to the horny layer and, normally does not
stimulate an inflammatory response. It is endemic in tropical
regions of the Caribbean, Asia, Africa, and South and Central
America and begins with fungal inoculation after local trauma,
mainly in women, before the second decade of life and in those
with hyperhidrosis.
The clinical findings are characteristic, with the onset of a
well-delineated, nondesquamate macular lesion. It is usually
single, brownish, with larger intensity of the pigmentation in
the periphery and is not usually accompanied by local symptoms (Fig. 11.2). Its most common location is the sole or palm,
although sites such as the neck, thorax, and other areas of the
body can also be affected.
The direct mycological examination reveals olive green or
brownish irregular septated hypha and yeast elements. The culture shows slow growth, and is composed of yeasts that have an
olive or black color and a shiny, mucus-like aspect. With maturation of the culture, a black or grayish aerial mycelium emerges.
For identification of the agent, some biochemical tests may be
necessary, such as assimilation of KNO3 and thermal tolerance.
Among the differential diagnoses, the melanocytic lesions
assume a prevailing role. Other pigmentation causes such as
Addison’s disease, syphilis, and postinflammatory hyperpigmentation should also be eliminated.
Spontaneous remission is rare, and for its treatment keratolytic substances, such as salicylic acid, and topical antifungal

Figure 11.2. Tinea nigra.

Infection in the Tropics — 155

agents, such as ketoconazole, miconazole, and itraconazole can
be used.

S U B C U TA N E O U S A N D D E E P M Y C O S E S

Sporotrichosis
Sporotrichosis is the most common and less severe of the
deep mycoses. It is caused by the dimorphic fungus Sporothrix
schenckii, which lives in nature, usually associated with plants.
Of universal occurrence, it is more common in tropical and
subtropical regions and is considered endemic in South and
Central America, as well as in Africa. It affects mainly healthy
young patients, usually under 30 years of age. It appears after
traumatic inoculation of the fungus in the skin or in the subcutaneous tissue and can, sometimes, occur by inhalation.
Zoonotic transmission may occur through scratches from
animals, like cats and rodents. In felines, the fungus can be
demonstrated in cutaneous lesions and nasal or oral cavities,
besides the possibility of disseminated infection. Factors such
as alcoholism, diabetes mellitus, neoplasia, use of immunosuppressant agents, and HIV predispose to acquisition of the
infection.
Several clinical forms (Figs. 11.3 and 11.4) have been suggested based on the virulence of the agent, size of the inoculum,
depth of the inoculation, and host conditions. The lymphocutaneous form is the most common and is characterized by the
appearance of hardened papules 2 to 4 cm in diameter, which
appear 7 to 30 days after inoculation. These papules evolve
into nodules with posterior ulceration, and new lesions appear
along the lymphatic pathway. Light systemic symptomatology
may occur, and regional lymphadenomegaly of the upper and

Figure 11.3. Sporotrichosis on the elbow.

Figure 11.4. Sporotrichosis in a patient with multiple myeloma.

lower limbs is common. A second form described is the fixed
cutaneous form because the lesions are restricted to the inoculation area and do not demonstrate lymphatic dissemination. The
lesions may resemble a folliculitis or present as an acneiform,
ulcerous, gummy, verrucous, or papillomatous aspect. It occurs
mainly on the face, neck, trunk, and lower limbs. The disseminated form occurs by hematogenic dissemination. The fungus
spreads from a cutaneous or pulmonary focus, and appears as
lesions on the skin and in multiple organs. This picture is associated with states of immunodeficiency such as in infection by
HIV, neoplasia, tuberculosis, organ transplants, and diabetes
mellitus. Another form has no cutaneous lesions and occurs by
inhalation or hematogenic dissemination of deep inoculums.
Osteoarticular manifestations with monoarthritis or tenosynovitis, pulmonary involvement resembling tuberculosis, and ocular
and even genital lesions can occur. Meningitis can arise, especially in HIV-positive patients.
Other infections such as leishmaniasis, tuberculosis, chromomycosis, and paracoccidioidomycosis should be excluded before
making the final diagnosis. Supplementary examinations should
be carried out. The elements of S. schenckii, in pus or tissues,
are small in size and scarce, which makes observation through
the microscope difficult. Histopathological examination reveals
a granulomatous and not very specific formation with epithelial
hyperplasia. Asteroid bodies can be seen and represent the fungal elements surrounded by eosinophilic radial protein material,
but these are also nonspecific.
S. schenckii is a dimorphic fungus and its two phases, filamentous and yeast-like, are obtainable from culture, which is helpful
in identification. The filamentous phase is obtained by cultivating the pus at 25°C and, after 3 to 5 days, white, star-shaped colonies grow, which turn a blackish color later on. The cultures show
delicate septated and branched hypha, isolated or in groups with
conidia displayed as flower petals. The yeast forms in cultures at
37°C, and shows white creamy colonies, comprising yeast elements in boat-shaped cigar or globular form.
Spontaneous resolution of sporotrichosis has been described.
In spite of this, treatment is requested in most cases. The medication of choice is itraconazole, in dosages of 100 to 200 mg/day
for 3 to 6 months, resulting in cure rates between 90% and 100%.

156 — Marcia Ramos-e-Silva, Paula Pereira Araújo, and Sueli Coelho Carneiro

For disseminated cases or in HIV-seropositive patients, the use
of amphotericin B is preferred, changing to itraconazole later for
maintenance. A saturated solution of potassium iodide remains
a low-cost therapeutic option, but should be sustained for up to
4 weeks after clinical cure.

Chromoblastomycosis
This polymorphic mycosis involves the skin and subcutaneous
tissues. It is a disease of urban distribution, with greater incidence in tropical and subtropical regions of hot and wet climates
of Latin America, Africa, and Asia. It also mainly affects male
farmers. There are five different agents; all are dematiaceous
(meaning dark brown or black color) fungi: Phialophora verrucosa, Fonsecaea pedrosoi, Fonsecaea compacta, Cladosporium carrionii, and Rhinocladiella aquaspersa.
Fungal inoculation occurs by trauma, most frequently unilaterally and in the lower limbs. The initial lesion is a papule or nodule
that ulcers and extends by contiguity, for months or years, assuming two clinical types: tumors or plaques (Figs. 11.5 and 11.6). The
tumor form comprises hard dry nodules, on a smooth or verrucous surface, sometimes covering extensive areas. In such cases,
microabscesses can be seen on the borders. The initial lesion
can also extend itself, leaving a central cicatricial area, covered
by smooth and shiny skin, with slightly squamous or finely
verrucous, raised borders. Different types of lesions have been

Figure 11.6. Chromoblastomycosis of the forearm.

described, resembling those of psoriasis, tuberculosis, syphilis,
or mycetoma.
In pus or histological sections, any of the five agents present
as a group of dematiaceous, globular structures with thick walls.
Some elements may be septated in one or more planes. They are
the typical moriform bodies, which are fumagoid or sclerotic,
and characterize the mycosis. The colonies have a relatively slow
growth and are velvety cotton-like with varied colors ranging
from olive green to brown and black. Differentiation of the five
species of agents of mycosis is made on the basis of the morphology of the fructification apparatus.
Chromoblastomycosis is considered a difficult to treat disease because of the varied response depending on the involved
species. Options include surgery, itraconazole 100 to 200 mg/day
for 12 to 24 months, 5-fluorocytosine, amphotericin B, and cryosurgery, among others.

Mycetoma

Figure 11.5. Chromoblastomycosis on the elbow.

Mycetoma is the name given to a group of mycoses acquired
through traumatic inoculation, whose etiologic agents are fungi
(eumycetoma) or aerobic actinomycetes (actinomycetoma).
They organize themselves in the tissues in an agglomerate of
hypha or bacterial filaments called grains. The primary focus of
infection is the subcutaneous tissue. The grains can present with
varied texture, size, and coloration and such characteristics can
aid in the causal agent’s definition. Actinomadura madurae, for
instance, is correlated to white-yellowish and soft grains, while
Nocardia brasiliensis is correlated to white and soft grains of less
than 1 mm. Madurella mycetomatis, however, generates black
and firm grains.
Mycetoma agents are saprophytes in nature. Some species
enjoy worldwide distribution, while others are more limited
geographically. Infection is more common in tropical and subtropical regions with high rainfall affecting mainly the masculine sex. Nocardia brasiliensis mycetoma is the most common in
the Americas. Eumycotic mycetoma has been reported with less
frequency.
Clinically, mycetomas present as volume increases in certain
areas, where abscesses fistulize, draininga purulent secretion
with grains visible to the naked eye. They are usually located in
the limbs and progresses by contiguity. The mycosis evolves with

Infection in the Tropics — 157

periods of remission and recurrence, until becoming an enormous tumor that deforms the member. Nodules, fistulae, and
scars can be seen in the skin that covers the tumor. The infection can extend to the muscles, fascia, bones, and tendons. The
lower limbs are the main sites affected and asymmetry is the rule
(Figs. 11.7 and 11.8).
The grain should be observed by the naked eye, under the
microscope, and, if necessary, Gram-stained to allow better
characterization, as well as in histological sections. Identification
of fungi is based on the characteristics of the colonies and in
the micromorphology they present in the cultures. In contrast,
identification of the actinomycetes is made by the study of their
morphology, of the chemical components of the cell wall, and by
other physiologic evidences.
Mycetomas are chronic lesions that can evolve into incapacitation. Treatment should be based on identification of the
etiologic agent. Therefore, for cases of bacterial nature, use of
antibiotics such as sulphones and amikacin are indicated. In
cases of fungal etiology, itraconazole and amphotericin B are the
main medications of choice. Some cases are very resistant and
difficult to treat, requiring amputation.

Lobomycosis
Lobo’s mycosis or keloidal blastomycosis, also known as Jorge
Lobo’s disease, is a chronic, polymorphic, and localized deep
mycosis, caused by a fungus, Lacazia loboi, whose habitat in
nature is unknown. Jorge Lobo described it in the northeast of
Brazil in a patient from the Amazon region. It has been described
in the intertropical regions of South America, and in countries
such as Brazil, Colombia, Suriname, Venezuela, Peru, French
Guyana, Guyana, Ecuador, and Bolivia. In Central America, it has
been observed in Costa Rica, Panama, and Mexico. Inoculation
seems to be via trauma. Its incubation period is 1 to 2 years, and
it affects mainly male rural workers in a proportion of ten men
to every one woman.
The lesions are keloid-like and may also resemble vegetations, infiltrations, nodules and, sometimes, ulcers or gummae
(Figs. 11.9 and 11.10). Preferred locations are ears and lower and
upper limbs. Lesions have pinkish or brownish color, are smooth
or with small scales or crusts, and slow growing. They are also
usually asymmetrical and confined to a single region or are confluent, sometimes covering large areas. More seldom, lesions are
macular or gumma-like. Pruritus may occur, but there is no systemic symptomatology. When lymph nodes are involved, they
are hard and there is no flotation. The patient maintains good
general health.

Figure 11.7. Mycetoma (courtesy Thais Dresch, Rio de Janeiro,
Brazil).
Figure 11.9. Lobomycosis (courtesy Arival de Brito, Belem, Brazil).

Figure 11.8. Mycetoma (Courtesy of Nurimar Fernandes, Rio de
Janeiro, Brazil).

Figure 11.10. Lobomycosis (courtesy Arival de Brito, Belem, Brazil).

158 — Marcia Ramos-e-Silva, Paula Pereira Araújo, and Sueli Coelho Carneiro

Differential diagnosis includes leprosy and leishmaniasis, as
well as keloids.
In tissue sections and especially in exudate, Lacazia loboi is
seen as spherical elements or in lemon form with thick walls and
more or less uniform size. In exudate or in histological sections
with Grocott’s stain, it is possible to observe the characteristic
form of the fungus: cells presenting a protuberance and, at the
opposite pole, a small cicatricial depression. These cells present
gemmulation in the lateral chain. The richness of parasite forms
in the dermis is remarkable, being separated from the epidermis by a Grenz zone. Culture of Lacazia loboi has not yet been
achieved.
There is no consensus on treatment, but some options may
be prescribed such as clofazimine, either isolated or in conjunction with itraconazole. Keloid lesions do not respond well to
drug therapy and, therefore, one should consider the possibility
of their surgical removal.

Paracoccidioidomycosis
Paracoccidioidomycosis is a systemic mycosis of great interest
for Latin American countries (from Mexico to Argentina), where
it is endemic. It is caused by inhalation of the dimorphic fungus
Paracoccidioides brasiliensis, and presents in a heterogeneous distribution, with areas of low and high endemic density. The main
factor for infection risk is working with soil contaminated by the
fungus, such as agriculture, earth moving, soil preparation, and
gardening, among others. Tabagism and alcohol addiction are
additional factors. Contrary to other systemic mycoses, paracoccidioidomycosis is not usually related to immunodepression, but
there are cases associated with HIV infection, neoplasia and,
more rarely, organ transplantion. An association with tuberculosis is reported in up to 12% of the cases.
The infection is acquired mainly in the first two decades of
life, with a peak incidence between 10 and 20 years. Presentation
of clinical manifestations or evolution of the disease is uncommon in this group, occurring with greater frequency among
adults between 30 and 50 years as reactivation of a latent endogenous focus. The rate of onset in adults varies, with a ratio of
10 to 15 men for each woman. During childhood, however, the
distribution is equal between sexes.
The clinical picture is variable, the disease therefore being
classified in different clinical forms. After inhalation of the fungus, there may be development of pulmonary forms that may
or may not regress or that spread by hematologic dissemination. The acute/subacute juvenile form prevails in children and
adolescents, but can eventually affect individuals up to 35 years.
It is characterized by a faster evolution, with the patients seeking medical care in 4 to 12 weeks after onset of the disease. The
main manifestations of the disease are fever, digestive manifestations, lymphadenomegaly, osteoarticular involvement, hepatosplenomegaly, and cutaneous lesions (ulcerated lesions, with
verruciform or papulonodular aspect). Possible complications
are obstructive jaundice, intestinal subocclusion or occlusion,
vena cava compression syndrome, diarrhea with malabsorption syndrome, ascites, adrenal involvement (asthenia, weight
loss, arterial hypotension, skin hyperpigmentation, abdominal
pains), and central nervous system involvement (headache,
motor deficiency, convulsions, alterations of behavior and/or
level of consciousness).

The chronic or adult form is responsible for more than 90% of
the cases and occurs, most commonly, between 30 and 60 years,
with a greater prevalence in males. The disease progresses slowly
and silently, and can take years until diagnosed. Pulmonary manifestations are present in 90% of the patients. It is called unifocal
presentation when it is restricted to a single organ, with the lungs
being the only affected site in up to 25% of the cases. There may
be coughing, dyspnea, and mucopurulent expectoration with
chest X-ray showing bilateral infiltration, predominantly of the
lower third. Usually, however, the disease is multifocal, affecting lungs, mucosa and skin. The so-called moriform stomatitis
of Aguiar-Pupo is considered characteristic. These are lesions
of the mouth and/or oropharynx with sialorrhea, odinophagia,
hoarseness, and evidence of fine granulation with hemorrhagic
dots on the surface. Cutaneous lesions are papular, ulcer-crusted,
or vegetating and may also present with hemorrhagic dots on
their surface (Figs. 11.11–11.13).
The golden standard for the diagnosis is the finding of fungal elements suggestive of P. brasiliensis in the examination of
fresh saliva or other clinical specimens (lesion smear; lymph
node aspirate) and/or fragments of biopsy of organs supposedly involved (Fig. 11.14). The cells are spherical, with refringent

Figure 11.11. Paracoccidioidomycosis of the face.

Figure 11.12. Paracoccidioidomycosis – vegetating lesion on the
lower lip.

Infection in the Tropics — 159

100%. Specific anti-P. brasiliensis antibody titer is related to the
severity of the clinical forms being higher in the acute–and subacute forms of the disease.
P. brasiliensis is sensitive to most antifungal drugs. For
mild to moderate cases, the best choice is itraconazole, at
doses of 200 mg/day for up to 24 months. The drugs to be used
in severe cases are intravenous amphotericin B or trimethoprin-sulfamethoxazole. The cure criteria in PCM are clinical
(disappearance of symptoms of the disease), radiological
(stabilization of the image pattern of pulmonary cicatricial
images), and immunological (with negative titers in double
immunodiffusion).

P ROTO Z OA

Chagas’ disease

Figure 11.13. Paracoccidioidomycosis on the palate.

Described in 1909, by Carlos Chagas, Chagas’ disease or trypanosomiasis americana, is caused by Trypanosoma cruzi, a
human parasite that also affects domestic and wild animals.
Transmission occurs through bites of a vector animal, the triatominae, “barbeiro” or reduviid bug (Fig. 11.15). Chagas’ disease
occurs in rural areas of the tropical Americas, being the main
cause of cardiac problems in some countries. In Latin America
it is considered a disease of the poor population, living in adobe
homes, which is a favorable environment for the vector. Age, sex,
and race do not influence disease incidence, despite the acute
phase being more common in children. Dermatologists must be
attentive for early signs of the disease, occurring at inoculation
sites, so that treatment can be started immediately and to avoid
future complications.
Two transmission cycles are known for this parasite in nature:
forest and domestic. The first occurs among wild animals and
the triatominae. Marsupials, rodents, monkeys, rats, and rabbits
are the main reservoirs. The domestic cycle results from invasion of uninhabited areas by man. Transmission occurs when
the infected vector bites animals living in the periphery of the
houses. The trypomastigote form that circulated in the peripheral blood of vertebrates undergoes a transformation in the vector’s organism, changing to the epimastigote form and multiplies
itself, passing later to metacyclic trypomastigotes in the digestive

Figure 11.14. Paracoccidioidomycosis – direct exam.

walls with single or multiple budding. Presence of a ship’s steering wheel aspect due to the multiple budding is typical. The culture presents slow growth, resulting either in the filamentous or
yeast form of the fungus. Specific serologic tests are important
not only as help to the diagnosis, but also for allowing an assessment of the host’s response to the specific treatment. Presently,
several methods are available, as double immunodiffusion (ID),
counter immunoelectrophoresis (CIE), indirect immunofluorescence (IFI), immunoenzymatic test (ELISA), and immunoblot
(IB), which reach a sensitivity and specificity between 85% and

Figure 11.15. Reduviid bug (Courtesy Luís Rey, Rio de Janeiro,
Brazil – with permission of Springer-Verlag).

160 — Marcia Ramos-e-Silva, Paula Pereira Araújo, and Sueli Coelho Carneiro

system of the triatominae. The latter then invades the domiciles
seeking sources for its sole food, which is the blood. The main
species of this arthropod are Triamota infestans (Argentina,
Bolivia, Brazil, Chile, Paraguay, Peru and Uruguay), Rhodnius
prolixus (Colombia, Guyanas, Surinam, Venezuela, and Central
America), and Panstrongylus megistus (Brazil). Transmission
occurs through stools of the triatominae, which usually defecates while feeding. Other forms of transmission are reported
such as vertical transmission, transfusion, congenital, accidental
andoral.
Most of the infected individuals remain asymptomatic. When
symptoms appear, there is an incubation period of approximately
one week. The acute Chagas’ disease is more frequently seen in
children and begins with inflammatory lesions at the site of the
inoculation. This can be in the skin or in the conjunctiva. When
penetration occurs through the ocular mucous membrane, there
is a periorbital edema, known as Romaña’s sign (Fig. 11.16). This
picture, also known as primary ophthalmo–lymph node complex, will manifest after 5 to 10 days of the agent’s penetration
and is unilateral, accompanied by conjunctivitis, dacrioadenitis,
and satellite adenitis.
The inoculation chagoma denotes that the entry site was
the skin and it is a macular or papulonodular erythematous
violet, hard and painless lesion that may ulcerate. This initial
lesion tends to regress in 3 weeks. Satellite lymphadenitis is
also usually present. Other signs of acute disease are fever,
indisposition, migraine, myalgia, hepatosplenomegaly, and
maculopapular, morbiliform, or urticariform cutaneous rashes
(schizotrypanids).
The phases that follow can produce megaesophagus, megacolon, and heart involvement. The latter, at its turn, can manifest
as myocarditis, arrhythmias, and complete heart blockade, typically the right and left anterior bundle branches being affected
more frequently.
The methods, which may assist in the diagnosis, will depend
on the phase of the disease. In the acute phase, direct search of
the protozoon (Fig. 11.17) and search for anti-T. cruzi IgM antibodies by indirect immunofluorescence and PCR are used. In
the chronic phase, serological tests of indirect hemoagglutina-

Figure 11.17. Trypanosoma cruzi in blood (Courtesy Luís Rey, Rio de
Janeiro, Brazil – with permission of Springer-Verlag).

tion, indirect immunofluorescence, and ELISA are the methods
with better results.
Therapeutics are unsatisfactory. Even when correct, the treatment does not alter the serological reactions or the heart function in the chronic phases, in spite of usually curing the patient
in the acute phase. The two main drugs are benzonidazole and
nifurtimox. Both are active against the circulating and tissue
forms and should be administered between 30 and 90 days. For
patients with stable chronic disease, the treatment should include
antiarrhythmics and control of the affected systems, with diets,
laxatives, and surgical procedures. The prevention of the disease involves sanitary education of the population and the use of
insecticides. Vaccines are being studied but are not yet available.

Mucocutaneous or Tegmental Leishmaniasis

Figure 11.16. Inoculation lesion on the eyelid – Romaña’s sign
(Courtesy João Dias & Luís Rey, Rio de Janeiro, Brazil – with
permission of Springer-Verlag).

Leishmaniases are anthropozoonoses including a set of diseases
with an important clinical spectrum and epidemiologic diversity.
The World Health Organization (WHO) estimates that about 350
million people are exposed to the risk with approximately two
million new cases per year. It has a worldwide distribution, being
considered a public health problem in 88 countries, distributed
in four continents (America, Europe, Africa and Asia). In the
American Continent there are records of cases from the extreme
south of the United States to the north of Argentina, except for
Chile and Uruguay. It is considered by the WHO as one of the six
most important infectious diseases, for its high rate of detection
and capacity of producing deformities.
In Brazil, in 1895, Moreira identified for the first time the existence of the endemic boil of the tropical countries, the so-called
endemic “Bahia boil” or “Biskra boil.” In 1909, Lindenberg
found leishmania forms in cutaneous and nasopharyngeal ulcers
in workers of deforestation areas in the interior of the state of
São Paulo. Splendore, in 1911, diagnosed the mucosal form of
the disease and Gaspar Vianna named the parasite Leishmania

Infection in the Tropics — 161

brazilienses, and was the first to use an effective drug, emetic tartar, for its treatment. In 1922, Aragão demonstrated the role of
the Phlebotomus in the transmission of the disease and Forattini,
in 1958, found parasitized wild rodents.
Leishmania belongs to the Trypanosomatidae family of
protozoa. It is an obligatory intracellular parasite of the mononuclear phagocytic system, with two main forms: flagellated, leptomonas or promastigote, observed in the digestive tube of the
vector insect, and aflagellated leishmania or amastigote, found
in the tissues of the vertebrate hosts. In the Americas 11 dermotropic species of Leishmania are recognized and eight species
described only in animals, all belonging to the subgenus Viannia
and Leishmania. The three principal species are L. (V.) braziliensis, L. (V.) guyanensis and L. (L.) amazonensis.
The vectors are insects called phlebotominae, belonging to
the Dyptera order, family Psychodidae, subfamily Phlebotominae,
genus Lutzomyia, known popularly, depending on the geographical location, as straw mosquito, tatuquira, and birigui, among
others. The reservoirs can be wild animals (as rodents and marsupials), synanthropic (species that, undesirably, cohabit with
humans, such as rats, cockroaches, flies, mosquitoes, fleas, hematophagous bats, pigeons, and others) and domestic (canines,
felines, and equines, considered accidental hosts of the disease).
Transmission occurs through the bite of infected transmitter
insects. There is no person-to-person transmission. There is no
preference for sex, race, or age. However, most of the cases occur
in men with ages between 20 and 40 years. In the countries of the
Old World, the cutaneous form of leishmaniasis, the Orient boil,
is more frequently observed in children. The incubation period
of the disease in humans lasts on average, 2 to 3 months, but can
vary from 2 weeks to 2 years.
Epidemiological analyses suggest that in the last decades
there were changes in the transmission pattern of the disease. It
was initially considered a wild animal zoonosis that, occasionally, affected people in forests. Later, the disease started to appear
in rural zones, already practically deforested, and in periurban
areas. The existence of three epidemic profiles is noted. The
first is forest, where transmission occurs in the areas of primary
vegetation (zoonosis of wild animals). The second is occupational, associated with the disordered exploration of the forest
and deforestation (anthropozoonosis) and the third is rural or
periurban. In periurban areas or “colonization areas” the vector
has adapted to the peridomicile area (zoonosis of residual forests
and/or anthropozoonosis).
Transmission cycles vary according to the geographical area,
involving a diversity of parasite species, vectors, reservoirs, and
hosts. Leishmania (Leishmania) amazonensis is present in areas of
primary and secondary forests of the Legal Amazon (Amazonas,
Pará, Rondônia, Tocantins, and Maranhão) and also in the states
of the following regions of Brazil: Northeast (Bahia), Southeast
(Minas Gerais and São Paulo), Midwest (Goiás) and South
(Paraná). It causes localized cutaneous ulcers and, occasionally,
some individuals can develop a classic picture of diffuse cutaneous leishmaniasis. Leishmania (Viannia) guyanensis, in Brazil, is
apparently limited to the north region (Acre, Amapá, Roraima,
Amazonas and Pará), extending into the Guyanas. It is found
mainly in dry land forests (areas that are not flooded in the rainy
period) and causes predominantly single or multiple ulcerated
cutaneous lesions, with the multiple lesions being consequences
of simultaneous bites of several infected mosquitoes or secondary

lymphatic metastases. Mucosal involvement is very rare for this
species. The disease affects mainly young and adult males in their
productive phase. Individuals infected commonly work in the socalled work fronts, which are areas associated with deforestation,
virgin forests, and military exercises. In endemic areas children
with the disease may be seen. L. (Viannia) braziliensis is the most
important species, not only in Brazil, but also in all Latin America,
with a wide distribution from Central America to the north of
Argentina and throughout Brazil. The lesions can occur in eyelids
or in areas usually covered by clothes, suggesting that the transmission often occurs inside the houses. The disease in humans
is characterized by a cutaneous ulcer, single or multiple, whose
main complication is the metastasis by hematogenic spread to
the mucous membranes of the nasopharynx, with corresponding
destruction of those tissues. Likewise, the remaining species have
their own characteristics regarding transmission cycles.
As they are introduced into the skin, the promastigotes
encounter the cells of the immune system, as T and B lymphocytes, macrophages, Langerhans cells, and mastocytes. Through
a mechanism not yet totally clarified, the parasite adheres to
the surface of the macrophages and Langerhans cells passing
into the intracellular media, and changes into the amastigote
form, characteristic of parasitism in mammals. The leishmanias
develop defense mechanisms capable of subverting the microbicide capacity of the macrophages, enabling them to survive and
to multiply until the rupture of the cell, when they are released to
infect other macrophages, thereby spreading the infection. Then
there is release of antigenic particles that will be presented to the
immune system. The location of amastigotes inside macrophages
makes the control of the infection dependent on the cell-mediated immune response.
Even with the diversity of Leishmania species, the spectrum
of clinical manifestations of the disease depends not only on the
species involved, but also on the infected individual’s immunologic condition. The cutaneous leishmaniasis (CL) represents
the most frequent clinical manifestation. In CL, the lesions are
exclusively cutaneous. These lesions are prone to healing and
present more frequently as single lesions, or in small numbers.
In more rare cases, the lesions can be multiple, characterizing
the form called disseminated cutaneous leishmaniasis. In CL,
the cellular immunity is preserved, thus enabling verification by
the positivity for the cutaneous test with leishmanin, intradermal reaction of Montenegro (IDRM), and other in vitro tests.
CL can be caused by all the dermotropic species of Leishmania,
but some particular characteristics have been attributed to the
different species. Thus, the lesions caused by L. (L.) amazonensis
have more infiltrated borders, containing abundant parasites. In
the lesions caused by species of the subgenus Viannia, there is a
reduced number of macrophages and parasites.
Some authors suggest a clinical classification based on criteria such as physiopathogeny of the site of the vector bite, aspect,
and location of the lesions (including nonapparent infections),
and lymph node leishmaniasis. The nonapparent infection, without clinical manifestation, is characterized by positive results
in serological tests and intradermal reaction of Montenegro in
seemingly healthy individuals, inhabitants of areas of transmission of leishmaniasis, with negative previous history and absence
of suggestive cutaneous scars of mucocutaneous or cutaneous
leishmaniasis. Lymph node leishmaniasis involves the discovery
of located lymphadenopathy in the absence of tegmental lesion.

162 — Marcia Ramos-e-Silva, Paula Pereira Araújo, and Sueli Coelho Carneiro

It can precede the tegumentary lesion and should be differentiated from the lymphangitis or satellite lymphadenomegaly.
CL develops with a typical painless ulcer and is frequently
located on exposed areas of the skin, that are round or oval, measuring from several millimeters to a few centimeters. It also has
an erythematous base, which is infiltrated and of firm consistency, with well-delineated, elevated borders, and a red bottom
with rough granulations. The associated bacterial infection can
cause local pain and produce a seropurulent exudate. Other types
of lesions are vegetating, papillomatous, and humid (of soft consistency). Or, the lesions can be verrucous with a dry rough surface that can include small crusts and desquamation. These two
can be primary or develop initially as ulcers. In nontreated cases,
the lesions tend to spontaneously resolve over a period of months
to a few years, but can also remain active for several years and
coexist with mucous lesions. When the lesions heal, they leave
atrophic depressed scars, with hypo- or hyperpigmentation and
fibrous areas. CL presents with varying clinical forms. The cutaneous form primarily affects the skin with an ulcer type lesion.
These lesions can be single or multiple (up to 20 lesions). They
have a tendency to spontaneously remit and respond well to treatment. In the North of Brazil, the multiple lesions are frequently
caused by L. (V.) guyanensis. The disseminated form of leishmaniasis is relatively rare, being observed in approximately only 2% of
the cases. The two species recognized as agents of this syndrome
are Leishmania (V.) braziliensis and Leishmania (L.) amazonensis.
The disease is characterized by the emergence of multiple papular
lesions of acneiform aspect, affecting several body segments, and
frequently involving the face and trunk. The number of lesions
may reach hundreds. The natural history of the disease in these
patients begins with one or several localized lesions with the classic characteristics of ulcers of a granular base and elevated borders. The satellite adenomegaly observed in more than half of
these cases in the localized form is rarely detected in patients with
the disseminated form and, if present, it is discrete. Later, after the
development of the primary lesions, a phenomenon of dissemination of the parasite through the blood or lymph systems occurs.
This happens within only a few days, sometimes even in 24 hours,
causing lesions distant from the original place of the bite.
Concurrent mucosal onset has been observed in up to 30%
of the patients and systemic manifestations, such as fever, general
indisposition, muscular pains, weight loss, and anorexia, among
others, can also appear. The finding of the parasite in the disseminated form is low, when compared with the diffuse form. The titers
of serum anti-Leishmania antibodies are high and the response in
IDRM is variable. Most of the patients require one or more additional rounds of treatment. Regarding the response to specific treatments, it can be stated that it presents satisfactory results, although
rounds of treatment. In HIV-positive individuals, ulcerated lesions
affecting several corporal segments prevail. This rare form of presentation is a sign of possible of co-infection with HIV and that
should alert the physician to investigate for infection of this virus.
The diffuse cutaneous form, in Brazil, is caused by L. (L.)
amazonensis. It is rare, severe, and occurs in patients with anergy
and specific deficiency to antigens of Leishmania in the cellular
immune response. Insidiously, a single lesion, appears, which
develops slowly into plates and multiple nonulcerated nodulations in vast areas of the skin. The response to therapy is poor
or absent and IDRM is usually negative. The cutaneous forms
should be differentiated from other diseases such as syphilis,

leprosy, tuberculosis, atypical mycobacterioses, paracoccidioidomycosis, histoplasmosis, lobomycosis, sporotrichosis, and
chromoblastomycosis, among others.
It is considered that 3% to 5% of the cases of CL develop
mucosal lesions. Clinically, mucocutaneous leishmaniasis is
expressed by locally destructive lesions in the mucous membranes of the upper airways. The classic form is secondary to the
cutaneous lesion and it is believed that the metastatic mucosal
lesion occurs by hematogenous spread or lymphatic dissemination. Patients with multiple cutaneous lesions and extensive
lesions of more than 1 year duration, located above the waist,
are the group with greater risk of developing metastases to the
mucosa. The lesion is usually painless and begins in the cartilaginous anterior nasal septum, near the nasal entrance. This
allows for easy visualization of the lesion. The etiologic causative
agent of mucocutaneous leishmaniasis in Brazil is L. (V.) braziliensis; however, cases attributed to L. (L) amazonensis and L
(V.) guyanensis have also been mentioned. This form of the disease is strongly positive for IDRM. However, due to the scarcity
of parasites, it is difficult to confirm their presence They have
a difficult therapeutic response, which demands greater doses
of drugs, and results in a more frequent recurrence (7.5%) than
in the cutaneous form (4.3%). It is also more susceptible to the
infectious complications and can result in death in 1% of cases.
The mucocutaneous form (Figs. 11.18–11.26) has nasal
obstruction, the elimination of crusts, epistaxis, dysphagia,
odynophagia, hoarseness, dyspnea, and coughs as the main
physical symptoms. There are rarely complaints of nasal itching
and pain. In the mucous membranes of the nose, perforation or

Figure 11.18. Leishmaniasis of the face (sister of patient in
Fig. 11.18).

Infection in the Tropics — 163

Figure 11.19. Leishmaniasis – vegetating lesion on the
lower lip (sister of patient in Fig. 11.17).
Figure 11.22. Leishmaniasis – verrucous lesion on the foot.

Figure 11.23. Leishmaniasis – verrucous lesion on the face.

Figure 11.20. Leishmaniasis on the nose and upperlip.

Figure 11.24. Leishmaniasis – partial destruction of the ear.

Figure 11.21. Leishmaniasis of the palate.

even destruction of the cartilaginous septa may occur and in
the mouth, perforation of the soft palate can occur. In chronic
and advanced lesions, mutilations with partial or total loss of the
nose, lips, and eyelids may occur, causing deformities and consequent social stigma. The differential diagnosis includes paracoccidioidomycosis, squamous cell carcinoma, basal cell carcinoma,
lymphoma, rhinophyma, lepromatous leprosy, tertiary syphilis,
rhinosporidiosis, entomophthoromycosis, traumatic perforation

164 — Marcia Ramos-e-Silva, Paula Pereira Araújo, and Sueli Coelho Carneiro

Figure 11.25. Leishmaniasis – total destruction of the nose.

Figure 11.27. Leishmaniasis – leishmania inside a macrophage.

Figure 11.26. Leishmaniasis – also destruction of the nose.

center of the reaction. There is also the possibility of ulceration
and local necrosis. In the diffuse cutaneous form IDRM is usually negative. Other methods like the detection of circulating
antibodies or PCR can also be used.
The drugs of first choice in the treatment of the leishmaniases are the pentavalent antimonials. There are two types of
pentavalent antimonials that can be used, the antimoniate of
N-methylglucamine and sodium stibogluconate. The latter is
not marketed in Brazil. The pentavalent antimonials are drugs
considered as leishmanicides, because they interfere in the bioenergetics of the amastigote forms of leishmania. It should not
be administered in pregnant women and there are restrictions to
the use of antimonials in patients over 50 years and in patients
with cardiopathies, nephropathies, hepatopathies, and Chagas’
disease. In the case of unsatisfactory response with pentavalent
antimonials, the drugs of second choice are amphotericin B and
pentamidines.
The criterion for cure is clinical, with a regular follow-up for
12 months being indicated. Cure is defined by the epitheliazation
of the ulcerated lesions and total regression of the infiltration and
erythema. Recurrence is defined as reappearance of the lesion in
any part of the body 1 year after clinical cure. Measures to prevent leishmania infection include use of repellents when exposed
to environments where the vectors can usually be found, avoidance of areas of exposure in vector activity periods (sunset and
night) and in areas of occurrence of L. umbratilis, avoidance of
exposure during the day and the night, use of mosquito nets of
fine mesh, screening of doors and windows, environmental handling through cleaning of back yards and land, and finally altering the environmental conditions that help the survival of the
vector’s immature forms.

or use of drugs, allergic rhinitis, sinusitis, sarcoidosis, Wegener’s
granulomatosis, and other rarer diseases.
In the occurrence of typical lesions of leishmaniasis, the
clinical and epidemiological diagnosis can be accomplished,
especially if the patient originates from endemic areas or was
present in places with cases of leishmaniasis. The clinical–
epidemiological diagnosis can be complemented by positive
IDRM and eventually by therapeutic response. Direct demonstration of the parasite is the procedure of first choice because
it is faster, of lower cost, and can be easily executed (Fig. 11.27).
Finding the parasite is inversely proportional to the length of
time the cutaneous lesion has been there. For example finding
the parasite after having the lesion for a year is rare. The isolation by cultivation in vitro is a method that allows the subsequent identification of the species of involved leishmania. The
intradermal tests (IDRM or leishmanin test) are based on the
visualization of the response of late cellular hypersensitivity.
Intradermal reaction usually remains positive after treatment
or healing of the treated cutaneous or spontaneously cured
lesion. It can be negative in weak-reacting individuals and in
those treated previously. It can also be negative in the first 4 to
6 weeks after the appearance of the cutaneous lesion. Patients
with mucosal disease present with exacerbated IDRM, with
several centimeters of induration and with vesiculation in the

P I T FA L L S A N D M Y T H S

There are still many habits and superstitions in Brazil that
can influence control of these diseases and the fear that they
instill.
The use of toothpicks made of vegetable fragments for cleaning of teeth, the habit of chewing vegetable leaves to pass time,
and the use of plant leaves for anal hygiene are hypotheses for

Infection in the Tropics — 165

contamination with P. brasiliensis, which is the agent for South
American blastomycosis.
There are certain tribes of Indians in the Amazon that consider piedra as an indispensable decoration for the hair. Tinea
corporis is still treated with pen ink in certain places in the interior of Brazil. There is also a belief that if herpes zoster reaches
both sides of the body and crosses the median line or closes a
circle around the body, that the patient will soon die. This belief
causes unnecessary fear.
The construction of houses in deforested areas, still close to
the forest, where the children play with reservoir animals, domestic or wild, and are continuously exposed to the vectors, can lead
to diseases like leishmaniasis, yellow fever, and malaria. The bad
habit of leaving old tires in back yards for children to play with
allows rain water or other sources to fill them, making them nurseries for Aedes, which is a vector of dengue and yellow fever.
The wattle and daub houses, where reduviid bugs hide in
crevices, facilitate infection with Chagas’ disease.
Besides superstitions and habits, there are also many regionalisms regarding those diseases that should always be taken into
consideration when examining patients from those areas.

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12

A Q UAT I C D E R M AT O L O G Y
Domenico Bonamonte and Gianni Angelini

H I STORY

The field of aquatic dermatology owes its development both to
modern man’s extreme mobility around the globe and to a growing attention to skin diseases provoked by the aquatic environment. Aquatic dermatoses are frequently observed in fishermen,
scuba divers, sailors, boatmen, bay watchers, swimming pool
attendants, swimming instructors, and workers at aquariums,
saunas, and Turkish baths, apart from bathers. The different
forms of dermatoses can be caused by either biotic or nonbiotic
(physical and chemical) agents.
The seas, rivers, lakes, ponds, swimming pools, and aquariums are populated by a myriad of animal and vegetable organisms.
During the course of evolution, multitudes of aquatic species have
developed both defensive and offensive mechanisms against their
predators, in the form of stings and bites that often include a venomous apparatus. These self-protective mechanisms are also used
against humans. Many species of marine vertebrates and invertebrates produce biotoxins, most of which serve to capture prey for
food (e.g. the toxins produced by Coelenterates). These toxins can
also have a simple defense function, like those present on the dorsal spines of the scorpionfish or the spine under the stingray’s tail.
From a chemical standpoint, the biotoxins identified up to now
are amino and phenol derivatives with a low molecular weight,
choline esters, or other more complex peptides or proteins. The
dermatological manifestations induced by marine organisms can
be associated with systemic reactions. These are sometimes of a
severe nature leading to shock, and even death. In this context, it
should be borne in mind that about 5% of fatal accidents occurring during underwater activities are due to accidental contact
with aquatic organisms that do not attack man. This fact is even
more significant when one considers that the mean total number of deaths worldwide caused by shark attacks is 6 per year.
Diseases caused by aquatic biotic organisms can arise due to three
different pathogenic events: toxic-immune, toxic-traumatic, and
traumatic. Traumatic lesions (e.g. an encounter with an electric
fish or shark) are not of dermatological concern and so will not
be dealt with in this chapter.

These belong to the Scyphozoa, Anthozoa, and Hydrozoa
classes (Table 12.1). These species share the same type of offensive organule, production of biotoxins, and inoculation mechanism used to capture their prey.
On the surface of the body and tentacles, Coelenterates have
a myriad of microscopic organules, variously known as cnidoblasts, cnidocytes, “urticant cells” or “sting capsules.” Cnidocytes

Table 12.1: The Phylum of Toxic Coelenterates
1. Scyphozoa (jellyfish)
Species:

Pelagia noctiluca
Rhizostoma pulmo
Cyanea capillata
Chrysaora quinquecirrha
Chironex fleckeri
Aurelia aurita

2. Anthozoa
Order:

Actinidae (sea anemones)

Species:

Anemonia sulcata
Actinia equina
Adamsia palliata
Calliactis parasitica
Condylactis aurantiaca

Order:

Scleractinia (corals)

Order:

Sagartidae

Species:

Sagartia elegans

3. Hydrozoa
Order:

Siphonophora

Species:

Physalia physalis
Physalia utriculus

D E R M AT I T I S F R O M C O E L E N T E R AT E S

Velella velella

Coelenterates or Cnidari (from the Greek knidi = nettle) are
animals with a simple symmetrical radial structure. Because of
the symptoms they cause they are also known as “sea-nettles.”
The Coelenterates phylum is abundantly present in tropical
and subtropical seas. Of the 9000 identified species, about 100
are known to be harmful to humans.

Order:

Leptomeduse (hydroids)

Order:

Milleporina

Species:

Millepora alcicornis (stinging
corals: not true coral)

167

168 — Domenico Bonamonte and Gianni Angelini

contain special globe-shaped bodies in the cytoplasm called
nematocysts that contain a very long, thin, spiral-shaped filament.
On contact with a foreign body, due to stimulation of their external receptors (cnidocilia), the cnidocytes eject their nematocysts. When these penetrate the body of the prey, the filament is
extruded and toxin is injected. Apart from physical contact with
the prey, a specific chemical stimulus produced by the prey is
needed to cause expulsion of the nematocysts. The whole expulsion process lasts less than 3 milliseconds.
The nematocysts vary in corpuscle shape and size, filament
length, and morphology according to species. They also contain
various biologically active toxic substances. The chemical structure of these is not known for all species. It was in 1902, in the
course of studying the toxins of the sea anemone, that Richet, the
French physiologist, discovered the phenomenon of anaphylaxis
which later won him the Nobel Prize in 1913.
From the tentacles of the actinia Anemonia sulcata, Richet
isolated three different components: hypnotoxin (that induces
somnolence and respiratory paralysis), thalaxin (that has an
urticant action and causes cardiac arrest), and congestin (that
causes anaphylaxis). As well as these, various other substances
have been isolated in Coelenterates (including tetramine, histamine and 5-hydroxytryptamine), which cause these animals to
be classified as venomous or actively toxic. Apart from some rare
exceptions (the Palythoa genus of the Zoantharia family), these
same organisms are not poisonous if ingested, because the protein toxins are inactivated by heat and then innocuously digested
by the proteolytic bowel enzymes. The skin effects (burning,
erythema and edema) are caused by tetramine, histamine, and
5-hydroxytryptamine. Some of the cytotoxic effects are attributable to damage to the cell membrane due to the toxic actions
on the mitochondria. Some species of anemones produce protease inhibitors that can act against trypsin and chemotrypsin. In
other cases, commonly in the Caribbean anemones, effects of the
toxins are brought about by blockage of the potassium channels
or glutamate receptor antagonism.

Table 12.2: Skin and Systemic Reactions to Jelly Fish
1. Local reactions: toxic reactions, angioedema, recurrent reactions,
persistent delayed reactions, reactions at a distance
2. Local sequelae: cheloids, dyschromia, atrophy, scarring, gangrene
3. Systemic reactions: asthenia, ataxia, muscle cramps, paraesthesia,
vertigo, fever, vomiting
4. Fatal reactions: toxic reactions (immediate cardiac and respiratory
arrest, delayed renal failure), anaphylaxis
5. Reactions after ingestion: pain and abdominal cramps, urticaria
6. “Indirect” dermatitis from Coelenterates: “dermatitis from
nudibranchs,”* dermatitis from antigenic substances in the water**
* Nudibranchs (Mollusks) feed on the tentacles and nematocysts of
Physalia. These nematocysts are not digested but migrate and are
stored in the dorsal papillae. Swimmers coming in contact with these
“armed” Nudibranchs can be stung by the nematocysts.
** when strong storms are blowing nematocysts can detache from
the tentacles of jellyfish and cause a dermatitis (“dermatitis caused by
nematocysts” without any contact with the coelenterate).

Reactions to jellyfish
Jellyfish are the most frequent cause of adverse reactions to
marine animals. There are about 150 million cases of jellyfish
stings reported each year. The pathogenic mechanism of such
reactions can be toxic or allergic. In the latter case they may be
either humoral or cell-mediated. Jellyfish venoms are difficult
to work with and are sensitive to pH, temperature, and chemical changes. The toxins produced by the nematocysts include
substances with an enzymatic action, compounds of quaternary
ammonium, catecholamines, histamine, and its release substances; serotonin and quinine-like substances.
In the Mediterranean, there are 11 species of jellyfish, six of
which are harmful to humans. Among the six, the most common
and toxic is Pelagia noctiluca, a small jellyfish whose entire body
and tentacles are covered with cnidocysts.
Reactions to jellyfish can present with different clinical–
morphological pictures and pathogenic mechanisms (Table 12.2).
The most common forms are localized toxic urticarial reactions.
Instant pain is followed by an immediate skin eruption, which
is characterized by figured urticarial lesions lasting from a few
minutes to several hours depending on the severity of the damage. Blistering, hemorrhagic, or necrotizing manifestations can

Figure 12.1. Figured erythematovesicular reaction to jellyfish.

also be observed (Figs. 12.1–12.3). Even diffuse urticarial reactions together with anaphylaxis (laryngeal edema, collapse) can
be frequent.
There have been cases of recurrent linear skin eruptions that
resulted from a single isolated sting and onset did not occur until
after a variable time interval (up to many months in some cases).
These delayed reactions appear 4 to 7 days after contact, are of
granulomatous type, and can persist for months. Histopathological
examination shows a dense dermal cell infiltrate, similar to that
seen in delayed hypersensitivity reactions. Apart from toxic reactions, there can also be allergic type reactions mediated by specific IgG or IgE antibodies. These antibodies persist for several
years and can cross-react. Jellyfish-induced dermatitis can leave
scarring outcomes in the form of keloids, dyschromia, scar tissue,
subcutaneous atrophy, and gangrene (Fig. 12.4).
In cases where the eyes come into contact with the animal,
photophobia, pain, and burning may develop. Chemosis, corneal ulceration and palpebral edema, iritis, increased intraocular

Aquatic Dermatology — 169

Figure 12.4. Figured scabs due to a reaction to jellyfish.
Figure 12.2. Figured erythematovesicular reaction to jellyfish.

Figure 12.3. Erythemato-vesico-pustular reaction to jellyfish.

pressure, mydriasis, and reduced accommodation can also occur.
These ocular lesions can be followed by anterior synechiae and
unilateral glaucoma in some cases.
Some jellyfish widely present in Southeast Asia and Australia
(i.e. Chironex fleckeri and Chiropsalmus quadrigatus) can provoke extremely severe systemic reactions that can even be fatal.
Among the causes triggering these reactions, a cardiotoxin, which
acts on the calcium channels, has been identified. A hemolytic
toxin has also been described. Chironex fleckeri venom is able
to produce a transient hypertensive response followed by cardiovascular collapse in anesthetized rats; boiling of the venom
abolished therefore this cardiovascular activity.

Reactions to actinias
Actinias, belonging to the Anthozoa class and also known as
“sea anemones” because they resemble the flower, cover seabeds with their tentacles. They are iridescent and may be a

Figure 12.5. Anemonia sulcata.

reddish, orange, or purple color. They are extremely variable in
shape. They generally live attached to the seabed like carnivorous flowers on a thick stem, while the long, slender tentacles
emerging from the apex oscillate gently in the water, creating elegant figures. The actinia most commonly found in the
Mediterranean is Anemonia sulcata (Fig. 12.5). This sea anemone is diffusely present in shallow waters and up to depths of
10 meters.
Particular attention has been paid by researchers to the toxins
produced by sea anemones because they have a greater stability
than those produced by other Coelenterates. There are more than
800 species of sea anemones. 40 of these 800 have been studied
from a toxicological standpoint. They produce large quantities
of three different classes of toxins: (1) toxins of 20 kDA with a

170 — Domenico Bonamonte and Gianni Angelini

cytolytic action (known as actinoporins); (2) neurotoxins of 3 to
5 kDA that can inactivate the sodium channels; (3) neurotoxins
of 3.5 to 6.5 kDA whose action is exerted on the potassium channels. Apart from the well-known toxins (hypnotoxin, thalaxin,
congestin, equinatoxin) isolated from various species of actinias,
some peptides from Anemonia sulcata and Condylactis aurantiaca have been individuated and characterized. These peptides
induce paralysis in crustaceans, fish, and mammals. Newer
peptide toxins, produced by the anemone Stichodactyla gigantea,
have recently been discovered. A few of these new toxins show
amino acid sequences that are homologous to the epidermal
growth factor (EGF) of mammals. Apart from their structural
homology, these toxins also seem to have functions comparable
to EGF. This discovery suggests that the phylogenetic origin of
EGF could have been as a toxin and that this toxic function could
have been lost during the course of evolution.
Sea anemones can induce the same skin picture that is seen
in jellyfish stings. In our experience, these reactions present with
much more severe symptoms than those provoked by jellyfish.
This is likely due to patients coming into closer contact with sea
anemones when patients are sitting or lying on the rocks where
the anemones are attached (Figs. 12.6 and 12.7). These lesions
are generally much more extensive and have many more bizarre
pathognomonic figures. From a morphological standpoint along
with being erythematoedematous, the lesions are often vesicular
or blistering (Fig. 12.8) and sometimes even necrotizing. Edema
is often severe and can feature an angioedematous picture. Some
isolated cases of allergic IgE-mediated reactions to certain species of anemones have caused anaphylactic shock, and acute
renal failure.
This disorder lasts from 15 to 20 to 30 days and can be associated with extreme subjective (intolerable pain and burning)
and systemic symptoms (malaise, asthenia, and muscle cramps)
(Table 12.3). Dyschromic or scarring sequelae (Fig. 12.9) are also
much more frequent after contact with sea anemones than with
jellyfish.

Figure 12.7. Figured erythematovesicular dermatitis from
Anemonia sulcata.

Figure 12.8. Figured erythemato-edemato-vesico-bullous reaction
from Anemonia sulcata.

Figure 12.6. Figured erythemato-edemato-vesico-bullous reaction
due to Anemonia sulcata.

Table 12.4 shows some principles of treatment regarding
reactions to Coelenterates. In nations with a high incidence of
reactions to Coelenterates, protective measures are often adopted
for preventative purposes. However, none of these measures have
been shown to be efficacious. A wetsuit leaves some skin areas

Aquatic Dermatology — 171

Table 12.3: Differential Characteristics between Reactions to Jellyfish and Sea Anemones
Reactions to Jellyfish

Reactions to Sea anemones

Incidence

Frequent

Less frequent

Type of contact

Generally superficial

Generally very close

Method of contact

Brushing while swimming

Sitting or lying on the rocks

Sites

All sites

Especially posterior face of the
thighs, back, and volar surface of
the wrists

Extension of dermatitis

Slight

Extensive

Morphology of the lesions

Figured, mainly linear figures

More bizarre and arabesque-like

Clinical lesions

Erythema, edema, rarely blisters
and necrosis

Erythema, severe edema,
frequent blisters and necrosis

Local symptoms

Pain, burning

Intolerable pain and burning
sensations

Systemic symptoms

Possible

Virtually constant

Clinical course

Few days

15–30 days

Sequelae

Infrequent

Frequent

Table 12.4: Principles of Treatment of Reactions to
Coelenterates
Local Treatment
Vinegar, alcohol, ammonia, urine, and salt water as hot as can be
tolerated.
Avoid the use of fresh water because it activates the nematocysts.
Avoid showers until the nematocysts toxins have been neutralized.
Wear gloves to remove tentacles. For this purpose a paste made of salt
water and bicarbonate or flour or talcum powder can be used. The
tentacles can be removed with a knife or sharp tool. If none of the
above powders are available dry sand can be used. Wash the affected
part with sea water.
In severe cases apply a hemostatic band above the dermatitis when a
limb is affected.
Administer local anesthetics and corticosteroids.
Systemic Treatment
Corticosteroids, antihistamines, epinephrine, cardiotonic drugs,
calcium gluconate, analgesics (aspirin, fenacetin, codeine).

Figure 12.9. Figured atrophic and dyschromic reaction to a sea
anemone sting.

exposed, while a mesh of protective nets is too wide to prevent the
passage of smaller Coelenterates. Recently, by exploiting the ability of the clownfish (genus: Amphiprion) to live unharmed within
the tentacles of sea anemones, a lotion has been formulated using
the mucous that coats the clownfish. This topical medication
seems to be able to prevent most contact reactions to jellyfish.
Sagartia, a sea anemone that lives symbiotically at the base
of sponges, causes severe skin and systemic reactions among
fishermen who collect sponges with their bare hands (“sponge

fisherman’s disease” or “maladie des pécheurs d’éponges nus”). The
onset of symptoms occurs a few minutes after contact with the sea
anemone and includes burning and itching, followed by erythematovesicular manifestations that are initially erythematous and
then turn purple. This picture can also be associated with systemic
symptoms (headache, vomiting, fever, and muscle spasms).

Sea bathers’ eruption
This affliction is observed in Florida, Mexico, and the Caribbean.
It is linked to several Coelenterates, including the larvae of the
jellyfish Linuche unguiculata and the sea anemone Edwardsiella

172 — Domenico Bonamonte and Gianni Angelini

lineata. This dermatitis develops as a result of bathing in sea
water, scuba diving, or windsurfing. It can present during or
after bathing, with papules (Figs. 12.10 and 12.11) that evolve
into pustules, blisters, and wheals. The patient will also report
malaise, fever, nausea, headache, abdominal pain, and diarrhea.
It generally affects covered areas. Removal of bathing attire and
showering immediately after bathing limits the extent of the
dermatitis, which evolves spontaneously over the course of two
weeks. From a pathogenic standpoint, sea bathers’ eruption can
be of either a toxic or allergic nature, as demonstrated by the
findings of specific IgG in some subjects. This disorder must
be differentiated from dermatoses induced by algae (observed
in Hawaii, in both fresh and salt water) and cercariae (in fresh
water, manifesting on uncovered skin areas).

Reactions to physaliae, corals, and hydroids
The Physalia genus includes two species: Physalia physalis
(“sea caravel” or “Portuguese man-of-war”), the most common species, which is present in the tropical Atlantic and the
Mediterranean, and Physalia utriculus, which is in the IndoPacific and south of Japan. The tentacles of a Portuguese manof-war can be as long as 10 meters. Stings from these species
cause extremely intense, unbearable pain that radiates from the
affected area and is accompanied by intense burning. The clinical picture features linear erythematous-edematous and vesiculobullous lesions. A few minutes after contact, there is onset of
the so-called “physalia syndrome” consisting of systemic symptoms, including anguish, lipothymia, myalgias, dyspnea, vomiting, bradycardia, and hypothermia. The affliction may resolve
benignly in a few days or may lead to coma, particularly in
tropical areas.
Skin lesions caused by corals can be of various types. Toxic
reactions due to contact with the nematocysts are relatively rare
and generally mild, whereas wounds caused by their sharp cutting points are quite frequent. These wounds rapidly evolve into
painful ulcerations or cellulitis and heal very slowly.
Hydroids, belonging to the Hydrozoa class, are small polyps
that form colonies 5 cm high. They are Coelenterates and are
prevalent in tropical and subtropical waters. They can provoke
immediate (contact urticaria) or delayed (papulous eruptions
with a hemorrhagic or zosteriforme evolution developing 4 to 12
hours after contact) reactions.

D E R M AT O S E S D U E T O E C H I N O D E R M S

Figure 12.10. Sea bather’s eruption: Erythemato-papulo-vesicular
dermatitis.

Echinoderms are animals with symmetrical pentameric rays. Of
the 6000 known species, 80 are poisonous or venomous. They are
subdivided into five classes according to their shape: Echinoids
(sea urchins), Asteroids (starfish), Ophiuroidea (sea serpents),
Holothuroidea (sea cucumbers) and Crinoidea (sea lilies).
Except for the Holothuroidea, all the other Echinoderms have a
rigid endoskeleton made of calcareous stone.

Reactions to sea urchins
Sea urchins are widespread in the Mediterranean (one of the most
common is Paracentrotus lividus) and frequently induce reactions of both immediate and delayed type after contact with their
spines. These spines are sharp and very fragile. At the moment of
contact they penetrate the skin and break off. The fragments are
then left inside the wound and are difficult to extract.

Figure 12.11. The same case as in Fig. 12.10.

Immediate reactions. Skin penetration by sea urchin spines
causes an immediate fiery burning pain that can persist for
some hours, followed by reddening, excoriation, and edema of
the body part affected (Fig. 12.12). In some cases the lesions will
bleed abundantly. The patient may develop torpor and muscle
pain. Secondary infections are quite common, and usually lead
to rejection of the spines. The dermatitis generally resolves in
1 to 2 weeks unless the spines remain inside the skin. For this
reason it is essential to remove all the fragments of the spines
completely. Treatment also consists of applying water as hot as
can be tolerated on the edematous, painful lesions.

Aquatic Dermatology — 173

Figure 12.12. Abrasions from sea urchin spine pricks.

Figure 12.14. Granulomas from Paracentrotus lividus.

Figure 12.13. Granulomas from Paracentrotus lividus.

Granulomas from sea urchins. This well-known delayed type
reaction develops 2 to 3 months after the original contact and
can persist for very long periods, although spontaneous healing is also possible. The resulting nodular lesions have a hard,
parenchymatous consistency and range from 4 to 5 mm to 1 to
2 cm in diameter. They may be bright or dark red (Figs 12.13
and 12.14). It is possible to elicit a delayed allergic reaction by
injecting an extract of the spines in a water–alcohol solution
intradermally.
There may be various histopathologic granulomatous findings in the nodular lesions. These types of granulomas may be
foreign body, sarcoidal, tuberculoid, or necrobiotic. Albeit rarely
Mycobacterium marinum has been identified in some granulomas caused by sea urchins, suggesting a possible causal role of
this germ in determining the infiltrate. In about 30% of cases, the
infiltrate is not of a granulomatous type but is instead characterized by a nonspecific chronic inflammation or suppurating type
dermatitis. The nodular lesions are treated with intralesional
injections of corticosteroids or liquid nitrogen.
Chronic traumatic lymphedema of the hands. This is another
type of diffuse delayed reaction on the back of the hands that
consists of a peculiar chronic scleredema. This form of trauma
is found in fishermen. It is caused by repeated penetration of
the sea urchin spines, constriction of the wrists by the wetsuit,
and the low water temperature. It manifests in the form of a

hard edema of the back of the hands and sometimes, also the
forearms. Initially the edema is recurrent, but over the years
it becomes persistent, very hard, and clearly delineated. It will
persist for many years even after retirement from the working
activity (Fig. 12.15). The scleredema can be associated with sea
urchin granulomas, functional limitations of movement of the
wrists and fingers, dystrophic alterations of the nails. And sometimes scleredema can also be associated with acrocyanosis, cigarette paper atrophy of the damaged skin, joint dysmorphisms,
and lymphographic alterations of the affected limb. This chronic
professional scleredema must be differentiated from deliberate,
self-provoked lesions created with various repeated mechanical
stimuli (hemostatic bands, occlusive bandaging, traumas) for
economic gain (generally pertaining to a retirement fund) or
due to psychiatric problems. It must also be differentiated from
acute or chronic lymphedema of other natures (lymphatic aplasia, recurrent erysipelas, deep thrombophlebitis, angioedema,
cold urticaria, filariasis, venous obstruction, complications of
surgical procedures, or radiotherapy for breast cancer or other
tumors).

Reactions to starfish
Starfish (about 2000 species) have spines that can secrete toxins
that spread throughout the water. These are saponins with a
hemolytic, antibiotic action that can irreversibly block neuromuscular transmission. In the presence of many such animals,
contact with the surrounding water can therefore induce a papulo-urticarial reaction.
Some starfish, like Acanthaster planci (or “crown of thorns”),
can inflict a painful sting that may cause granulomatous lesions.

174 — Domenico Bonamonte and Gianni Angelini

This is a pruriginous eruption complicated by hyperkeratosis
and ragade-like fissures. The pathogenic mechanism may occur
at various stages including: trauma during manoeuvres while
cleaning the lobster, contact with seawater, and the sensitizing
action of some seasonal algae.

D E R M AT I T I S F R O M S P O N G E S

Figure 12.15. Intense chronic traumatic scleredema of the hands and
forearms in a fisherman.

The spines of A. planci can easily penetrate through gloves and
thin-soled shoes.

D E R M AT O S E S F R O M M O L L U S K S

The Mollusks phylum includes about 45,000 species that are
present all over the world. Some of their biotoxins are urticant
while others are much more toxic. There are three main
classes: Lamellibranchs (bivalves), Gasteropods (conidae), and
Cephalopods (octopus, squid, sepia).
Cephalopods (Octopus vulgaris) can inflict small bites
with their sharp bony beaks, and cause a lacerated star-shaped
wound with edematous margins. The wound causes a burning
pain that can spread to the whole limb and bleeds abundantly.
Above all, during the summer, the Australian coasts are populated by a small octopus (Hapalochlaena maculosa, also known
as the “blue-ringed octopus” because it has two blue rings on
the yellowish-brown background of the body), whose bite may
be fatal because of muscle and respiratory paralysis. A bite from
the more toxic tropical and subtropical Conidae (shells: Conus
aulicus, C. geographus, C. gloria maris) can induce intense burning and pain, ischemia and cyanosis, and even death after coma
and cardiac arrest. For preventive purposes, gloves must be worn
and the shells should be picked up only by their wide, posterior
extremity and dropped immediately if the animal extends its
rod-like shaft.

Sponges (Poriphera), stationary animals attached to the seabed or riverbed, have always been known not to be completely
innocuous. In fact, various toxins have been isolated. Sponge
fishing is carried out in the Mediterranean, Florida, Cuba, and
the Bahamas and hence are the areas where dermatoses from
sponges can be observed. When the sponge is detached or its
branches are broken off, the fisherman feels a burning, pricking sensation. In a few hours, pain, edema, rigidity of the hands,
erythema, and blisters develop. The dermatitis resolves within
about 2 days. Sometimes, a multiforme erythematous eruption
may also appear. Some of the sponges colonizing the Red Sea
(Latruncula magnifica or “red sponge”), the coasts of Florida
(Tedania ignis or “fire sponge,” Fibula nolitangere or “touch menot-sponge,” Microciona prolifera), and Australia (Tedania anhelans) are particularly toxic.
Other sponges can induce traumatic dermatitis because
of contact with the skeletal spikes made of silicone dioxide or
calcium carbonate. Gloves must be worn when handling live
sponges.

D E R M AT I T I S F R O M A L G A E A N D
B RYO Z OA N S

Dermatitis from algae
About 30,000 species of algae have been identified in salt and
fresh waters. Those producing biotoxins belong to the classes:
Cyanophyceae (among the Prokaryotes) and Dinophyceae
(among the Eukaryotes).
Lyngbya majuscola, a cyanophycea seaweed, causes dermatitis epidemics (“bather’s itch”) among Hawaiians on the Island
of Oahu and in Australia in the northern area of Moreton Bay
(Queensland). In this last locality it seems that no less than 34%
of the inhabitants have reported symptoms that could be correlated with exposure to the alga. The toxins mainly incriminated
are lyngbyatoxin A and debromoaplisiatoxin. A few minutes
after swimming, intense itching and burning develop, followed
by bullous lesions that leave painful erosions, especially at the
level of the genitals and the anal and perianal regions. The eruption involves all zones covered by the swimming costume, and
must be differentiated from “bather’s eruption.” Contact allergy
to Sargassum muticum, a brown alga in European seas that proliferates massively from March to October, has been reported.

LESIONS FROM ARTHROPODS

Unlike poisonous land arthropods, marine arthropods do not
contain toxins. The harmful effects of crustaceans (crabs, prawns,
lobster, limpets) are thus purely mechanical (lacerated wounds),
and caused by the action of the claws of these large animals.
Dermatitis of the hands has been reported in lobster fishermen.

Protothecosis
Skin protothecosis is an exceptional opportunistic infection by
Prototheca, an achlorotic mutant of the green seaweed Chlorella.
The affliction is mainly linked to the species P. wickerhamii. More
than 80 cases of protothecosis have been reported worldwide,

Aquatic Dermatology — 175

but the infection is particularly common in tropical areas and
the southeastern United States.
The natural habitat of Prototheca is the mucilage of trees
and waste waters but it can also be found in cats, dogs, seawater,
lakes, and ponds.Protothecosis affects the cutaneous and subcutaneous layers. The incubation time is unknown, but is probably
some weeks or months. Clinically, protothecosis may manifest in
three forms: (1) cutaneous lesions; (2) olecranon bursitis, which
occurs in 25% of cases; and (3) systemic protothecosis. A local or
systemic immunosuppressive factor is found in half of the cases.
A few cases of peritonitis due to P. wickerhamii in peritoneal
dialysis have been reported.
There is no specific skin picture. Most cases manifest with
papulous or eczematous lesions at the entry site, which is generally the face or limbs. The lesions have a slow evolution, with a
centrifugal extension. Other possible lesions are blisters, cellulitis, verrucous nodules, pustules, plaques, and ulceration.
Diagnosis is not easy, and is based on the search for the
microorganism in the tissues, confirmed in culture (Sabouraud
dextrose agar). Histological examination shows numerous
organisms among the collagen fibers, adnexa, and epidermis;
in sections stained with hematoxylin-eosin (H&E) they appear
intensely basophilic with a clear halo.
Treatment is also quite difficult, especially in immunocompromised patients, who are more susceptible. Rarely, the infection can resolve spontaneously. Localized lesions should be
surgically excised. In some cases oral ketoconazole, itraconazole,
intravenous amphotericin B, or a combination of amikacin and
tetracycline have given good results.

Dermatitis from Bryozoans
Bryozoans (“sea moss”) are invertebrate animals that for
a long time were mistakenly identified as algae and corals
because their colonies, attached to the seabed, assemble to
form either coral-like masses encrusting various substrates
or free masses appearing as fine threads forming a branching
shape resembling algae. Those responsible for contact dermatitis are mainly Alcyonidium gelatinosum, Alcyonidium hirsutum, Alcyonidium topsenti, and Electra pilosa. A. gelatinosum
is widespread in the northern hemisphere and, in particular,
in the Atlantic Ocean, Baltic Sea, North Sea, Arctic Ocean,
and the English Channel. Dermatitis due to Bryozoans is
quite disabling in fishermen. It was first reported in the North
Sea (named “Dogger Bank itch” after the Dogger Bank in the
North Sea). It starts with an allergic mechanism and recurs
each summer. The distribution of the eczema might well be
due to an additional photoallergic reaction. Fishermen come
in contact with “sea moss” when they pull the nets on board,
filled not only with fish but also other marine organisms.
The dermatitis presents with dry lesions or acute exudative
manifestations. The hands and forearms are first affected by
direct contact, and then the face and neck by airborne contact
through drops of water containing the allergenic matter. The
dermatitis can also become generalized. In the case of A. gelatinosum the allergen is 2-hydroxy-ethyldimethylsulfoxone.
Prick tests are made with fragments of freshly collected live
Bryozoans, sea water containing the allergen, and aqueous
and acetone extracts of “sea moss.”

D E R M AT O S E S F R O M A Q UAT I C WO R M S

These organisms are classified in the phyla of the Platyhelminths,
Nemertines, Nematodes, and Anellids. Some salt and fresh water
species contain biotoxins.

Dermatitis from cercariae
Dermatitis from cercariae (“swimmer’s itch” or schistosomial dermatitis) is due to skin penetration by cercariae of the
Schistosomatidae family (Platyhelminths). The skin picture of
dermatitis caused by nonhuman schistosomes is different from
that of visceral and skin schistosomiasis, or bilharziosis, caused
by human schistosomia.
It is most often caused by Trichobilharzia ocellata, Trichobilharzia stagnicolae, Gigantobilharzia huronensis, and Schistosomatium douthitti. The intermediate hosts, that is, mollusks, belong
to the species Lymnaea, Physa, Planorbis, and Stagnicola.
Dermatitis from cercariae is common everywhere, and apart
from swimmers, it can affect subjects working with fresh irrigation waters, farmhands, and rice pickers. The probability of
developing swimmer’s itch increases with the days of water use
and at locations with onshore winds. Similarly, the severity of
episodes increases with the time spent in the water and at the
same locations. Three different pictures have been identified,
according to the definitive host involved. Dermatitis from fresh
water cercariae, for which the definitive host is a bird, has also
been reported in swimmers in rapids and, in Italy, in female rice
pickers in the Padania Plain. Nowadays, technological changes in
rice growing have made this form an exceptional observation.
Dermatitis from sea water cercariae has a sea bird as the
definitive host, and has been reported in the United States,
Australia, and Hawaii. In workers in oriental rice fields (India,
Malaysia, China) and in East Africa, dermatitis from fresh water
cercariae has been observed. The definitive hosts for these cercarial are buffalos, sheep, and goats. The clinical manifestations
develop because of a hypersensitivity phenomenon in allergic
subjects and involve the epidermis because cercariae seem to be
unable to cross the papillary dermis. Initial itching is followed by
an urticarial eruption that resolves in about half an hour, leaving
maculae; after several hours these transform into very pruriginous papules. The dermatitis resolves in 1 to 2 weeks but may be
complicated by abrasions due to scratching and secondary infection featuring the formation of pustules.
Individual protection is essential as a preventive measure
(wearing protective clothing and washing carefully), as well as
environmental clean-up (molluscicides). Dermatitis from cercariae must be differentiated from “bather’s itch” and dermatitis
from algae (Table 12.5).

Onchocercosis
Onchocercosis, or onchocerciasis, is an infection by Onchocerca
volvulus, a thread-like nematode that parasitizes only humans
and the gorilla. The adult worms live in the dermis and subcutaneous tissues. Some are free while others gather in masses surrounded by a fibrous capsule (onchocercomas). The disease is
transmitted by the females of the diptera of the Simulium genus
(black fly) that deposit eggs on plants and rocks washed by rapid

176 — Domenico Bonamonte and Gianni Angelini

Table 12.5: Differential Diagnosis among Dermatitis from
Cercariae (DC), Bather’s Eruption (BE), and Dermatitis
from Algae (DA)
DC

BE

DA

Localization

Ubiquitous

Atlantic Coast

Hawaii

Etiology

Cercariae

Larvae of
cnidari

Algae

Type of water

Especially fresh Salt

Fresh and salt

Skin sites

Exposed

Covered

Coveredexposed

running waters (torrents, rivers, waterfalls). Mobile larvae hatch
from the eggs and live in running waters, growing into adult
insects. Simulids become infected by stinging a parasitized individual, and then transmit the larvae to another host, again by
stinging.
Onchocercosis is present in Sub-Saharan Africa (Senegal,
Congo), Saudi Arabia, Yemen, and Central and South America
(Mexico, Guatemala, Venezuela, Colombia, and Brazil).
The organs affected are the skin, lymphatic apparatus, and
the eyes. The skin manifestations start with intense, diffuse
itching that can persist for a long time, caused by migration of
the microfilaria and lysis of adult worms. Males and juvenile
worms migrate through the host tissue, thanks to the production of matrix-degrading metallo- and serine proteinases in
excretory-secretory worm products; the enzymes may be essential for migration of the mobile stages. After incubation for 3 to
36 months, an acute, pruriginous erythemato-papulous exanthema appears (with elements measuring 1–3 mm in diameter)
in various sites: the trunk and lower limbs in the African form,
lower limbs in the Saudi Arabia and Yemen forms, and the head
and chest in the American form. This is followed by a chronic
phase of diffuse lichenification, with a possible hypertrophic
and verrucous appearance. In a later phase, onchodermatitis
presents with hypotrophy or atrophy and hypoachromic lesions,
leading to the typical “leopard-skin” picture. The late onset skin
form manifests with onchocercomas, nodular single or multiple lesions generally measuring 2 to 5 cm, mobile against the
underlying planes, but no evolution to ulceration and suppuration. Involvement of the eye (conjunctivitis, irreversible keratitis, uveitis, iridocyclitis, chorioretinitis, blindness) is observed
in cases where the head is affected or in long-standing infections
(10–15 years).
Widespread lymphadenopathy is possible. Laboratory tests
show eosinophilia, increased total IgE and ESR. Histopathology
reveals microfilaria extended or twisted inside the papillary and
superficial dermis among the collagen fibers. Microfilaria can
also be found in the epidermis and above all in onchocercomas,
where adult worms are also visible. Among the immunological
tests, it is important to search for direct antibodies against the
specific antigen OV-16; these antibodies are present in the circulation even before there is any evidence of microfilaria in the
dermis.
The etiological treatment of choice is based on a combination of ivermectin and albendazole. Onchocercomas can be surgically removed.

Reactions to leeches
Leeches are segmented fresh water worms of the Hirudinea class
and Anellida phylum. These slender invertebrates, 5 to 7 cm
long, attach themselves to the skin and suck blood until they are
engorged, doubling their volume and then fall off. Their saliva
has local anticoagulant and fibrinolytic and anesthetic properties
so the victim bleeds abundantly but feels no pain. They live in
ponds and rivers and feed off the blood of vertebrates, especially
mammals. Leeches can also live in the sea and earth (in the tropical rainforests). Man can be attacked in summer months when
entering infested waters.
With its bite the leech injects an anticoagulant, hirudin, as
well as other unknown antigenic substances. In nonsensitized
subjects the wound bleeds and heals slowly. In allergic subjects
urticarious, bullous, and necrotic reactions, and sometimes even
anaphylaxis can develop.

Dermatitis from Polychaetes
The Polychaetes class of the Anellida phylum includes some species that are widespread in the seas, such as Hermodice carunculata (the “dogworm” of dark, rocky depths), which is ubiquitous
in the Mediterranean, and Aphrodite aculeata (the “sea mouse”
of sandy and muddy sea bottoms). These worms have bristles on
their surface, which provoke an intensely itchy, painful erythemato-edematous reaction if they penetrate the skin. If a joint is
affected, there may be painful swelling and functional limitation.
Unless they are removed (with a sticking plaster) the spines can
give rise to a purulent, granulomatous swelling. The mechanical
effect of the bristles (“bristle worm dermatitis”) can be associated with a toxic reaction to an as yet unidentified biotoxin with
cardiorespiratory effects.

Dermatitis from contact with bait
Fishermen using rods can develop a peculiar contact dermatitis,
albeit rarely. This affects the finger pads, perionychium, and nails
of the left hand and manifests with desquamation, ragades, and
onycholysis (Fig. 12.16). This painful dermatitis is provoked by
a sea worm used as bait. It develops 10 to 24 hours after contact,
and resolves with suspension of the use of the bait.
This dermatitis, also known as “escavenite,” has been
described in Italy, France, and Spain and has been attributed
to some anellida, namely, Nereis diversicolor (Fig. 12.17) and
Lumbrinereis impatients. When the bait is fixed on the hook, the
coelomic fluid of the anellid impregnates the fisherman’s fingers
causing the clinical picture, which can be defined as a protein
contact dermatitis.

Dermatitis from Nematodes
Larva migrans cutanea
This dermatosis, also known as “creeping eruption,” is caused by
Nematode larvae, including the species Ancylostoma brasiliense,
Ancylostoma caninum and Uncinaria stenocephala, the natural
parasites of dogs and cats. The affliction is frequently observed
in tropical and subtropical areas. In Europe and in temperate
zones cases due to local contact are less frequently observed.
Man is an occasional host in the parasite’s life cycle. The larva

Aquatic Dermatology — 177

with topical thiabendazole suspension at 10% in eucerine or 2%
in dimethyl sulfoxide (DMSO). In extensive forms the same drug
can be administered orally at doses of 20 to 50 mg/kg/day for
7 to 10 days. Some valid alternatives are albendazole (400 mg/
day for 3 to 7 days) and ivermectin (0.2 mg/kg in a single oral
administration).

D E R M AT I T I S F R O M F I S H

Figure 12.16. Protein contact dermatitis to bait.

There are 250 species of venomous fish, equipped with glandular
structures or apparatus that can secrete toxic substances. These
serve to paralyze prey and can be inoculated by biting or stinging. Humans can be accidental victims of these animals both in
the water, generally due to a defensive reaction by the animal,
and outside the water, due to clumsy handling.
Venomous fish belong to two classes, the Chondrichthyes
(fish with a cartilaginous skeleton) and Osteichthyes (fish with a
bony skeleton) (Table 12.6).
The Chondrichthyes are known as rays. They have a flat rhomboid or trigonal shape and a long tail with one or more spines on
the dorsal surface. They vary from a few centimeters to several
meters in length. Rays generally live in sandy or muddy waters,
half-hidden under a thin layer of sand. The venomous apparatus is
in the caudal spine, a caduceus formation situated in the proximal
part of the tail. Glandular and ductal structures are present inside
the spine, which can secrete and inoculate toxic substances.
Accidents normally occur when the subject inadvertently
steps on the body of the ray or falls in the water onto the animal.
Pressure induces it to arch its tail and violently project the spine

Table 12.6: Fish that Induce Toxic Reactions

Figure 12.17. Nereis diversicolor.

is unable to pass through the dermis, probably lacking the necessary enzymes, and migrates within the epidermis or between
the epidermis and the dermis. This migration lasts a limited
time and the larva generally dies within one month. Its progress varies from a few millimeters to a few centimeters per day,
except for “larva currens” (Strongyloides stercoralis) that moves
10 cm a day. The sites most often affected are the feet, hands,
and buttocks, which are the body parts most likely to come into
contact with earth contaminated by dog and cat feces. The incubation time varies and can even be a few months. In general, 24
to 48 hours after the time of larval penetration, an erythematous-papulous lesion forms at the site of entry, and one or more
snaky tunneling formations extend out of it. The linear lesion
is about 2 to 4 mm wide, bright red, and slightly raised above
the skin plane. The affliction resolves spontaneously. Atypical
clinical presentations, with vesiculo-bullous or frankly bullous
lesions, are possible as well. Histologic isolation of the larva is
very difficult because the larva generally lies beyond the visible
lesion. Cryotherapy with liquid nitrogen or carbon snow, applied
beyond the margins of the visible migration line, is generally efficacious in moderately severe disease. Good results are obtained

1. Class:

Chondrichthyes

Order:

Rays (stingrays or trigoni)

Family:

Dasyatidae

Species:

Dasyatis pastinaca
Dasyatis violacea
Dasyatis centroura

2. Class:

Osteichthyes

A. Family:

Trachinidae (weeverfish)

Species:

Trachinus araneus
Trachinus draco
Trachinus vipera
Trachinus radiatus

B. Family:

Scorpaenidae (scorpionfish)

Species:

Scorpaena porcus
Scorpaena scrofa
Scorpaena ustulata
Scorpaena dactyloptera

C. Family:

Muraenidae (moray eels)

Species:

Muraena helena

178 — Domenico Bonamonte and Gianni Angelini

against the victim, most often at the level of the foot or leg. The
poison, consisting of substances with a protein structure (serotonin, 5-nucleotidase, phosphodiesterase), acts on the cardiovascular, respiratory, and neurological systems. The wound caused
by the spine of a stingray is wide and lacerated.
Venomous Osteichthyes belong to the Trachinidae family
(weeverfish) and Scorpoenidae family (scorpionfish). The toxicity of Muraedinae (moray eels) is still under debate.
Weeverfish are relatively small fish measuring 10 to 50 cm
present along the coasts of the Mediterranean and the Northeast
Atlantic (European coasts). All species have spines connected
to cells that secrete toxic substances. Weeverfish live in shallow
waters half-hidden under the sand. Accidents are due to treading
on the animal or careless handling.
Scorpionfish are the most actively toxic fish. These brightly
colored fish live near the bottom of the sea (they prefer a rocky
seabed) and have a plump body, large fins, and venomous spines.
Contact with these fish generally occurs during deep-sea fishing
and scuba diving.
The clinical symptoms of stings from a venomous fish are
typical (Fig. 12.18). There is constant, immediate, and extremely
violent pain. This is even worse in the case of a sting from a weeverfish. The pain radiates all along the limb within 30 minutes
and persists for 12 to 48 hours. In all cases it is so severe that
the victim suffers malaise, functional impotence of the limb,
and lipothymia. The appearance of the wound is falsely reassuring. Stings from a stingray have lacerated edges whereas those
from a weeverfish are pointed. The sting is followed by a violent
inflammatory reaction with ischemic necrosis, pallor, cyanosis,
and blood-serum bullous lesions. Then there is onset of a hard,
painful edema with lymphangitis and satellite lymphadenitis.
The tearing pain can bring on anguish, tachycardia, dyspnea,
and hypotension, and even syncope and death. Neurological
signs include vertigo, contracture and muscle spasms, convulsions, and delirium. In the Mediterranean the outcome is invariably good. Immediate treatment must be administered at the site
of the event (Table 12.7).
Contact with moray eels generally occurs when capturing
the animal and pulling it on board. There is strong, burning local
pain after a bite from a moray eel, which may be accompanied by
dyspnea and shock.

Figure 12.18. Weeverfish lesion with intense edema of the arm.

Table 12.7: Principles of Treatment for Reactions to Fish
Wash the area with sea water.
Open the wound and remove fish spine residues.
Use a hemostatic band if a limb is affected.
Immerse the limb in water as hot (45°C) as can be tolerated for 30–90
minutes.
If the face or trunk is involved, apply warm compresses or rinse the
wound with hot water. Heat inactivates the heat-sensitive component
of the toxins.
Systemic treatment in an intensive care unit.

Fish with an electrical defense mechanism
The Torpenidae family includes fish with kidney-shaped electrical organs arranged on each side of the back. These organs
can produce electric shocks up to 200 volts. In an emergency,
the torpedo ray uses higher voltage and amperage. Repeated
shocks gradually lose their power. Contact is again during capture or handling the animal, and may be direct or mediated by
the metal harpoon. In general, the shock induces only a slight
stupor.

D E R M AT O S I S D U E T O A Q UAT I C
BACTERIA

Infection by Mycobacterium marinum
Mycobacterium marinum is a slow-growing (10–28 days) photochromogenic bacterium belonging to group I of Runyon’s classification. It grows best at a temperature of 25°C to 32°C. M.
marinum is present in temperate salt and fresh water, and causes
disease in fish and humans. In the latter case the infection usually manifests as “swimming pool granuloma” and “aquarium
granuloma.”
In swimming pools, the bacillus is most likely to be found
at the water entry tubes and on the walls. It can be destroyed by
high concentrations of chlorine (10 mg/L). The form of granuloma incurred is generally localized to the elbows and knees.
Aquarium granulomas can be occupational (aquarium sales
staff or workers) or nonoccupational (when cleaning an aquarium in the home). The sites affected are the hands and forearms.
There is usually only one lesion initially. It presents as a reddish
or reddish-blue nodule with a soft consistency and a diameter
of up to 5 to 6 cm (Fig. 12.19). This initial lesion may undergo
ulceration or colliquation, and turn into an open wound. It can
also present a verrucous surface. There are rarely disseminated
lesions except in immunosuppressed subjects. Sporotrichoid
forms are common, featuring various nodules along lymphatic
drainage lines (Fig. 12.20). There may be mild involvement of the
regional lymph nodes. The infection may resolve spontaneously
after a few months but can persist for many years.
The incubation time is 2 to 3 weeks. M. marinum, antigenically correlates with M. tuberculosis and does not confer immunity, so re-infection is possible. A firm diagnosis is based on
culture of the mycobacterium from biopsy or aspirate samples
in Löwenstein–Jensen culture medium. The culture is positive in

Aquatic Dermatology — 179

A strong clinical suggestion of M. marinum infection
warrants initial empirical treatment to prevent progression to a
deep-seated infection.The treatment should preferably be preceded by an antiobiogram. The most efficacious drugs are minocycline, tetracycline, rifampicin, isoniazid, sulfamethoxazole,
and clarithromycin. Polytherapy is sometimes necessary.
In recent years, we have observed 11 cases of granulomas
from aquariums, all of a professional nature. 6 patients presented
with a single lesion and 5 nodular lesions with a sporotrichoid
arrangement. 3 of these had an ulcerative evolution. All the cases
were caused by trauma of the hands during maintenance of an
aquarium. In all cases, specific PPD was positive, while culture
gave positive results in only nine cases. Apart from one case
that was successfully treated with rifampicin and isoniazid and
another with clarithromycin, all other cases resolved with minocycline therapy.

Erysipeloid

Figure 12.19. Fish tank granuloma.

Also known as Baker-Rosenbach’s erysipeloid, this is an
acute infection that rarely becomes chronic. It is induced by
Erysipelothrix rhusiopathiae, a gram-positive nonsporogenous,
nonmobile bacterium that usually has elongated filaments.
Infection is frequent in pigs, horses, sheep, turkeys, and other
animals as well as in freshwater and seawater fish. For this reason, it is most frequently observed in fishermen and butchers.
The complaint has also been reported in housewives who suffered a puncture wound from fish gills or chicken bones.
The onset of erysipeloid is generally observed in the later summer months, when infection of animals is most common. After
about 3 days from contagion, a dark erythematous skin patch
develops at the site of the inoculation, with an irregular centrifugal extension and distinct, raised polycyclical margins. The sites
most often involved are the hands and forearms. In 10% of cases,
fever develops. Pain and itching may also be present. The skin
patch reaches a maximum diameter of 10 cm and spontaneously
resolves within 2 to 3 weeks. Rarely, generalized skin pictures have
been described, as well as systemic forms with endocarditis. The
disease leaves no immunity, so re-infection is possible. The bacterium responsible can be cultured after biopsy in the margin of the
skin lesion, or in the blood in systemic forms. One week’s treatment with penicillin and tetracycline should cure the disease.

P I T FA L L S A N D M Y T H S

Figure 12.20. Sporotrichoid
fish tank granuloma.

70% to 80% of cases. Intradermal tests with PPD of M. marinum
yield positive results.
Searches for the bacillus in samples taken from the lesions
or biopsy samples stained with the Ziehl–Neelsen method are
nearly always negative. The bacillus can sometimes be isolated
in dead fish in the aquarium, or in the filter. Histopathological
analyses show an aspecific inflammatory infiltrate in the first
months, while older lesions are usually characterized by a granulomatous structure.

Various skin eruptions caused by marine biotic agents can
develop, each with a specific clinical–morphological picture. Such pictures may also mimic other forms of dermatosis.
Generally, from the clinical–differential diagnosis standpoint,
the most important element is the clinical history. In fact, in
the great majority of cases the history will reveal a close contact
with biotic agents while bathing in a sea, river, or lake. Another
important point is the time of onset of the complaint, especially
if it is during or immediately after a visit to an exotic area. Again,
with regards to clinical history, any manipulation of a fish tank is
an important point. Details on working activities are also useful,
especially involving cases of sailors, fishermen, scuba divers, or
patients pursuing amateur aquatic activities and hobbies, such
as fishing.

180 — Domenico Bonamonte and Gianni Angelini

Aquagenic complaints caused by biotic agents have a
polymorphic morphology. Lesions can be strictly localized or
widespread all over the skin. In most cases, there are subjective
symptoms, like itching, burning pain, and sometimes systemic
signs with involvement of internal organs. In fact, the toxins of
aquatic agents can wreak havoc on several organ systems simultaneously. A list of the most common skin complaints from
which a differential diagnosis from aquagenic dermatitis caused
by biotic agents can be made is shown in Table 12.8.
Forms of urticarial contact dermatitis are most often induced
by Coelenterates. In localized forms, which are often linked to
contact with jellyfish, differential diagnoses with urticaria is relatively easy. However, it is much more difficult in diffuse forms,
which are more frequently induced by sea anemones. In the latter case, urticaria from various causes and cold urticaria (that
could be secondary to swimming in cold waters) both need to
be excluded. However, it must be borne in mind that in common
urticaria the wheals last for a few hours (“short-lived” lesions)
whereas dermatitis manifestations caused by Coelenterates are
not only extremely figured but also last for several hours or even
days.
In cases involving the face (lips and eyelids) and hands,
Coelenterates can induce pictures that mimick angioedema.
Apart from the clinical history, evidence that the dermatitis is
due to Coelenterates includes a bright red erythema, the simultaneous presence of blistering-bullous lesions, and the longer
persistence of the symptoms. Finally, unlike urticaria or angioedema, dermatitis caused by Coelenterates can leave the skin atrophic or scarred.
Erysipeloid, a relatively rare disease, and occupational chronic
traumatic scleredema must be differentiated from other acute
or chronic forms of lymphedema, such as recurrent erysipelas,
angioedema, deep thrombophlebitis, and chilblains. All these
afflictions are accompanied by a specific set of subjective and
objective symptoms and signs. In particular, erysipelas is accompanied by septic fever with an acute onset, intense pain, and satellite adenopathy. Fishermens’ scleredema, on the other hand,
features a very slow evolution over time and is irreversible.
The erythematous-edematous-vesicular or erythematouspustular pictures provoked by contact with Coelenterates sometimes pose problems of differential diagnosis with contact
dermatitis and contagious impetigo, respectively. Contact dermatitis is linked to chemical causes that are present in the living

Table 12.8: Skin Diseases That Mimic Aquagenic Dermatitis
Induced by Biotic Agents
Urticaria
Angioedema
Erysipelas
Contact dermatitis
Contagious impetigo
Localized bullous dermatitis
Verrucous tuberculosis
Granulomas caused by foreign bodies
Sporotrichosis

or working environment. It is strictly related to contact of the
skin area involved with the harmful substance, and has a chronic,
recurrent course. Impetigo shows pustulous or more often bullous lesions and is generally observed in the pediatric age group
and affects particular sites (i.e. the periorifices and hands). It may
be accompanied by satellite adenopathy and fever. In doubtful
cases, microbiological examination of the pus will confirm or
exclude the presence of cocci.
Dermatitis caused by contact with Coelenterates can sometimes present with erythemato-bullous lesions. Clearly, in these
cases a differential diagnosis is with physical (burns) or chemical
(topical drugs, photosensitizing plants) causes. The more figured
nature of the clinical manifestation will make the diagnosis of
dermatitis induced by Coelenterates more likely.
Isolated granuloma from M. marinum clinically mimics the
papulo-verrucous lesions induced by M. tuberculosis or M. bovis
(verrucous tuberculosis). Amateur or professional manipulation of fish tanks will favor a diagnosis of M. marinum whereas
granuloma due to M. bovis is observed in workers on farms, in
those milking cows, and in veterinary surgeons. An intradermal test with mycobacteria may be positive in both diseases.
Culture of tissue biopsies or aspirate from the lesions will dispel any doubt. In fact, M. marinum is photochromogenic, and
grows in 3 to 4 weeks in Löwenstein–Jensen medium. Moreover,
it develops at a temperature of 31°C to 32°C rather than at 37°C.
Histopathologic examination is also diagnostic. Unlike the constant, classic tubercular picture of verrucous tuberculosis, in
cases of fish tank granuloma, there is no evidence of caseous
necrosis, giant cells are rarely present, and the infiltrate is often
aspecific.
In the more common sporotrichoid variant, fish tank granuloma must be differentiated from sporotrichosis. Both complaints are characterized by nodulous-granulomatous lesions
with a possible ulcerative evolution, arranged as “a rosary” along
a lymph tract. Culture reveals Sporothrix schenckii in the case of
sporotrichosis, in which the intradermal reaction to the mycobacterium will be negative. The site for fish tank granuloma is
the upper limbs whereas sporotrichosis is more commonly localized on the lower limbs. “Ex adiuvantibus” therapeutic criterion
is also very useful.
Granulomas caused by sea urchins need to be differentiated
from granulomas caused by other foreign bodies. The clinical
history reveals occupational or amateur fishing for sea urchins.
Sea urchin granulomas are almost always localized on the hands,
and sometimes the knees or elbows.
There are two important points to be remembered. Firstly,
although many aquagenic complaints can resolve spontaneously,
it is essential not to underestimate them. Even if they are of an
apparently modest entity, they can be accompanied by serious
systemic symptoms, including anaphylactic and life-threatening
reactions. In all cases immediate intervention with appropriate
treatment is necessary, especially bearing in mind that most such
“accidents” with aquatic agents happen far away from the nearest
hospital facility. First aid locally followed by admission to a hospital as soon as possible is vital in many cases.
From the medical standpoint, the complex problems arising
due to marine organism toxins have yet to be entirely elucidated.
Even the clinical manifestations are often unknown to the public and sometimes even the clinician, especially in “imported”
forms.

Aquatic Dermatology — 181

In conclusion, in the presence of strange, uncommon, and
unfamiliar clinical pictures with skin eruptions, the possibility of
an etiology involving contact with marine biotic agents should
always be entertained.

SUGGESTED READINGS

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PA R T I V: I N F E C T I O N S I N S E L E C T E D
PAT I E N T P O P U L AT I O N S

13

S K I N I N F E C T I O N S I N H I V PAT I E N T S
Joseph S. Susa and Clay J. Cockerell

Treating cutaneous infections requires that the provider be aware
of the spectrum of challenges that may be faced in an immunosuppressed patient. An unusual infection or even a common
infection that is recalcitrant to treatment may be a clue that can
suggest a diagnosis of immunosuppression or HIV infection. In a
patient who has already been diagnosed, it becomes important to
realize that immunosuppression can modify the course of common diseases. Unusual presentations, resistance to traditional
treatments, increased risks of a more aggressive course, disease
progression, and complications are all common challenges in
this population subset. Although the epidemiologic incidence of
opportunistic infections has decreased with the onset of highly
active antiretroviral therapy (HAART), the clinician still must
be familiar with the presentation of infections that occur more
frequently in immunosuppressed patients as well as the possibility of other unusual infections that need to be considered in
the differential diagnosis of a cutaneous infection for HIV positive patients. Certain dormant infections, such as mycobacterial
disease or varicella zoster, may flare up following the initiation
of HAART in what is known as the immune reconstitution
inflammatory syndrome (IRIS). The detection of opportunistic
infections also provides a clue to the degree of immunosuppression since certain infections are associated with decreased CD4
levels. Several cutaneous infections can also be AIDS defining.
Worldwide, and in the individual patient with advanced immunosuppression, these infections can result in significant morbidity and even death. It is the purpose of this chapter to survey the
more common cutaneous infections seen in patients with HIV
infection.

H I STORY

Before AIDS was formally described, a trend of increasingly
unusual infections began being reported on the continent of
Africa, and in 1981 in the United States, case reports involving cohorts of gay men who were developing Kaposi’s sarcoma
(KS) and Pneumocystis carinii pneumonia began coming to the
attention of the medical personnel due to a disease that would
eventually become known as acquired immune deficiency syndrome (AIDS). AIDS then clinically became defined by a cellular
immunodeficiency and by the numerous opportunistic infections
that started becoming its inevitable consequence. In 1983, the
etiologic virus, later termed the human immunodeficiency virus
(HIV), was isolated. During the initial years of the epidemic, the
natural course of the disease included a morbidity and mortality of stunningly high rates. By 1984, there had been 7699 AIDS
cases and 3665 AIDS deaths in the United States alone. KS and

other cutaneous manifestations such as bacillary angiomatosis
and disseminated fungal infections were the predominant visible
markers of HIV infection during this time period.
Initial treatments were only limited to the management of
infections or other complications secondary to the disease. In
1987, azidothymidine (AZT) became the first approved antiretroviral drug to treat HIV by the U.S. Food and Drug Administration
(FDA). Later, additional reverse transcriptase inhibitors were
approved and by the mid-1990s, multidrug combination therapy
had demonstrated an ability to delay disease progression and
prolong life in HIV positive patients. Pharmacologic advances
have continued to improve, and new classes of drugs like protease inhibitors and fusion inhibitors have also now been introduced. Several novel therapeutic approaches also continue to
be tested. The combination of multiple drugs and of different
classes of antiviral drugs is known as highly active antiretroviral therapy or HAART. Introduction of HAART has markedly
decreased the incidence of opportunistic infections in these
patients. While certain cutaneous manifestations of HIV such as
bacillary angiomatosis have decreased, others, including zoster,
dermatophyte infections, and recalcitrant folliculitis have actually become more frequent. With slowed disease progression and
prolonged survival, recognizing the cutaneous manifestation of
HIV will take on additional importance with regard to quality of life concerns and as a marker of disease progression and
immunosuppression.

ACUTE EXANTHEM OF HIV INFECTION

Within days of acquiring the HIV infection and before complete
seroconversion (which can up take 6 weeks), 25% to 80% of
patients will have prodromal symptoms known as acute retroviral syndrome or seroconversion illness. Systemic symptoms can
include lympadenopathy, fatigue, fever, headache, nausea, diarrhea, and night sweats. Cutaneous findings include a viral exanthem that is characterized by a morbilloform eruption with pink
oval to round macules and papules affecting the trunk, chest,
back, and extremities. Approximately 25% will also have mucosal
ulcerations. The usual clinical course is resolution within 4 to 5
days without sequelae. Rarely, a more severe form of acute HIV
infection characterized by pneumonitis, esophagitis, meningitis,
abdominal pain, and melena can develop. These patients may
demonstrate more severe cutaneous manifestations such as oral
ulceration, urticaria, alopecia, desquamation of palms and soles,
and even Stevens–Johnson syndrome. These patients are also
more prone to secondary co-infections with candida spp. and
herpes viruses. The prognosis in these patients is poorer than for
185

186 — Joseph S. Susa and Clay J. Cockerell

those without symptoms or those having only mild symptoms.
Early institution of antiretroviral therapy helps rapidly resolve
symptoms of acute retroviral syndrome and preserve CD4
counts.

Herpes simplex virus
Infections with HSV types 1 and 2 can result in recurrent, painful
grouped vesicles with an erythematous base localized mainly on
the lips genital and perianal areas. HSV-1 is most commonly
associated with oral lesions, whereas HSV-2 is most commonly
associated with genital lesions. However, there is considerable
overlap between the two viruses. Sometimes, ulceration takes
place without well-defined vesicles ever being noted clinically. It
is possible to establish the specific diagnosis by means of polymerase chain reaction (PCR), biopsies, and/or viral cultures.
Culture from tissue can be positive even if a swab and Tzank
preparation is negative. PCR, however, has a two- to four-fold
higher sensitivity in diagnosing genital ulcer disease when compared to viral cultures. Distinction between HSV-1 and -2 can be
achieved with culture and PCR techniques.
While the immune system is intact, the course of disease is
similar to that found in noninfected individuals. If left untreated,
these lesions may enlarge and become persistent, confluent
ulcerations that show slow healing and often become secondarily infected with bacteria. In immunosuppressed patients, the
lesions more commonly become persistent. With deterioration of
immune status due to onset or advanced stages of AIDS, lesions
of herpes simplex become clinically atypical. These atypical features can be roughly divided into three forms: chronic ulcerative herpes simplex, generalized acute mucocutaneous herpes
simplex, and systemic herpes simplex. Chronic ulcerative herpes simplex exhibits recalcitrant, painful ulcerations occurring
at the usual sites (perioral and perigenital regions) that enlarge,
deepen, and become confluent (Fig. 13.1). Nonhealing ulcers
that persist for greater than 1 month, with or without therapy are
recognized as AIDS-defining lesions.
An aggressive therapeutic approach should be used with
these patients, as they may be poorly responsive to the standard treatment and HSV infection increases the probability of
HIV transmission and shedding. Oral acyclovir in doses of up to

Figure 13.1. Large and confluent Herpes virus infection in an HIVpositive male.

400 mg five times a day for 10 days should be used for primary
infections. Alternatively, valcyclovir given in doses of 1g twice
daily may be preferential to acyclovir given its lower dosing
requirements. For suppressive therapy, 800 mg of acyclovir can
be given 2 to 3 times daily to prevent HSV reactivation. In severe
cases, hospitalization for administration of high-dose intravenous acyclovir may be required. Foscarnet is recommended in
patients in whom acyclovir resistance is suspected.
Generalized acute mucocutaneous lesions of herpes simplex
can occur following a localized skin lesion. The disseminated,
vesicular lesions clinically resemble those of varicella or small
pox. Patients exhibit high fever and other systemic symptoms.
Death can occur without obvious visceral involvement. Systemic
infection of herpes simplex is an exceedingly rare sequela even
in AIDS patients. It usually follows outbreaks of oral or genital
herpes. The most frequently involved internal organs are lungs,
liver, adrenal glands, pericardium, and brain.
Herpetic whitlow manifests as a deep-seated, painful ulcer
involving the volar aspect of distal phalanges. This form of herpetic infection most frequently occurs in young children who
suck their fingers and in healthcare workers who perform oral
examinations or procedures on a daily basis. Periungual infection may also occur. Herpetic folliculitis is a herpes simplex–inflicted inflammation of hair follicles that most commonly occurs
on the face.

Varicella-zoster virus
The incidence of herpes zoster is higher in AIDS patients than in
general population. The development of recrudescent varicellazoster virus (VZV) infection in a patient at risk for HIV infection
may be a sign of the presence of HIV and should alert the clinician
to screen the patient for the disease. Primary infection, known as
varicella or colloquially as chickenpox, produces crops of vesicles
on an erythematous base, beginning on the head and spreading
cetrifugally. In children or previously unexposed adults, primary
infections can be more severe, causing extracutaneous diseases
such as pneumonitis, pancreatitis, and encephalitis. It may even
be fatal in some cases. The CDC recommends live, attenuated
VZV vaccination for HIV-infected children and in adults with
early stage HIV infection. If a known exposure occurs in a VZVnaive, immunocompromised patient, immunoglobulin should
be administered as a prophylactic measure within 96 hours.
After primary infection, VZV exists in a dormant state in the
neural dorsal root ganglia. With reactivation, the virus progresses
downward through the nerve tracts of a solitary dermatome, leading to the characteristic zosteriform distribution of painful tense
vesicles in the skin. In individuals who have HIV infection, the
infection may be recurrent and severe, with more than one dermatome involved, and it may run a protracted course associated
with residual postherpetic neuralgia and scarring. Disseminated
herpes zoster is not as common but may be more common in
HIV-infected individuals. Atypical presentations of VZV include
verrucous zoster, follicular zoster, and ecthymatous or crusted
zoster. Chronic lesions, also known as verrucous or ecthymatous
zoster, can often be a presenting sign of HIV disease.
Occurrences of VZV are common after initiation of HAART
as part of the IRIS. The diagnosis of VZV is largely based on
its classical clinical presentation. Swabing for direct immunofluorescence is a rapid and effective way to diagnose atypical

Skin Infections in HIV Patients — 187

presentations. High doses of acyclovir (up to 800 mg five times
daily for 7 days) are used to treat these patients. Systemic administration may be necessary. Famciclovir given in doses of 250 mg
three times daily may improve patient compliance and decrease
adverse side effects, while still providing the same efficacy supplied by acyclovir.

Cytomegalovirus
Cytomegalovirus (CMV) is the most common cause of serious opportunistic viral infection in patients who have AIDS,
but cutaneous involvement is rare. In the skin, CMV can have
diverse manifestations including ulcerations, keratotic verrucous
lesions, hyperpigmented plaques, morbilliform eruptions, and
palpable purpuric papules. The perianal region, perineum, and
genitalia are frequent sites of involvement (Fig. 13.2). Because
the mucocutaneous lesions caused by CMV do not have specific features, tissue biopsy or immunoglobulin titers (IgG and
IgM) and viral cultures, are required for definitive diagnosis. The
treatment of choice for CMV infection is intravenous ganciclovir
5 mg/kg every 12 hours. Foscarnet should be used if ganciclovir resistance is suspected. In those with CD4 counts <100 mm3,
valganciclovir prophylaxis can be given in doses of 900 mg by
mouth every 24 hours.

Epstein–Barr virus
The primary infection of Epstein–Barr virus (EBV) is infectious
mononucleosis. After primary infection, the majority of adults
harbor latent EBV within B lymphocytes. With advanced immunodeficiency, EBV reactivation occurs, leading to oral hairy
leukoplakia (OHL), Burkitt’s lymphoma, or EBV-associated
large cell lymphoma. OHL manifests as single or multiple white
plaques on the lateral margins of the tongue with a verrucous
surface. These plaques are often asymptomatic (Fig. 13.3).
The presence of oral leukoplakia correlates with moderate to
advanced immunodeficiency and has also been correlated with
progression from HIV infection to AIDS. OHL will respond to
systemically administered acyclovir and valcyclovir, or topical
podophyllin. However, many clinicians elect not to treat patients
because the lesions are asymptomatic and because recurrence

Figure 13.3. White verrucous plaques on the lateral aspect of the
tongue typify oral hairy leukoplakia.

is common following discontinuation of treatment. OHL may
regress with highly active antiviral therapy alone.

Poxvirus
Molluscum contagiosum (MC) is a common disease, present in
10% to 20% of AIDS patients. It is caused by Molluscipoxvirus,
which is a member of the Poxvirus family. MC is transmitted by
direct skin-to-skin contact and produces cutaneous lesions, and
also more rarely mucosal lesions. In adults, it is most commonly
transmitted by sexual contact. Molluscum contagiosum is characterized by dome-shaped, umbilicated, translucent, 2 to 4 mm
papules that develop on any part of the body but especially on the
face and genital areas. In AIDS patients, these lesions are widespread, may be larger than 1 cm, and can become confluent and
disfiguring (Fig. 13.4). Most patients who have extensive molluscum contagiosum associated with HIV infection have CD4+
counts well below 250 cells/mL. The diagnosis should be confirmed by histologic examination in any case that is questionable
because it may resemble more serious infections such as cutaneous pneumocystosis, histoplasmosis, Penicillium marneffei infection, or cryptococcosis. Treatment options include cryotherapy,
electrodessication, curettage, topical application of podophyllin,
tretinoin, or imiquimod cream.

Human papillomavirus

Figure 13.2. Erosions and ulcerations due to cutaneous CMV
infection.

The human papillomaviruses comprise over 120 genotypes. They
cause a variety of warty lesions in the skin and mucous membranes including common verrucae, epidermodysplasia verruciformis (EDV), and condyloma accuminata. This family of
viruses is the cause of cervical and anal intraepithelial dysplasias,
bowenoid papulosis, cervical cancer, and anogenital squamous
cell carcinoma.
Common types of warts that can be observed include
filiform, flat, and plantar types. In patients with HIV, warts can
be widespread and can develop in unusual locations, such as on
the lips, tongue, and oral mucosa. EDV consists of a widespread
papular eruption of pink-red, flat, wart-like lesions distributed
mostly on sun-exposed areas of the skin. These can be related to
an autosomal recessive impairment of cell-mediated immunity

188 — Joseph S. Susa and Clay J. Cockerell

Human Herpes Virus 8
Human herpes virus 8 (HHV-8) was originally known as
Kaposi’s sarcoma (KS)–associated herpes virus, owing to its
original discovery in KS in AIDS patients. Its discovery changed
the thinking that KS was a low-grade sarcoma and introduced
the concept that KS is actually a diffuse vascular hyperplasia
in response to a viral infection. Early lesions appear as violaceous or sometimes even yellowish-green ecchymotic macules.
In time, these can enlarge and become confluent, forming papules, plaques, nodules, and tumors. These lesions are violaceous, red, pink, tan, and eventually become brown-purple
(Fig. 13.5). The morphology of these lesions defines three clinical stages as patch, plaque, or tumor. Lesions are usually unilateral at the onset of disease and progress to become bilateral
over time. Oral mucosal involvement presents as violaceous
plaques (Fig. 13.6). Lymphedema of the involved areas may
be present and is secondary to confluent lesions involving the
lymphatics vessels and lymph nodes. Extracutaneous KS is also
frequently encountered in the lymph nodes, gastrointestinal
tract, and lungs. Diagnosis is generally based on the finding
of violaceous skin lesions in the appropriate clinical setting
in conjunction with concordant histological findings. HHV-8
is also associated with other malignancies including primary

Figure 13.4. In immunosuppressed patients, lesions of
molluscum contagiosum can be much larger than the
typical 2 to 4 mm umbilicated papules usually seen.

to certain EDV associated HPV subtypes. EDV and common
warts are often treated with cryotherapy, electrocauterization,
or topically with caustic agents such as podophyllin, imiquimod,
trichloroacetic acid, and 5-fluorouracil. Howevermost of these
lesions are resistant to these modalities and require repeated
treatments.
Condyloma accuminata are soft sessile lesions with fingerlike projections. Imiquimod, podophyllotoxin solution or resin,
80% trichloroacetic acid, 5-fluorouracil injectable gel, interferon
alpha, cidofovir, cryotherapy, electrocautery, thermocoagulation,
laser, and excision are all treatment options.
Certain subtypes of HPV are considered to be high risk
(16, 18, 31, 33, 35, 39, 45, 51 and others) and others to be low
risk (6, 11, 12, 43, 44, 54, 61, 70, 72, and 81) for development
of anogenital intraepithelial neoplasia and associated squamous
cell carcinoma. Cervical, vulvar, and anal intraepithelial dyplasia may manifest as a flat condyloma with viral cytopathic effect
but without raised warty lesions. A solution of 2% to 5% acetic acid is helpful in delineating HPV lesions (acetowhitening).
Colposcopy or anoscopy may also reveal atypical vascular patterns in areas of intraepithelial dysplasia. HIV is associated with
an increased incidence of high-grade dysplasia, and increases the
risk of progression to invasive squamous cell carcinoma. HPV
has been detected in more than 95% of cervical cancers and
in more than 50% of anal cancers. Given the increased risk of
HPV infection, cytologic screening for dysplasia via cervical and
anal Papaniculou smears should be obtained regularly in HIV
patients.

Figure 13.5. Numerous violaceous-brown nodules and tumors of
Kaposi’s sarcoma.

Figure 13.6. Oral mucosal plaque of Kaposi’s sarcoma.

Skin Infections in HIV Patients — 189

effusion lymphoma and the plasma cell variant of Castleman’s
disease. Angiolymphoid hyperplasia with eosinophilia is also
HHV-8 associated.

BACTERIAL INFECTIONS

Folliculitis
Bacterial folliculitis is common in HIV-infected patients, and
appears as a widely distributed acneiform rash with papules
and pustules. Recurrent bacterial folliculitis may serve as a
clue for underlying HIV infection. It is important to screen
these patients for possible HIV infection. Folliculitis may be
more severe than typical cases and present as a plaque-like folliculitis in HIV patients. Most cases of folliculitis are caused
by Staphylococcus aureus. However, other organisms such as
Staphylococcus epidermidis and Pseudomonas aeruginosa. Micrococcus spp., gram-negative bacteria such as Acinetobacter baumanni, dermatophytes, pityrosporum yeast, or demodex mites
can also be etiologic. Patients with HIV often have risk factors for contracting methicillin-resistant Staphylococcus aureus
(MRSA). Such risk factors include intravenous drug use, hospitalization, men who have sex with men, frequent use of antibiotics, or incarceration. Hospitalized patients are at an increased
risk of contracting nosocomial infections. Bacterial folliculitis in
HIV-infected patients is often resistant to standard treatment,
and prolonged use of systemic antibiotics may be required. Risk
factors for drug-resistant or unusual organisms should also be
considered when deciding on a treatment plan. Patients with
HIV may also get eosinophilic pustular folliculitis, or Ofuji’s disease, which is an acneiform eruption of uncertain etiology characterized by folliculitis with numerous eosinophils on biopsy
and intractable itching. Treatment with HAART, as well as with
corticosteroids and antihistamines, may reduce lesions. Empiric
treatment with antimicrobial, antifungal, or antimite therapy has
also been shown to alleviate symptoms.

Mycobacterial infections
HIV-infected individuals are susceptible to a number of
mycobacterial infections that can produce a wide variety of
cutaneous infections. Since the presenting lesions of cutaneous
infections have nonspecific morphology, tissue biopsy and culture are requisite for diagnosis. Clinical suspicion is important
since mycobacterial cultures can take up to 6 weeks to perform.
PCR for Mycobacterium tuberculosis or atypical mycobacterial
infections may accelerate the diagnosis.
Infections with M. tuberculosis may be the result of a primary
infection at the site of broken skin that results in a local verrucous
lesion. However, it can also be the result of a systemic disseminated infection. Many manifestations of cutaneous tuberculosis
such as scrofuloderma, lupus vulgaris, and orofacial tuberculosis
represent host reactions to tuberculosis infection. These manifestations require intact cellular immunity and do not occur at
significantly increased rates in the setting of HIV.
Cutaneous miliary tuberculosis, however, occurs in the setting of advanced immunosuppression when active tuberculosis
spreads secondarily to the skin. This presentation occurs most
frequently when the CD4 count is less than 200 cells/mL. Lesions
of miliary tuberculosis may occur as macules, papules or nodules
with small vesicles. Cutaneous tuberculosis is treated with the
same regimens as pulmonary or extrapulmonary disease.
Cutaneous infection by Mycobaterium avium-intracellulare
occurs in the setting of profound immunosuppression and may
present as a variety of skin lesions including erythematous papules, pustules, nodules, ulcers, abscesses, folliculitis, panniculitis,
plaques, verrucous lesions, or draining sinuses.
The patient with HIV may be susceptible to a variety of other
less common mycobacterial infections as well. Case reports have
documented infection by Mycobaterium kansaii, Mycobaterium
genavense, Mycobaterium marinarum, and Mycobaterium leprae.
The incidence of infection by Mycobacterium leprae, the organism responsible for the various manifestations of leprosy, does
not seem to be increased in the setting of HIV.

Bacillary angiomatosis
Impetigo, abscesses, cellulitis, and necrotizing
fasciitis
Impetigo, a superficial intraepidermal bacterial infection,
is usually caused by group A β-hemolytic Streptococci or S.
aureus. It is seen most commonly on the face, shoulders, and
axillary or inguinal areas. The infection begins with painful red
macules. These macules later become vesicles and pustules that
contain purulent fluid. These soon rupture and give rise to the
characteristic honey-colored crust. When impetigo produces
painful plugged folliculitis, it is known as impetigo of Bockhart.
Patients with HIV are at an increased risk of soft tissue and
deep-seated bacterial infections such as cellulitis and abscesses
due to MRSA. By direct extension, these can lead to pyomyositis or necrotizing fasciitis, which would manifest as diffuse,
red, warm, tender areas in the skin, and can be associated with
severe toxemia. Frequently these abscesses are polymicrobial.
Excision and drainage of pyogenic abscesses has been reported
as an effective treatment modality in community-acquired
MRSA cases containing abscesses, even in the absence of antibiotic treatment.

Bacillary angiomatosis (BA) is an infection which may appear at
first impression to be a vascular neoplasm. The disease is caused
by infection by Bartonella henselae or Bartonella quintana and
presents in advanced stages of HIV when the CD4 count is less
than 200 cells/mL. While once considered a hallmark of HIV,
this disease has now become uncommon. Perhaps this is related
to the effects of HAART or as a result of antibiotic prophylaxis
with trimethoprim–sulfamethoxazole against Pneumocystis. The
earliest and most common lesions appear as discrete pinpoint
red-purple papules that resemble pyogenic granulomata (Fig. 13.7).
These lesions may ulcerate and become crusted. Another variant consists of subcutaneous nodules that may extend into the
underlying skeletal muscle and bone. Patients who have BA may
have systemic signs and symptoms, including fever, chills, night
sweats, and weight loss. In advanced cases, the liver and spleen
may also be involved. Because the clinical presentation of this
infection can easily be confused with pyogenic granuloma, biopsy
should be performed if the diagnosis is suspected. Bacillary
angiomatosis responds to treatment with macrolide antibiotics such as erythromycin, clarithromycin, and azithromycin or

190 — Joseph S. Susa and Clay J. Cockerell

Figure 13.7. Solitary vascular papule that resembles a pyogenic
granuloma. Biopsy proved that this lesion was actually bacillary
angiomatosis.

doxycycline. A 2- to 3-month course of erythromycin (500 mg/
QID) or doxycycline (100 mg BID) is effective against BA.
Recurrence is common.

S E X UA L LY T R A N S M I T T E D D I S E A S E

The accurate diagnosis of sexually transmitted diseases (STDs)
is of exceptional importance in individuals at high risk for HIV
infection because their presence increases the risk of transmitting and acquiring HIV infection. Studies have demonstrated
that, in some populations, the pattern of HIV acquisition parallels that of STDs.

Syphilis
A high prevalence of syphilis, active as well as latent, has been
found among AIDS patients in the United States. In HIVinfected patients, the infection begins as it does for immune
competent hosts. There is a single chancre that occurs at the site
of inoculation, although recent studies have reported multiple
chancres that can be aggressive and slower to heal. Chancres are
described as 1- to 2-cm, painless, nonpurulent, round to oval
ulcers with raised, indurated borders. Secondary syphilis may
occur in a number of forms in patients who have HIV infection.
It can range from the classic papulosquamous form with involvement of palms, soles, and mucous membranes to unusual forms
such as verrucous plaques, extensive oral ulcerations, alopecia,
keratoderma, deep cutaneous nodules, or widespread gummata
(Fig. 13.8).
Malignant syphilis, or lues maligna, is a rare, ulcerating,
widespread form of secondary syphilis. Papulopustular lesions
enlarge into sharply bordered ulcers that can be associated with
fever, malaise, and ocular disease. Cases of malignant syphilis
have been rising and mostly affect those with the lowest CD4
counts.
Syphilis may progress faster from secondary to tertiary disease in HIV-seropositive patients than in noninfected individuals. Those with CD4 counts below 350 mm are at a 4-fold higher
risk for neurosyphilis. Early central nervous system (CNS)

Figure 13.8. Extensive macular and subtle popular eruption
of secondary syphilis. Polymorphous presentations have
earned syphilis the title of “The great masquerader.”

relapse and unresponsiveness to treatment can also be more
common in HIV-infected individuals.
Co-infection with syphilis and HIV is somewhat common,
and shares risk factors for transmission. Therefore it is recommended that all patients with syphilis should undergo screening
for HIV. Serologic negativity may not rule out secondary syphilis in HIV-infected individuals as false-negative serologic studies can be seen with both the FTA-ABS and VDRL tests. This is
due to the because of loss of antibody production in advanced
HIV. If there is a discrepancy between clinical suspicion and
serologic tests, skin biopsy for demonstration of spirochetes
by special stains may be necessary to establish the diagnosis.
Dark field microscopy will also directly visualize the organisms. Current treatment involves a single dose of long-acting
benzathine penicillin (2.4 million units IM) or ceftriaxone
(1g daily for 8–10 days).

Other Sexually Transmitted Diseases
Although granuloma inguinale, alternately called donovanosis,
is a relatively uncommon STD in the United States and other
developed countries, this condition is quite common in certain
hotspots such as South Africa, Papua New Guinea, Brazil, India,
and among aborriginal Australians. It is caused by the gramnegative rod Calymmatobacterium granulomatis and manifests
clinically as vegetating lesions on the penis associated with
pseudobuboes in the inguinal crease. HIV-positive patients may
present with ulcers that are slow to respond to treatment and

Skin Infections in HIV Patients — 191

cause extensive local tissue destruction. Culture and skin biopsy
for identification of the safety pin-shaped organisms (Donovan
bodies) is required to establish the diagnosis. Current first-line
CDC-recommended treatments are either doxycycline 100
mg orally twice a day or trimethoprim–sulfamethoxazole (800
mg/160 mg) orally twice a day for 3 weeks.
Lymphogranuloma venereum (LGV) is a disease caused
by Chlamydia trachomatis that is uncommon in HIV-infected
patients in the United States, but is endemic in some developing nations. It presents as a generalized lymphadenopathy with
vulvar or penile edema with recurrent ulcerations and erosions.
Inguinal lymph nodes may be fluctuant or may form draining
sinuses. Diagnosis for LGV is presumptive based on clinical findings, and can be confirmed by serologic testing or PCR confirmation. Those thought to be infected with LGV should be started on
a course of 100 mg of doxycycline twice daily for 21 days.

Figure 13.9. Sharply demarcated patch and annular plaque of tinea
corporis, likely caused by Trichophyton rubrum.

FUNGAL INFECTIONS

Candidiasis
Recurrent or persistent oral candidiasis may be the initial sign
of HIV infection in many individuals and has been shown to be
a predictor of progression from HIV infection to AIDS. Most
commonly, infections are caused by Candida albicans, but infections with nonalbicans species including Candida glabrata,
Candida tropicalis, Candida parapsilosis, Candida krusei, and
Candida dubliniensis are becoming more frequent. The most
common clinical presentation is that of thrush. Thrush is a painful, whitish exudate present on the tongue or buccal mucosa that
can easily be scraped away. Candida is also implicated in causing
angular cheilitis, chronic paronychia, onychodystrophy, distal
urethritis, and persistent intertriginous infections. Esophageal
candidiasis is an AIDS-defining condition. Disseminated cutaneous lesions present as clusters of asymptomatic pustules on an
erythematous base or as nodules with central necrosis. Systemic
dissemination can produce candidal septicemia, brain abscesses,
and meningitis. Invasive, chronic, or recurrent disease should
be treated with oral fluconazole (100 mg/d) after a single loading dose of 200 mg, or itraconazole (100 mg two times per day).
Fluconazole resistance has recently emerged, probably as a result
of prolonged azole prophylaxis. If disseminated disease or resistance occurs, amphotericin B can be used.

Dermatophytosis
Cutaneous dermatophytosis is more common in patients with HIV
than in the general population and can be extensive and severe.
In any individual with extensive Tinea corporis or Trichopyton
rubrum, the possibility of underlying HIV infection should be considered. Tinea coporis, often caused by Trichophyton rubrum, can
present as a widespread dermal infection with multiple fluctuant
erythematous ulcerative nodules seen mostly on the extremities
(Fig. 13.9). Infection of the hair follicle with secondary rupture
is known as Majocchi’s granuloma and will present as firm violaceous folliculocentric nodules. Subungual proximal superficial
onychomycosis, which is rarely seen in the HIV negative population, appears as white plaques under the proximal nail. Diagnosis
can be established by skin scraping and direct visualization with

potassium hydroxide preparation, or by skin biopsy with special
stains or culture. If topical treatment is not successful, systemic
therapy, such as terbinafine for onychomycosis, may be needed.
Deep dermal infections may require systemic treatment with oral
fluconazole or itraconazole.

Pneumocystosis
Pneumocystis jiroveci, previously known as Pneumocystic carinii,
is most often associated with pneumonia that occurs when the
CD4 count is significantly depressed. It is an AIDS-defining illness, and it may rarely involve the skin in patients who use aerosolized pentamidine for prophylaxis of P. jiroveci pneumonia. The
lesions are friable reddish papules or nodules, most often in the
ear canal or nares. Small translucent molluscum contagiosum–
like papules, bluish cellulitic plaques, and deeply seated abscesses
have also been observed. Extrapulmonary disease is treated with
the same regimens as for Pneumocystis pneumonia.

Cryptococcus
The most common opportunistic fungal infection to affect the
skin in HIV-seropositive patients is cryptococcosis. However,
with the increased use of HAART the incidence has decreased
considerably. Cutaneous involvement may be seen with disseminated disease and is an AIDS-defining and life-threatening condition. Cryptococcus usually occurs when the CD4 count is less
than 100 cells/µL. Umbilicated papules similar to molluscum
contagiosum, nodules, pustules, ulcers, and erythematous papules are all common manifestations (Fig. 13.10). If cutaneous
cryptococcus is diagnosed, a thorough investigation for extracutaneous disease should be undertaken to initiate early life-saving
treatment. Cutaneous cryptococcus can be treated with fluconazole (200–400 mg/d) or itraconazole (400 mg/d). Disseminated
disease is treated with amphotericin B plus flucytosine.

Histoplasmosis
Histoplasmosis is a frequent opportunistic infection in patients
with HIV/AIDS. The infection begins with a flu-like illness, and
cutaneous lesions represent hematogenous dissemination that

192 — Joseph S. Susa and Clay J. Cockerell

Figure 13.10. Crusted umbilicated papules in a cutaneous
Cryptococcus infection.

usually manifests after the CD4 cell count falls below 150 cells/
mL. A variety of lesions are seen including nodules, vesicles, erythematous scaly plaques, necrotizing lesions mimicking pyoderma
gangrenosum, purpura, petechiae, and pustules with or without
ulceration (Fig. 13.11). Biopsy with histologic confirmation is an
important method of diagnosis because histoplasmosis can be
difficult to culture and serologic tests for histoplasmosis may be
falsely negative in HIV-infected patients. Treatment consists of 2
weeks of amphotericin B followed by itraconazole. Primary prophylaxis with itraconazole 200 mg/day is given to HIV-infected
individuals with CD4 counts less than 150 cells/µL.

Coccidiomycosis
Coccidiomycosis is an infection endemic to the southwestern
United States and arises from inhalation of arthroconidia. Initial
symptoms are nonspecific and include fever, malaise and a flulike illness that begins 1 to 3 weeks after infection. Up to 50%
of patients will have an associated inflammatory skin manifestations such as erythema nodosum, erythema multiforme-like
reaction, or toxic erythema. In a small percent of individuals,
the infection will progress beyond pulmonary disease. The
majority of HIV patients have CD4 counts below 250 cells/µL
at the time progressive disease occurs. Skin is the most common
site for disseminated disease to present. Common cutaneous
lesions include morbilliform eruptions, violaceous or ulcerating
plaques, papules, and pustules. If a patient has cutaneous disease,
a search for other systemic manifestations should be initiated.
Diagnosis can be established by culture, serology, or histology.
HIV patients with nonmeningeal, pulmonary, and disseminated
disease should be treated initially with amphotericin B (0.6 – 1.0
mg/kg/day). AIDS patients and any patient with disseminated
disease should be placed on lifelong azole therapy. Secondary
prophylaxis with either fluconazole 400 mg/day (first line) or
itraconazole 200 mg twice daily is recommended as standard of
care when patients respond to initial treatment.

Aspergillosis
Invasive aspergillosis is rare in AIDS, but when present, has
a very poor prognosis. It occurs predominantly in patients
with advanced HIV with leukopenia and neutropenia. CD4

Figure 13.11. An ulcerated erythematous plaque is one of
many possible presentations of cutaneous histoplasmosis.

lymphopenia has been identified as an important risk factor for
HIV-1–associated aspergillosis, and CD4 cell counts less than 50
cells/µL have been reported in the majority of cases. Other factors that may predispose patients to infection include extended
use of high-dose corticosteroids, exposure to broad-spectrum
antibacterial therapy, or previous underlying lung disease.

Paracoccidiomycosis
Paracoccidioides brasiliensis is an important chronic, progressive, systemic deep mycosis that is endemic in South America.
The usual course involves predominantly the pulmonary system
with lymphadenitis, although mucocutaneous sites can become
secondarily involved. The disease is most commonly acquired by
inhalation of airborne conidia produced in the mycelial phase
of this dimorphic fungus. Direct inoculation of either skin or
oral mucous membranes is a less common route of infection that
accounts for uncommon cases of cutaneous lesions without pulmonary involvement.

Penicilliosis
Penicilliosis is due to the dimorphic fungus Penicillium marneffei,
and is the third most common opportunistic infection in HIVinfected patients of countries of southeast Asia and southern parts
of China. The majority of cases of penicilliosis are seen in patients
with CD4 counts <50 cells/µL. The most common clinical presentation is fever, cough, weight loss, anemia, and disseminated papular skin lesions (Fig. 13.12). Umbilicated papules present over the

Skin Infections in HIV Patients — 193

Figure 13.12. Papular eruption of penicillosis.

face, pinnae, extremities, and occasionally the genitalia. Diagnosis
can be established by fungal isolation from blood culture or
other specimens, or by histopathologic demonstration of organisms on biopsy or by Wright-stained scrapings. Treatment is with
amphotericin B 0.6 mg/kg/day IV for 2 weeks, followed by oral
itraconazole solution in a dose of 400 mg daily for a subsequent
duration of 10 weeks. Simultaneous administration of treatment
for penicilliosis and initiation of HAART may improve outcome.
On completion of initial therapy, secondary prophylaxis with oral
itraconazole 200 mg daily should be given for life.

Other Fungal Infections
Blastomycosis and sporotrichosis have also been observed in
HIV-seropositive patients albeit rarely. Mucocutaneous lesions
associated with systemic fungal infections consist of pustules,
ulcers, papules, and nodules and less often as patches or plaques.
Since mucocutaneous fungal infections assume a number of
morphologies that may mimic other disorders including HSV
infection, cellulitis, or molluscum contagiosum, a tissue biopsy
of the lesion should be performed for histologic evaluation and
confirmatory microbiologic cultures. The HIV-associated disseminated form of sporotrichosis can also involve the eyes, joints,
lungs, liver, spleen, intestines, and meninges. Definitive diagnosis at any site requires culture isolation of Sporothrix schenckii
from a normally sterile body site.

HIV. The clinical presentation can vary from discrete scattered
pruritic papules and slight scale to a widespread papulosquamous
eruption that resembles atopic dermatitis. A common clinical
presentation is that of hyperkeratotic plaques present on the
palms, soles, trunk, and extremities in addition to intense pruritus that is worse at night. Contacts are almost always infected.
In HIV-infected patients who have CD4 cell counts less than
150 cells/mL, or in patients who have advanced peripheral neuropathy and diminished sensation, scabies infection may be
severe and have a much greater number of mites than normal.
This presents as crusted or “Norwegian” scabies. In rare cases,
complications from a scabetic infection could include secondary bacteremia and sepsis. The diagnosis can be confirmed by
microscopic examination of scrapings for mites or ova. Topical
treatments include permethrin and benzyl benzoate. Ivermectin
can be given orally.

Demodicidosis
The causative agent of demodicidosis is the mite Demodex. It
presents as a persistent pruritic follicular eruption of the face,
trunk, and extremities. Demodicidosis has also been associated
with the pathogenesis of rosacea-like dermatoses, perioral dermatoses, and blepharitis. Diagnosis is by clinical and pathologic
correlation, since Demodex are normal skin fauna.

Acanthamebiasis
Acanthamebiasis caused by several species of the free-living
amoebae Acanthamoeba sp. can have an aggressive course in
the setting of immunosuppression. The cutaneous presentation is that of painful red to violet nodules that ulcerate and
arefrequently located on the trunk and extremities (Fig. 13.13).
HIV-positive patients are at risk for granulomatous amoebic
encephalitis or disseminated amoebic disease, which are both of
which life threatening conditions. Cutaneous lesions may serve
as a source for these more serious infections. Acanthameobic keratits is not increased in HIV. The organism is identified histologically. Treatment is not standardized but a case that involved only
the skin was treated successfully with intravenous pentamidine,

PA R A S I T I C A N D E C T O PA R A S I T I C
INFECTIONS

HIV-seropositive individuals may present with a wide variety of
parasitic and ectoparasitic infections, including scabies, demodicidosis, acanthamebiasis, and leishmaniasis. These infections can
manifest either as localized conditions or as disseminated disease.
The clinical presentation may be unusual and the use of cultures
and skin biopsies is essential to render an accurate diagnosis.

Scabies
The causative agent of scabies is the mite Sarcoptes scabei. Scabies
is the most common ectoparasitic infection seen in the setting of

Figure 13.13. Ulcerated plaques and nodules on the arm and hand of
an HIV-positive patient. These lesions would have started as deep red
to violet nodules or pustules.

194 — Joseph S. Susa and Clay J. Cockerell

topical chlorhexidine gluconate, and 2% ketoconazole cream,
followed by oral itraconazole.

Leishmaniasis
Leishmaniasis is more difficult to treat when associated with
HIV infection. Amastigotes persist for years in macrophages
and actually accelerate compromised immunity in hosts by
increasing viral HIV replication. Leishmaniasis has three classifications: cutaneous, mucocutaneous, and visceral (also known
as kala-azar). Cutaneous leishmaniasis lesions in immunosuppressed patients mirror those seen in immunocompetent. The
skin lesions present as scaly lichenified depigmented plaques.
Nonulcerated nodules on the extensor surfaces of the limbs overlying the joints have also been described. Mucocutaneous disease
begins with single or multiple lesions that eventually heal. These
lesions can be painful and disfiguring. Given the prevalence of
HIV infection in the Americas, the incidence of leishmaniasis in
these patients is surprisingly low.

P I T FA L L S A N D M Y T H S

There are many cutaneous manifestations of HIV/AIDS that
are not infectious. HIV is associated with an increase in certain
malignancies such as leukemias and lymphomas that may present as ulcerated nodules that mimic infections. Patients with HIV
may be taking multiple medications and are at an increased risk
for drug reactions. Drug reactions can have varied morphologies
but may resemble a viral exanthem.
Since immune suppression commonly alters the course of a
disease and the body’s host response, treatment regimens should
be modified to each patient according to published guidelines.
In general, HIV-positive patients may require prolonged treatments and sometimes, increased dosages of medications.

SUGGESTED READINGS

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AIDS. Clin Infect Dis 1996; 22:S128–S132.

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2000;30:688.

14

INFECTIONS IN ORGAN TRANSPLANT
PAT I E N T S
Daniela Kroshinsky, Jennifer Y. Lin, and Richard Allen Johnson

Bacterial infections represent the major cause of morbidity in
patients undergoing solid organ transplantation (SOT). Soft tissue infections from bacteria generally occur in the first month
after transplantation when the skin is disrupted by the surgery
itself or by indwelling catheters and lines. Incidence of wound
infections in solid organ transplant patients ranges from 2% to
56%, depending on surgical technique, host characteristics, and
antibiotic prophylaxis.
The skin flora is also the culprit when introduced to less tolerant tissue such as the transplanted organ itself. This can lead
to pyelonephritis and cystitis in renal transplant recipients,
cholangitis, and intra-abdominal abscesses in liver transplants,
and bronchitis and pneumonia in the lung transplant recipient.
Frequently, bacteremia ensues and may again come to the attention of a dermatologist as a subcutaneous abscess from hematogenous spread.
In the setting of immunosuppression, it is helpful to characterize pathogens by their pathophysiology:
(1) True pathogens – infection originating in skin and being
typical of that which occurs in immunocompetent persons,
albeit with the potential for more serious illness
(2) Sometime pathogens – extensive cutaneous involvement with
pathogens that normally produce trivial or well-localized
disease in immunocompetent patients
(3) Opportunistic pathogens – infection originating from a cutaneous source and caused by opportunistic pathogens that
rarely cause disease in immunocompetent patients but that
may cause either localized or widespread disease in compromised persons
(4) Indicators of visceral pathogens – cutaneous or subcutaneous infection that represents metastatic spread from a noncutaneous site
With this framework, we will explore the common cutaneous bacterial pathogens.

H I STORY

The immunosuppressive regimens required to maintain organ
viability in transplant patients puts these individuals at risk for
infection. The skin is an organ that is easily infected, but can also
be a window to internal infections. Early recognition and treatment of these infections can minimize long-term morbidity and
mortality in this vulnerable population.

BACTERIAL DISEASE
I N T R A N S P L A N TAT I O N

Staphylococcus aureus
Staphylococcus aureus causes the majority of all pyodermas
and soft tissue infections seen in solid organ transplant (SOT)
patients. Although not one of the cutaneous resident flora, it
colonizes the anterior nares in up to 30% of healthy individuals
at any given time, and more than 50% of chronically ill individuals. The incidence of S. aureus nasal carriage is higher in SOT
patients, as it is in other immmunologically compromised individuals, such as those with HIV disease, diabetes mellitus, or
neutropenia.
Ensconced in the nares, S. aureus is able to colonize and infect
superficial skin breaks such as around hair follicles, skin disruptions from secondary dermatologic disorders (i.e., eczematous
dermatitis, herpetic ulcer, molluscum contagiosum), or via vascular access line and drainage tubes. The spectrum of pyodermas
includes folliculitis, furuncles, carbuncles, abscess, impetigo,
bullous impetigo, and ecthyma (Fig. 14b.1).
Once established in the skin, S. aureus is able to invade
more deeply into the soft tissue with resultant infections such
as cellulitis and necrotizing cellulitis (Fig. 14b.2). S. aureus can
also reach the skin via dissemination from another source of
infection. In this form of hematogenous seeding, the lesions
can appear nonspecific as petechiae, hemorrhages, subcutaneous nodules, soft tissue infections, and pyomyositis. Systemic
symptoms that would normally herald the onset of an infection,
such as fever, may be masked if the patient is on steroids for
immunosuppression.
S. aureus colonization has been associated with increased
risk of soft tissue infection, especially in the first 2 months after
transplantation. This has been well characterized in the liver
transplant patients where pretransplant colonization with methicillin resistant S. aureus (MRSA) and methicillin-susceptible
S aureus (MSSA) were independent variables for increased
S. aureus infections (bacteremia, pneumonia, abscess, wound
infection, sinusitis). MRSA has emerged as the leading cause of
postoperative resistant infections in liver transplant patients in
some hospitals. In some cases, colonization can be tied to use of
urinary catheters, postoperative bleeding at the surgical site, and
fluoroquinolone use in the months preceding transplantation.
MRSA colonization has not been definitively tied to increased
long-term morbidity or mortality. MRSA infection in liver transplant patients, however, has been associated with a higher rate
of posttransplant complications and longer stays in the intensive
care unit.
195

196 — Daniela Kroshinsky, Jennifer Y. Lin, and Richard Allen Johnson

Figure 14b.1. Erythematous edematous warm fluctuant plaque with
central erosion, consistent with an abscess; cultures grew MRSA.

Figure 14b.3. Yellow crusted erosions in a child with a history
of eczema, consistent with impetigo.

scarlet fever or TSS. SSSS is characterized by fever, skin pain, and
an erythematous or scarlatiniform rash with subsequent blister formation and superficial desquamation. It results from the
elaboration of epidermolytic toxins from S. aureus and has been
reported in SOT patients.
Standard perioperative antibiotics are administered to eradicate potentially active infections and cover skin flora. A firstgeneration cephalosporin is most commonly used. Cultures
must always be taken, however, in STIs because of increased
prevalence of MRSA and the potential for atypical organisms
such as fungal and mycobacterium. Vancomycin or linezolid is
employed where MRSA is of significant concern.

B-hemolytic streptococcus

Figure 14b.2. Erythematous, edematous plaques consistent
with cellulitis.

Treatment of S. aureus carriage with topical mupirocin has
been successful in decreasing the rate of infections post cardiothoracic surgery. It is still unclear whether the same effect will be
achieved for SOT patients for several reasons: (1) patients may
be colonized in areas on the skin other than nares, (2) there is
an increased rate of mupirocin-resistant S. aureus, and (3) many
patients subsequently become recolonized. Decolonization
of liver transplant patients has been reported with intranasal
mupirocin three times daily with daily chlorhexidine baths.
Various strains of S. aureus are capable of producing a variety of toxins, which cause the clinical syndromes of staphylococcal scalded skin syndrome (SSSS), staphylococcal scarlet fever,
and toxic shock syndrome (TSS). TSS is a febrile, multiorgan
disease caused by the elaboration of staphylococcal toxins, characterized by a generalized scarlatiniform eruption, hypotension,
functional abnormalities of three or more organ systems, and
desquamation in the evolution of the exanthem. Cellulitis caused
by strains of S. aureus that produce TSS toxins can be accompanied by the cutaneous and systemic findings of staphylococcal

Group A β-hemolytic streptococci (Streptococcus pyogenes)
(GAS) commonly colonizes the upper respiratory tract, and secondarily infects (impetiginizes) minor skin lesions from which
invasive infection can arise. Impetigo often appears as golden
crusts with small vesicles and pustules (Fig. 14b.3). Certain
strains of group A streptococci have a higher affinity for the skin
than the respiratory tract and can colonize the skin, subsequently
causing superficial pyodermas or soft tissue infections.
Other streptococci, such as Group B streptococci, commonly
colonize the perineum and may cause soft tissue infections at
this site. Morbidity and mortality are relatively high for group B
streptococcus infections, with a high incidence of bacteremia.
S. pneumoniae can cause a range of infections including otitis media, sinusitis, and more rarely, cellulitis. Clinically, affected
skin is characterized by bullae, brawny erythema, and a violaceous hue. Approximately 50% of cases are the result of pneumococcal bacteremia, often from a pulmonary source with an
associated high morbidity. Transplant patients, especially pediatric patients who have the highest exposure risk, are also more
likely to have recurrent disease, with a mean time of 5.4 months
between the first and second infections.
Studies have demonstrated decreased pneumococcal antibody
titers 3 months after transplantation secondary to the suppression of cell-mediated immunity. In the past, prophylaxis has been

Bacterial and Viral Disease in Transplant Recipients — 197

Figure 14b.4 Erthythematous, edematous, tender plaque consistent
with bullous cellulitis.

controversial but recent studies suggest that the polyvalent polysaccharide pneumococcal vaccine is safe and effective for patients
with well-functioning allografts, and the conjugate vaccine is similarly efficacious in generating a functional antibody response.

Necrotizing fasciitis
Necrotizing fasciitis is a severe form of soft tissue infection extending into the subcutaneous fat and deep fascia. Immunosuppressed
patients are particularly prone to this type of infection. Causes
can be monomicrobial (i.e., Group A β-hemolytic streptococcus), or polymicrobial (nongroup A streptococcus plus anaerobes). Transplant patients are also prone to infections caused by
Pseudomonas, Klebsiella, and Serratia. Pain out of proportion
to physical findings in a patient with evidence of a systemically
toxic condition should raise the clinical suspicion of necrotizing
fasciitis. Very rapidly, the clinical picture can change, with skin
becoming erythematous to dusky and edematous, and with pain
transforming into anesthesia. Cases in transplant patients often
have subcutaneous emphysema, and finding gas on imaging can
be helpful in making the diagnosis.
Necrotizing fasciitis arising in the setting of transplantation
is classified as early (within ten days of transplantation) or late
(greater than one year after transplantation). While the majority
of cases are late, these infections tend to be less aggressive.
Treatment for necrotizing fasciitis includes early surgical debridement, antibiotics, and intensive care monitoring. Some success has been noted with intravenous γ-globulin use as well. The
mechanism is thought to involve antibody-mediated neutralization of contributing superantigens and a reduction in circulating inflammatory cytokines. In the setting of a life-threatening
infection, diminishing or temporarily halting immunosuppressive therapies can be considered.

Gram-negative bacilli
E. coli and other gram-negative bacilli (GNB) such as Klebsiella
pneumonia, Escherichia coli, Pseudomonas aeruginosa, Proteus
mirabilis, and enterobacter can rarely cause soft tissue infections,

most notably occurring in patients with hepatic cirrhosis,
nephritic syndrome, and immunosuppression. Spontaneous cellulitis secondary to gram-negative bacilli has been reported post
transplantation, particularly in the setting of edema with no clear
portal of entry. More than 80% have associated secondary bacteremia from sources such as pneumonia (48.9%) and central line
infections (22.2%) and as such, blood cultures should be obtained
when cellulitis arises in an SOT patient. Presentation can be
characterized by cellulitis, bullous lesions, ulcers, abscesses, or
extensive cutaneous necrosis with prominent vascular involvement on pathology (Fig. 14b.4).
Initial empiric coverage with gentamicin is helpful until cultures from the blood and skin biopsy return. The rate of mortality and graft loss is increased in patients with GNB infections,
and can be as high as 60% in the presence of bacteremia.
Pseudomonas aeruginosa causes the necrotizing soft tissue
infection ecthyma gangrenosum (EG), which occurs as a primary skin infection or as a complication of pseudomonal bacteremia. EG occurs commonly as a nosocomial infection, especially
in immunocompromised patients. P. aeruginosa gains entry into
the dermis and subcutaneous tissues via adnexal structures or
in areas where epidermal integrity has been breached (pressure
ulcers, thermal burns, and trauma). EG occurs most frequently
in the axillae or anogenital regions but can arise at any cutaneous site. Clinically, EG first presents as an erythematous, painful
plaque that then quickly undergoes necrosis. Established lesions
show bulla formation, hemorrhage, necrosis, and surrounding
erythema. If effective antibiotic therapy is not initiated promptly,
the necrosis may often extend rapidly. Bacteremia occurs soon
after the onset of EG, and may result in metastatic spread of P.
aerations with subcutaneous nodules and abscesses. Intravenous
antibiotic treatment is typically required. Of note, in one study
of resistant P. aerations, ciprofloxacin susceptibility was inferior
to that with imipenem, gentamicin, and tobramycin, emphasizing the need to obtain cultures for sensitivities and to offer initial
double coverage in this susceptible population.

Vibrio vulnificus
Vibrio vulnificus is a naturally occurring marine, gram-negative
rod, occasionally contaminating oysters and other shellfish.
Either ingestion of raw seafood or exposure of open wounds to
seawater can result in Vibrio bacteremia and soft tissue infections. The cutaneous lesions begin as erythematous plaques,
rapidly evolving into hemorrhagic bullae and then into necrotic
ulcers. Infection by the Vibrio species can lead to necrotizing
fasciitis or fulminant sepsis in compromised hosts, and patients
should be warned about eating uncooked seafood. Doxycycline
100 mg PO BID is the preferred treatment.

Bacillary Angiomatosis
Bacillary angiomatosis (BA) is characterized by angioproliferative
lesions resembling pyogenic granulomas or Kaposi’s sarcoma. It
has been reported in cardiac, renal, and liver transplant patients
with significant immunosuppression. BA is caused by infection
with fastidious gram-negative bacilli of the genus Bartonella,
namely, Bartonella henselae and Bartonella quintana.
Clinically, the cutaneous lesions of BA are red-to-violaceous,
dome-shaped papules, nodules, ranging in size from a few mm

198 — Daniela Kroshinsky, Jennifer Y. Lin, and Richard Allen Johnson

up to 2 to 3 cm in diameter. While cutaneous involvement is the
most common manifestation of Bartonella infection, the organism can also cause bacteremia, meningitis, neuroretinitis, endocarditis, necrotizing lymphadenitis, pneumonia, and peliosis
hepatitis. The diagnosis should be suspected in patients with skin
lesions, signs of systemic infection, and a history of cat exposure. The antibiotics of choice are erythromycin, doxycycline, or
azithromycin continued for several weeks to months. Relapses
are frequent if the duration of treatment is shortened.

Nocardiosis
Nocardia is an aerobic, ubiquitous environmental actinomycete
that can cause a localized or disseminated, life-threatening infection called nocardiosis in the compromised host. While more
than 50 species exist, the most common causative organism is
Nocardia asteroides. Nocardia can cause a variety of clinical scenarios, most often as an opportunistic infection in persons with
decreased immunity.
These gram-positive, weakly acid-fast bacteria can be directly
introduced into the skin of immunocompromised patients or,
more often, represent metastatic spread from a primary pulmonary infection. Primary cutaneous infection uncommonly
occurs and can present nonspecifically as cellulitis, papules, nodules, pustules, abscesses, ulcers, granulomas, soft tissue infection,
mycetoma, and sporotrichoid infection. It is most likely to be
seen following trauma to the extremities or face, after exposure
to soil or sand, or via inoculation during medical procedures.
Secondary cutaneous infection from a pulmonary focus is
the most common type of cutaneous nocardiosis in the immunocompromised patient and can present as pustules, abscesses,
or nodules. At least one-third of cases of pulmonary nocardiosis
result in dissemination to other organs, with skin involvement
being observed in 10% of the cases In the majority of transplant
patients, cutaneous nocardiosis results in disseminated disease
with involvement of other organs.
Isolation of Nocardia by culture is preferable but may take
several days to grow. Trimethoprim–sulfamethoxazole (TMPSMX) is the treatment of choice but SOT patients on prophylactic therapy for P. carinii have still been shown to acquire the
disease. Minocycline, aminoglycosides, ceftriaxone, fluoroquinolones, imipenem, and linezolid have been reported as effective second-line therapeutics. Long-term therapy is important to
prevent reactivation of quiescent disease.
Given the myriad of cutaneous findings associated with
nocardiosis, a high level of suspicion must be maintained in
the SOT patient, especially in the first year after transplantation
when the risk of nocardia infection is highest.

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V I R A L D I S E A S E I N T R A N S P L A N TAT I O N

Viral pathogens have emerged as the most significant microbial agents infecting solid organ transplant (SOT) recipients.
Cytomegalovirus (CMV) is the most common opportunistic
organism encountered during the 1- to 6-month posttransplantation period of maximal immunosuppression. Prophylactic
regimens have been carefully developed to counter its virulence.
Several other viruses manifest at mucocutaneous sites during this
period, ranging from cosmetically disfiguring facial molluscum
contagiosum virus (MCV) lesions to extensive common or genital warts due to human papillomavirus (HPV) to life-threatening
or invasive HPV-induced squamous cell carcinoma. In the great
majority of cases, viral opportunistic infection (OI) represents
reactivation of latent viral infection, that is, herpes family of
viruses or of subclinical infection with HPV or MCV.

Herpetoviridae (human herpesviruses)
The human herpesviruses (HHV) – herpes simplex virus (HSV)
types 1 and 2, cytomegalovirus (CMV), varicella-zoster virus
(VZV), Epstein-Barr virus (EBV), and human herpesvirus 6, 7,
8 (HHV-6, HHV-7, HHV-8) – share three characteristics that
make them particularly effective pathogens in the compromised
host: latency, cell association, and oncogenicity. Latency refers to
the fact that once infected with the virus, the individual remains
infected for life, with immunosuppression being the major factor
responsible for reactivation of the virus from a latent state. These
viruses are highly cell associated, rendering humoral immunity
inefficient as a host defense and cell-mediated immunity paramount in the control of these infections. All herpes group viruses
should be regarded as potentially oncogenic, with the clearest
demonstration of this being EBV-related lymphoproliferative disease. Of the herpes group viruses, those with the greatest impact
on the mucocutaneous tissues of the compromised host are HSV,
VZV, CMV, HHV-8, and, to a lesser extent, EBV.

Herpes simplex virus (HSV) -1 and -2
The greater majority of HSV-1 and HSV-2 infections occurring
in the compromised host are reactivations of latent infections of
the oropharynx or genitalia. They typically occur within the first

3 months following transplantation, with up to 50% in the first
3 weeks. Pretransplant HSV seropositivity in SOT recipients is
said to mirror that of the general population, with higher percentages seen in liver and kidney transplantees as compared to
cardiac transplantees, given the lower mean age at transplantation in cardiac patients. In latency, viral genetic material persists
in host tissues without the formation of virus particles or clinical
infection. Reactivation results in disease manifestation or silent
viral shedding. Risk factors for HSV reactivation include physical trauma, immunosuppression, severe illness with intubation,
and surgical manipulation of the trigeminal root ganglion. The
degree of reactivation is common, with 40% to 50% noted in some
studies. In some instances, oral reactivation can be detected by
polymerase chain reaction (PCR) with only 1 out of 12 patients
demonstrating clinical disease.
Recurrent HSV is characterized by an itching or tingling sensation at the site, often before any visible alteration. Ulcerated,
crusted lesions in perioral, anogenital, or digital locations are
usually HSV in etiology, in spite of occasional atypical clinical
appearances in SOT patients. With increasing immunosuppression, recurrent HSV infection may become persistent and
progressive, forming large, deep ulcers. Large atrophic scars
remain even after these lesions heal. Herpetic infection of one or
more fingers can form large, painful whitlows. HSV can then be
inoculated into nearly any site including the ears and toes. Local
spread can occur from the oropharynx onto esophageal mucosa
or lower respiratory tract and from the anogenital area to rectal
tissue.
Primary HSV infection after organ transplantation is less
common, but in the background of immunosuppression, it can
have a more fulminant presentation such as acute liver failure in
the liver transplant recipient. Both primary and reactivated HSV
can result in dissemination to visceral organs. Disseminated
HSV can involve the skin, or, of more concern, the viscera –
particularly the lungs, liver, and brain. This is associated with significant morbidity and mortality. Reactivation is not associated
with patient or allograft mortality except in the setting of CMV
co-infection, which results in reduced patient and allograft survival. Rarely, HSV-negative recipients of an HSV-positive graft
can develop fulminant HSV infections presenting as febrile illness in the absence of cutaneous lesions. As such, HSV should be
included in the differential diagnosis of isolated febrile illnesses
in the setting of HSV-negative SOT recipients. In addition, HSV
hepatitis can present indirectly as disseminated intravascular
coagulation with fever, abdominal pain, and elevated transaminases. Clearly, a high level of suspicion is warranted.
HSV can be diagnosed by isolation of the virus or identification of HSV antigen on lesional smears or biopsy specimens.
If indicated, the isolate can be tested for sensitivity to various
antiviral agents. Multinucleated giant epidermal cells on histopathology are indicative of HSV or VZV infection. A Tzanck smear
looks for giant epithelial or adnexal cells, preferably multinucleated, after scraping the base of the lesions. This test is useful but is
not always positive even in frank herpetic lesions; its reliability is
completely dependent on the skill of the practitioner and microscopist. Lesional biopsy is helpful when it demonstrates giant epidermal cells, but cannot distinguish HSV from VZV infection.
Viral culture of a lesion has a high yield in making the diagnosis. The PCR can detect VZV and HSV DNA sequences from a
variety of sources including formalin-fixed tissue specimens.

200 — Daniela Kroshinsky, Jennifer Y. Lin, and Richard Allen Johnson

Currently, three drugs are available for oral therapy of HSV
infections: famciclovir, valaciclovir, and acyclovir. These agents
can be given to treat primary or reactivated infection or prophylactically to suppress reactivation. Intravenous acyclovir (5 mg/kg
every 8 hours) may be given for severe infections. Improved bioavailability of famciclovir and valaciclovir makes oral therapy
with these agents preferable to oral acyclovir. Foscarnet, cidofovir, and trifluridine are administered intravenously for infections
caused by acyclovir-resistant HSV. Cidofovir is a broad-spectrum
antiviral medication with efficacy against HSV, human papilloma virus (HPV), VZV, EBV, HHV-6, -7, and –8, and pox-,
polyoma-, and adenoviruses. Cidofovir gel has been effective as
a topical therapy for acyclovir-resistant HSV infections. The use
of chronic HSV suppression is controversial. In the management
of chronic herpetic ulcers, immunosuppressive therapy should
be reduced when possible. Fortunately, acyclovir resistance has
not been as commonly seen in the transplant population as in
the HIV population. In a study of acyclovir susceptibilities in 18
SOT patients after viral prophylaxis with either acyclovir or ganciclovir, all isolates were susceptible. Prophylaxis can be achieved
with acyclovir, valacyclovir, or famciclovir.

Figure 14v.1 Multiple vesicles and punched-out erosions in a patient
with AIDS, concentrated over dermatome but extending over the
entire body – consistent with disseminated zoster.

Varicella-zoster virus (VZV)
Varicella is the most contagious of the human herpes viruses.
Two percent to 5% of adult SOT recipients are VZV seronegative,
with a greater number of seronegative children. Primary VZV
infection manifests as varicella (chickenpox) while reactivation of
VZV in seropositive patients occurs from a dorsal root ganglion
or cranial nerve ganglion and manifests as herpes zoster (HZ). In
the compromised adult host, VZV disease is almost always due
to reactivation. In these individuals, VZV can present as severe
varicella, dermatomal HZ, disseminated HZ (sometimes without
dermatomal HZ), and chronic or recurrent HZ (Figs. 14v.1 and
14v.2). The first manifestation of zoster is often pain and paresthesias in the dermatome that subsequently manifests as the
classical grouped vesicles on an erythematous base. Disseminated
HZ is defined as more than 20 lesions outside of two contiguous dermatomes, or systemic infection (hepatitis, pneumonitis,
encephalitis, pancreatitis, and disseminated intravascular coagulation). Occasionally, in SOT patients, the dermatomal eruption
may be bullous, hemorrhagic, necrotic, and can be accompanied
by severe pain.
Rarely, reactivation of VZV can produce pain without any
cutaneous lesions (zoster sine Herpe). The compromised host
previously infected with VZV is still subject to exogenous reinfection with VZV. Overall, zoster occurs in 5% to 15% of SOT
patients, usually within the first year post transplantation but
later than HSV or CMV (median onset of 9 –14 months).
In this chronically immunosuppressed group, risk of dissemination is as high as 40%. Despite antiviral therapy, mortality
rates range from 4% to 34%. The most common complications are
cutaneous scarring (18.7%) and postherpetic neuralgia (PHN)
(42.7%), defined as pain persisting for more than 6 weeks after
the development of cutaneous lesions. In SOT patients, complications from reactivated VZV tend to be more severe, including
progressive small-vessel encephalitis or central nervous system
myelitis. Ophthalmic zoster has the highest incidence of serious complications, which include corneal ulceration, variable
decrease of visual acuity, and retinal necrosis.

Figure 14v.2 Vesicles on an erythematous base in an otherwise
healthy woman, consistent with primary varicella.

Viscerally disseminated HZ in a compromised host can
be life threatening, involving the lung and liver. It manifests as
fever, abdominal pain, disseminated intravascular coagulation,
and hepatitis, with or without concomitant pancreatitis or pneumonitis, and is considered an emergency. The development of
cutaneous lesions is often delayed, and PCR can be helpful in
confirming the diagnosis in the absence of visible lesions.
In the immunocompromised patient, reactivated cutaneous
VZV lesions can persist for months, in either the localized or the
disseminated form, as chronic verrucous or ecthymatous VZV
infection. The lesions consist of hyperpigmented and/or hyperkeratotic painful nodules often with central crusting, ulceration
and/or bordering vesicles. Verrucous/ecthymatous VZV was
first described in HIV patients, typically those with low CD4
counts (<100/mm3). There are now reports in the literature of
verrucous VZV following kidney transplantation on tacrolimus
and prednisolone.

Bacterial and Viral Disease in Transplant Recipients — 201

Primary VZV after SOT is rare and tends to present later,
usually, within 3 years, depending on exposure. It is more commonly seen in the pediatric transplant population. Primary varicella in immunosuppressed children and adults can be severe,
prolonged, and complicated by internal dissemination (pneumonia, hepatitis, encephalitis, and pancreatitis), disseminated intravascular coagulation, bacterial superinfection, and death.
The diagnosis of varicella and HZ can be made clinically,
but as with HSV, the diagnosis can be confirmed by detection
of viral antigen on a smear of the base of a lesion or in a biopsy.
A positive Tzanck test confirms the diagnosis of either VZV or
HSV. Isolation of VZV by culture is more difficult than isolation
of HSV. Lesional biopsy is also helpful in establishing a diagnosis, especially in unusual manifestations of VZV infection such
as ecthymatous or chronic verrucous lesions. The diagnosis can
be confirmed by detection of VZV antigen on direct immunofluorescence testing. Immunoglobulin serologies are now routinely screened before transplantation and there are reported
rates of 1.6% VZV serology-negative patients. It is important to
note that a negative VZV serology does not necessarily preclude
prior infection, and that these patients can still manifest herpes
zoster.
The drugs approved for treatment of HSV are also effective
for treatment of VZV infection: famciclovir, valaciclovir, and
acyclovir. Intravenous acyclovir (10 mg/kg every 8 hours) is
given for severe zoster or primary varicella. As with HSV infections, acyclovir-resistant strains can emerge following prolonged
acyclovir treatment; most of these resistant strains respond to
foscarnet, cidofovir, or trifluridine therapy.
The routine antiviral prophylaxis used for preventing CMV
disease appears to reduce CMV-induced mortality but does not
affect the incidence of zoster. Prophylactic regimens for zoster
are not practical because of late onset of disease and low proportion of affected individuals.
Varicella vaccination in the SOT population has slowly been
emerging as more evidence indicates its safety. Seropositivebone marrow transplant (BMT) patients immunized with the
vaccine had greater protection from varicella. Vaccination is
currently recommended before transplantation in children and
adolescents. Pretransplantation vaccination has been successful
in inducing seroconversion, though transplantation must then
be postponed for 3 months to avoid iatrogenic immunosuppression following vaccination. While live attenuated Oka strain vaccination is not FDA-approved for use in immunocompromised
individuals because of the risk of potential disseminated varicella and isolated reports of acute graft rejection, the vaccine has
been safely used post transplantation in adults and children. One
study evaluating use post renal transplantation demonstrated no
adverse effects and a 66% rate of seroconversion. Vaccination
post transplantation can induce suboptimal immunogenicity, with protection waning each year after vaccination in some
individuals. In these individuals, any subsequent disease is usually mild; alternatively, a second “booster” vaccine dose can be
administered. Some series report maximal protection at 1 year
post vaccination. In addition, postponing pediatric SOT live vaccinations until at least 1 year of age improves seroconversion and
diminishes vaccine side effects, though some recommend starting the vaccination process at an earlier age and at a faster rate.
Zostavax, the vaccine approved for zoster prophylaxis in immunocompetent adults aged 60 or older contains a significantly

higher dose of live virus than the vaccine for varicella and has
not been described or recommended for transplant patients.
Unvaccinated, seronegative individuals should avoid exposure
to individuals with varicella or zoster. Should contact occur,
varicella-zoster immune globulin (VariZIG) should be administered within 96 hours of exposure, but may not have efficacy
once clinical disease develops.
Ideally, a pretransplant program should assess individual
immunity and vaccinate any susceptible individuals. In addition,
immunization of household contacts and healthcare workers
should take place.

Epstein-Barr virus (EBV)
EBV selectively infects cells of the B-lymphocyte lineage and certain types of squamous epithelium. The majority of adults have
been infected with EBV and harbor the latent virus. Primary
cutaneous EBV-associated posttransplant lymphoproliferative disorder (PTLD) is the most common severe manifestation of EBV in SOT patients. PTLD can present in several ways
including isolated or multiple lymphoid tumors, an infectious
mononucleosis-like pattern, generalized lymphadenopathy, and
rapidly progressive and widespread disease. PTLD can be seen in
any organ site and the incidence ranges depending on organ type
from 1% of renal transplant patients to 5% of heart–lung transplant recipients. Disease localized to the skin is even rarer and
the appearance is polymorphic: single or multiple erythematous
nodules, ulcers, or morbiliform eruptions. At the onset, PTLD
is polyclonal and often responds to a reduction of immunosuppression. The disease can become a rapidly progressive and ultimately fatal monoclonal disease. Predisposition to developing
PTLD is intimately related to CMV infection and CMV D+/ R–
SOT patients are most susceptible.
Posttransplant cutaneous B-cell lymphoma, associated with
EBV infection, is an uncommon complication of SOT. Findings
are usually confined to the limited regions of the skin; systemic
involvement is not common. Treatment is usually directed at the
lesions, with surgery or radiotherapy.

Cytomegalovirus
Cytomegalovirus (CMV) is the major microbial pathogen in
SOT patients. Pathogenicity is by (1) causing infectious disease
syndromes, (2) augmenting iatrogenic immunosuppression via
cytokine and chemokine production, and (3) contributing to
graft failure. CMV infection occurs in 20% to 60% of all transplant recipients, the rate of infection being related to the serologic
status of both the donor and recipient and the degree of immunosuppression. The CMV-seronegative recipients of organs from
seropositive donors (CMV D+/ R– patients) develop primary disease and represent the highest risk group. The highest incidence
of immunosuppression and CMV disease is seen in heart–lung
transplant recipients, followed by pancreas and kidney–pancreas,
and finally kidney, heart, or liver transplants alone.
Seroprevalence studies of CMV infection indicate that 50%
of the general population is infected by age 50 years. Primary
infection is usually asymptomatic, but can produce symptoms
of fever, pneumonitis, esophagitis, colitis, myalgias, leukopenia, thrombocytopenia, and transaminitis. Following primary
infection, CMV enters a latent phase of infection, during which

202 — Daniela Kroshinsky, Jennifer Y. Lin, and Richard Allen Johnson

asymptomatic viral shedding in saliva, semen, and/or urine is
extremely common. In the compromised host, CMV disease
occurs via (1) primary CMV infection, (2) reactivation of latent
CMV infection, or (3) re-infection with a new CMV subtype.
As with the other members of the herpesvirus family, CMV disease usually represents reactivation of latent virus. This typically
occurs in the first 3 months post transplantation when immunosuppression is most intense.
Reactivated CMV can cause hepatitis, pneumonitis, chorioretinitis, encephalitis, and colitis/esophagitis in transplant recipients. Cutaneous CMV infections are rare, presenting as nodules,
ulcers, plaques, vesicles, petechiae/purpura, bullous lesions, or
nonspecific maculopapular exanthems. Cutaneous ulcers and
morbilliform eruptions are the most common presentation of
cutaneous CMV involvement. Cutaneous manifestations may be
seen in 10% to 20% of systemic CMV infections and are associated with a poor prognosis. This association has been postulated
to be a marker of severe immune compromise as CMV generally
does not replicate well in the dermis.
Chronic CMV infection predisposes the SOT patient to acute
and chronic graft failure, as well as secondary immune deficiency
and further risk of opportunistic infections.
Infection can be detected by a greater than four-fold increase
in CMV IgG or on culture from urine, skin, respiratory secretions, or blood. Skin and other organ biopsy will demonstrate
characteristic “owl-eye” inclusion bodies, or CMV can be demonstrated by immunoperoxidase staining of tissue. PCR is considered to be the “gold standard” of diagnostic methods, with a
sensitivity of 95% to 100% but low specificity.
Treatment of choice for CMV is intravenous valganciclovir for 2 to 3 weeks. Prophylactic regimens can be used and the
standard is ganciclovir (15 mg/kg TID × 14–90 days). Oral prophylaxis with both ganciclovir and valganciclovir is effective at
decreasing the incidence of infection in the CMV D+/ R– SOT
group. As a side benefit, the prophylactic regimen helps control other herpes virus family members such as HSV, VZV, and
even EBV. More recently, late onset CMV infections occurring
a year after transplantation suggest the need to alter the length
of prophylaxis regimen to extend for a longer period. Doing
so, however, has been shown to delay disease onset and elicit
atypical presentations of disease. In addition, this practice may
increase rates of viral resistance, and ganciclovir-resistant strains
cause severe disease with increased graft loss and mortality. The
reported incidence of ganciclovir-resistant infections in SOT
patients on prophylactic regimens ranges from is up to 13%. Use
of hyperimmune CMV globulin (CMVIG) alone does not provide sufficient prophylaxis in SOT patients, but can diminish the
severity of disease in this patient population. It has demonstrated
efficacy when used in combination with ganciclovir. For resistant
virus strains, foscarnet 40 mg/kg IV every 8 hours is employed.
Its use is limited by nephrotoxicity.

Human herpesvirus-8
Kaposi’s sarcoma (KS) is a proliferation of endothelium-derived cells, first reported by Moritz Kaposi in 1872 as “idiopathic pigmented sarcoma of the skin.” Classical KS occurs in
men of Mediterranean or Eastern European origin. African KS
was described in young patients from equatorial Africa. In the
1960s, a third variant of iatrogenic KS was described in patients

on long-term immunosuppressive therapy but became most
strongly associated with the HIV/AIDS epidemic as a marker
of end-stage AIDS. The prevalence of KS in SOT is anywhere
from 0.1% to 5%, depending on the type of immunosuppression,
HHV-8 status of donor and recipient, and country of origin.
HHV-8 is a lymphotropic, oncogenic herpesvirus that was
first detected in KS in 1994. HHV-8 has also been detected in
other neoplasms such as body cavity–based lymphoma and
Castleman’s tumor. Reported cases of HHV-8 transfer from
donor to recipient in heart and lung transplantations with resulting KS also strongly implicate this member of the herpesvirus
family as the cause of SOT-associated KS.
The clinical course of SOT-associated KS may be quite variable with frequent occurrence of widespread cutaneous and
visceral lesions. Early lesions of KS present as slight discolorations of the skin, usually barely palpable papules, and, if very
early, macules. Over a period of weeks-to-months-to-years,
these early lesions enlarge into nodules or frank tumors, and the
color darkens to a violaceous, Concord grape color, often with
a yellow-green halo. As lesions enlarge, epidermal changes may
occur, showing a shiny, atrophic appearance if stretched, or, at
times, hyperkeratosis with scale formation. In late lesions, tumor
necrosis may occur with erosion or ulceration of the surface.
Oral lesions are common, and may be the first site of involvement, occurring typically on the hard palate as a violaceous stain
of the mucosa.
The course of KS depends upon restitution of immune function. Few patients die from complications directly related to KS.
An occasional patient will develop KS lesions involving internal
organs in the absence of any visible mucocutaneous involvement. Although the diagnosis of KS can usually be suspected
clinically, in most instances histological diagnosis on a lesional
punch biopsy specimen can be done.
In the management of KS, the initial therapeutic focus is
reduction in immune compromise by changing immunosuppressive drug therapies. In particular, the addition of rapamycin as an
immunosuppressant in place of other drugs such as cyclosporine
has been associated with regression of KS. Localized cutaneous
disease can be approached with application of an intralesional
injection of vinblastine, cryotherapy, surgical excision, or radiation. Indolent, disseminated cutaneous KS is best treated with
systemic immunotherapy or chemotherapy.

Molluscum contagiosum virus
MCV commonly infects keratinized skin subclinically, and can
cause lesions at sites of minor trauma and in the infundibular
portion of the hair follicle. Transmission is usually via skin-toskin contact, occurring commonly in children and sexual partners. MCV infection is common in SOT patients with a reported
6.9% incidence in pediatric transplant patients.
Clinically, MCV infection presents as skin-colored papules
or nodules, often with a characteristic central umbilicated keratotic plug. Lesions larger than one centimeter in diameter (giant
molluscum), can be seen in the immunosuppressed population.
In males, lesions are often confined to the beard area, the skin
having been inoculated during the process of shaving.
Therapeutically, the most efficacious approach toward MCV
infection is correction of the underlying immunodeficiency.
Otherwise, treatment is directed at controlling the numbers and

Bacterial and Viral Disease in Transplant Recipients — 203

bulk of cosmetically disturbing lesions. Liquid nitrogen cryospray
is the most convenient therapy, and usually must be repeated
every 2 to 4 weeks. Imiquimod 5% cream has also demonstrated
success in healthy and immunocompromised patients. The molecule binds Toll-like receptor 7, activating dendritic cells, macrophages, and monocytes, leading to Th1 cytokine production
and local stimulation of both cell-mediated and innate immune
responses. Side effects include an expected, mild erythema at the
site of application, and while systemic immune stimulation has
been reported, it has not been substantiated.

Human papillomavirus infections
Subclinical infection with human papillomavirus (HPV) is nearly
universal in humans. With immunocompromise, cutaneous
and/or mucosal HPV infection reemerges from latency, presenting clinically as verruca, condyloma acuminatum, squamous cell
carcinoma in situ (SCCIS), or invasive squamous cell carcinoma
(SCC). HPV colonizes keratinized skin producing common
warts (verruca vulgaris, verruca plantaris) in many healthy individuals. The greater majority of sexually active individuals are
subclinically infected with one or multiple HPV types. HPV-6
and -11 infect mucosal sites (genitalia, anus, perineum, oropharynx) and cause genital warts (condyloma acuminatum); HPV-16
and -18 have greater malignant potential and can cause precancerous lesions, squamous intraepithelial lesion (SIL), SCCIS,
and invasive SCC. A significant number of SOT candidates are
HPV-positive before transplantation. Chronic immunosuppression can increase the likelihood of progression to and persistence
of clinical lesions. In addition, the incidence of these lesions
increases as the duration and degree of suppression increases.
In SOT recipients and other compromised hosts, the initial
morphology, number, or response to treatment of verrucae are
not atypical. They are, however more often distributed over sunexposed sites in adults. With time, verrucae can enlarge, become
confluent, and become unresponsive to therapy. The incidence
and severity of warts are related to the degree of immunosuppression, with previously acquired latent virus being reactivated
with institution of immunosuppressive therapy. Warts are the
most common skin finding in pediatric SOT population, affecting 53.8%. The prevalence in renal transplant patients increases
with length of immunosuppression, from 11% in first year post
transplantation, to as high as 92% in >5 years of immunosuppression. Verruca vulgaris and verruca plantaris appear as welldemarcated keratotic papules or nodules, usually with multiple
tiny red-brown dots representing thrombosed capillaries; palmar and plantar warts characteristically interrupt the normal
dermatoglyphics. The warts may be numerous and confluent,
giving the appearance of a mosaic. Verruca plana, or flat warts,
appear as well-demarcated, flat-topped papules, which lack the
dots seen in other types of verrucae. When occurring in the
beard area, hundreds of flat warts may be present. All types of
verrucae may have a linear arrangement because of koebnerization or autoinoculation.
Condylomata acuminata or genital warts are usually asymptomatic, although voluminous lesions may be painful and
may bleed. Lesions may be numerous and become confluent.
Oropharyngeal HPV-induced lesions resemble anogenital condyloma, pink or white in color. Extensive intraoral condyloma
acuminatum (oral florid papillomatosis) presents as multiple

large plaques, analogous to anogenital giant condylomata acuminata of Buschke–Löwenstein, and can also transform to verrucous carcinoma.
In compromised patients, HPV-induced lesions have the
potential for malignant transformation, particularly in sunexposed areas of the body. Squamous cell carcinoma (SCC)
arising in sites of chronic sun exposure occurs 36 times more
frequently in renal transplant recipients than in the general population, some clearly arising within warts. HPV DNA is demonstrable within the tumors and is detected more frequently in
SCC arising in transplant recipients than in immunocompetent
individuals. Ultraviolet radiation in combination with immunosuppression can activate HPV. Rapidly enlarging hyperkeratotic
verrucae should also be investigated for transformation to rule
out squamous cell carcinoma.
As many as 23% of newly transplanted patients are anal HPV
positive, with this number more than doubling in established
SOT patients. HPV-induced anogenital in-situ and invasive
squamous cell carcinoma (SCC) is also ten times more common in transplant recipients and HIV-infected individuals; these
persons should be screened for in situ and invasive SCC with
Pap test of the anus and cervix and lesional biopsy when indicated. The appearance of white micropapules or macules after
the application of 5% acetic acid (white vinegar) to the anogenital epithelium or “acetowhitening,” can be helpful in defining the
extent of HPV infection.
Efficacy of treatment of verrucae vulgaris and condyloma
acuminatum in SOT patients varies with the degree of immunocompromise, and can be very recalcitrant. In patients with
early disease, these lesions should be managed as in the normal
host. Cryotherapy remains a common choice but for extensive
lesions, management includes bleomycin injections, topical salicylic acid, topical retinoids, laser ablation, curettage and dessication, cimetidine, podophyllotoxin, intralesional interferon,
or a combination of the above. More recently, imiquimod has
been introduced for condyloma, and studies suggest safe usage
in SOT population. Topical and intralesional cidofovir has also
demonstrated efficacy in SOT patients with HPV-associated skin
lesions. The role of chemoprevention with systemic retinoids
still awaits final determination. Management of patients with
extensive warts should include avoidance of sun exposure, use
of strong sunscreens, reduction in immunosuppressive therapy
when possible, and careful observation for the development of
malignant lesions. Prophylactic vaccination in transplant candidates may be of value to prevent primary HPV infection. In some
cases, modification of the immunosuppressive regimen can help
modify the size and number of warts in SOT patients. Ultimately,
immunosuppressed patients may never completely clear their
HPV, and lesions often recur.

P I T FA L L S A N D M Y T H S

The opportunity to identify an infection in the immunosuppressed population is often hindered by the subtlety of the
skin findings and the absence of common signs of infection.
Classically, skin infections are characterized by rubor, calor, tenderness, and/or edema of the affected areas. These signs and the
clinical features of a rash can be reduced or absent in individuals
who are unable to mount a full immune response to infection.

204 — Daniela Kroshinsky, Jennifer Y. Lin, and Richard Allen Johnson

As such, it is important to vigilantly monitor the skin for any
changes and to evaluate all new or changing lesions with skin
culture, biopsy, and tissue stains as appropriate. Concern for a
deep tissue infection warrants obtaining a sterile skin biopsy for
tissue culture.
Obtaining a prompt diagnosis and rapid intervention may be
hindered if biopsy is delayed because of concerns of breach in skin
integrity or possible iatrogenic infection. The actual risk of this
is very low when the skin is prepared appropriately with alcohol,
iodine, chlorhexidine, or other skin cleansing agents and when
the biopsy is performed properly with sterile equipment. When
possible, obtaining tissue for biopsy or culture should take place
from the most cephalad location possible to facilitate wound
healing. Postprocedural wound care with newer topical antibiotic agents such as mupirocin or retapamulin will also minimize
risk of subsequent infection in this patient population.

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15

C A N C E R PAT I E N T S A N D S K I N
INFECTIONS
John C. Hall

The two basic components of cancer therapy have long been
chemotherapy and radiation therapy. Both these modalities,
especially chemotherapy, were based on the cytotoxic effect
they exerted on cancer cells. Their cytotoxicity, of course, carried over to both rapidly dividing normal cells and nonmalignant host cells. The most commonly affected cells were those of
the lymphatic and hematopoietic systems. Destruction of these
cells, most notably the neutrophil, could leave the patient with
less cancer, but it would also leave the patient with less immunity, and therefore, more susceptibility to infection. Death in
these patients was frequently due to infection rather than
malignancy.
Oncology has now progressed to the point that survival for
extended periods of time can take place with control as opposed
to eradication of the cancer. Although a patient is less immunocompromised with receptor blockers, monoclonal antibodies,
tyrosine kinase inhibitors, antiangiogenic therapy, and therapies
yet to be discovered, there is still immune suppression and a
larger window of time for infections to develop. There is also a
much larger number of patients for whom infection, not cancer,
becomes the life-threatening event.
The seminal laboratory finding that is most often associated with these infections is decreased numbers of neutrophils.
Also, most of these infections will occur when the neutrophil
count is at its lowest. Improvement conversely occurs when the
neutrophil count begins to return to normal. Prophylactic antibiotics are often used when the neutrophil count is drastically
reduced.
Leukemia and lymphoma are more capable of interfering
with neutrophil function and numbers. As a result, both of them
are more likely to present with skin infections at the onset. Solid
tumors, unless they have extensively invaded the bone marrow,
however, are more likely to present with skin infections after
chemotherapy has begun and the neutrophil count has been
suppressed.

H I STORY

It has longed been recognized that a major cause of morbidity
and mortality in cancer patients whether they are on or off therapy is infection. The skin is often the organ where these infections are first apparent.
An excellent example is with leukemia, bacteria, and
Staphylococcus aureus, which are the commonest malignancy,
the most common offending organism, and the most common
offending bacteria respectively. In 1980, Sotman et al. examined
370 leukemia cases, 95% of which were granulocytopenic (WBC
206

counts less than 1,000 μL), and found 9% with Staphylococcus
aureus bacterial infection. The commonest sites for primary
infection were the skin and lower respiratory tract.

EPIDEMIOLOGY

Since cancer patients cannot put up a sustained immune
response, they tend to acquire whichever organism is present in their environment. An example of this is aspergillosis,
which can be stirred up at hospital work sites by construction work. The change of organisms in the community greatly
affects the infections these patients acquire just like in the general population. A recent example is cases of infection caused
by coagulase-positive Staphylococcus aureus that have now
been replaced by methicillin-resistant Staphylococcus aureus
with a new genotype. This has not only changed the antibiotics
used to treat cutaneous staphylococcus infections, but has also
changed the nature of the infection itself with early abscess
formation and the requirement for early surgical incision and
drainage to treat cutaneous staphylococcus infections.

DIAGNOSIS

The clinical appearance of these infections may be altered from
what is usually seen since a lack of immunity leads to florid
growth of the infecting organism. This feature is useful when
there is suspicion of an underlying cancer in a previously undiagnosed patient. Any infection that is poorly responsive to therapy
(Fig. 15.1), unusually fulminant (Fig. 15.2), or present at a location or in a population that is highly unusual (Fig. 15.3) should
be suspect (see Table 15.1). Chronic lymphocytic leukemia is the
classic systemic malignancy associated with cutaneous infections. This probably occurs because of the relative frequency of
this cancer, its occurrence in the elderly population, the prolonged course before treatment is necessary, and the prolonged
course often seen after treatment is begun.
For patients in whom malignancy is already known, the
index of suspicion of cutaneous infection rises since chemotherapy decreases the neutrophils in the peripheral blood. The
most important principle to remember in these patients is that
all tissue biopsy specimens should be sent for culture of acid-fast
bacilli, fungi, bacteria in sterile saline as well as viral transport
media for herpes simplex and herpes zoster. This should be done
even if inflammatory conditions or solid tumors are suspected
since the normal clinical signs that are usually thought of in these
cases may be absent (Fig. 15.4).

Cancer Patients and Skin Infections — 207

Table 15.1: Cutaneous Infections That May Be Indicative
of an Underlying Cancer
Bacterial Infections
Streptococcus of Streptococcal (group A beta hemolytic) cellulitis:
Consider if severe and recurrent and no other explanation is present
such as poor circulation.
Viral Infections
Herpes Simplex: Consider if very severe, has run a prolonged course,
or is disseminated over wide areas of the skin or internal organs.
Herpes Zoster: If it occurs more than once, is severe, and/or
disseminates beyond a dermatomal distribution to become a
generalized varicella.
Figure 15.1. Severe cellulitis of the lower extremity poorly responsive
to normal dosages of antibiotics that would be expected to be effective. The patient had widespread non–Hodgkin’s lymphoma.

Warts: If they disseminate over large areas of the body or if they
appear destructive such as under the nail or over the genitalia. In
these two locations, warts may actually become squamous cell cancer.
Size over 1 cm is worrisome.
Fungal Infections
Aspergillosis: If the site is cutaneous and occupational exposure is
not an issue.
Other organisms that do not usually cause skin infections: Most
commonly Rhizopus and Mucor spp. A very long list of saprophytes
is also included in this category.

Figure 15.2. Severe herpes zoster infection with dissemination of the
virus to involve all the skin in a patient with chronic lymphocytic
leukemia.

Figure 15.4. Severe necrotic lip lesion caused by herpes simplex in
a patient with chronic lymphocytic leukemia. The severity of the
infection has caused loss of the normally expected clinical setting of
grouped vesicles on a red base.

THERAPY

The therapy for cutaneous infections in cancer patients is similar
to the therapy for noncancer patients and the various chapters in
this book can be consulted for more specific recommendations.
However, some general guidelines can be used (See Table 15.2).

Figure 15.3. Aspergillosis in the skin or the pretibial in a patient with
acute myelogenous leukemia. Pulmonary aspergillosis was also diagnosed. Rare cutaneous infection would cause concern for underlying
malignant disease.

P I T FA L L S A N D M Y T H S

Although skin disease morphology may mimic an infection, at
times it can actually be a malignancy. As may be expected, the

208 — John C. Hall

Table 15.2: Principles of Therapy in Cancer Patients with
Cutaneous Infections
1. Therapeutic intervention usually must be continued until the
neutrophil count is at least partially restored.
2. Medication dosage often needs to be higher and of a longer
duration than in noncancer patients.
3. Local care such as surgical debridement can prevent dissemination
and be lifesaving.
4. Therapeutic maneuvers are greatly altered when a noncutaneous
nidus of infection is discovered. Therefore, these sites of infection
should be searched for vigorously by the clinician.
5. Culture and sensitivity studies of fluids and tissue should help
serve as a guide for therapy whenever possible. Specimens for these
studies must be collected appropriately, and grown at an appopriate
temperature on an appropriate culture media.
6. Staining methods should be used on tissue specimens whenever
applicable to help identify potential pathogens. Sometimes
polymerase chain reactions and antibody tests are indicated.

Figure 15.5. Cutaneous T-cell lymphoma (mycosis fungoides) mimicking
a cellulitis on the right breast.

7. Prophylactic antibiotics are often given to cancer patients when the
neutrophil count drops to a critical level.

Table 15.3: Skin Disease That Appears Infectious but Is
Malignant
1. Lymphoma
2. Leukemia
3. Inflammatory breast cancer
4. Stewart–Treves syndrome
5. Angiosarcoma
6. Verrucous carcinoma
7. Lethal midline granuloma (nasal NK/T-cell lymphoma)

Figure 15.6. Metastatic B-cell lymphoma on the inner thigh. The
tumors appear vesicular, seem in a dermatomal distribution, and
arose rapidly to mimic a herpes zoster infection.

8. Squamous cell carcinoma
9. Keratoacanthoma
10. Cancer that is metastatic to the skin

more vascular cancers look the most like infections due to their
increased rubor, swelling, and sometimes increased warmth.
Usually, the two most important clinical features are a lack of
pain or tenderness and the chronicity of the malignancy. Both
infection and cancer can be invasive and destructive. They can
also be seen in toxic, febrile patients. Examples of skin malignancies that can mimic infection are given in Table 15.3.
Lymphoma of the skin can either be a metastatic process
or a primary lymphoma of the skin, which is usually cutaneous
T-cell lymphoma (CTCL). Lymphomas in the skin may have a
surrounding acute inflammatory reaction of nonmalignant cells.
This causes both clinical confusion with infection (Fig. 15.5)
and histologic confusion with infection or other inflammatory
processes. Therefore, a superficial biopsy will miss the primary
pathology and make the diagnosis of infection seem more likely.
Ways to avoid this pitfall include deep punch or ellipse biopsies

as well as multiple biopsy attempts if the index for cancer is
high. Skin biopsies can easily be repeated since these procedures
have little or no morbidity or mortality associated. Special histologic stains may also be helpful in the diagnosis, especially
T- and B-cell markers, where monoclonality is often associated
with malignancy. Gene rearrangement studies can also be helpful when genetic defects are seen in the cancer. This can only
be meaningfully achieved if a large enough number of cells are
available for evaluation on the skin biopsy. Lymphoma in the
skin can also mimic a vesicular eruption due to the fact that lymphedematous blebs or tumors on the skin mimic blisters (Fig.
15.6). Chronic draining ulcerative, fungating tumors can sometimes mimic a more chronic granulomatous infection (Fig. 15.7)
such as deep fungal infections, maduromycosis, lupus vulgaris,
or leishmaniasis. Sometimes, an elevated border can even cause
confusion with a dermatophyte infection (Fig. 15.8).
Benign inflammation such as from another infection can
mimic leukemia cutis because the cells are atypical and share
some of the morphologic characteristics of leukemia. This is a
very important differentiation. Leukemia when seen in the skin
is a very poor prognostic sign. Breast cancer tends to mimic

Cancer Patients and Skin Infections — 209

Figure 15.7. Cutaneous T-cell lymphoma on
the anterior arm just proximal to the elbow
with a chronic fungating, destructive ulcer
mimicking a chronic granulomatous skin
infection.

Figure 15.8. Cutaneous T-cell lymphoma on the medial malleolus
with an elevated border and central clearing, suggestive of corporis.

infection both as primary inflammatory breast cancer and recurrent metastatic breast cancer. Primary disease is suspicious for
infection when axillary lymphadenopathy due to local cancer
spread clinically mimics an enlarged lymph node due to cellulitis. Both of these conditions show wide areas of bright red chest
wall induration that can be tender and warm. Biopsy is required
to make a correct diagnosis.
Stewart–Treves syndrome, which is an angiosarcoma that
arises at sites of chronic lymphedema, occurs most notably at
sites of mastectomies for breast cancer and axillary lymph node
resections. This angiosarcoma is filled with blood vessels that
give it a reddish-purple discoloration and also may have associated warmth and pain.
Angiosarcoma usually arises as a primary malignancy without lymphedema on the scalp and head of elderly men. Again, it
can mimic an infection due to its great vascularity and redness.
Verrucous carcinoma can occur in three locations. On the
bottom of the foot, it is referred to as epithelioma cuniculatum. On
the genital area, it is referred to as giant condyloma acuminatum

Figure 15.9. Verrucous tumor on the lower leg
mimicking a wart but with a size much greater
than 1 cm.

of Lowenstein and Buschke. In the oral cavity, it is referred to
as florid oral papillomatosis. Rarely, it has been reported in the
larynx, nasal fossa, back, hands, and lower legs (Fig. 15.9). These
tumors are locally aggressive and rarely metastasize. If metastasis
does occur, it usually goes to local lymph nodes. It mimics a wart
clinically and is most likely viral in origin. Clinically, it eventually
becomes more destructive than a wart. Another clue that there is
a malignancy is when the size of the lesion is greater than 1 cm.
Subungual squamous cell carcinoma may also mimic a wart or
arise in a wart especially in the location under the thumbnail.
Occupational radiation exposure in physicians holding X-ray
plates was once a common etiologic factor.
Lethal midline granulomas were originally thought to be
a form of granulomatous vasculitis. They are very destructive
midline facial lymphomas. The infection these lesions mimic is
a chronic granulomatous infection such a tuberculous lupus vulgaris, deep fungi, or a zygomycosis. Since these lymphomas are
chronic and slow growing, they are even more likely to be considered a chronic granulomatous infection. This cancer is often
fatal and has been associated with Epstein-Barr virus.
Some malignancies such as squamous cell cancer also mimic
slow-growing, chronic granulomatous infections. These infections can be very destructive locally just like malignancies.
Location on chronically sun-exposed areas such as the face,
ears, dorsal hands, balding scalp in men, and extensor forearms
is most common. However, non–sun-exposed skin can also be
involved. Long-standing granulomatous infections can develop
over time into squamous cell cancer. A histologic pitfall is that
epitheliomatous hyperplasia can mimic the overproduction of
keratin and squamous cells in malignancies such assquamous
cell cancer. Dyskeratotic cells, which are a characteristic sign of
squamous cell cancer, can also be seen.
Keratoacanthoma was at one time thought to be a skin infection since there were anecdotal reports of spontaneous resolution. It is now believed, however, that it is a locally aggressive
squamous cell cancer without evidence of metastasis caused
by chronic sun exposure and occurring on sites of chronic sun

210 — John C. Hall

Figure 15.10. Keratoacanthoma of the forehead that grew to this size
in a matter of weeks.

Figure 15.11. Metastatic lung cancer to the skin mimicking herpes
zoster or bacterial cellulitis.

exposure such as the face (Fig. 15.10), extensor forearms, and
hands. Its main confusion with infection relates to the fact that it
grows very rapidly unlike squamous cell cancer, which it mimics
histologically. It also has a verrucous or warty appearance, which
can make differentiation from a viral wart very difficult.

Figure 15.12. Lung cancer metastatic to the skin behind the ear. The
central erosion has the clinical appearance of a bacterial furuncle.

Solid tumors metastatic to the skin usually do not have an
infectious appearance or growth pattern. However, occasionally
a solid tumor metastasis will grow quickly and have an erythematous appearance, therefore mimicking an infection (Fig 15.11). A
malignancy can mimic a furuncle in clinical appearance when it
erodes into the surface and is covered with a serous or hemorrhagic crust (Fig. 15.12).
There are two important points to remember. First, perform
culture and sensitivities on all inflammatory and tumor-like
skin lesions in cancer patients so that an infection will not be
missed. Second, it is very important to make sure that biopsies
are of appropriate depth so that a malignancy is not missed. It is
not uncommon for a malignancy in the skin to have surrounding superficial tissue that is inflammatory and benign. In addition, if the suspicion for cancer is high, repeat biopsies should
be done.

SUGGESTED READING

Sotman SB, Schimpff SC, Young VM: Staphylococcus aureus bacteremia
in patients with acute leukemia. AM J Med 1980;69(6):814–818.

16

S K I N I N F E C T I O N S I N P E D IAT R I C
PAT I E N T S
Michelle R. Wanna and Jonathan A. Dyer

INTRODUCTION

The topic of infectious diseases of the skin in children is quite
broad, and an exhaustive review in a single chapter is not possible. Those infections with particular importance to pediatric
patients will be emphasized.

H I STORY

Cutaneous infections are a major cause of morbidity in the
pediatric population. It is estimated that one in five children
presenting to their primary care provider have at least one skin
complaint, and cutaneous infections represent the largest portion
of these complaints. Certain cutaneous infections are unique to
or more common in the pediatric population. Most recently, the
rise of community-acquired methicillin-resistant staphylococcus
aureus (CA-MRSA) and its spread in the pediatric population
has highlighted the ever-changing nature of the battle against
infectious disease. This chapter will review such conditions.

GRAMPOSITIVE BACTERIA

Impetigo
Impetigo is the most common bacterial skin infection in children, and has two different clinical presentations: nonbullous
and bullous. Since the 1980s, nonbullous impetigo, which
accounts for at least 70% of the cases, has been caused primarily by Staphylococcus aureus. Those infections caused by group
A β-hemolytic streptococci (GABHS) cannot be distinguished
clinically, but most frequently occur in preschool age children.
Staphylococcus aureus is the cause of bullous impetigo, and it is
most commonly caused by phage group 2, type 71.
Nonbullous impetigo presents as a small vesicle or pustule
on sites of prior trauma. This vesicle or pustule then ruptures and
results in honey-colored papules and plaques predominantly on
the face, neck, and extremities (Fig. 16.1). Children also often
have regional lymphadenopathy. Untreated skin lesions may
progress slowly, but typically resolve within a 2-week period.
Lesions of bullous impetigo usually occur on nontraumatized skin of the face, trunk, extremities, buttocks, and perineum.
They begin as transparent, flaccid bullae that easily rupture,
leaving a rim of scale surrounding shallow erosions (Fig. 16.2).
Pathophysiologically, these are localized lesions of staphylococcal
scalded skin syndrome (SSSS), induced by exfoliative toxin A.
Complications of nonbullous and bullous impetigo include
cellulitis, sepsis, septic arthritis, osteomyelitis, and pneumonia.

Cases related to GABHS can result in lymphadenitis, lymphangitis, scarlet fever, guttate psoriasis, and acute poststreptococcal
glomerulonephritis. A 2003 Cochrane review analyzed the treatment options for impetigo. Some patients were simply followed
and not treated. In patients with limited skin involvement, topical
treatments with mupirocin or fusidic acid were at least as effective
as, and sometimes more effective than, oral antibiotic therapy.
For those with more extensive disease, it was unclear whether
oral or topical therapy was more effective, and in cases where
oral treatment is warranted, local antibiotic-resistance patterns
should be considered when choosing a macrolide, β-lactamaseresistant antibiotic, or cephalosporin. Treatment has no impact
on the risk for poststreptococcal glomerulonephritis.

Ecthyma
Ecthyma is caused by GABHS and occurs commonly on the buttocks and lower extremities of children. The lesions begin in a
manner similar to that of nonbullous impetigo. A small vesicle or
pustule in a previously traumatized area becomes a shallow ulcer.
An adherent crust then develops over several days, and healing occurs slowly over weeks, with scar formation. Antibiotics
with gram-positive coverage and local wound care are adequate
treatments.

Erysipelas
This condition is discussed in Chapter 1.

Figure 16.1. Impetigo. Honey-colored crusted patches around the
nares.
211

212 — Michelle R. Wanna and Jonathan A. Dyer

antiseptics can also be useful in speeding resolution. Eradication
should be ensured with posttreatment swab culture.

Blistering Dactylitis
Blistering distal dactylitis is characterized by 10- to 30-mm bullae
containing white fluid of the volar fat pads, most frequently of the
hands. Involvement of the toes, however, can be seen as well. It
occurs commonly in children up to 16 years of age and is relatively
asymptomatic despite the impressive bullae. It is most commonly
caused by GABHS, but S. aureus and S. epidermidis have also been
reported as causes. Treatment involves incision and drainage, antistaphylococcal antibiotics, and wet to dry dressings.

Scarlet Fever

Figure 16.2. Bullous impetigo. Spreading circular superficial
erosions, some with honey-colored crusts, others with
remaining flaccid bullae roofs at the perimeter. Culture was
positive for methicillin-sensitive staphylococcus aureus.

Perianal Streptococcal Dermatitis
Perianal streptococcal dermatitis occurs in children aged 6
months to 14 years, with a slight male predominance. The
majority of cases are caused by group A β-hemolytic streptococci, although there are reports of streptococci and S. aureus as
etiologic agents. The dermatitis manifests as a well-demarcated
erythema, tenderness, and edema of the perianal area. Painful
defecation, incontinence, constipation, anal fissures, bloodstreaked stools, pruritus, and drainage may also be present.
Vulvovaginitis and balanitis can be associated as well.
Some seasonality of disease with spring and winter predominance is noted, and pharyngeal streptococcal infections have
been seen concurrently in more than 90% of cases. This suggests
that the disease may be related to oral–perineal autoinoculation or gastrointestinal passage of organisms from the pharynx.
Complications include disseminated infection, abscess, proctitis,
myositis, and post-streptococcal glomerulonephritis. Infections
may trigger guttate psoriasis, and poststreptococcal digital
desquamation can also occur.
Swab cultures of the perianal area should be obtained, and
some advocate obtaining cultures of family members and close
contacts as familial transmission and day care outbreaks have
been reported. Urinalysis should also be obtained in suspected
cases to rule out glomerulonephritis with repeat testing following
the course of treatment. Local resistance patterns should be
considered when selecting antibiotic therapy, but a 2- to 3-week
course of penicillin V, a macrolide, amoxicillin, amoxicillin/clavulanic acid, or clindamycin is appropriate. Topical antibiotics and

Scarlet fever is caused by GABHS and is most common in children aged 4 to 8. Sources of GABHS include the pharynx, the tonsils, and less frequently the skin. Primary spread of disease is via
respiratory droplets. Winter and spring outbreaks are common.
Fever, headache, sore throat, and vomiting occur 1 to 4 days
following exposure. Twenty-four to 48 hours later, erythematous
patches of the chest, axillae, and infra-auricular areas are seen.
These then spread into blanching patches on the trunk, extremities, and face. These patches feel like sandpaper. The oropharynx
becomes erythematous and the tongue becomes white with an
associated erythema of the papillae. Over the next few days, the
white coating resolves, leaving a “strawberry tongue.” Cutaneous
manifestations are more prominent in body folds and are accompanied by erythematous streaks, or Pastia’s lines. Desquamation
follows approximately 1 week later.
Leukocytosis with a left shift, eosinophilia, and positive
oropharyngeal cultures can be seen on laboratory evaluation.
Oral penicillin V or benzathine penicillin intramuscularly is the
treatment of choice. Erythromycin can also be used.

Staphylococcal Scalded Skin Syndrome
Staphylococcal scalded skin syndrome (SSSS) typically occurs in
children less than 5 years of age and is caused by Staphylococcus
aureus, phage group II, subtypes 71, 3A, 3B, 3C, and 55. Children
usually have signs and symptoms of preceding conjunctivitis or
pharyngitis. This is followed by erythematous, tender patches,
which develop flaccid bullae with a positive Nikolsky sign on
the perineum, axillae, face, and neck. The ruptured bullae reveal
an erythematous, moist base. Fever and malaise accompany the
cutaneous findings.
This constellation of clinical findings is mediated by exfoliative toxins A and B, which are both produced by S. aureus, with
toxin A being more prominent. Exfoliative toxin induces cleavage of desmoglein 1, which results in an intraepidermal split at
the granular layer. Desmoglein 1 is also the target for related diseases like bullous impetigo, which is also caused by an exfoliative toxin, and pemphigus foliaceus. The mechanism of action
for the effect that exfoliative toxin exerts on desmoglein 1 has
yet to be elucidated. Some patients with SSSS have detectable
anti-desmoglein 1 antibodies, suggesting that the toxin may trigger the desmosomal protein to become a self-antigen, thereby
eliciting an immune response.

Skin Infections in Pediatric Patients — 213

Treatment involves prompt diagnosis, initiation of antistaphylococcal antibiotics, wound care, and supportive measures.
Potential sources of S. aureus infection, such as conjunctivitis,
an abscess, pneumonia, omphalitis, endocarditis, septic arthritis,
or pyomyositis, all of which can act as triggers, should be investigated. Childhood cases carry a mortality rate of 4%.

Toxic Shock Syndrome
This condition is discussed in Chapter 25.

Furuncles and Carbuncles
This condition is discussed in Chapter 1.

Cellulitis
This condition is discussed in Chapter 1.

treatment, trimethoprim-sulfamethoxazole (8–12 mg/kg/
day trimethoprim and 40–60 mg/kg/day sulfamethoxazole
divided BID) or a tetracycline (doxycycline 2–4 mg/kg/day
divided BID-QID) is first-line therapy. Treatment of colonization sites, such as the nares, with mupirocin has shown some
effectiveness in reducing carriers, but resistance is increasing.
Antibacterial soaps and twice weekly bleach baths have also
shown improvement. Local resistance patterns should be considered when choosing antibiotic therapy as clindamycin and
fluoroquinolone resistance is increasing. Caution should also
be used in patients with in vitro erythromycin resistance and
clindamycin susceptibility as there are reports of inducible
clindamycin resistance, which produce a positive “D-zone”
test. Such strains are usually reported as clindamycin resistant.
Those patients with systemic symptoms, underlying medical
problems, and children less than six months of age are at a
higher risk for infection and hospitalization with parenteral
therapy may be required. See chapter 1 for a more detailed
discussion.

Periorbital and Orbital Cellulitis
Periorbital cellulitis is an inflammatory process anterior to the
orbital septum, which is the continuation of the orbital periosteum between the eyelids, characterized by painless erythema
and edema of the eyelid. S. aureus and S. pyogenes are the most
frequent causes, often following periorbital trauma. These are
also the two most common bacteria to precede or infections
with varicella or herpes simplex virus. Sinusitis and bacteremia
related to Haemophilus influenzae type b (Hib) or S. pneumoniae
are also etiologic agents for periorbital cellulitis. Buccal cellulitis
is related to bacteremia with these organisms as well. With the
advent of the H. influenzae type b conjugate vaccines, the incidence of disease related to H. influenzae has dropped approximately 90%.
Orbital cellulitis most commonly results from the contiguous spread of bacteria arising from ethmoid sinusitis. It can also
occur if the orbital septum is breached by trauma. While it is difficult to isolate the pathogen in either periorbital or orbital cellulitis, S. aureus, S. pyogenes, Hib, S. pneumoniae, and anaerobes
are the most commonly identified organisms in orbital cellulitis. Decreased visual acuity, proptosis, and pain should prompt
ophthalmologic consultation and radiologic examination with
computed tomography. This can be complicated by subperiosteal
abscess and cavernous sinus thrombosis.
Clinicians should have a low index of suspicion for meningitis and sepsis. A lumbar puncture should be performed and
blood cultures obtained in suspected cases. Treatment with ceftriaxone or cefotaxime in addition to clindamycin is excellent
empiric therapy. This treatment regime can also be modified if
the pathogenic organism is identified. Parenteral antibiotics and
hospitalization are necessary for patients with orbital cellulitis.

Methicillin-resistant community-acquired
staphylococcal infection
Skin abscesses less than five centimeters in size in immunocompetent children without systemic symptoms can be treated
with incision and drainage alone. A culture of the purulent contents should be obtained. In those patients requiring antibiotic

Necrotizing Fasciitis
Necrotizing fasciitis is a rare infection of the subcutaneous tissue
and superficial fascia. It can be rapidly fatal. It is more common in adults, but can also be seen in children and neonates. It
frequently presents on the trunk or extremities, or is related to
omphalitis in infants. The affected area becomes exquisitely tender out of proportion to clinical findings and erythematous, with
firm edema and systemic symptoms. The systemic symptoms
include fever, hypotension, vomiting, and malaise. Skin lesions
can then rapidly become blue-gray with necrosis, hemorrhagic
with bullae, anesthetic with destruction of cutaneous nerves, and
crepitant. Leukocytosis, anemia, and thrombocytopenia can be
seen. Risk factors in children include varicella with GABHS as the
causative organism, malnutrition, immunosuppression, surgery,
and trauma. Mixed infections with anaerobes, gram-negative,
and gram-positive organisms can frequently be seen. Reported
risk factors in infants include fetal scalp electrode monitoring,
circumcision, omphalitis, and temperature monitoring with rectal thermometers.
Necrotizing fasciitis is a medical and surgical emergency with
prompt debridement necessary for confirmation of diagnosis and
treatment. Liquid necrosis of the superficial fascia is the diagnostic finding. Antibiotic treatment should be promptly initiated with
clindamycin and cefoperazone sodium while monitoring culture
results. Multisystem organ failure, sepsis, and DIC can occur if
untreated, with an average mortality in children of 20%.

Folliculitis
Folliculitis is a hair follicle infection of the follicular ostium, is
common in children, and usually occurs on the extremities and
buttocks. The most common infectious etiology is S. aureus, but
streptococci, gram-negative organisms, Demodex, Pityrosporum,
and dermatophytes can also be seen. Bockhart’s impetigo, or
superficial folliculitis, presents with small pustules with central
hairs on an erythematous base. Extensive eruptions may require
a systemic antibiotic, but the majority of cases will resolve with
topical antibiotics and antibacterial soaps.

214 — Michelle R. Wanna and Jonathan A. Dyer

Erythrasma
Erythrasma is caused by Corynebacterium minutissimum, a
gram-positive bacillus, and presents as well-demarcated, erythematous patches, most commonly in the intertriginous areas
such as crural folds, inframammary areas, axillae, and gluteal
creases. Interdigital involvement is characterized by fissuring, maceration, and scaling. Erythrasma is the most common
bacterial infection of the foot in children. Risk factors include
diabetes mellitus, obesity, immunosuppression, warm climate,
hyperhidrosis, and poor hygiene. The diagnosis can be made
by visualizing the porphyrins produced by the bacteria using
a Wood’s lamp, which elicits the characteristic coral red fluorescence. Other diagnostic options include gram staining of
the tissue scrapings under oil immersion, or culture on special
media.
In cases of mild disease, antibacterial soaps may be adequate
for treatment. In those patients with more extensive disease,
oral erythromycin is the treatment of choice. Tetracycline may
also be used in children older than 8 years. Topical therapy with
clindamycin or Whitfield’s ointment (6% salicylic acid and 12%
benzoic acid) daily for 4 weeks is recommended in addition to
oral antibiotics in intertriginous areas. If oral treatment is not an
option, topical clindamycin is also effective.

Trichomycosis Axillaris
Trichomycosis axillaris is caused by Corynebacteria and produces
nodules or sheaths of axillary and pubic hair. The lesions can be
black, yellow, or red and can cause red staining of the clothing
from sweat. Antimicrobial soaps and shaving of the affected area
are curative for axillary lesions while erythromycin, clindamycin, or mupirocin can be used for pubic hair involvement.

Pitted Keratolysis
Pitted keratolysis manifests as small, 1- to 7-mm depressed pits
of stratum corneum most commonly on weight-bearing areas of
the plantar foot. These pits may eventually coalesce into erosions
(Fig. 16.3). It was originally proposed that the causative organism
was Corynebacterium, but Micrococcus (Kytococcus) sedentarius
has also been implicated. Research has shown that Micrococcus
produces two proteolytic enzymes capable of degrading keratin
and inducing the crater-like pits of pitted keratolysis. Patients
frequently note an unpleasant odor and sliminess, as well as an
underlying hyperhidrosis. Treatments include topical erythromycin, clindamycin, and management of hyperhidrosis. There
have also been recent reports of resolution of refractory cases
following injections of botulinum toxin.

Erysipeloid
Erysipeloid is caused by Erysipelothrix rhusiopathiae, a grampositive rod. It is the cause of swine erysipelas, and has a clinical presentation in animals that ranges from polyarthritis and
endocarditis to sepsis. It is also carried asymptomatically in the
lymphoid tissue of 30% to 50% of all swine. Humans encounter
the organism primarily via occupational exposure, with veterinarians, butchers, and fishermen at highest risk. The manifestations of human infection are termed erysipeloid and take three

Figure 16.3. Pitted keratolysis. Honeycomb pitting on the sole in
a patient with hyperhidrotic feet who presented complaining of
significant foot odor. Treatment with topical agents and increased
frequency of changing socks was curative.

forms: localized cutaneous (erysipeloid of Rosenbach), diffuse
cutaneous, or septicemia and endocarditis.
The most common type is localized cutaneous disease, which
presents as a painful, edematous, violaceous plaque of abraded or
traumatized skin, 5 to 7 days after the initial injury. It frequently
occurs on the fingers or hands and may spread peripherally with
central clearing. When the lesions continue to progress with formation of bullae, involvement of proximal areas, and systemic
symptoms of arthralgias and fever, the condition is termed diffuse cutaneous disease. Uncommonly, patients develop the more
severe manifestations of endocarditis or sepsis, which are associated with a high mortality rate. Cardiac involvement is more
common in males, and usually afflicts left-sided, native, damaged,
cardiac valves with a higher propensity for the aortic valves.
Erysipelothrix can be identified on blood culture, but culture
of skin lesions must be prepared on special media and may be
of low yield. Organisms can be seen on a Gram stain. Both the
localized and diffuse cutaneous forms may resolve spontaneously
over weeks, but respond well to penicillin, ceftriaxone, or ciprofloxacin. Erysipelothrix is resistant to vancomycin. In patients
with endocarditis, penicillin should be included as empirical
antibiotic therapy for suspected cases. Preventive measures and
regular cleaning of potential sources of infection with disinfectants resistant to organic matter in those persons at highest risk
should be employed.

G R A M  N E G AT I V E BA C T E R IA

Ecthyma Gangrenosum
Ecthyma gangrenosum is most commonly seen in patients with
Pseudomonas aeruginosa bacteremia, and occurs on the buttocks,
perineum, and extremities. It begins as an erythematous macule,
which then becomes a hemorrhagic bulla. An ulcer with central,
black eschar and inflammatory borders follows. Predisposing factors include neutropenia from an underlying immunodeficiency
or chemotherapy. Cases of ecthyma gangrenosum in previously

Skin Infections in Pediatric Patients — 215

healthy children should prompt evaluation for occult immunodeficiency. Early treatment with an antipseudomonal penicillin
and an aminoglycoside is necessary.

Rocky Mountain Spotted Fever

Pseudomonal Folliculitis and Hot-Foot Syndrome

Ehrlichiosis

Pseudomonal folliculitis is related to improperly chlorinated
swimming pools, hot tubs, or whirlpools, and results in follicular, erythematous pustules primarily in areas covered by
swimsuits, but can be widespread, one to two days following
exposure. Lesions usually resolve spontaneously. Some patients
may complain of headache, malaise, arthralgias, and fever and
can be treated with fluoroquinolones. Adequate cleaning and
proper chlorination of the source will prevent re-exposure.
Children can also develop erythema and painful nodules of
the weight-bearing areas of the plantar foot following exposure
to Pseudomonas aeruginosa. Outbreaks have been reported following exposures at public wading pools and hot tubs. Lesions
usually resolve within two weeks, but some patients can develop
fever, lethargy, and significant leukocytosis requiring fluoroquinolone therapy.

Bacteria of the family Anaplasmataceae cause the infections
termed ehrlichiosis with three species being predominant in
humans. Ehrlichiosis is a tick-borne disease, and patients present with fever, myalgias, headache, thrombocytopenia, leukopenia, and elevated liver enzyme levels. Infection occurs most
commonly in the spring and summer, which directly correlates
with tick activity.
Human monocytic ehrlichiosis (HME) is caused by Ehrlichia
chaffeensis and is prevalent in the southern United States in areas
where the vector Amblyomma americanum, or the lone star tick,
is found. A rash is seen most frequently in HME and is petechial, macular, or a combination of the two in appearance. These
patients are also more likely to have meningitis, encephalitis,
and shock. A. americanum also carries Ehrlichia ewingii, which
is the cause of human ewingii ehrlichiosis in the United States.
Anaplasma phagocytophilum is the etiologic agent in human
granulocytic anaplasmosis (HGA), which occurs internationally.
Ixodes persulcatus ticks, including Ixodes pacificus, Ixodes scapularis, Ixodes ricinus, and I. persulcatus, are the vectors.
Diagnosis can be made with a peripheral blood smear, noting morulae in neutrophils in HGA and monocytes in HME.
PCR, culture, and serologic antibody testing can also be used.
Doxycycline is the treatment of choice, including seriously ill
children less than 8 years of age. Treatment adversely affects
diagnostic results. Rifampin has also been used in situations
where doxycycline is contraindicated.

Meningococcemia
See Chapter 25.

Gonorrhea
See Chapter 24.

Cat-Scratch Disease
Bartonella henselae is the cause of cat-scratch disease. It is the most
common manifestation of Bartonellosis in children. Cats are the
reservoir and vector, with seroprevalence being highest in young
cats in warm environments. It has been proposed that the cat flea
is involved in transmission between felines. Red-brown, asymptomatic papules develop over several days to 1 month following
inoculation of the organism via the scratch or bite of a cat. These
then become vesicular and crusted with painful enlargement of
regional lymph nodes. Lymphadenopathy can last as long as 1 year,
but typically resolvs within 2 months. Some patients complain of
headache, malaise, anorexia, and arthralgias. Serologic evaluation
is used most frequently for diagnosis. Other options include PCR
testing available in some laboratories, direct observation of the
organism with Warthin-Starry silver staining of affected lymph
nodes, and culture(which can become positive after weeks of incubation). Treatment is not required in immunocompetent patients,
as the disease is normally self-limited. However, azithromycin,
trimethoprim–sulfamethoxazole, erythromycin, rifampin, doxycycline, and ciprofloxacin may offer some improvement.
Atypical cat-scratch disease can manifest as Parinaud’s
oculoglandular syndrome, which is characterized by a unilateral
preauricular lymphadenopathy and conjunctivitis. Inoculation
of the organism into the eye occurs indirectly, and infection is
usually self-limited. More serious complications of atypical catscratch disease include encephalopathy, Leber’s idiopathic stellate
retinopathy and endocarditis. Immunocompromised patients
can develop bacillary angiomatosis and reticuloendothelial
involvement, which is known as bacillary peliosis.

See Chapter 25.

SPIROCHETES

Lyme Disease
Lyme disease in the United States is caused by Borrelia burgdorferi with I. scapularis and I. pacificus as the vectors of disease.
Children and adults are affected by Lyme disease and clinical
manifestations are consistent in each stage. Of note, children
older than 8 years may be treated with doxycycline. Amoxicillin
can be used in children 8 years of age and younger, with cefuroxime as an alternative for amoxicillin or doxycycline allergic
patients. Refer to the discussion in the Chapter 7 on arthropodborne infections for further review of Lyme disease.

Endemic treponematoses
Yaws, endemic syphilis (bejel), and pinta are nonvenereal
treponematoses. They are commonly seen in children less than
15 years of age who also have poor hygiene and are living in
rural areas of developing countries. They have characteristic stages of disease with periods of latency. Transmission is
through contact of skin and mucous membranes. There is no
congenital disease.
Nonvenereal and venereal treponematoses cannot be
distinguished with current serologic testing. The nontreponemal
tests, venereal disease research laboratory (VDRL) and rapid
plasma reagin (RPR), if reactive, can identify an active infection

216 — Michelle R. Wanna and Jonathan A. Dyer

and a treated or untreated recent infection. They can also produce a false-positive result. Nontreponemal titers can be useful
for monitoring response to treatment. A four-fold decrease in
titers will be seen with adequate treatment. There can also be a
four-fold increase in titers with relapse or re-infection. Following
treatment, the treponemal tests, enzyme-linked immunosorbent assays (ELISA), fluorescent treponemal antibody absorption test (FTA-Abs), and agglutination assays for Treponema
pallidum (TPHA), can remain positive for many years or even
for life. T. pallidum can also be identified on dark-field microscopy. Research is conflicting regarding the potential for crossimmunity between treponematoses. Some studies show no
protection while others reflect some component of immunity
related to the severity of the initial infection.
Treatment is the same for all three endemic treponematoses.
Active early or late infections are treated with 1.2 million units of
benzathine penicillin as a one-time dose. Children less than 10
years of age should receive 0.6 million units of benzathine penicillin. Alternative antibiotics include tetracycline, doxycycline,
and erythromycin.
Treponema pallidum subspecies pertenue is the cause of
yaws. It occurs in areas of the world with a high rainfall and
temperatures greater than 80˚F. The initial lesion, or “mother
yaw,” occurs at sites of initial infection, which are frequently
on the lower extremities or buttocks. It is highly infectious,
and manifests 10 days to 3 months following inoculation as
an erythematous papule that enlarges into an ulcerated nodule. It may be accompanied by local lymphadenopathy. This is
followed months to years later by diffuse papules and necrotic
nodules with an infectious, exudative serum that is frequently
on moist areas of the body. Hyperkeratotic plaques of the soles
and palms, polydactylitis of the hand or foot, and osteoperiostitis of the leg or forearm are also seen. The final stage, which
is characterized by destructive tissue lesions, is seen in 10% of
patients. Cutaneous findings include gummas, periarticular
nodules, hyperkeratosis of the palms and soles, and mottled pigmentation of the anterior lower extremities, hands, and wrists.
Curvature of the tibia, termed saber shin, results from chronic
osteitis. Perforation of the nasal septum or palate can also occur
and this is referred to as gangosa.
Endemic syphilis, or bejel, is seen in hot, arid areas of the
world with frequent transmission through drinking vessels in
addition to skin contact. The reservoir for the T. pallidum subspecies endemicum is children between the ages of 2 and 15. The
initial finding is a small papule or ulcer of the perioral area or nipple of nursing women. This is followed by second-stage periostitis, lymphadenopathy, mucous patches of the oral mucosa, and
angular stomatitis of the oral commissures, which is also known
as split papules. Periarticular nodules, saber shins, gangosa, and
gummas can be seen in the late stage of disease.
T. carateum is the causative organism for pinta and was frequently seen in the forested areas of Central and South America.
It only manifests in the skin and can occur in all age-groups,
which makes it unique among the endemic treponematoses. It
begins 15 to 30 days following infection as one or more papules
or erythematous plaques. These lesions then slowly increase in
size with central clearing and lymphadenopathy later develops. Secondary lesions, known as pintids, are scaly papules and
plaques of a variety of colors, which include blue and grey, or
hypopigmented. Two to 4 years later, symmetric, depigmented,

atrophic or hypertrophic lesions of the bony prominences characterize the late-stage. Treponema carateum is present in the skin
from onset through the late stage.

OTHER

Pseudofolliculitis Barbae
Pseudofolliculitis barbae is a common disorder, frequently of
African-Americans and patients with curly hair, characterized by
erythematous, perifollicular papules and pustules of the anterior
neck, chin, mandible, cheeks, and neck. It is related to a repenetration of the epidermis or hair follicle by a sharp hair shaft
following close shaving. This results in a foreign-body inflammatory response. Treatments include using electric razors, depilatory creams, eflornithine, chemical peels, topical retinoids, and
topical antibiotics. Current research has shown promise with
Nd:YAG and diode (810 nm) laser treatment.

Eosinophilic Pustular Folliculitis
Eosinophilic pustular folliculitis (EPF) is a skin disease of
unknown etiology. Three forms have been described: classic
EPF, infancy-associated EPF, and immunosuppression-associated EPF. Only infancy-associated EPF, which begins within a
few weeks of birth, will be discussed here. In contrast to adults,
who typically present with erythematous, follicular papules and
pustules in an annular or grouped configuration on the face
and trunk, infants predominantly have scalp involvement, and
lesions are scattered. Lesions can occasionally be found on the
face and extremities. Infancy-associated EPF typically responds
well to mild-to-moderate potency topical steroids.

Noma (cancrum oris)
Noma is a disease of unknown etiology seen most commonly
in children ages one to four in Africa, Asia, and Latin America.
It causes swelling of the gingiva or cheek followed by necrotizing stomatitis of the alveolar margin. This rapidly progresses
to necrosis of the overlying cutaneous structures with eventual
full thickness tissue loss, frequently exposing bony tissue. It
can involve the nose, infraorbital areas, maxilla, and mandible.
Systemic signs and symptoms including fever, pain, foul odor,
anorexia, and excessive salivation can occur. Children often
reside in unsanitary conditions and have underlying medical
problems. Risk factors include malnutrition, poor oral hygiene,
and preceding infection with malaria or measles. Treatment
is aimed at early recognition with improvement of underlying
medical issues and broad spectrum antibiotics. Reconstructive
surgery is needed to correct the resulting defects.

FUNGAL INFECTIONS

Many types of fungi can lead to cutaneous infections in children,
and some cutaneous fungal infections are relatively common in
pediatric patients. Cutaneous fungal infections may be divided
into the superficial and deep forms. There are three common
causes of superficial cutaneous fungal infections: dermatophytes,
tinea versicolor, and candidiasis (moniliasis).

Skin Infections in Pediatric Patients — 217

Dermatophytes
Dermatophyte fungi are contracted from multiple sources such
as animals (zoophilic such as Microsporum canis), humans
(anthropophilic such as Trichophyton tonsurans), and the environment (geophilic such as Microsporum gypseum). These fungi
are adapted to live on the skin and derive nutrients from it.
Infections with these fungi are called tinea and they are typically
classified by the body location they affect.
Tinea capitis (fungal infection of the scalp and hair) is the
most common dermatophytosis of childhood. The incidence of
infection in the United States is estimated at 1% to 8% in children and may be more common in urban settings.
Asymptomatic carriage (positive scalp fungal culture with no
signs/symptoms of disease) is a major reservoir for disease, especially for the anthropophilic strains Trichophyton tonsurans and
Trichophyton violaceum. Most carriers are African-American.
Asymptomatic carriage can present as a seborrheic dermatitislike eruption with a mild or absent inflammatory response.
Dermatophyte carrier prevalence correlates with the incidence
of tinea in a community. The asymptomatic carriage rate is estimated at ~15%.
There is a clear role for fomites in the spread of dermatophyte
infections as well. Fungal material remains viable on fomites for
months. The incubation period of dermatophyte infections can
be relatively short (1–3 weeks but as fast as 2–4 days).
The type of fungus and the morphology seen in tinea capitis
has changed with time. While Microsporum audouinii was the
most common cause of tinea capitis in the United States during the mid-1900s, it is now uncommon. Infections with T. tonsurans increased in the 1970s, and it continues to be the most
frequent agent today.
There are multiple clinical presentations of tinea capitis.
As noted earlier, infection can be subtle, and can present as a
mild seborrheic dermatitis-like scaling with minimal hair loss.
Patients more commonly present with patches of alopecia with
variable scaling of the alopecic scalp. When scale is present, it
may be termed “gray type” tinea capitis. “Black dot” tinea refers
to the appearance of the ends of hairs, broken at their exit from
the skin surface, with minimal inflammation, that is seen especially with those dermatophytes capable of endothrix invasion of
the hair shaft. Diffuse pustular forms can also occur.
Some patients develop an intensely inflammatory, boggy
edematous eruption of the affected scalp with alopecia, pustules,
and occasional purulence, termed a kerion. Aggressive therapy
is indicated for these patients in order to prevent a scarring
alopecia.
Favus, a form of tinea capitis rarely seen in the United States,
is caused by Trichophyton schoenleinii. The scalp exhibits scaling,
erythematous patchy lesions with striking yellow adherent crusts
often with a central hair shaft (termed scutula) that form from
hairs matted together by debris and hyphae. A cheesy or mouselike odor may also be present. This condition also often leads to
scarring alopecia.
Lymphadenopathy, especially cervical or postauricular, is
common in patients with tinea capitis. Secondary infection of
involved areas may occur, with nearly half of cases being caused
by Staphylococcus aureus.
Dermatophytid (autoeczematization/Id) reactions occur
occasionally in patients with tinea capitis especially when a

kerion is present. These hypersensitivity reactions typically present with small lichenoid papules that may be pruritic. They may
also occur after initiation of antifungal treatment and may raise
the concern for a drug reaction. Symptomatic treatment is typically effective.
Diagnosis
Potassium hydroxide preparation can be helpful, although longer digestion times are required for detection of fungal elements
within the hair shaft itself. Hairs for examination may be plucked
using forceps or hemostats. However, hair extraction can be painful. The ability of dermatophytes to invade hair varies depending
on the strain. Ectothrix strains exhibit fungal growth on the exterior of the hair shaft, and may fluoresce under a Wood’s lamp.
Whereas, endothrix fungi are able to invade the hair shaft and do
not fluoresce under Wood’s lamp. Favus (T. schoenleinii) shows
infectious material with large spores interspersed with air bubbles in the hair shaft. The Wood’s lamp emits filtered UV light at
365 nm, which can induce fluorescence in ectothrix strains but
this is positive in only one-half of culture-positive Microsporum
canis patients.
Fungal culture remains the gold standard diagnostic test for
tinea capitis, though it can be falsely negative in up to 50% of
cases. Recent reports suggest that vigorous rubbing of moistened
premade bacterial culture swabs sent for fungal culture is as
effective as more aggressive sampling techniques.
Treatment
Systemic treatment of tinea capitis is usually warranted as penetration of the hair follicle is necessary for cure. However, in
infants topical therapies may be effective if avoidance of systemic
antifungals is desired. Treatment of a kerion may require the
addition of antibacterial therapy or systemic steroids.
The issue of school attendance often arises for school age
children with tinea capitis. It is not practical to keep children
with tinea capitis out of school as spore shedding can occur
asymptomatically and such carriers may be the major source of
transmission. The use of selenium sulfide or ketoconazole antifungal shampoos can suppress the carrier state and decrease
potential transmission, thus alleviating anxiety for parents and
teachers alike.
Systemic therapy
Griseofulvin is the only systemic antifungal medication licensed
in the United States for use in children. Fungistatic in vitro, it
interferes with spindle microtubule function, and leads to defective DNA synthesis and defective cell wall formation. Available
as both tablets and a suspension, it is absorbed best when taken
with fatty foods. Variable bioavailability and resistance among
dermatophyte strains lead to some unpredictability in its ability
to treat tinea capitis successfully. Thus, recent recommendations
suggest higher dosing schedules than previously suggested with
doses of 20 to 25 mg/kg/day divided twice daily for at least 8
weeks. A small percentage of patients exhibit headache, nausea,
or rashes during treatment. While internal organ monitoring is
not necessary for healthy patients on normal courses at standard
doses, it may be prudent for those children on extended drug
courses (>8 weeks).

218 — Michelle R. Wanna and Jonathan A. Dyer

Table 16.1: Antifungal Medications for Treatment of Tinea capitis in Children
Drug

Mechanism of Action

How supplied

Pediatric dose

Duration of therapy

Griseofulvin
(microcrystalline)

interferes with spindle
microtubule function

Tablets
Suspension
(125mg/5cc)

20–25mg/kg divided twice daily

Continuous: > 8 weeks

Itraconazole

inhibits lanosterol
14-demethylase

Capsule
Suspension

5mg/kg/D
3mg/kg/D

Continuous: 4–6 weeks
Pulse: 1 week repeat after 3 weeks

Fluconazole

inhibits lanosterol
14-demethylase

Capsule
Suspension

Continuous: 6mg/kg/D
Pulse: 8mg/kg/week

20 days
4–6 weeks

Terbinafine

inhibits squalene
epoxidase

Tablets

<20kg–62.5mg/D
20–40 kg – 125mg/D
>40kg–250mg/D or 4–5 mg/kg/D

Continuous: 4 weeks

Itraconazole, fluconazole, ketoconazole, and terbinifine
have all been used to successfully treat tinea capitis in children.
Table 16.1 shows recommended dosage schedules and regimens
of standard antifungals in children.
Corticosteroids are rarely used in the treatment of tinea capitis but may be helpful in decreasing swelling and inflammation
in extremely pronounced cases of kerion. They can also improve
symptoms in diffuse Id reactions.
Concomitant use of topical antifungal shampoos may
decrease the risk of transmission of the causative dermatophyte
to others. Both selenium sulfide and ketoconazole shampoos
(twice weekly) may be used. If pets are affected, they should be
treated for dermatophytes. Dosing for affected cats is itraconazole 1.5–3 mg/kg/day for 15 days.
One difficult clinical scenario is the diagnosis of tinea capitis
in children less than 1 year of age. Tinea capitis is rare in the first
year of life and occurs more frequently in male infants. In this
age-group it is often due to M. canis and M. audouinii. Typically,
an adult caregiver is the source of the infection. Alopecia is often
seen, along with scaling of the affected areas. Topical therapy
may be of greater efficacy in these young patients and can be a
reasonable therapeutic choice. Griseofulvin may be the systemic
drug of choice, due to its long record of safety. Fluconazole, however, can also be safely used in infants.

Tinea faceii
Dermatophyte infection of the face is called tinea faceii.
Involvement of the non–hair bearing face is relatively common
in children compared to adults. These lesions may resemble the
classic lesions of tinea corporis or may be more subtle.
Fungal infection of the beard is termed tinea barbae and
typically affects adolescent and adult males.
Tinea corporis is the classic “ringworm” infection. Often
presenting as annular erythematous patches, it occurs in patients
of all ages but is more common in children and in the immunosuppressed. It is more frequent during warm, humid times of the
year or in such climates. Patients with disorders of keratinization
are more frequently affected and can present with atypical clinical findings. The causative agents include Trichophyton sp. and
Microsporum sp.
Tinea corporis is frequently seen in wrestlers, transmitted by
skin-to-skin contact or fomites and is termed tinea gladiatorum.

In cases of frequent infections, prophylactic antifungals have
been used. Pets are a common source of M. canis infections and
such zoophilic tinea infections tend to be more inflammatory
than anthropophilic infections even progressing to bullae formation (Fig. 16.4).
Tinea cruris refers to infection of the genital area.
Involvement of the scrotum or labia should suggest candidal
infection as dermatophytes rarely affect the skin in those locations. Heat, moisture, and maceration predispose patients to
dermatophyte infection in these areas. Patients with active tinea
cruris often have tinea pedis as well, and this often serves as a
source of infection.
Tinea pedis, or athlete’s foot, is an uncommon dermatophyte
infection in children with an increased incidence after puberty.
It is the most common dermatophyte infection after puberty,
whereas tinea capitis is the most common dermatophyte infection before puberty.
Tinea of the hand (tinea manuum) is rare in childhood.
Tinea incognito refers to dermatophyte infections in
any location previously treated with a topical steroid or
with a combination topical steroid/antifungal preparation.
The use of corticosteroids can suppress the inflammatory
response to dermatophytes and eliminate the erythema and
scale. This makes diagnosis of tinea clinically difficult since
erythema and scaling are the hallmarks of tinea infection.
Immunosuppresion by topical corticosteroids may also promote the growth of the dermatophyte. Such lesions may show
little to no clinical findings; yet potassium hydroxide preparation reveals numerous fungal hyphae on the skin surface.
Directed treatment of the dermatophyte without corticosteroids is recommended.
Tinea unguium or onychomycosis is rare in children compared to adults, with an estimated incidence of ~0.6% in children in Europe (vs. 10%–20% of European adults). It has been
proposed that the smaller surface area of children’s nails, the
decreased frequency of nail trauma, and the less frequent exposure to areas with a high prevalence of dermatophytes account
for this low prevalence among children. Trauma is an important causative factor as onychomycosis is ~1.5 times more common in sports-active children compared to those who are not
sports active. In ~50% of children with onychomycosis, a firstdegree relative also has tinea. Often there is a positive family
history or active infection in first-degree family members. In

Skin Infections in Pediatric Patients — 219

Topical therapy for onychomycosis exhibits greater potential
than in adult patients. The thinner nail plates of children may
enhance drug penetration and the more rapid growth of the nail
may increase the efficacy of topical therapy.
Several reports describe the use of topical antifungals alone
or in combination with chemical nail debridement such as urea
with good results. The following treatments have been used
successfully to treat onychomycosis in extremely young infants:
Cicloprox and Amorolfine nail lacquers, Tolnaftate solution,
clotrimazole 1% solution and Bifonazole (1%) combined with
urea (40%) creams applied for 15 days until the affected nail
was removed, followed by bifonazole 1% cream daily for 4
weeks. Systemic therapies are listed in Table 16.2.

Tinea imbricata (Tokelau)

Figure 16.4. Bullous tinea – Tinea manuum. Pruritic vesiculobullous
scaling eruption of the palmar aspects of the fourth digit and hand.
While some of the vesicles appear herpetic in nature, the patient was
a veterinarian and KOH examination of lesional scale revealed florid
fungal hyphae. Antifungal therapy was rapidly curative.

addition to trauma, other predisposing factors include contact
with animals, swimming, and immunosuppression. There is
also a higher incidence in patients with Down’s syndrome.
The most common pathogen in children is Trichophyton
rubrum. T. mentagrophytes var. interdigitale, Epidermophyton
floccosum, and Candida albicans are also reported. One report
also noted Epidermophyton floccosum and T. violaceum as causative agents. Scopulariopsis brevicaulis is the most common mold
responsible. Males are more commonly affected, and most manifest
a distal and distolateral subungual hyperkeratosis. Onychomycosis
in neonates is often due to Candida, which may be congenital.
Clinically the distal subungual type is most common. It presents with distal onycholysis and subungual thickening with occasional discoloration. It is more frequent on the toes. The proximal
subungual form is more often seen in patients with HIV.
Diagnosis
The diagnosis can be confirmed by potassium hydroxide examination or periodic acid-Schiff (PAS) staining of clippings from
the affected nail. Fungal culture can be definitive and allows
identification of the specific dermatophyte, but false negatives
are common.

Tinea imbricata (TI) is a chronic dermatophyte infection of
glabrous skin caused by Trichophyton concentricum, an anthropophilic dermatophyte belonging to the same fungal group as
T. schoenleinii.
TI is seen in three main areas: southern Asia (China/India),
the South Pacific islands, and South and Central America. The
South Pacific, Polynesia, and Melanesia are the most important
endemic zones in the world, with 9% to 18% of the population
being infected. All are rural regions with high humidity. TI is
found in both sexes and all ages from infants to the elderly.
Farmers and land workers are more frequently infected. The
susceptibility to infection is possibly inherited with studies
favoring autosomal recessive inheritance even though there are
some cases of autosomal dominance. T. concentricum spreads
via close contact, especially from mother to child.
TI begins in childhood, often on the face, then spreads to
other body areas. Patients exhibit erythematous scaly concentric
and overlapping plaques mainly involving the thorax and limbs
including the palms and soles. Onychomycosis, most commonly of the distal subungual type, can occur. TI can involve
the scalp, creating seborrheic-like lesions, but does not infect the
hair or follicle. With time the areas become lamellar and develop
abundant thick scale with adherence to one side (overlapping
or “imbrex”), which can lead to an ichthyosiform appearance.
Pruritus is the most frequent symptom.
Treatment
Griseofulvin has been the traditional therapy for TI for many
years but has a high recurrence rate, and azoles do not show
good effectiveness. Terbinafine appears to be the best therapeutic
option, when used at standard doses. Topical treatments include
keratolytic creams such as Whitfield’s ointment or the combination of systemic and topical agents. Maintenance of good skin
hygiene is also helpful in treating TI.

Treatment
Onychomycosis can present a therapeutic dilemma when present in young patients. The necessity of treating onychomycosis
in children has been debated. The risks and duration of systemic
antifungal therapy must be weighed with the severity of infection, the likelihood of permanent sequelae, and the age of the
child. Parents should be given as much information as possible
to make an informed decision.

Tinea versicolor (Pityriasis versicolor)
Multiple treatments are effective including selenium sulfide 2.5%
shampoo applied in a thin layer for 10 minutes prior to rinsing,
daily for 1–2 weeks. Less frequent applications (every other week
or less) may maintain clearance. Ketoconazole 2% shampoo is
also effective using a similar regimen. Terbinafine spray appears
effective when used once to twice daily for 1–2 weeks. Severe

220 — Michelle R. Wanna and Jonathan A. Dyer

Table 16.2: Antifungal Medications for Treatment of Onychomycosis in Children
Drug

Mechanism of Action

How supplied

Pediatric dose

Duration

Griseofulvin (microcrystalline)
[not recommended]

interferes with spindle
microtubule function

Tablets
Suspension
(125mg/5cc)

5–10 mg/kg divided twice daily

9–18 months

Itraconazole

inhibits lanosterol
14-demethylase

Capsule
Suspension

Pulse: (1 wk. on/ 3 wks. Off )
5mg/kg/D
3–5mg/kg/D

FN: 2 pulses TN: 3 pulses

Fluconazole

inhibits lanosterol
14-demethylase

Capsule
Suspension

Pulse: 3–6 mg/kg/week

FN: 12 wks. TN: 26 wks.

Terbinafine

inhibits squalene
epoxidase

Tablets

<20kg – 62.5mg/D
20–40 kg – 125mg/D
>40kg – 250mg/D
OR 4–5 mg/kg/D

FN: 6 wks. TN: 12 wks.

Abbreviations: FN: fingernail; TN: toenails
Source: Sethi A and Antaya R. Systemic antifungal therapy for cutaneous infections in children. Pediatr Infect Dis J. 2006;25(7):643–644.

Gupta AK and Skinner AR. Onychomycosis in Children: A brief Overview with Treatment Strategies. Pediatr Dermatol.
2004;21(1):74–79.

or recurrent disease or follicular involvement may mandate oral
therapy with ketoconazole (400mg with exercise afterward and
allowing sweat to remain on skin for approximately 12 hours
prior to rinsing and repeated in 1 week), itraconazole 400mg for
one dose, or a single dose of 400mg fluconazole. See chapter 3 for
a more detailed discussion.

Tinea nigra
Tinea nigra is a superficial cutaneous infection with the pigmented
fungus Phaeoannellomyces werneckii. This infection is seen in warm
humid areas such as the Caribbean as well as in Central and South
America. It produces an asymptomatic light to dark brown or black
macule, typically involving palmar skin. Scaling is rare but potassium hydroxide preparation reveals pigmented hyphae and yeast
cells. Culture is confirmative and topical antifungals are curative.

Piedra
This fungal infection of the hair shaft has two clinical types.
Black piedra is caused by Piedraia hortae and is seen in Asia,
Africa, and Central America. The hair shafts of affected patients
exhibit small, hard, dark nodules. Fungal culture can confirm
the infection and traditionally the head was shaved to eradicate
the infection. Terbinafine, however, appears to be as effective a
treatment without taking such drastic measures. White piedra
is caused by infection of the hair shaft with Trichosporon beigelii,
and occurs in more temperate zones including the United States,
where infections in recent immigrants are occasionally seen.
Soft, white-to-tan nodules on the hair shafts can mimic hair casts
or nits. Pubic hair may be involved. Fungal culture will confirm
the infecting agent. Traditional treatment involved shaving of
the head but itraconazole may have efficacy against T. beigelii.
T. beigelii may cause disseminated infections in low birth weight
infants or immunocompromised patients. Skin lesions in such
disseminated infections are similar to those seen with other

disseminated fungal infections such as candida and take the
form of purpuric papules and nodules with areas of necrosis.
Treatment may be difficult as T. beigelii often exhibits resistance
to amphotericin B.

Candidiasis
There are nearly 200 species of Candida and approximately 20
cause infections in humans and animals, with C. albicans being
the main pathogen. Recently non–albicans candida (C. glabrata,
krusei, parapsilosis, tropicalis, guilliermondii) infections have
increased in incidence, likely because of the use of azole antifungals. Now they represent 35% to 65% of all candidemias.
Drug resistance to azoles is increasingly being reported. It
was first noted in chronic mucocutaneous candidiasis patients
on long-term suppressive ketoconazole therapy and now is also
seen in patients with HIV. Some forms of candida are inherently
resistant to antifungals, such as C. krusei and C. glabrata (both
resistant to fluconazole) and C. tropicalis (resistant to ketoconazole). Some strains of C. albicans also exhibit increasing azole
resistance. Cross-resistance (resistance to one azole implying resistance to alternative azoles) has also been noted but is
variable.
C. parapsilosis has caused bloodstream infections, especially
in neonates and those in NICUs (neonatal intensive care units),
possibly from parenteral nutrition. One NICU survey found
nearly 30% of Candida blood stream infections to be due to
C. parapsilosis, which easily attaches to inert polymer surfaces
and forms biofilms.
The oral, vaginal, and gastrointestinal tracts are sources of
Candida. Candida carriage in the vagina increases with pregnancy with 20% to 40% of women being culture positive at the
time of delivery. Approximately 30% of health care workers will
be Candida culture positive on one or more occasions.
Predisposing factors for Candida infection include
infancy, pregnancy, old age, occlusion of epithelial surfaces,

Skin Infections in Pediatric Patients — 221

immunodeficiency (primary or secondary), chemotherapy,
immunosuppression, antibiotic use, carcinoma, and primary
epithelial disease leading to a defective barrier.
Clinical
Mucocutaneous candidiasis refers to infections of the skin,
nails, and mucosa. Deep-seated candidosis includes infections
of internal organs. Disseminated candidal disease has markedly risen in incidence over the last few decades. It carries a significant mortality rate (~30% even with treatment). Preexisting
granulocytopenia is a risk factor for the development of systemic
candidiasis.
Oropharyngeal candida (thrush) is common in infants, the
elderly, immunosuppressed patients, and following antibiotic
therapy. Oropharyngeal candida (thrush) appears as lacy white
to whitish gray patches or plaques on the oral mucosa. The
mucosa may be skin colored or quite erythematous.
The plaques may be difficult to remove and doing so may
reveal oozing of blood at the base. Infected infants may be irritable or asymptomatic. Oral colonization with Candida occurs
rapidly in the first weeks of life, most frequently at 4 weeks of age.
Candida appears to better adhere to cells from young patients.
It is usually acquired either from maternal genital tract or from
the hands of caregivers. Thrush is increased eight-fold in infants
whose mothers had active infection and can also be acquired
during breastfeeding.
The pseudomembranous form presents as solitary or confluent white plaques on the oral mucosa that are easily removed
with scraping. Some patients exhibit erythematous oral lesions
with loss of papillae, which is termed the erythematous form.
Esophageal infection often occurs in patients with AIDS who
have oropharyngeal infection.
Persistent or recurrent oropharyngeal lesions can develop
due to asymptomatic maternal infection with contamination
of nipples, pacifiers, or other frequently mouthed objects. Oral
antifungals, especially fluconazole, are rapidly effective in such
cases. Topical treatment for mucocutaneous candidiasis in the
past utilized gentian violet, but presently nystatin is typically
prescribed at one dropper full in each cheek four times a day
for 7 to 14 days, along with massage of the medication onto the
mucosa.
Skin infection with candida includes intertrigo, which often
presents as a beefy red erythema in flexural areas. Staphylococcal
overgrowth can also contribute to lesion development. Treatment
considerations include drying of the skin to decrease maceration as well as antifungal therapy aimed at reducing Candida.
Interdigital infections can occur if the areas are very moist.
Paronychia and candidal onychomycosis are seen most often
with CMC (chronic mucocutaneous candidiasis), Raynaud’s,
Cushing’s, or with steroid therapy. CMC patients are also prone
to dermatophyte and HPV infections. In such patients, attempts
to avoid maintenance therapy whenever possible is reasonable
because of the development of azole resistance.
Diaper dermatitis (monilial diaper dermatitis) caused by
Candida is common and affected infants are usually colonized
in the gastrointestinal tract. They may exhibit concomitant oral
thrush. Clinically, beefy red erosions are noted, often with scattered surrounding satellite pustules. Candidiasis of the diaper
area should be considered if a diaper rash does not respond to

normal treatment. Candidiasis can also develop after treatment
with systemic antibiotics.
Often considered a disease of adults, candidal vulvovaginitis
accounts for roughly 60% of childhood/adolescent gynecologic
examinations.
Angular cheilitis (perleche) is common with fissuring and
inflammation at the commissures of the mouth. Childhood
cases may be caused by dental malocclusion, orthodontics, or
lip licking. Correction of the underlying predisposition is key
to achieving resolution. Low-strength topical steroids may help,
occasionally combined with topical antifungals if necessary.
Chronic paronychia is usually caused by C. albicans. Loss of
the cuticle is typically seen. In children, it can be caused by finger/thumb sucking. Topical antifungals are usually helpful, but
oral therapies may be needed.
Congenital candidiasis is a rare, congenital form of candidal
infection with skin lesions developing between birth and 6 days.
Contrastingly, lesions of neonatal candidiasis begin after the first
week of life. Neonatal candidiasis is acquired from infection during passage through the birth canal.
Congenital candidiasis can be associated with premature
labor. It is relatively benign in term infants but can cause invasive fungal dermatitis in ultra-premature infants. It presents
with a maculopapular, vesicular or pustular eruption. Typically
self-limited, it resolves in 1 to 2 weeks. Palmoplantar pustules
are common and are a helpful diagnostic finding. Occasionally,
nail changes are noted and they can be the only finding in some
patients. Potassium hydroxide preparation or fungal culture
allows a definitive diagnosis.
Systemic candidiasis usually occurs in low birth weight
infants with an onset around 2 to 6 weeks of life. It exhibits a
high mortality rate and requires aggressive therapy.

Invasive fungal dermatitis
Premature infants have a weakened cutaneous barrier with
barrier function not maturing until the second week of life.
Extremely low birth weight infants are at risk for Candida during the first 2 weeks of life. Candida may present as erosive
lesions with significant crusting that was not present at birth.
Biopsy shows invasion of fungal elements throughout the epidermis and into the dermis. Blood cultures are typically positive. In one series the mean gestation of affected neonates was
24 weeks and mean weights were <700 g. Significant associations included vaginal birth, postnatal steroid use, and hyperglycemia. In experimental studies C. albicans can penetrate
an animal epidermis in 24 to 48 hours. Other fungi can cause
invasive fungal dermatitis. The treatment of invasive fungal
dermatitis is with systemic antifungals, usually amphotericin B.
Prevention involves monitoring skin integrity and prevention
of local trauma. It is unclear if occlusive topical ointment use
plays a role.

Chronic mucocutaneous candidiasis
Chronic mucocutaneous candidiasis (CMC) represents a spectrum of disorders with persistent/recurrent candidal infections
of the skin, nails, and mucous membranes. Some are genetic but
all have a common immunologic defect in the production of
cytokines needed to induce cell-mediated immunity to Candida,

222 — Michelle R. Wanna and Jonathan A. Dyer

typically C. albicans. Despite their chronic infections, it is rare
that CMC patients develop candidal sepsis or parenchymal organ
infections. A familial variant of CMC occurs in consanguineous
families, and consists of chronic and recurrent oral candidiasis.
Onset of this variant is by the age of 2.
Chronic oral candidiasis is characterized by recurrent
oropharyngeal Candida without esophageal Candida or skin/
nail lesions. It is more common in middle-aged and elderly
women and may occur along with iron deficiency and/or HIV
infection. The presence of oral candidiasis has prognostic value
for HIV-infected subjects, with affected patients more likely to
progress to AIDS.
Autoimmune polyendocrinopathy-candidiasis-ectodermal
dystrophy (APECED) syndrome patients exhibit recurrent oral
candidiasis and diaper rashes from candida. Lesions spread to the
scalp, extremities, nails, and other sites. Keratitis may be present
in approximately one-third of patients. The polyendocrinopathy may manifest as hypothyroidism, adrenal failure, gonadal
failure, insulin-dependent diabetes mellitus, gastric parietal
cell failure, autoimmune hepatitis, or intestinal malabsorption.
Hypoparathyroidism occurs in approximately 79% of patients,
hypoadrenalism in 72%, and ovarian failure in 60%. About 60%
of APECED patients have two or more conditions, and nearly
50% have four or five of these disorders. The endocrinopathies
may have an onset later than childhood or adolescence and these
patients require annual evaluation of endocrine function. The
disorder is caused by autosomal recessive defects in the AIRE
(autoimmune regulator) gene.
Lesions of chronic localized candidiasis are also known as
candidal granulomas. Affected patients present with skin lesions
characterized by hypertrophic, adherent crusts on the scalp and
face, with some patients developing striking lesions similar to
cutaneous horns. Most also have oral Candida. Lesion onset is
in early childhood (before age 5) with an equal sex distribution.
There is no clear genetic cause.
The hyper-IgE syndrome, an autosomal dominant syndrome
characterized by high serum IgE levels as well as impaired
cell-mediated immune responses can exhibit chronic candidal
infections of the skin and nails in 83% of patients. Importantly,
one report noted a 50% incidence of additional non-candidal
infections in CMC patients.
Treatment of CMC may be topical or systemic. Patients frequently relapse upon discontinuation of therapy. The timing of
response to treatments is variable and if long-term therapies are
employed appropriate monitoring should be performed.

C O N G E N I TA L I N F E C T I O N S

Congenital infections may be caused by multiple infectious
agents including viruses, bacteria, or parasites. Most important
are the so-called TORCH infections: Toxoplasmosis, Others
(such as syphilis, varicella, and HIV), Rubella, Cytomegalovirus,
and Herpes.

Congenital toxoplasmosis
Toxoplasmosis is caused by infection with the parasite Toxoplasma
gondii, an intracellular protozoan that can invade multiple tissues including the heart, liver, spleen, CNS, and lymph nodes.

In normal hosts most infections are asymptomatic and limited.
Pregnant women are more susceptible and can have poor fetal
outcomes if fetal infection occurs, including seizures, mental
retardation, and blindness. The greatest risk for transplacental
transmission occurs from primary maternal infection during the
third trimester, however, the severity of fetal infections is worse
with first-trimester infections. T. gondii is acquired through the
consumption of raw or poorly cooked meat such as pork, mutton, and wild game or via ingestion of oocysts from feline fecal
matter.
Fetal toxoplasmosis can cause stillbirth or prematurity with
signs and symptoms occurring at birth or developing in the first
weeks of life. The classic clinical triad of toxoplasmosis includes
chorioretinitis, hydrocephalus, and intracranial calcifications.
Clinical findings include fever, vomiting, diarrhea, and malaise.
Lymphadenopathy, microphthalmia, hepatosplenomegaly, cataracts, microcephaly, pneumonitis, a bleeding diathesis, and seizures can also occur. Up to 80% of patients will have visual or
learning disabilities later in life.
Skin lesions associated with toxoplasmosis include the classic “blueberry muffin”-like lesions and a rubella-like maculopapular eruption that typically spares the face, palms, and soles.
Skin lesions occur during the first week of illness and may last
up to 1 week with postinflammatory desquamation or hyperpigmentation. Patients may exhibit anemia, thrombocytopenia,
eosinophilia, and occasionally severe leukopenia. Diagnostic
testing includes T. gondii-specific IgG and IgM antibodies. A
diagnostic quandary is the persistence of T. gondii-specific IgM,
even though the presence of these antibodies does not necessarily indicate an acute infection. In addition, the presence of IgG
only in the first 6 months may be due to maternal transplacental
transmission. In questionable cases, more elegant testing methods can usually resolve such dilemmas.
Most infected infants show few to no symptoms. However,
because of the high frequency of later neurologic sequelae all
patients should be treated regardless of symptoms. Treatments
for both mother and child include sulfadiazine, pyrimethamine,
folinic acid, and spiramycin..

Congenital syphilis
While rare in most developed countries, worldwide, congenital
syphilis is a major health problem. In recent years, the incidence
of syphilis in the United States and some European countries has
increased. The rate of syphilis in pregnant women in some Asian
and African countries varies between 3% and 10%.
Syphilis is caused by Treponema pallidum with transplacental infection occurring after 14 weeks of gestation. It is
estimated that up to 40% of infected pregnancies result in
fetal loss and that two-thirds of affected live born infants are
symptom free at birth. The risk of vertical transmission from
an untreated infected mother to her fetus decreases as maternal
disease progresses. This finding is termed Kassowitz’s law. The
risk of transmission during primary syphilis is 70% to 100% but
is approximately 40% for early latent syphilis and only 10% for
late latent disease.
Clinical findings of congenital syphilis are divided into early
(onset <2 years of age) and late (onset >2 years of age).
The earliest sign of congenital syphilis is frequently a nasal
discharge, termed snuffles which occurs 1 to 2 weeks before the

Skin Infections in Pediatric Patients — 223

onset of a syphilitic maculopapular eruption. The discharge
results from ulceration of the nasal mucosa, which, if deep
enough, can later lead to saddle nose deformity. It is teeming with spirochetes and provides a medium for diagnostic
testing.
Additional early findings include hepatosplenomagaly, jaundice, lymphadenopathy (epitrochlear is considered characteristic), and a rash. The more pronounced the early manifestations,
the poorer the outcome for the patient.
The eruption of congenital syphilis is seen in one-third to
one-half of infants and exhibits variable appearances. It most
typically resembles the eruption of secondary syphilis seen
in adults, including palmoplantar involvement. Palmoplantar
vesiculobullous lesions are rare but are proposed to be highly
suggestive of congenital syphilis. Either can be followed by
desquamation. Condyloma lata-like lesions may be seen in
warm, moist areas such as the anogenital region, around the
nares, and at the angles of the mouth. Mucous patches are present in approximately one-third of infants. Both forms of these
lesions are teeming with spirochetes and are highly infectious.
Fissures may develop at mucocutaneous junctions, which can
later lead to deep wounds that heal with characteristic radiating,
ragged scars, known as rhagades.
The umbilical cord may exhibit a necrotizing funisitis,
leading to spiral areas of red and blue discoloration with internal white streaks, termed a barber pole umbilical cord. This
occurs in premature neonates and is associated with a high
mortality.
Bony lesions are not common at birth but are present by
the second month in 90% of patients. Although any bone can
be involved, involvement of the long bones of the extremities is
most common. Osteochondritis, the most common and earliest
lesion, is often asymptomatic but severe lesions can cause subepiphyseal fractures leading to dislocation and “pseudoparalysis
of Parrot.” Periosteal inflammation of the frontal bones can lead
to the flattened forehead described in congenital syphilis and
frontal bossing is noted in 30% to 60% of patients. The periosteal
inflammation is diffuse, in contrast to the osteochondritis, and
can lead to thickening of the external portions of the bony cortex. When this occurs on the tibia it can cause anterior bowing,
the so-called “saber shins.”
Late stigmata of congenital syphilis are also well described.
Most pronounced are dental changes such as Hutchinson’s incisors, which show central notching and tapering toward the free
edge of the tooth. When seen along with interstitial keratitis and
eighth nerve deafness (a rare complication, typically of sudden
onset around 8–10 years of age). These findings are classically
referred to as Hutchinson’s triad. Mulberry molars are lower
first molars malformed because of crowded, poorly developed
crusts on the crown. These decay early in life and are often lost
by puberty, but are considered pathognomonic for congenital
syphilis when present.
Unilateral thickening of the inner third of the clavicle has
been termed Higoumenakis sign and is considered a finding of
congenital syphilis. However, similar lesions can be produced
from clavicular fractures at birth, thus this sign is not considered
pathognomonic. Focal erosion of the inner proximal tibia leads
to metaphyseal destruction. The radiologic changes associated
are termed Wimberger’s lines. Clutton’s joints, of hydrarthrosis,
typically involve the knees and elbows with an onset between

8 and 15 years of age. Late skin changes are typically nodules or
gummas.
Diagnosis and Treatment
Routine screening of maternal serology for syphilis is performed for most women seeking prenatal care. While there
are inadequacies in the testing methods, currently recommendations are for newborns of seropositive mothers to be
tested using the same nontreponemal test (VDRL/RPR) as
their mother. A four-fold higher titer in the infant is considered a probable infection. Confirmation using a treponemal
test (FTA-Abs/ MHA-TP) is reasonable. Additionally, examination of the placenta in suspected cases (including dark-field
microscopy of the umbilical vein or moist lesions) may be
positive.
Treatment of congenital syphilis is with parenteral penicillin G 100,000 to 150,000 IU/kg/day IV for 10 days. Both the
World Health Organization and Centers for Disease Control and
Prevention recommend that asymptomatic infants born to seropositive mothers be treated with a single dose of benzathine benzylpenicillin at 50,000 IU/kg. Close follow-up with appropriate
laboratory studies are strongly recommended.

Congenital rubella
Rubella is also known as German measles as it was first described
in the German literature. It is typically a mild disease but its
effects on the developing fetus have led to widespread vaccination. If acquired in the first 12 weeks of pregnancy, more than
80% of fetuses will exhibit congenital defects.
Rubella is a togavirus, an RNA virus with a surrounding capsid and envelope. Congenital rubella is quite rare, with
most recent cases occurring in unvaccinated immigrants. In the
United States, young Hispanic women may represent an at-risk
population.
Exposure of the fetus after 16 weeks gestation rarely results in
any sequelae. An infection before 12 weeks gestation may result
in the classic triad of abnormalities called the congenital rubella
syndrome. It includes cataracts, heart defects, and sensorineural
deafness.
Some manifestations of congenital rubella syndrome are
transient such as low birth weight, thrombocytopenia, hepatosplenomegaly, and meningoencephalitis. These findings tend
to resolve over days or weeks, but they may exhibit failure to
thrive during infancy. The purpuric eruption occurs in the first
few days of life and exhibits a “blueberry muffin” appearance.
These lesions may represent true purpura or extramedullary
hematopoiesis. Other skin findings reported include urticarial
lesions, reticulate erythema, and generalized, nonpurpuric
eruptions.
Permanent defects include heart defects which are found in
more than 50% of children infected during the first 8 weeks of
gestation. Patent ductus arteriosus is the most common finding. Pulmonary artery stenosis and hypoplasia are also seen.
CNS defects include mental retardation, psychomotor retardation, microcephaly, speech, and language delay. Eye defects, such
as cataracts, which occur in one-third of cases and are bilateral
in 50%, micropthalmia, and “salt and pepper” retinopathy are
also noted. Deafness (sensorineural or central auditory) is the

224 — Michelle R. Wanna and Jonathan A. Dyer

single most common defect and may be the only finding when
infection has occurred after 12 weeks gestation.
Late onset defects may not show themselves until after several years of life, especially defects in development, hearing, or
ocular function.
Diagnosis
The virus may be isolated from nasopharyngeal swabs, urine,
or other bodily fluids. Congenital rubella is most easily diagnosed by the detection of rubella-specific IgM in the serum
or oral fluid before 3 months of age. A negative result at this
time indicates that the diagnosis of congenital rubella is highly
unlikely.
Treatment
Nursing patients in isolation can avoid spreading the infection
because of high excretion of rubella virus for up to 1 year. Close
long-term follow-up including ophthalmology is warranted.

Congenital Cytomegalovirus
CMV is an enveloped DNA virus of the herpes virus family.
Following primary infection, it establishes lifelong latency. It is
spread via contact with contaminated body fluids. It is one of the
most common viral congenital infections in developed countries
and is a major cause of hearing loss and neurodevelopmental disabilities in children. It affects 0.15% to 2% of newborns. Primary
CMV infections occur in 1% to 4% of seronegative mothers during pregnancy, with a risk of fetal transmission of 30% to 40%.
CMV reactivation during pregnancy occurs in 10% to 30% of
seropositive females with a 1% to 3% transmission risk. Only
approximately 5% to 15% of infants with congenital CMV will
be symptomatic.
There is a wide range in clinical sequelae. While most infections are vertical with transplacental spread or during birth,
breast milk is also a source of CMV, and infants with low birthweight and early postnatal virus transmission are at the greatest
risk for symptomatic infection.
Up to one-third of symptomatic infants are delivered prematurely. Various findings such as fetal hydrops, intrauterine growth
retardation, microcephaly, ventriculomegaly, and periventricular
calcifications may be detected during prenatal ultrasounds and
suggest the diagnosis.
Skin lesions may be petechial or purpuric, creating a blueberry muffin–like eruption similar to rubella and toxoplasmosis.
However, nonspecific maculopapular exanthems may also be seen.
Additionally, hepatosplenomegaly, jaundice, anemia, thrombocytopenia, and interstitial pneumonia can occur.
Most symptomatic cases are fatal in months, with survivors
exhibiting severe deficits. In contrast, asymptomatic infants
rarely (5%–15%) show any future findings. Diagnosis can be
made with viral culture or strongly positive IgM anti-CMV antibody testing. No consistent pharmacologic drug exists for CMV.
The efficacy of ganciclovir in this setting is unclear.
Children with congenital CMV will shed the virus for years.
Overall, 80% to 90% of children with congenital CMV have a
normal outcome and one-third of children with symptomatic
congenital CMV will have a normal outcome.

Congenital and neonatal herpes simplex
virus (HSV)
Congenital HSV due to intrauterine infection is rare,
representing only about 5% of neonatal HSV cases. Such infections may be acquired in an ascending manner or possibly
after maternal viremia via the placenta. Up to 70% of cases
are caused by HSV type 2. Most infants (85%) acquire infection during birth and 10% acquire it postnatally. Transmission
of infection is influenced by type of maternal infection (primary vs. secondary), maternal immunity, duration of membrane rupture, mucocutaneous barrier integrity, and method
of delivery. Infants born to mothers during a primary episode
of genital HSV are at a much higher risk (57%) than those
with recurrent disease (2%) for the development of neonatal
HSV. The incidence of neonatal HSV is estimated at 1:3200 live
births. Most infants with neonatal HSV are born to mothers
who are asymptomatic.
Clinically, infants with congenital HSV may have chorioretinitis, microphthalmia, abnormal brain imaging, and microcephaly. Cutaneous lesions may be active vesicles or simply scars
from intrauterine vesiculation. The range in severity of clinical
lesions is broad.
Neonatal HSV may have a variety of presentations including disseminated disease involving multiple organs, central nervous system disease in the presence or absence of skin lesions,
and finally only superficial lesions limited to the skin, eyes, and
mouth. Those infants with primary CNS disease tend to present
later (16–19 days) than infants with disseminated or superficial
disease (10–12 days). Most infants become ill within the first
month of life.
The incidence of disseminated disease has decreased with the
introduction of effective antiviral therapies. Over 20% of infants
with disseminated disease do not exhibit cutaneous vesicles during their infection. These infants may clinically appear septic and
present around 10 to 12 days of age and often exhibit hepatitis
and pneumonitis. Consider HSV if bacterial cultures are negative after 2 to 3 days and the infant is not responding to antimicrobial therapy. Disseminated disease has an overall mortality
approaching 60%.
Nearly one-third of all infants with HSV infection have some
form of CNS involvement. Approximately two-thirds of infants
with CNS involvement will have cutaneous vesicular lesions at
some point in the course of infection. The localized superficial
form of neonatal HSV infection is typically seen in about 20% of
cases although this frequency has increased with the more frequent early institution of antiviral therapies. Cutaneous lesions
may exhibit a variety of appearances from erythematous macules
to vesicles. Vesicles often become pustular in 1 to 2 days followed
by crusting and ulceration. Occasionally, patients will have large
bullae reminiscent of epidermolysis bullosa. Others may appear
purpuric, petechial or even zosteriform. Often, the presenting
aspect of the infant is the area most severely involved. Ocular
lesions are less common.
Diagnosis
Viral culture remains the definitive modality for diagnosis.
Serology is not greatly helpful in diagnosing neonatal HSV. PCRbased assays may prove helpful in the future. Direct fluorescent

Skin Infections in Pediatric Patients — 225

antibody–based assays are rapid and allow differentiation
between viral types. Their sensitivity, however, is lower.
Known risk factors for fatal outcomes include CNS and disseminated disease, impaired consciousness at presentation/onset
of treatment, and prematurity. For infants with disseminated disease the presence of pneumonitis and disseminated intravascular
coagulation are poor prognostic indicators.
Mothers with active HSV lesions should be delivered by
Caesarean section. The role of acyclovir is unclear. Avoidance of
fetal scalp electrode monitoring in such cases may also be helpful.
A newborn with suspected HSV lesions should be isolated
using contact precautions, treated with empiric antiviral therapy,
and aggressively evaluated. Ophthalmologic evaluation and prophylactic topical antivirals are critical. Within 1 month after discharge, 5% to 10% of infants with neonatal HSV will present with
a flare of lesions requiring treatment.
The recommended treatment of suspected neonatal HSV
is acyclovir 60 mg/kg/day divided every 8 hours for 21 days
unless limited only to superficial lesions, where 14 days will suffice. Neutrophil counts should be monitored during therapy.
Additionally, all patients should have lumbar puncture at completion of therapy to allow confirmation of PCR negativity. If
the patent is PCR positive, therapy is continued until a negative
result is obtained.

Figure 16.5. Herpes simplex virus type 1. Grouped umbilicated
vesicles on an erythematous base on the neck.

can lead to death in some cases. The greatest risk occurs in pregnancies with infection before 20 weeks gestation with fetal loss
occurring in 2% to 9% of patients.

Congenital varicella
The group of developmental abnormalities associated with
congenital varicella infection, termed congenital varicella syndrome, occur after maternal infection and in the first 13 to 20
weeks of gestation. The incidence following maternal infection
is 0.5% to 1.5% above the background risk for major malformations. Thus, most women who acquire varicella during pregnancy deliver unaffected infants. Maternal zoster is almost never
associated with any untoward sequelae for the fetus unless it is
disseminated.
Clinical findings of congenital varicella infection include
ophthalmologic defects such as microphthalmia, cataracts, and
chorioretinitis, low birth weight, limb hypoplasia, neurologic
defects, and gastrointestinal and genitourinary defects. Some
infants exhibit scars or even vesicles in a dermatomal distribution. The erosions in some cases resemble cutis aplasia.
Neonatal varicella is most severe if maternal rash occurs
between 5 days before to 2 days after delivery. These infants must
be treated immediately with Varicella-zoster immune globulin
(VZIG) and intravenous acyclovir as mortality approaches 30%.
Maternal eruptions before or after these periods are typically
associated with mild infections, if any.

Congenital parvovirus B19
Parvovirus B19, the only parvovirus to infect humans, is one
of the smallest viruses, nonenveloped and made up of singlestranded DNA. Maternal infection during pregnancy can cause
fetal infection due to the high viral loads during the 6 to 8 days of
most significant infection. Nearly two-thirds of pregnant females
are immune to parvovirus and most infants born to mothers
who are infected during pregnancy are normal. Viral targeting of
erythroid precursor cells and possibly fetal cardiac tissues leads
to severe anemia, edema, heart failure, and fetal hydrops, which

VIRAL DISEASES OF THE SKIN

Herpes simplex virus
Outside the neonatal period, most primary HSV infections in
children and infants are asymptomatic. HSV-1 is typically transmitted through contact with lesions or oral secretions, whereas
HSV-2 is transmitted through sexual activity or contact with
genital secretions. Typical cutaneous HSV lesions are shown in
Figure 16.5.
Primary HSV gingivostomatitis is likely the most common clinical manifestation, which is usually caused by HSV-1
and occurs in children between 1 and 5 years of age. An ulcerative painful enanthem of the gingival and oral mucous membranes, it often leads to decreased oral intake with dehydration
as an occasional complication. Affected areas may exhibit
swelling with friability and easy bleeding. Vesicles rapidly
progress to erosions and ulcers. Affected children may exhibit
fever as well as localized lymphadenopathy. Spread of lesions
to the lips, cheeks, and chin will occur in a majority of patients
to some degree. Resolution within 10 to 14 days is typical and
acyclovir may be helpful if therapy is initiated early enough.
Children with a history of eczema should be monitored closely
for dissemination and may require antiviral therapy outside of
this time range to suppress the infection. A similar eruption
due to HSV-2 is described in sexually active adolescents/young
adults.
Eczema herpeticum is a widespread eruption of HSV occurring in patients with preexisting skin diseases such as atopic
dermatitis, Darier’s disease, pemphigus, or burns. Patients
become febrile and ill with the sudden outbreak of widespread
vesicles. Viral lesions are often worse or more concentrated in
areas of active skin disease. Multiple complications can occur,
including keratoconjunctivitis, secondary bacterial infections,

226 — Michelle R. Wanna and Jonathan A. Dyer

dehydration, and systemic viremia. Early systemic therapy is
mandatory and typically parenteral. Ophthalmogic evaluation
is important. Skin care utilizes bland emollients early to aid
healing followed by topical anti-inflammatory agents to control dermatitis.
Herpetic whitlow involves single or multiple, painful, deepseated HSV vesicles, typically on the distal aspects of a digit. It
can arise via autoinoculation from oral or genital HSV or as an
occupational dermatosis in those who come into contact with
such secretions. Resolution in 2 to 3 weeks is typical.
Herpes gladiatorum occurs in wrestlers or rugby players, where repeated skin trauma along with skin-to-skin contact and skin-to-fomite contact predisposes to transmission
of HSV. Approximately one-third of wrestlers develop herpes
gladiatorum at some point. Lesions typically involve areas of
skin contact and may not have a typical vesicular appearance.
Occasionally, patients exhibit systemic symptoms. Treatment is
indicated and athletes are allowed to return to play once lesions
have crusted. Episodic or prophylactic therapy may also be
indicated.
HSV keratoconjunctivitis occurs with primary HSV infection
of the eye, leading to severe inflammation with superficial corneal
erosions or ulcers. HSV is the leading cause of recurrent keratoconjunctivitis with eventual corneal opacification and blindness.
Viral culture and HSV PCR on tear film can confirm the infection, although corneal scrapings may be better sources of the
virus. Topical and/or oral antivirals are the mainstays of therapy.
Herpes genitalis may be caused by HSV-1 or HSV-2. While
the cause of infection is typically HSV-2, the frequency of genital HSV-1 infection is increasing among young adults/college
students. Frequency of HSV-2 infection directly correlates with
the number of sexual partners, and transmission is dramatically
reduced with condom use, offering another reason for the strong
promotion of condom use among sexually active adolescents.
The diagnosis of genital HSV in a child should prompt concern
regarding sexual abuse. Recurrence rates of HSV tend to be
higher in the first years after initial infection.
HSV is the most common cause of erythema multiforme
(EM) minor in both children and adults. Recurrences of HSV
are followed by the eruption of tender, inflammatory, targetoid lesions, often acral and especially on the palms and soles
(Figs. 16.6 and 16.7). Control of the HSV infection often prevents recurrence of the EM.
HSV lesions in immunosuppressed patients may present
with a variety of atypical skin manifestations including verrucous, pustular, crusted, necrotic, or exophytic presentations. A
high index of suspicion with a low threshold for appropriate testing allows earlier diagnosis of such outbreaks. HSV may cause
persistent or recurrent ulcers in immunosuppressed patients
such as those with AIDS. Widespread or large lesions may be
seen (Figs. 16.8 and 16.9).
Primary varicella zoster virus (VZV) infection has become
infrequent in the USA with the advent and widespread administration of the live attenuated varicella vaccine. It is highly contagious with a 14–16 day incubation period; traditionally it was
most common in the colder months of the year. Spread occurs
from person to person via respiratory droplets and children are
no longer contagious within 7–8 days of rash onset. Affected
patients often exhibit a low grade fever early in the illness with
the generalized eruption beginning on the scalp or trunk. Lesions

Figure 16.6. Erythema multiforme simplex due to HSV. Tender
targetoid lesions on palms in a patient with a recent outbreak of
orolabial HSV.

Figure 16.7. Bullous erythema multiforme simplex. Early bullous
lesion from the lateral distal upper extremity. Note targetoid
appearance of lesion and early central bullae.

begin as erythematous macules but rapidly become vesicular,
crust and begin to heal (see Figure 16.10). Mucous membrane
lesions are common and the pruritus from skin lesions is often
intense. Varicella often exhibits a more severe course in older
patients and very young infants. The most common complication of primary varicella is secondary infection of the skin
lesions, usually caused by Staphylococcus and group A streptococcal infections. Serious infections such as necrotizing fasciitis
and purpura fulminans can occur. Tzanck preparations, direct
fluorescent antibody testing, and viral culture from vesicular
fluid can aid diagnosis. The differential includes some forms of
enteroviral exanthems which can produce clinical lesions mimicking varicella. Children with primary varicella are no longer
contagious once all the lesions have crusted.
Herpes zoster is more common in children who are immunosuppressed or who had their primary varicella infection in
the first year of life. With implementation of the varicella vaccine, cases have occurred due to apparent reactivation of the

Skin Infections in Pediatric Patients — 227

Figure 16.8. Recurrent chronic HSV in an immunosuppressed host.
Note widespread angulated ulcers with punched out lesions on
periphery.

viral VZV strain. Hutchinson’s sign refers to varicella lesions of
the nasal tip, which can reflect involvement of the nasociliary
branch and signal a risk of corneal lesions. Such patients require
prompt initiation of antiviral therapy and ophthalmologic
consultation. Treatment is with high-dose antivirals, and severe
or disseminated infections should be treated parenterally.
Treatment of both primary and secondary VZV infections is
supportive in uncomplicated cases, mainly focused on control of
pruritus and prevention of excoriation which could increase the
chance of secondary skin infections. If systemic therapy is necessary acyclovir is the treatment of choice. Immunosuppressed or
other high risk patients may require passive immunization with
varicella zoster hyperimmune globulin (VZIG).

Figure 16.9. Disseminated herpes simplex virus. Widespread
vesicular lesions arising on erythematous bases in an
immunosuppressed patient. Tzanck preparation was positive
for multinucleated giant cells and viral culture revealed herpes
simplex virus type 1.

Verruca
Human papillomavirus (HPV) is a double-stranded DNA virus that
causes various clinical lesions. Infection of squamous cells leads to
the formation of benign tumors called warts, verruca, or papillomas. Lesions on acral surfaces are most common and children are
the most common hosts, with an incidence estimated at 10%.
Condylomas are HPV-induced lesions of the genital tract
and are one of the most common sexually transmitted diseases.
Multiple modes of transmission exist: vertical spread (perinatal);
benign (nonsexual) inoculation from a parent or caregiver; autoinoculation; fomite spread; and sexual contact. Clinically they
appear as soft, verrucous, occasionally pedunculated, skin colored papules. Although commonly located in the perianal region
they can be located anywhere in the genital area. Typically, they
are asymptomatic although some lesions may exhibit bleeding
and pain if irritation occurs. An important consideration in

Figure 16.10. Disseminated varicella. Immunocompetent patient;
note umbilication creating resemblance to pox virus infections.
Image courtesy of Mike Swann, MD.

the differential of condyloma in young children is the perianal
pyrimidiform protrusion, a flesh colored to pink soft tissue swelling along the median raphe more commonly seen in females.
The lesions may be mistaken for condylomas but often appear in
association with a history of diarrhea or constipation. They often
resolve with normalization of the gastrointestinal function.

228 — Michelle R. Wanna and Jonathan A. Dyer

Diagnosis of condyloma in children should raise the possibility of sexual abuse as the mode of HPV acquisition. While HPV
typing is often considered in the work-up of such patients, it does
not allow differentiation between the forms of viral transmission.
A directed history is necessary, screening for timing of onset, as
well as maternal history of HPV infection or abnormal PAP smears
and the personal or family history of verruca. An appreciation of
the child’s social environment is helpful. The risk of sexual abuse
as a cause of condyloma in children is higher for those patients
older than 3 to 4 years. Infections are believed to be acquired in a
nonsexual manner in the following instances; children <3 years of
age (especially with lesions that began in the first year of life), the
presence of other nongenital warts verrucae in close contacts, a
positive maternal history and no physical findings for abuse. Any
suspicion of abuse should prompt referral to a child protective services team and consideration of a SAFE exam.
Treatment of verrucae is challenging, as there is no one perfect effective therapy. Spontaneous resolution may occur in at least
54% of patients within 5 years from their diagnosis. Because of
this observation, minimal intervention can be a reasonable therapeutic choice. Overly painful or aggressive therapies or those that
could scar are usually avoided. The choice of therapy is variable,
depending on the individual child and the parents’ input. Though
parents may occasionally press for aggressive (and thus painful)
therapies for their children, always consider the risk–benefit ratio
for the child and recommend therapy accordingly.
Topical therapies such as salicylic acid may be used with
or without occlusive dressings. Resolution of the verruca may
require 2 to 12 weeks.
Cryotherapy, ideally using liquid nitrogen, is effective but painful. Use of a cotton-tipped applicator to apply the liquid nitrogen
may be less frightening for small children rather than using a cryogen spray gun. When using cryotherapy, care must be taken not to
freeze the skin too deeply, or hypopigmentation and/or scarring
can result. In addition, debriding the hyperkeratotic material from
the surface of the verruca before cryotherapy can speed improvement. Treatments are then continued every 3 to 4 weeks.
Additional treatments for verruca involve modulation of the
immune response, such as cimetidine (30 mg/kg/day divided
into three doses for 6 to 8 weeks of therapy), topical imiquimod
applied with varying frequency (three times per week on thin
or genital skin – more frequently, up to twice daily on more
keratinized surfaces), and stimulation of allergic contact dermatitis using squaric acid dibutylester or diphenylcyclopropenone
(DPCP). Use of these agents is painless and is well tolerated even
by the youngest patients. Pulsed dye laser therapy has been used
with reasonable efficacy but the cost of this modality limits its
use to those verruca resistant to other therapies.
Care must be taken when treating verruca plana with destructive therapies so as not to induce undue scarring or hypopigmentation. For this reason and because large areas are often involved
by these lesions, topical agents such as imiquimod and/or topical
retinoids may be preferred.
The high rate of spontaneous involution for condyloma
makes observation a reasonable option for therapy. Topical
destructive agents such as podophyllin or trichloracetic acid may
be used. Imiquimod is also highly effective. Surgical debulking
of large lesions may be necessary. Destructive modalities such as
cryotherapy and pulsed dye laser may be used but may require
sedation in children or adolescents.

Figure 16.11. Epidermodysplasia verruciformis. Otherwise healthy
patient with widespread flat-topped lesions. Histopathology was
consistent with human papillomavirus infection. Improved greatly on
isotretinoin.
Image courtesy of Karen Edison, MD.

Oral HPV infection is associated with respiratory papillomatosis as well as cervical and genital lesions. Respiratory papillomatosis, the most common laryngeal neoplasm of children,
is caused by HPV types 6 and 11, usually acquired via vertical
transmission and is not considered a marker of sexual abuse.
Recent work suggests that oral HPV acquisition before 1 year
is typically via vertical transmission. Heck’s disease is one form
of oral verruca characterized by unique HPV subtypes 13, 24,
and 32. In the absence of Heck’s disease, mucosal strains of HPV
such as types 6 and 11 are often detected. In these patients, the
epidemiology of HPV acquisition likely mimics that of condyloma. Younger children are more likely to have been infected
with HPV via innocuous transmission, while older children are
more likely to have had sexual transmission.
Epidermodysplasia verruciformis is a genetically mediated
disease. Affected patients have an increased susceptibility to wart
infections. The disease is caused by mutations in two novel genes
EVER1 and EVER2. It is estimated that ~50% of affected patients
will undergo malignant degeneration of lesions in adulthood. The
onset of skin lesions is in early childhood and patients often present with widespread hypopigmented macules that can mimic tinea
versicolor in addition to verruca plana–like lesions. More verrucous lesions may be found on the face and extremities (Fig. 16.11).
Cutaneous malignancies typically occur in sun-exposed areas, and
strict aggressive sun protection measures are necessary.
An autosomal dominant syndrome has been described with
patients exhibiting hypogammaglobulinemia, infections, and
myelokathexis (retention of white blood cells in the bone marrow), in addition to widespread verrucae. This has been termed
the WHIM syndrome.

Molluscum and poxviridae
Molluscum contagiosum is now a common viral skin infection of childhood caused by the molluscum contagiosum virus
(MCV). Recent decades have seen a significant increase in MCV
infection frequency and MCV is now the main disease causing

Skin Infections in Pediatric Patients — 229

Figure 16.12. Molluscum. Umbilicated, pearly papules located on the
inner thigh.

poxvirus in humans. While in adults MCV infection is associated
with immunodeficiency or sexual transmission, in children it is
typically acquired innocuously. Several forms of MCV have been
identified with the MCV-1 form typically causing MC in children and the MCV-2 form being more often sexually transmitted. MCV is easily spread via skin-to-skin contact or via fomites.
Swimming pools are thought to be a major source of transmission. Autoinoculation and koebnerization are common modes
of spread once infected. Patients with underlying skin disorders,
especially children with atopic dermatitis, are particularly susceptible to disseminated MC lesions.
Clinically MC appears as pearly, pink-to-flesh colored papules of variable size. Often a central umbilication is present
(Fig. 16.12). The immune response to these lesions is variable
but when severe, the deep-seated inflammation can lead to tenderness and drainage similar to what is seen in a furuncle.
Molluscum dermatitis is an eczematous reaction occurring
around MC lesions or clusters of lesions that may represent virally
induced modulation of the local immune system. Pruritus from the
dermatitis may lead to scratching and further spread of the virus.
Eyelid lesions can be problematic as conjunctivitis or superficial
punctate keratitis can occur if an inflammatory response develops.
Course
Most patients with MC will undergo spontaneous remission
between 6 months and 2 years after the onset of infection. For this
reason, watchful waiting is a reasonable mode of management
although pruritus, pain, concerns over spread to other children
or classmates, and the cosmetic impact of lesions may prompt
parental requests for more aggressive treatments.
Treatment
Modalities employed in the treatment of MC in adults such as
curettage and cryotherapy may not be tolerated by small children.
Application of cantharidin, an extract from the blister beetle, is a
painless alternative and produces a superficial blistering reaction
that can result in removal of MC lesions. This treatment is usually well tolerated without any resultant discomfort and thesmall

vesicles typically resolve within a few days. Postinflammatory
hyperpigmentation may occur and parents should be cautioned
about this temporary side effect. Parents should also be counseled that, as a poxvirus, MC infections can leave a residual
“pock mark” that, while small and often innocuous, represents
a scar caused by the infection. These marks, which develop from
~7% of lesions, often fade with time as the child grows but can be
disturbing to parents when first noticed.
Other treatments used for MC include topical imiquimod,
topical retinoids, tape stripping, keratolytic agents, pulsed dye
laser, and oral cimetidine.
Other poxviruses may infect pediatric patients. Orf (ecthyma
contagiosum) and milker’s nodules are caused by exposure to
infected goats and sheep (orf) or cattle (milker’s nodules). Both
are caused by parapox viruses and after onset, the clinical infection progresses through several typical clinical stages. The first
stage begins as macules that develop into papules and then into
vesicles. These vesicles then erode to become weeping nodules,
which then evolve into verrucous lesions, eventually develop a
dry crust and then shed with wound healing. Occasionally, erythema multiforme may occur. Lesions typically heal without
scarring over 4 to 8 weeks. No other treatment is needed. These
lesions are rarely seen in a dermatology clinic as most patients
involved in the husbandry of susceptible animals recognize the
infection and realize it will resolve with no therapy.

Monkeypox
In the spring of 2003, an outbreak of febrile illness with associated
vesiculopustular lesions led to the identification of the first outbreak of monkeypox in the Western Hemisphere. Several of the
patients including the index case were children, infected via bites
from or exposures to ill pet prairie dogs, which had acquired the
illness from an infected Gambian giant rat. While several patients
became quite ill, all recovered. Cutaneous lesions were variable in
appearance and often made up of deep-seated vesiculopustules,
some with pronounced surrounding erythema. In most patients,
a variable number of satellite and disseminated lesions developed
over several days. Larger lesions often resolve with scars.

Vaccinia and Variola
Concern over weaponization of smallpox, or variola major, though
eradicated from the planet since 1977, has been on the rise due to
recent terrorist events. This has led to resumption of smallpox vaccination using vaccinia virus in at-risk persons such as military
personnel and certain workers in the medical community. Thus,
familiarity with both smallpox and the complications associated
with vaccination against smallpox is now much more important.
Acquisition of variola occurs via the respiratory tract with
viral replication in regional nodes followed by viremia. Onset
of symptoms typically occurs after an incubation period of 7
to 17 days. An enanthem of erythematous macules on the oral
mucosa (palate, tongue, and pharynx) begins 1 to 2 days before
the exanthem. The exanthem is characterized by erythematous
macules progressing to vesicles and then pustules over a 4 to 7
day period with most lesions at the same developmental stage
in each area of the body. The pustules are deep seated and firm
(in contrast to varicella) due to their dermal location. Lesions
typically begin on the face and spread downward. Crusting of

230 — Michelle R. Wanna and Jonathan A. Dyer

lesions begins at 8 to 9 days, and healing leaves significant scarring. The mortality is ~30%. Variant presentations such as the
hemorrhagic and malignant forms are almost universally fatal.
Variola minor (alastrim) occurs when individuals with some
preexisting immunity are infected with variola and has a much
lower mortality rate. Once infection occurs, patients are infectious for ~10 days from the onset of the rash. Suspected cases
must be isolated. Cidofovir may help in treatment.
Another major concern with resumption of smallpox vaccination is risks from the vaccine. Most importantly, eczema
vaccinatum can occur when a person with active or a past history of certain skin diseases, such as atopic dermatitis or Darier’s
disease, is exposed to vaccinia. Worsening of the eruption can
happen quickly with rapid viral dissemination. While no cases
of eczema vaccinatum had been reported since the late 1980s,
recently eczema vaccinatum has occurred in a male child with
severe eczema and a history of failure to thrive. After exposure
to his father, who had recently been vaccinated for smallpox
in preparation for deployment, the child became febrile and
then began to develop vesicular skin lesions. Dissemination of
the infection led to a clinical presentation similar to smallpox.
Aggressive treatment was necessary, the child required intubation and administration of vaccinia immune globulin as well as
cidofovir and an investigational drug.
Complications can include secondary infection, shock, and
even death. Vaccinia immune globulin has been approved since
2005 for treatment of eczema vaccinatum. People that are vaccinated for smallpox should avoid contact with people who have a
history of generalized dermatoses. At present, smallpox vaccination is not recommended for those under 18 years of age.

I N F E S TAT I O N S

Pediculosis
Pediculosis humanus capitis infestation is usually seen in children aged 3 to 12 and has no socioeconomic barriers. The oval
hair shafts of African-Americans are somewhat resistant to
infestation. Lice are transmitted via direct contact or via fomites
that have a less than 24-hour survival off the scalp of the human
host. Eggs, or nits, are firmly attached to the base of the hair
shaft by the female louse at a rate of approximately ten per day.
They hatch in 10 to 14 days. The life cycle from nit to adult louse
is approximately 3 weeks. Nits are often found in the posterior
auricular area and occipital scalp. Pruritus begins 3 to 4 weeks
after the first infestation, allowing for the development of a
delayed hypersensitivity response to the louse saliva.
Treatment with pediculicides is the first line of treatment.
Many over-the-counter products exist and are effective in the
treatment of head lice. Pyrethrins, in addition to piperonyl
butoxide, are found in a shampoo form, which is neurotoxic to
the lice. A 10-minute incubation period on dry hair is recommended, followed by rinsing with cool water to minimize cutaneous absorption. This treatment is partially ovicidal as well,
but approximately 30% may persist. Therefore, a second treatment is recommended in 7 to 10 days. Resistance does occur,
and patients with ragweed or chrysanthemum sensitivity should
avoid this product, as there is potential for allergic reaction.
The treatment of choice is permethrin 1%, a synthetic pyrethroid, which can be found over-the-counter as a cream rinse. It

should be applied to damp hair following shampooing and the
hair should be allowed to dry for ten minutes before rinsing. This
is pediculocidal and partially ovicidal and repeat treatment in
7 to 10 days is recommended.
Lindane should be used cautiously as CNS toxicity can produce seizures in children. It is available as a prescription shampoo,
has low ovicidal activity, and resistance has been noted. Malathion
carries a risk of flammability and respiratory depression with
ingestion, but does have ovicidal activity. Permethrin 5% and crotamiton 10% have had some effectiveness in patients with pediculosis, but have not been studied extensively. Oral treatment with
sulfamethoxazole–trimethoprim in combination with pediculocidal agents has been effective but carries the potential for serious side effects including Stevens–Johnson syndrome. Ivermectin
is not recommended in children weighing less than 15 kg as they
are at higher risk for penetration of the blood–brain barrier.
Studies in children have shown that only 20% to 30% of children with nits develop infestation with adult lice, which should
encourage schools to eliminate the “no nit” policy seen in some
school districts. Treatment should be advised for children and
close contacts with evidence of live lice, or nits within 1 cm of the
scalp as these are more likely to be viable. Following treatment,
removal of nits from wet hair with a fine-toothed comb can be
done but may not be necessary. Bedding, clothing, and personal
care items should be cleaned. Objects, which cannot be washed,
may be vacuumed or placed in a closed plastic bag for 2 weeks.
The body louse, Pediculus humanus humanus, infests individuals in crowded, unsanitary conditions. The louse resides
in the clothing of affected individuals and can be found along
the seams. It also has a preference for warmer areas of the body.
The louse is larger than Pediculus humanus capitis and has a life
span of 18 days. Approximately 3 weeks are required for a nit to
develop into a mature louse. The body louse can live for 3 days
without feeding. Treatment involves cleaning affected clothing
and improving personal hygiene.
Pthirus pubis, or the crab louse, is transmitted via sexual contact, and can be visualized with the naked eye attached to the hairs
of the pubic and adjacent body areas. The body of the louse is wide
with clawed legs, which allow it to grasp the hairs. Adult lice live
approximately 2 weeks and require 3 weeks to progress from nits
to the mature adult. Blue-gray macules on the trunk and thighs,
known as maculae ceruleae, can be seen in chronic infections.
Nits may also be noted on the eyelashes, and scalp involvement
can occur as well. Patients should be screened for other sexually
transmitted diseases as there is a 30% rate of concurrence between
the two infections. Permethrin 5% cream is recommended for the
treatment of pubic lice, with petrolatum for eyelash involvement.
Patients should also be advised to abstain from sexual intercourse
and to thoroughly cleanse all linens and garments.

Mites
Sarcoptes scabiei var. hominis is the mite responsible for the manifestations of scabies and is transmitted by human-to-human
contact. A worldwide distribution is seen, but is very common
in areas of poverty, in persons with dementia, in persons with
nutritional deficiencies, in persons with poor hygiene, and in the
homeless. It also occurs frequently in children.
Skin manifestations include burrows, which are usually found
in the digital web spaces, or at the elbows, wrists, umbilicus,

Skin Infections in Pediatric Patients — 231

nipples, and genital areas. Erythematous, sometimes excoriated
papules can also be seen. Bullous lesions can be seen in the
elderly or immunosuppressed, but cases have been reported in
children as well. Generalized pruritus occurs 3 to 4 weeks following initial infection, as it is a delayed hypersensitivity response
to the eggs, scybala, or saliva of the mite. In reinfested patients,
pruritus occurs within a few days of infection.
Lesions in children may become secondarily infected with
S. aureus or S. pyogenes. Infants normally develop nodules,
vesicles, and pustules of the face, head, axillae, and genital area.
Palmoplantar involvement can also be seen. Red-brown, pruritic
nodules of the male genitalia and axillae, described as nodular scabies, are seen in 7% of patients. These are hypothesized
to be manifestations of an exuberant hypersensitivity reaction.
Immunosuppressed patients may develop Norwegian, or crusted
scabies, which is characterized by acral, hyperkeratotic plaques
and subungual involvement.
Female mites lay one to three eggs in burrows created in the
stratum granulosum. The larval forms hatch in 2 to 4 days and
undergo a molting process, with mature mites being produced in
10 to 14 days. The average patient carries 10 to 15 adult female
mites, while patients with crusted scabies may be infested with
more than one million organisms. The life cycle then repeats,
with male mites dying after mating.
Diagnosis can be made by microscopic visualization of mites,
eggs, or scybala after scraping a burrow with a blade coated in
oil. Dermatoscopy can be useful in some cases, but histologic
exam is only consistent with an arthropod bite reaction unless
the organism or eggs are noted.
Permethrin 5% cream, a synthetic pyrethroid, is the most
effective topical treatment and is safe to use in children older
than 3 months. It can cause irritant cutaneous reactions and
rarely dystonic reactions. There is no potential for allergic reaction in patients with chrysanthemum sensitivity. Lindane should
be used with caution in children and avoided in infants as neurologic symptoms including seizures and irritability can occur.
Infants can be treated with crotamiton 10% cream, which has
been shown to be more effective than permethrin in infants
and children. Potential side effects include conjunctivitis and
erythema. Systemic treatment with ivermectin is not recommended in children less than 5 years of age as safety has not yet
been established, and permeability of the blood–brain barrier
has been seen in some patients. Pruritus can persist for weeks
following treatment. Patients should be advised to use sensitive
skin care measures and given topical steroids and antihistamines
for symptom control.
Harvest mites, or chiggers, are in the family Trombiculidae
and frequently cause skin lesions in the summer and fall. The
larval form is found on the ground and painlessly feeds on the
lower extremities or waistline. Pruritic papules appear within 24
hours and resolve over weeks.
Cheyletiella blakei, Cheyletiella yasguri, and Cheyletiella parasitvorax are mites of cats, dogs, and rabbits, respectively. They are
the cause of pruritic papules, which may become vesicular, pustular, and crusted in areas of the body where pets are frequently
in contact with the patient. The animals are asymptomatically
infected, and microscopic examination of fur scrapings will
identify the organisms as they are rarely found on the affected
human. Eradication of the mites is curative and skin lesions can
be treated symptomatically.

Spiders
Brown recluse spiders, Loxosceles reclusa, can be seen in the
southern United States from Nebraska to Ohio with the Gulf of
Mexico as the southernmost border. The tan spider can be identified by the characteristic violin marking of the head and thorax,
and its three pairs of eyes. The brown recluse does not bite unless
provoked and can be found under rocks, in basements, and in
boxes. Bites may initially cause slight discomfort followed by
increasing pain and erythema. Subsequent necrosis occurs in 48
to 72 hours. Systemic symptoms of fever, chills, arthralgias, nausea, and serious complications of hemolytic anemia mediated
by the sphingomyelinase D toxin, renal failure, and pulmonary
edema are more common in children. Treatment involves rest
and elevation with antibiotic coverage in cases where secondary infection is a concern. Supportive measures are indicated in
patients with systemic effects.
Lactrodectus mactans is the most common species of black
widow spiders in the United States and can be identified by the
red hourglass located on the abdomen of the black spider. It lives
on webs in the protected areas of buildings. Bites can be painful
and are incurred after disruption of the spider’s habitat. Neuronal
depolarization occurs following inoculation of the α-latrotoxin
resulting in erythema and piloerection at the site, with systemic
symptoms of abdominal pain, nausea, vomiting, paresthesias,
hypertension, and headache. Antivenin can be used in severe
cases. Benzodiazepines and calcium gluconate are also helpful.

Scorpions
Scorpions are found predominantly in the southwestern United
States and stings cause burning pain followed by anesthesia.
Scorpions retaliate if they are disturbed or trapped. Stings related
to Centruroides exilicauda are of particular concern in children
as they are potentially fatal. Children should be monitored in
an intensive care unit as the scorpion’s neurotoxin can cause
respiratory distress, vision changes, muscles spasms, and slurred
speech. Antivenin and supportive measures are the treatments of
choice. Centruroides scorpions can be identified by a spine at the
base of their stinger.

Papular urticaria
Papular urticaria is caused by an arthropod bite-induced hypersensitivity reaction. The most common pathogens are Cimex lectularius, Ctenocephalides canis, C. felix, and Pulex irritans, which are
bedbugs and the cat, dog, and human fleas, respectively. Children
require prior exposure to these arthropods to mount the hypersensitivity response. This allows infants to be relatively spared,
and teens often develop hyposensitization with chronic exposure. Cutaneous lesions are commonly seen on the arms and legs
and manifest as urticarial, sometimes vesicular, papules that are
extremely pruritic. Symptomatic treatment of pruritus with antihistamines and mild topical steroids is helpful, but the primary
focus should be on elimination of the source of infection.

Fleas
Fleas can cause a papular, pruritic dermatitis, which results
from the injection of antigenic saliva into the skin. Treatment

232 — Michelle R. Wanna and Jonathan A. Dyer

is symptomatic and eradication of the organism is key, as some
species of Xenopsylla are vectors for typhus and bubonic plague.
The sand flea, or Tunga penetrans, can also cause tender, pruritic
nodules of the feet secondary to burrowing of the flea into the
skin. This infection is known as tungiasis with potentially serious
complications of secondary infection and occasionally digital
amputation.

Bedbugs
Cimex lenticularis is seen in developing countries and lives in
cracks in paint, wallpaper, and furniture. They feed nocturnally and typically bite painlessly. Bites tend to be grouped or
linear, and pruritic papular lesions with a central punctum are
the result. Treatment should focus on symptomatic management
and prevention of secondary infection.

Stinging Insects
The order Hymenoptera contains three families of stinging
insects. Honeybees are in the family Apidae. They commonly
live in buildings or hollow trees and sting only when provoked,
leaving the stinger and venom sack in the skin. Phospholipase A2
is the primary allergen in honeybee venom.
Wasps, hornets, and yellow jackets are members of the
Vespidae family. Hornets are aggressive and commonly make
nests in trees and shrubs. Honeycomb nests in shrubbery and
protected areas of buildings are the homes of wasps. Yellow
jackets reside in walls, hollow spaces, and the ground. They are
attracted to food and garbage and tend to be very aggressive. The
major allergen in yellow jackets and hornets is antigen 5, which
has significant cross-reactivity. Wasps, however, show only a
moderate cross-reactivity.
Reactions to insect stings can be categorized as normal,
large local, anaphylactic, and toxic. Most components of the
reaction are mediated by the vasoactive amines, peptides, and
proteins found in the venom. Tenderness, swelling, and erythema, that resolves within a few hours are considered normal
reactions. Patients with 24 to 48 hours of increasing local symptoms followed by slow resolution have large local reactions.
These carries a slightly higher but less than 10% risk of more
severe reactions to future stings for these patients. Toxic reactions can occur following inoculation of significant quantities
of venom. These are manifested physiologically as reactions to
the venom components. Urticaria, angioedema, hypotension,
bronchospasm, and shock can be seen in 0.5% to 1.5% of stings
and are classified as anaphylactic reactions. Children are more
likely to have an anaphylactic reaction, but atopy only minimally increases this risk.
Care should be taken in the removal of residual stingers, as
additional venom can be inoculated if the venom sac is compressed. The recommendation is to scrape the stingers from the
skin. Treatment for local reactions is primarily symptom driven.
Patients with large local reactions may consider carrying selfinjectible epinephrine, which is mandatory in patients with anaphylactic reactions. Immunotherapy following skin testing by
an allergist can reduce the risk of severe reactions to less than

5% in patients with a history of anaphylaxis. Avoidance measures
should also be utilized.
Stinging ants are in the family Formicidae with Solenopsis
invicta as the most common fire ant species in the United States.
They live in large groups in nests or mounds and are aggressive,
resulting in multiple stings per insect. Their venom is primarily alkaloid and produces a pustule within 24 hours at the site
of stings. Reactions are categorized in the same manner as the
flying insects and immunotherapy can be used to treat severe
reactions as well.

Blister beetles
Blister beetles of multiple species produce a characteristic dermatitis when crushed. Vesicles and bullae occur after cantharidin,
which is produced by the beetles, comes in contact with the skin.
This phenomenon is used therapeutically in controlled settings
to treat other infectious disease in children such as verrucae and
molluscum contagiosum. Treatment involves cleansing the area
to remove the chemical and wound care for bullous lesions.

Caterpillars and Moths
Lepidopterism is the term used to describe the cutaneous and
systemic effects related to moths, caterpillars, and butterflies of
the order Lepidoptera. The fine hairs, or setae, of these organisms
are responsible for the manifestations of disease, which may be
mediated via toxins, hypersensitivity reaction, or mechanical irritation. Tape stripping of the setae following exposure is helpful in
treatment. Outbreaks can occur in areas of high concentration,
such as those reported at Boy Scout camps. Linear, erythematous,
pruritic papules are most commonly seen, but urticaria and exacerbation of underlying respiratory problems can occur as well.
Some Lepidoptera produce a distinct cutaneous manifestation,
such as the painful, tram-track lesions that are seen following the
sting of Megalopyge opercularis, or the puss caterpillar.

P I T FA L L S A N D M Y T H S

Cutaneous infections in children are common. While many diagnoses are straightforward, many common infections may present
with atypical clinical features, which can delay the diagnosis or
lead to an initial misdiagnosis. Additionally, some skin diseases
common to childhood may mimic infectious processes, such as
the frequent misdiagnosis of granuloma annulare as tinea corporis. Familiarity with the timing, presentation, and course of these
typical cutaneous infections of childhood is important and can
allow for more rapid testing, diagnosis, and treatment.

SUGGESTED READINGS

Paller, Amy S, and Mancini, Anthony J. Hurwitz Clinical Pediatric
Dermatology, 3rd edition. Saunders: Elsevier, 2006.
Schachner, Lawrence A and Hansen, Ronald C. Pediatric Dermatology,
3rd edition. Mosby, London, 2003.

17

S K I N I N F E C T I O N S I N T H E E L D E R LY
Noah S. Scheinfeld

INTRODUCTION

“All things collapse the center can not hold,” wrote W.H. Auden.
While he was likely speaking of politics in Western Europe before
World War II, he might well have been speaking of the skin in
old age. The skin of old age is the product of a gradual loss of skin
structures and a decrease in skin integrity that occurs through
adulthood and middle age.
Skin infections of all types are more common in the elderly
than in the young. The reasons for this are multifold and include
the following:
(1) Decreased skin integrity due to
(a) the decreased function and number of sweat glands
(b) the decline in the ambient moisture content of the skin
(c) thinning of the epidermis and dermis and
(d) decreases in fascial function, which facilitates the ingress
of fungi into the skin and nails
(2) Cardiovascular impairment, which
(a) decreases skin integrity
(b) hinders immune cell deployment and
(c) sometimes leaves parts of the skin and nails as virtual
cul-de-sacs outside regulation of the body’s various
homeostatic systems
(3) Decreased immune function, which manifests with
(a) inability to mount fevers
(b) a tilt toward the TH2 arms of immune function at the
expense of the TH1 arm
(c) fewer and less functional immune cells
(4) Physical factors such as pressure effects on weakened skin,
leading to breakdown secondary to a sedentary life style,
immobility, or neuropathy
(5) malnutrition and
(6) hormonal alterations that include decreased estrogen and
testosterone levels and insulin resistance.
I will expend on these points further.
The symptoms that surround infections in the elderly are less
florid. The elderly are less able to mount a fever or increase their
white blood cell count in response to infection. Acute disorientation, anorexia and weakness, and simple erythema of the skin are
all nonspecific signs that can be the presenting signs of infection,
making the diagnosis of infection difficult.
Diseases that provide the foundation for infection increase
in incidence in the elderly. Specifically, diabetes and cancers
decrease the function of the immune system. Diseases that
undermine the cardiovascular system such as coronary artery
disease, peripheral vascular disease, hyperlipidemia, and

hypertension decrease blood flow to the skin decreasing the
capacity of the elderly to defeat infection. Decreased blood
flow slows healing, increases xerosis, and decreases epidermal
integrity. This decrease in epidermal integrity permits bacteria
and fungi to enter broken skin, such as cuts, sores, abrasions,
erosions, ulcers, and fissures. Ulcers can occur on the feet as a
result of neuropathy secondary to diabetes in many cases and
get infected (Fig. 17.1).
As the implications for missing a diagnosis are high and
the potential for a confusing clinical picture is great, elderly
patients who are examined should be approached with a high
index of clinical suspicion. Initiation of treatment should be
considered as soon as an infection is suspected. Apposite diagnostic testing should be performed promptly. Culturing pus,
fluids, blood, and scale should be considered before treatment
is started.
When assessing the results of laboratory tests, some results
may be suggestive of a diagnosis rather than diagnostic. Some
positive culture results represent colonization rather than infection of the skin. Inflammatory skin diseases and systemic diseases can mimic skin infection. To achieve a definitive diagnosis,
tests such as a Gram stain, blood chemistry tests, urine analysis,
and skin biopsy can be helpful.

H I STORY

The sixth age shifts
Into the lean and slipper’d pantaloon,

Figure 17.1. Malperforans ulcer in an elderly diabetic with secondary
infection.
233

234 — Noah S. Scheinfeld

With spectacles on nose and pouch on side,
His youthful hose, well saved, a world too wide
For his shrunk shank; and his big manly voice,
urning again toward childish treble, pipes
And whistles in his sound. Last scene of all,
That ends this strange eventful history,
Is second childishness and mere oblivion,
Sans teeth, sans eyes, sans taste, sans everything.
Shakespeare’s As You Like It
The burden of skin disease has always weighed on the elderly.
Before the middle of the 20th century, relative to today, few persons reached age 65. The atrophy of skin and waning immune
function affected people before 1950, particularly and intensely.
This was due in part to the fact that effective antibiotic and antifungal agents were not available. Few classical authors attributed
skin disease to old age although they did note the wrinkles and
sagging skin of old age. As people lived better and longer, starting in the 20th century skin diseases could be separated more
readily between those of the adult and those of the elderly.

BACTERIAL INFECTIONS

The most common pathogens associated with infections of the
skin are Staphylococcus aureus and Streptoccocal species. Rarely,
gram-negative organisms can be involved, and this should be
remembered when starting empirical treatment. These pathogens result in a variety of infections that include cellulitis (in
particular of the lower legs), erysipelas, necrotizing fasciitis,
folliculitis, impetigo, folliculitis, and furunculosis.

Cellulitis and Erysipelas
In the elderly, cellulitis and erysipelas are common infections.
Cellulitis should be clinically distinguished from erysipelas.
Erysipelas involves the dermis, most commonly involves the
legs, and tends to be sharply demarcated. Cellulitis also most
commonly occurs on the lower legs, but also involves the subcutaneous fat. It is deeper andless demarcated. A classic sign of
both cellulitis and erysipelas is the orange-peel (peau d’orange)
texture of affected skin. Vesicles and bullae may be present in
areas affected by cellulitis and erysipelas. Streptoccocal species
are the most common cause of cellulitis and erysipelas. S. aureus
and gram-negative organisms can cause cellulitis and are more
serious than cellulitis caused by Streptococcus.
Prompt treatment of cellulitis and erysipelas is necessary as
cellulitis and erysipelas can evolve into septicemia, thrombophlebitis, septic arthritis, osteomyelitis, and endocarditis.
Cellulitis and erysipelas require antibiotic treatment. In most
cases, these infections should be treated with intravenous antibiotics if complicated, if of significant extent or if present with
coincident disease. The most common antibiotics used to treat
cellulitis and erysipelas are penicillins and cephalosporins. Other
therapeutic options include clindamycin, quinolones, and macrolides. With the increase of methicillin-resistant pathogens, the
use of glycopeptides (particularly vancomycin) has increased.
And vancomycin is now first-line therapy until a pathogen and
its susceptibilities are identified. The typical duration of therapy
is 10 to 14 days for simple skin and skin structure infections.

Figure 17.2. Stasis Dermatitis with secondary infection.

Complicated skin and skin structure infections such as cellulitis
associated with leg ulcers usually requires longer courses of intravenous treatment. These courses can last up to 3 to 4 weeks.
The entity most often confused with cellulitis/erysipelas is
stasis dermatitis. The former is usually warm to the touch, unilateral rather than bilateral, and sometimes painful. The latter
is of the same temperature as the surrounding skin, is more
often brown than red, is bilateral rather than unilateral, and is
not painful. While stasis dermatitis can be colonized or impetiginized, even in such cases, it is not an interchangeable entity with
cellulitis/erysipelas (Fig. 17.2). Other entities that can mimic
cellulitis/erysipelas include allergic contact dermatitis and deep
venous thrombosis. If cellulitis and deep venous thrombosis are
confused when a leg is red and painful, a Doppler ultrasound
or related imaging test should be carried out to rule out thrombophlebitis and clotting.

Impetigo, folliculitis, and furunculosis
Staphylococcus aureus and β-hemolytic streptococci are the most
common organisms that cause impetigo, folliculitis, and the
more serious infections of cellulitis and erysipelas.
Impetigo appears as honey-colored crusted erosions. Care
givers should obtain a sample of fluid or pus for a Gram stain
and culture it to define the causative organism. However, the
diagnosis of impetigo can usually be made clinically. Methicillinresistant S. aureus is the cause of a higher and higher percentage
of hospital- and community-acquired skin infections. A nasal
culture of the patient and other family members is often helpful in assessing if nasal carriage of S. aureus is the source of the
infection (up to 20%–25 % of persons carry S. aureus in their
noses).
Folliculitis refers to a bacterial infection of the pilosebaceous
unit. Folliculitis occurs on body surfaces with hair such as the
scalp, neck, beard area, axillae, buttocks, and limbs. A fungal
folliculitis (Majocci granuloma) can occur if a superficial fungal

Skin Infections in the Elderly — 235

infection is treated with topical steroids. A furuncle or boil is
the manifestation of a deeper infection of the hair follicle generally with S. aureus. It results in a red, hot, tender inflammatory
nodule (a boil) from which pus can be expressed. Carbuncles are
multiloculated or multiple furuncles. The differential diagnosis
for a furuncle is an inflamed epidermal or pilar cyst. Although
antibiotics may help treat an inflamed cyst because it is secondarily infected or because antibiotics may have anti-inflammatory
effects, the definitive treatment of an epidermal cyst is surgical.
A variety of conditions may increase the likelihood of infections of the superficial skin and hair follicle. These factors include
bacterial carriage in the nostrils, scabies, vigorous scratching of
the skin, diabetes mellitus, obesity, lymphoproliferative neoplasms, malnutrition, and the administration of glucocorticosteroids and other immunosuppressive drugs.
The optimal treatment begins with culture of eruptions that
are suspected of having infectious etiologies. Empiric treatment
should be started if an infection is suspected. While resistance
and atypical organisms can be the cause of a skin infection, treatment should be directed toward gram-positive organisms with
the expectation that some response will be seen in 2 to 3 days. If
the patient has systemic symptoms (fever, malaise, nausea, vomiting) or the infection occurs on a sensitive area (e.g., genital or
ocular sites), the patient should be admitted to the hospital and
treated with intravenous antibiotics. If the culture of fluid of a
folliculitis or furunculosis reveals that the infection is resistant
to the initial therapy, treatment should be altered. Alternatives
for organisms resistant to penicillins include intravenous vancomycin and oral linezolid. Typical courses of therapy are 7 to
10 days.

Necrotizing fasciitis
Necrotizing fasciitis describes a destructive, usually polymicrobial, infection causing rapidly advancing deep tissue necrosis,
which can result in significant morbidity and mortality. The
etiologies of necrotizing fasciitis are diverse and include prior
injury, surgery, irradiation, cancer, diabetes mellitus, alcoholism,
and malnutrition.
Treatment for necrotizing fasciitis requires surgical intervention in combination with multiantibiotic therapy using drugs
effective against gram-positive and gram-negative pathogens as
well as pathogens that are aerobes and anaerobes. Proper nutrition, hydration, close monitoring, and supportive care are essential if the patient is to recover from necrotizing fasciitis.

HERPES ZOSTER

Herpes zoster involves the recrudescence of infection with
varicella-zoster virus whose source is a quiescent virus residing in a nerve, which usually spreads along a single dermatome
(Fig. 17.3). Herpes zoster has a different profile in the elderly
than it does in the young. Herpes zoster is a disease of old age
and is best considered an exception in the young. The incidence
of herpes zoster increases constantly with age so while it is rare
in the young, it is not uncommon in those older than 65. Zoster
rates are highest among individuals over age 80 (10.9 per 1,000
person-years, i.e., 1% of persons are suffering from it at any
time). Secondly, disseminated zoster, while rare, is a disease

Figure 17.3. Herpes Zoster in an 81-year-old male patient in his groin
area.

associated with non–Hodgkin’s lymphoma, which is a disease
that is most common in the old and very old. Finally, postherpetic neuralgia (PHN) is most common and most severe in the
elderly.
In recent years, the approach toward the treatment and
prevention of zoster has changed with the approval of a vaccine
for zoster. This vaccine is significant in that it prevents the recrudescence of disease rather than its genesis. The vaccine is identical
in content to the childhood vaccine for the prevention of chickenpox except the herpes zoster vaccine provides a higher dose
of the active ingredient. The use of the zoster vaccine diminished
the burden of illness due to herpes zoster by 61.1%, diminished
the incidence of PHN by 66.5%, and diminished the incidence of
herpes zoster by 51.3% (P<0.001). Patients who develop herpes
zoster have a milder clinical course if they have been vaccinated.
Reactions at the injection site when present were generally mild
and were more frequent among vaccine recipients.. Tricyclic
antidepressants, topical lidocaine, gabapentin, nerve root injections with steroids or aneshetics, acupuncture, and opiates may
all be used as treatments for PHN.

FUNGAL INFECTIONS

The incidence of all fungal infections, with the exception of tinea
versicolor, increases with age. This is true of onychmycosis, tinea
pedis, cutaneous candiadias, perléche, and intertrigo.

Candidiasis
Candidiasis is a yeast infection most commonly due to Candida
albicans that increases in incidence in diabetic or obese patients.
These patient groups have a higher prevalence in the elderly. It is
also more common for elderly patients to be on chronic antibiotics, chronic oral and topical corticosteroids, immunosuppressive
drugs, and have poor nutrition. These factors lead to an increased
incidence of candidal infections. Obese elderly patients are more
apt to be poorly mobile and this increases prolonged occlusion,
moisture, and warmth in skin flexures. Once again these are
conditions that lead to candida.
Oral candidiasis, termed thrush, occurs commonly in elderly
persons. Poor dentition, immunosupression, systemic and oral

236 — Noah S. Scheinfeld

corticosteroid use are all predisposing factors. Thrush manifests
as white plaques that can be easily removed, and overly erosions
or ulcerations on the buccal, palatal, or oropharyngeal mucosa.
These plaques overly areas of mucosal erythema. Candida infection or superinfection of erosions and inflammation occurring at
the mouth’s lateral angles is termed angular cheilitis or perléche.
Denture stomatitis presents as chronic mucosal erythema typically beneath the site of a denture and is a related condition.
Maceration of the finger web spaces (most commonly seen
in the third web space between the middle and ring fingers) is
caused by candida and gram-negative bacteria and is termed erosio interdigitalis blastomycetica (interdigital candidiasis). Liquid
exposure played out against a background of a weakened epidermis, obesity, diabetes and immunosuppression seems to be the
basis for erosio interditalis blastomycetica. Erosio interdigitalis
blastomycetica responds to drying agents and topical antiyeast
agents.

Treatments exist for onychomycosis. Treatment is not uniformly effective as elderly patients possess special risk factors for
poor response to therapy for onychomycosis, including frequent
nail dystrophy, slow growth of nails, and increased prevalence
of cardiovascular and peripheral vascular disease and diabetes
mellitus. Onychomycosis can be treated with oral terbinafine
(250 mg daily for 3 months) oral itraconazole, topical amorolfine
or ciclopirox nail lacquer. Terbinafine is the most effective agent
with the fewest drug interactions. Terbinafine is only effective
against dermatophytes while itraconazole is effective against
yeasts and molds. Topical application of urea 20% to 50% gel
or cream, breaks down keratin and softens the nail plate. It may
enhance penetration of topical antifungal drugs when used in
tandem. After therapy is initiated, it can take up to 6 months to
assess therapeutic effect. Combinations of treatments (e.g. oral
and topical or oral/topical and surgical) seem to enhance cure
rates.

Onychomycosis

Tinea Pedis and Manuum

Onychomyocosis is an infection of nails by fungi and is more
difficult to treat than fungal infections of the skin. The prevalence of onychomyocosis increases constantly with age. The
prevalence of fungal nail infections is about 20% in the 60
to 79 years age-group compared to ~1% in patients younger
than 21 years. Onychomycosis is a common disease affecting
as much as 8% of the general population. A greater prevalence
of onychomycosis is associated with greater age, male gender,
diabetes mellitus, family history of onychomycosis, psoriasis, concurrent intake of immunosuppressive drugs, and cardiovascular and peripheral vascular disease. Onychomycosis
can cause pain or limited mobility impairing quality of life.
Difficulty walking and wearing shoes and embarrassment are
common complaints. Moreover, in patients with recurrent cellulitis, onchomycosis and tinea pedis are thought to provide
portals of entry for bacteria and are thus a predisposing factor
for cellulitis.
Dermatophytes are the most commonly cultured organisms,
appearing in ~75% to 91% of nails with fungal involvement.
Tinea rubrum is the most common dermatophyte to cause onychomycosis or tinea unguium. Other species of tinea including
T. mentagrophyte can cause onychomycosis. Candida (Candida
Parapsilosis, Candida guilliermondii, Candida albicans) and nondermatophyte molds and related pathogens (e.g. Scopulariopsis
brevicaulis, Aspergillus spp., Alternaria spp., Curvularia spp., and
Fusarium spp.) can also cause onychomycosis. Periodic acid–
Schiff (PAS) stain of the nails is the best test for diagnosing onychomycosis but it will not distinguish between species of tinea.
As terbinafine will cover all dermatophytes (but not Candida or
nondermatophyte molds) speciation of tinea is not important.
A PAS is useful because nail dystrophy from psoriasis, lichen
planus, and eczema can result in an onychodystrophy that may
resemble onychomycosis.
Onychomycosis is divided into four types: distal subungual
onychomycosis, proximal subungual onychomycosis, white superficial onychomycosis, and candidal onychomycosis. Distal subungual onychomycosis, which manifests with thickened and friable
nails with associated discoloration and subungual hyperkeratosis,
is the most prevalent type and accounts for 75% to 85% of cases.

Tinea pedis (athlete’s foot) and manuum commonly occur in the
elderly. Tinea commonly occurs on both feet and one hand for
unknown reasons. Tinea pedis manifests as maceration in the
interdigital toe web folds and as scaly plaques on the feet, often
in a moccasin distribution. Treatment involves the use of topical antifungal (e.g. ketoconazole, ciclopirox) gels, creams, foams,
or solutions with or without a keratolytic agent (e.g., lactic acid,
urea or salicylic acid). The examination of a KOH preparation
can establish the diagnosis for tinea pedis. Tinea pedis and
manuum must be distinguished from xerosis, allergic contact
dermatitis, and dyshydrotic eczema, which can be accomplished
by examination of a KOH preparation.
Tinea corporis commonly occurs on the torso of elderly persons. Tinea corporis has a variety of presentations that include
nummular patches, annular plaques with a rim of scaly erythema,
and polycyclic annuli (Fig. 17.4). Examination using a KOH preparation can establish the diagnosis of tinea corporis. Tinea corporis can be treated effectively with a topical antifungal agent.

Figure 17.4. Tinea Corporis in an elderly patient under a leg brace.

Skin Infections in the Elderly — 237

Elderly people with diabetes should be treated for
onychomycosis to prevent secondary bacterial infections and
subsequent complications. Terbinafine is the drug of choice for
dermatophyte onychomycosis, with greater mycological cure
rates, less serious and fewer drug interactions, and a lower cost
than continuous itraconazole therapy. Adjunct debridement
may improve the clinical and complete cure rates compared with
terbinafine alone. Common adverse effects of terbinafine in the
elderly include nausea, sinusitis, arthralgia, and hypercholesterolemia. For onychomycosis caused by Candida or nondermatophyte molds, there is no superior systemic therapy. In general,
topical nail lacquers, amorolfine and ciclopirox, are not practical for elderly patients because of the recommended frequency
of application, periodic routine debridement of affected nails,
and long duration of therapy. However, nail lacquers may be a
good option as monotherapy or in combination with systemic
antifungal therapy.

P I T FA L L S A N D M Y T H S

A key pitfall in diagnosing skin infections in the elderly is
that they do not present in the same manner as infections in

adulthood. That is, “atypical presentations” occur commonly.
The host response of the elderly can be less vigorous and thus
the hallmarks of infection – i.e. rubor, calor, and dolor can be
less pronounced. Thus, those who examine the elderly must
have a high index of clinical suspicion. Another pitfall is clinically not appreciating the role that the impaired integrity of the
integument plays in the facilitation of infection and that for
infection to be dealt with, breaks in the skin from xerosis and
poor circulation must be dealt with. Finally, it is important to
understand that florid stasis dermatitis is not the same thing as
cellulitis.

SUGGESTED READING

Insinga RP, Itzler RF, Pellissier JM Saddier P, Nikas AA. The incidence
of herpes zoster in a United States administrative database. J Gen
Intern Med 2005;20(8):748–753.
Scheinfeld N, Mones J. Seasonal variation of transient acantholytic
dyskeratosis (Grover’s disease). J Am Acad Dermatol 2006;55(2):
263–268.
Scheinfeld N. Infections in the elderly. Dermatol Online J 2005;
11(3):8.

18

S K I N I N F E C T I O N S I N AT H L E T E S
Brian B. Adams

INTRODUCTION

Cutaneous infections afflict athletes sometimes in epidemic
proportions. Several aspects of sporting activities place the
athlete at a greater risk of developing and transmitting these
infections. First, many athletic endeavors involve intense, close
skin-to-skin contact, which facilitates the spread of infectious
microorganisms between athletes and among teams. Second,
sweating, inherent to athletics, results in a macerated epidermis
that easily facilitates the penetration of microorganisms. Third,
many athletes wear occlusive equipment, which provides an ideal
environment for the growth of microorganism (warm, dark, and
moist). Finally, trauma (gross or micro) related to athletic activities further impairs the stratum corneum’s barrier.
The microorganisms that plague athletes of all skill levels
include bacteria, viruses, fungi, atypical mycobacteria, and parasites. Knowledge of these infections in the context of athletics
permits the clinician to treat the athletic patient more effectively.
Through this focused approach, the clinician can minimize disruption to an individual’s athletic activities and prevent team and
league epidemics.
H I STORY

Sports dermatology began with several isolated case reports of
unusual skin conditions in athletes. Interest in the field blossomed
with the identification of epidemics of viral, fungal, and bacterial
skin infections among those involved in sports of all kinds. The
transmission of herpes virus among athletes with close skin-toskin contact (primarily among wrestlers) has predominated in
the sports dermatology literature. Research and close observation in the 1990s and early 2000s also documented epidemics
of tinea corporis gladiatorum. With the advent of epidemics of
community-acquired methicillin-resistant Staphylococcus aureus
(MRSA), attention has turned to the role of athletic participation and the transmission of MRSA. Considerable practice time
and competition is lost to skin infections and our attempts at
adequately preventing the transmission of these skin infections
in athletes remains at its infancy.

AAU wrestling championship. S. aureus, MRSA, Streptococcus
pyogens, and Streptococcus agalactiae can all cause impetigo.
Athletes with close skin-to-skin contact (wrestlers; rugby
[“Scrum strep”], football, and basketball players) and others
wearing occlusive equipment (fencers; hockey and soccer players) seem particularly susceptible. The lesions are distributed
over areas of skin-to-skin contact or areas occluded by equipment. Well-defined erythematous, yellow-crusted papules or
plaques develop in these exposed athletes (Fig. 18.1). Mature
lesions demonstrating these clinical features make the diagnosis
straightforward. However, early lesions may lack characteristic
findings. As such, clinicians may mistake beginning lesions of
impetigo for acne, papular dermatitis, or other infectious conditions related to sports such as herpes gladiatorum or tinea corporis gladiatorum. Termed “scrum kidney,” poststreptococcal
nephritis has developed as a complication of impetigo in rugby
players.
Furunculosis
A significant body of work exists regarding the epidemiology of
furunculosis in athletes. Epidemics ranging from 9% to 56% have
plagued football and basketball teams at the high school, collegiate, and professional levels. Caused by S. aureus and increasingly by MRSA, athletically related furunculosis occurs on areas
of skin-to-skin contact. Not infrequently, however, athletes (such

BACTERIAL INFECTIONS

Clinical Features
Impetigo
While impetigo routinely affects athletes of all sorts, only one
epidemiologic study exists that noted an epidemic at a national
238

Figure 18.1. This is a typical lesion of impetigo in an athlete.
Reprinted from Sports Dermatology © 2006, Brian B. Adams, MD,
MPH Chapter 1, Figure 1 with permission from Springer Science and
Business Media LLC.

Skin Infections in Athletes — 239

as soccer and field hockey players) develop furunculosis beneath
protective equipment on the lower legs. Tight-fitting garments
also predispose athletes to furunculosis.
Several studies have highlighted important risk factors that
place athletes at a high risk for infection. Athletes with turf
burns (caused by frictional trauma with the playing field) or who
practice body shaving demonstrate a six to seven times higher
prevalence of furunculosis compared to athletes without those
characteristics. Increasing weight among football players appears
to increase the risk of infection. A player’s position on the field
also tends to play a role. Cornerbacks experience a 17.5 times
higher risk of Staphylococcal infection, and in another study,
lineman had a 10 times higher risk.
Well-defined, tender, erythematous nodules develop in locations of skin-to-skin contact and/or beneath occlusive equipment. Very early lesions may mimic acne, papular dermatitis,
herpes gladiatorum, or tinea corporis gladiatorum.

Table 18.1: Prevention Techniques That May Help Avoid
Skin Infection Epidemics

Folliculitis

Reprinted from Sports Dermatology © 2006, Brian B. Adams, MD,
MPH Chapter 1, Table 1–1 with permission from Springer Science
and Business Media LLC.

Unlike impetigo and furunculosis, no epidemiology of folliculitis
in athletes exists. Caused by S. aureus and increasingly by MRSA,
folliculitis in athletes occurs in areas of skin-to-skin contact. Not
infrequently, however, athletes develop an infectious folliculitis
beneath protective equipment on the lower legs (such as soccer
and field hockey players). Tight-fitting garments also tend to predispose athletes to staphylococcal folliculitis. Erythematous papules and follicular pustules occur at these sites but can be easily
confused with other infections such as molluscum contagiosum
and noninfectious entities such as acne mechanica.

Diagnosis
Culture confirms the diagnosis of these bacterial infections.
Occasionally, biopsies are required, especially early in the course
of the infection and with very small lesions. During epidemics or
in cases of recurrent disease, clinicians should culture the nares
of the infected individuals and consider cultures of asymptomatic teammates. Fomites play an unknown role in the transmission of these infections. Multiple studies have failed to document
the presence of these bacteria on mats or equipment.

Therapy and Prevention
Treatment varies with the severity of disease. First and foremost,
athletes should apply warm moist washcloths to the affected
area for 10 minutes three times per day. Oral (dicloxacillin or
cephalexin) and topical (mupirocin) antibacterial agents for 7 to
10 days clear the eruption. Folliculitis, furunculosis, or impetigo
caused by MRSA clears with sulfamethoxazole–trimethoprim.
Athletes with positive S. aureus or MRSA nasal cultures require
twice daily application of mupirocin ointment or cream to both
nares for 10 days; this regimen can be repeated every 6 months
or more frequently depending on the rapidity of recurrence of
colonization. Clinicians should also consider applying mupirocin (ointment or cream) to the perianal region and the axilla.
Prevention is paramount. In one highly publicized epidemic
among professional football players, rampant towel sharing
(three athletes to one towel), improper cleaning of weight room
equipment, and inadequate access to hand sanitizer for training

Frequent, if not daily, skin checks by athletes and trainers
Daily showers immediately after practices or competition
Routine antibacterial soap use in the showers
Frequent hand washing by trainers and affected athletes
Universal availability of alcohol-based, waterless, soap cleansers
Regular laundering of equipment and clothing
Mandatory no-sharing policy for equipment and personal items
Required personal towels
Meticulous covering of all wounds
Periodic formal education for the athletes, coaches, and trainers

staff were identified as the major risk factors. Athletes should
practice impeccable hygiene that includes showering immediately after practice and competitions, washing with antibacterial
soaps or Hibiclens, and not sharing equipment or towels. While
no evidence exists that these approaches decrease the incidence
or transmission of folliculitis, furunculosis, or impetigo, these
hygienic measures only seem reasonable. Athletes with recurrent
disease should also minimize the amount of skin exposed during
skin-to-skin contact. Long-sleeved moisture-wicking synthetic
clothing allows the athlete’s skin to stay dry and helps prevent
the transmission of infectious organisms among other athletes
(Table 18.1).
Disqualification of athletes from competition remains quite
a controversial issue. At the high school athletic level, regulations vary among states while the National Collegiate Athletic
Association (NCAA) has uniform regulations regarding disqualification of infected athletes from competition. For example, skin
checks, starting with the lowest weight categories and proceeding
up, occur at all wrestling competitions. Certified athletic trainers
or physicians make the final determination at the venue. At high
school competitions, the referee, who may or may not have any
medical training, makes the disqualification determination.
NCAA guidelines note that in order for these athletes with
bacterial infections to be eligible to compete, they must not have
any new lesions less than 48 hours before competition, must have
taken oral antibiotics for at least 72 hours before competition,
and must also have covered the area with a bandage that cannot
be dislodged (Table 18.2).

Pitted Keratolysis
Caused by micrococcus or cornybacteria species, pitted
keratolysis occurs in athletes even though its epidemiology is
not yet well documented. Runners and tennis and basketball
players seem particularly prone. The warm, dark, and moist
environment of the athletic shoe provides an ideal climate for
these two organisms. Well-defined, pitted lesions particularly

240 — Brian B. Adams

Table 18.2: Guidelines for Return to Competition
for Impetigo/Furunculosis (Based on NCAA Guidelines)
1) Take 72 hours of oral antibiotics
2) Lack new lesion for at least 48 hours
3) Cover lesion with non-permeable bandage
NCAA 2006 Wrestling Rules and Interpretations. Appendix D Skin
Infections.

distributed on the weight-bearing aspects of the sole typify pitted
keratolysis. The soaking of the sole enhances the prominence of
the pits. Treatment includes topical antibiotics (clindamycin or
erythromycin) or topical benzoyl peroxide or both. To prevent
pitted keratolysis, athletes can apply aluminum chloride solution
to decrease exertional hyperhidrosis. Synthetic moisture-wicking
socks, available at most athletic specialty stores, can keep the sole
dry and cool.

knees, hands, and wrist caused by Fusobacterium ulcerans. In
areas of traumatic abrasions, resulting from their sport, the
rugby players demonstrated many well-defined, shallow ulcers
with indurated borders. Cultures confirm the diagnosis.
Hot Foot Syndrome
One case series studied 40 children swimmers who developed
this condition caused most likely by Pseudomonas aeruginosa. Their median age was 6 years. The pathogenesis of this
condition is not well understood. Ten to 40 hours after pool
exposure, these mostly young swimmers developed intensely
painful, erythematous, and violaceous nodules on the soles.
Some swimmers in this study also had fever, nausea, and
fatigue. The lesions may persist for 2 weeks but resolve spontaneously. The differential diagnosis includes athletically related
neutrophilic eccrine plantar hidradenitis and plantar urticaria.
Neutrophilic eccrine plantar hidradenitis, however, typically
develops after repeated pounding trauma on the soles, while
sports-related plantar urticaria resolves rather quickly (few
minutes to few hours). No effective therapy exists except for
symptomatic relief.

Gram-Negative Infections (Hot tub folliculitis,
green foot, tropical ulcers, hot foot syndrome)
Hot Tub Folliculitis
Hundreds of epidemics of hot tub folliculitis have occurred
involving both athletes and nonathletes. Athletes are at risk this
infection, caused by Pseudomonas aeruginosa, due to exposure
to hot tubs after practice or during rehabilitation. Inadequate
chlorination allows the organism to proliferate. The hot, turbid
water and heavy usage by athletes dissipates the chlorine. On any
submerged skin surface, but often concentrated on areas covered
with clothing, and sparing the palms and soles, follicular erythematous papules and pustules develop. In rare case reports the
presence of green pustules has been documented. Systemic manifestations often occur and include pharyngitis, lymphadenopathy, and malaise. The differential diagnosis includes other types
of folliculitis including those resulting from Staphylococcus, pityrosporum, acne, and anabolic steroid use.
No treatment for the immunocompetent athlete is necessary
as hot tub folliculitis resolves spontaneously in 7 to 10 days and
those athletes treated with antibiotics risk recurrence. Proper
cleaning and chlorination of the hot tubs prevent hot tub folliculitis. Heavily used hot tubs in the training room need more
frequent cleaning and chlorination than a typical hot tub.
Green Foot
Athletes may acquire a green discoloration on their feet and
toenails as a result of contact with Pseudomonas growing in their
shoes. The discoloration does not wipe away and takes about
1 month to resolve. By making the link between athletic participation and subsequent culture of the organism from the insole,
the clinician can best reassure the athlete and prevent future
recurrences.
Tropical Ulcers
Seven members of one rugby team who competed in an
international competition developed painless ulcers on their

VIRAL INFECTIONS

Herpes Simplex Virus
Reactivation
Outdoor athletes exposed to excessive ultraviolet radiation risk
reactivating their herpes labialis. Snow-related sports place the
athlete at even greater risk because of chapping of the skin and
reflection of sunlight off the snow. At high altitudes, the atmosphere absorbs less ultraviolet radiation and the snow reflects up
to 100% of the ultraviolet radiation. About 12% of skiers (with
a history of herpes labialis) will develop herpes labialis during
a 1-week stay at the slopes. The median time to development of
lesions after arriving at the ski slopes is 3.5 days. Athletes should
take 2 grams of valacyclovir twice in one day at the first sign of
the prodrome.
To prevent reactivation of herpes labialis, outdoor athletes
with a history of HSV should take daily suppressive dosing of
valacyclovir or famcyclovir. These athletes also need to apply
sunscreen. One study documented herpes labialis lesions in
71% of skiers not wearing lip sunscreen and in 0% of individuals
wearing lip sunscreen.
Skin-to-skin transmission
Researchers have extensively delineated the epidemiology of
HSV-1 infection primarily in wrestlers and rugby players. The
median prevalence was 20%. Of all skin infections in athletes,
herpes gladiatorum (wrestlers) and herpes rugbeiorum (rugby
players) can cause the most individual morbidity and team disruption. Wrestlers transmit their skin infections as a result of
intense and repeated skin-to-skin contact (such as the “lock-up”
position), while, rugby players experience close contact during
the scrum. An unaffected wrestler competing with an infected
wrestler has a one-third probability of obtaining the infection.
When the nonaffected wrestler develops herpes gladiatorum, the
lesion develops between 4 to 11 days after exposure.

Skin Infections in Athletes — 241

Table 18.4: Guidelines for Return to Competition for
Herpes Gladiatorum (Based on NCAA Guidelines)
1) All lesions must be dried with an adherent crust and
2) The wrestler must have been on oral antiviral therapy for 120
hours and
* Evidence-based data suggest 96 hours is sufficient
** Valacyclovir’s one time dosing would allow competition 96
hours later
3) No systemic symptoms of herpes gladiatorum and
4) No new blisters within 72 hours of precompetition skin check-in
Reprinted from Sports Dermatology © 2006, Brian B. Adams, MD,
MPH Chapter 2, Table 2–6 with permission from Springer Science
and Business Media LLC.
Figure 18.2. Herpes gladiatorum of the ear.
Reprinted from Sports Dermatology © 2006, Brian B. Adams, MD,
MPH Chapter 2, Figure 2 with permission from Springer Science and
Business Media LLC.

Table 18.3: Clinical Appearance of Lesions
of Herpes Gladiatorum or Herpes Rugbeiorum
Based on Duration
Clinical Appearance

Age of Lesion

Red papule

Very early, 1–2 days

Grouped blisters

2–6 days

Crusted papule

5–14 days

Reprinted from Sports Dermatology © 2006, Brian B.
Adams, MD, MPH Chapter 2, Table 2–3 with permission
from Springer Science and Business Media LLC.

Mature lesions of herpes gladiatorum demonstrate welldefined, grouped vesicles on an erythematous base (Fig. 18.2),
whereas crusted lesions typify late lesions. Very early-detected
lesions may not have vesicles or the grouped morphology, which
makes prompt diagnosis challenging (Table 18.3). These lesions
predominantly develop on the upper extremities, head, and
neck regions. Headache, fever, and chills occur in one-quarter
of infected wrestlers. The differential diagnosis includes impetigo, tinea corporis gladiatorum, acne, and subacute dermatitis.
Tzanck preparation represents the quickest method to confirm
herpes gladiatorum but it is technically difficult. Viral cultures
take 24 hours but direct immunofluorescence yields results in
hours. Early detection allows rapid institution of therapy and
proper athlete isolation to prevent epidemics. One state’s high
school wrestling program suffered an epidemic after many competitors were incorrectly diagnosed and subsequently returned
to competition. Of the misdiagnosed wrestlers (90% of wrestlers with herpes gladiatorum), 70% were initially diagnosed
with impetigo, while 20% were thought to have either dermatitis
(10%) or tinea corporis gladiatorum (10%).
First and foremost, athletes should apply warm moist
washcloths to the affected area for 10 minutes three times per
day. Infected athletes should at the first sign of the prodrome

take 4 g total of valacyclovir in one day (in two separate doses
of 2 g each). After 96 hours, no viral shedding exists and the
wrestler can safely return to wrestling. Current NCAA regulations, however, allow for safe return to wrestling after 120
hours from the initiation of oral antiviral agents. The competitor must also be free from systemic symptoms, have no new
lesions in the past 72 hours, and possess at most only crusted
lesions (Table 18.4).
Clinicians caring for these athletes should recognize
the complications associated with herpes gladiatorum.
Secondary bacterial infections can occur as well as monoarticular arthritis, keratitis, and conjunctivitis. Cognizant
athletes (typically at the high school level), in an attempt to
escape detection and possible disqualification, may modify the grouped vesicle morphology by using sandpaper or
bleach. These maneuvers can cause significant disruption to
the epidermal barrier.
To prevent the transmission of herpes gladiatorum, clinicians
must identify, treat, and potentially isolate athletes as early as
possible in the course of their disease. Athletes should practice
impeccable hygiene that includes showering immediately after
practice and competitions, washing with antibacterial soaps or
Hibiclens, and not sharing equipment or towels. While no evidence exists that fomites transfer the viral organism, it seems
only reasonable to avoid sharing equipment (such as pads and
headgear) and towels. Athletes with recurrent disease should also
minimize the amount of skin exposed during skin-to-skin contact. Long-sleeved moisture-wicking synthetic clothing allows
the athlete’s skin to stay dry and helps prevent the transmission
of HSV among other athletes (Table 18.1). Pharmacologically,
high-risk athletes should take 1 g of valacyclovir daily during
the entire season. One study documented a decrease in herpes
gladiatorum prevalence from 33% to 8% using this season-long
prophylaxis.

Molluscum
Caused by the Poxvirus, molluscum contagiosum infects athletes
that come into contact with swimming pools and other infected
athletes’ skin. Athletes who share protective equipment such
as pads, gloves, and helmets are also at risk for infection. One
study of over 7,000 individuals demonstrated that swimmers

242 — Brian B. Adams

Table 18.5: Guidelines for Return to Competition
for Molluscum (Based on NCAA guidelines)
1) Curette all lesions
2) Cover solitary lesions with op-site or bioclusive
3) Cover with stretch tape
NCAA 2006 Wrestling Rules and Interpretations. Appendix D Skin
Infections.

Figure 18.3. Molluscum contagiosum (especially small lesions) can be
confused with folliculitis).
Reprinted from Sports Dermatology © 2006, Brian B. Adams, MD,
MPH Chapter 2, Figure 5 with permission from Springer Science and
Business Media LLC.

experienced two times the risk of infection with molluscum
compared to nonswimmers. Another interesting report highlighted an epidemic wherein 8% of 1,400 cross-country runners developed molluscum. The researchers theorized that the
runners transmitted the organism through their use of shared
courses through the woods or shared towels.
Most athletes develop small, white, occasionally slightly
erythematous papules on their skin under protective equipment or on the head, neck, and extremities (sites of close skinto-skin contact). The cross-country runners, in the previously
mentioned epidemic, demonstrated lesions on the anterior
knees and thighs. Mature lesions present with central umbilication, but early lesions often lack this characteristic finding
(Fig. 18.3). The differential diagnosis includes infectious folliculitis and acne mechanica. Curettement of the lesions cures
the athlete. Athletes should return for follow-up as microscopic
lesions may exist and grow within several weeks after removal.
Without an easily accessible curette, clinicians in the training
room can fabricate one by splitting a tongue depressor longitudinally (Fig. 18.4). NCAA regulations mandate the removal of
molluscum before competition. Solitary lesions may be covered
with bioclusive or op-site and then subsequently covered with
stretch tape (Table 18.5).
Athletes should practice impeccable hygiene that includes
showering immediately after practice and competitions, washing with antibacterial soaps or Hibiclens, and not sharing
equipment or towels. While no evidence exists that fomites
transfer the viral organism, it seems only reasonable to avoid
sharing equipment (such as pads and headgear) and towels.
Athletes with recurrent disease should also minimize the
amount of skin exposed during skin-to-skin contact. Longsleeved moisture-wicking synthetic clothing should be recommended since it allows the athlete’s skin to stay dry and helps
prevent the transmission of molluscum among fellow athletes
(Table 18.1).

Figure 18.4. A tongue depressor split longitudinally provides a readily
available curette to remove molluscum. The curved end can scoop
out the lesions quickly.
Reprinted from Sports Dermatology © 2006, Brian B. Adams, MD,
MPH Chapter 2, Figure 7 with permission from Springer Science and
Business Media LLC.

Verruca
Caused by the human papilloma virus, verrucae of all varieties plague the athlete. Several studies have implicated swimming pool decks and locker room showers in the transmission
of these infections. One study demonstrated that crewmembers
developed verruca 2.5 times more frequently than cross-country
runners. The use of gloves and weight rooms seems to be associated with this increased prevalence. Athletes may harbor these
viruses in calluses that are intrinsic to several different sporting
activities.
Clinicians need to differentiate among calluses, warts, and
corns. Paring the well-defined hyperkeratotic lesion will demonstrate pericapillary hemorrhages in verrucae, a central core in
corns, and no loss of skin ridges in calluses. While destructive
methods seem to best remove verruca, athletes often require therapies that minimize loss of practice or competition. The blisters
and pain induced by liquid nitrogen or cantharidin may detrimentally affect (in some cases dangerously so) an athlete’s grip
or gait. Topical medications such as salicylic acid, 5-fluorouracil,
and imiquimod under occlusion (duct tape or coban) provide
often a more gradual destruction. However, on occasion, this
chemical approach can induce pain as well. Athletes should never
walk barefoot in the locker room.

Skin Infections in Athletes — 243

Table 18.6: Epidemiology of Tinea Pedis among Various
Sports in One Study
Sport

Prevalence (%)

Relative Risk (compared
to nonathletes)

Basketball

39

2

Judo

23

1

Running

56

4

Soccer

44

2.6

Swimming

55

4

Water polo

53

3.7

FUNGAL INFECTIONS

The three main cutaneous fungal infections that afflict athletes
include tinea pedis, tinea corporis gladiatorum, and tinea cruris.
Tinea cruris, as it pertains to athletes, does not vary significantly
from that in nonathletes. Details of tinea cruris are described
elsewhere in this book (see Chapter 3).

Tinea Pedis
All three varieties of tinea pedis (namely moccasin, interdigital,
and vesicular) affect athletes. Trichophyton rubrum predominantly causes the moccasin and interdigital variants, whereas
Trichophyton mentagrophytes mainly causes the vesicular or
inflammatory variety. Trichophyton mentagrophytes dominates
as the primary organism causing occult disease. The dark, moist,
warm nature of sports’ shoes places the athletes at an increased
risk of developing tinea pedis. Several studies have documented
a higher prevalence of tinea pedis among athletes compared to
the nonathletic population. In a study of over 100,000 individuals, those people involved in sports experienced a 1.6- to 2.3fold increase in tinea pedis compared to nonathletes.
Different sports were also studied together in one large
study (Table 18.6). A recent study identified an unknown epidemic wherein 61% of soccer players (69% of professional players and 57% of collegiate players) had tinea pedis. No difference
in prevalence existed between genders or between professional
and collegiate athletes. Interestingly, clinical examination of the
professional soccer players’ toenails slightly overestimated the
prevalence of tinea pedis. The duration and intensity of activity
experienced by the professional players may cause a skin trauma
that mimics tinea pedis (especially the interdigital variant).
Another study examined poolside areas along walkways and
discovered 54 dermatophytes/mm2. Other researchers found that
77% of their cultures taken from the pool deck, locker rooms,
and springboard grew dermatophytes. The springboard area
accounted for nearly 50% of all positive cultures.
Athletes with interdigital tinea pedis demonstrate scaling
plaques between the toes, whereas the inflammatory variant
presents with pruritus, scaling, vesicular papules, and plaques
that are located most often on the instep. Close inspection
excludes other diagnoses that occur on athletes’ soles such as pitted keratolysis and allergic contact dermatitis. Sports clinicians

Figure 18.5. A well-defined, erythematous scaling round papule
typifies tinea corporis gladiatorum.

and athletes themselves most often confuse the moccasin variety with dry skin. However, potassium hydroxide examination
will reveal hyphae among the scale.
Therapy for tinea pedis is discussed elsewhere in this book
(see Chapter 3). However, athletes can employ specific preventative measures. Athletes should wear synthetic moisture-wicking
socks that can be found in most cities at local sports specialty
stores or on the Internet. Athletes should change socks frequently,
dry their feet completely before putting on their socks, and alternate their athletic shoes every other day to allow them to dry. By
wearing sandals in the locker room and showers as well as using
antifungal powders, athletes can prevent tinea pedis. Prompt
diagnosis and therapy by the clinician will also help stop epidemics. Most athletes with tinea pedis fail to recognize the condition
and do not bring it to the attention of proper medical personnel.

Tinea Corporis Gladiatorum
Multiples names exist for tinea corporis in athletes (most often
occurring in wrestlers). These terms include tinea gladiatorum and trichophytosis gladiatorum. Studies have shown that
20% to 75% of individuals on any given team can be affected
at any given time. The large difference in prevalence relates to
study methodology. Some teams had known epidemics whereas
other teams were studied without previous knowledge of an
epidemic. Unlike typical tinea corporis, in which Trichophyton
rubrum dominates as the leading organism, both T. rubrum
and Trichophyton tonsurans share the top spot in tinea corporis
gladiatorum. The high prevalence of T. tonsurans in lesions of
tinea corporis gladiatorum suggests a possible link to asymptomatic scalp shedding by some athletes. The mats play little
role in transmission of these infectious organisms. Only very
rarely have investigators demonstrated dermatophytes on the
wrestling mats. If mats did play a role, lesions on the legs would
not be as uncommon as they are.
Well-defined, round, erythematous, scaling papules and
plaques typify tinea corporis gladiatorum (Fig. 18.5). The annular morphology, typical of tinea corporis, is often not found.
Lesions of tinea corporis gladiatorum occur most commonly on

244 — Brian B. Adams

Table 18.7: Guidelines for Return to Competition for Tinea
Corporis Gladiatorum (Based on NCAA Guidelines)
1) Use a topical fungicidal agent for at least 72 hours
2) Wash with ketoconazole shampoo
3) Cover with naftifine or terbinafine
4) Cover with op-site or bioclusive
5) Cover with tape
NCAA 2006 Wrestling Rules and Interpretations. Appendix D Skin
Infections.

the head and neck (32%), upper extremities (38%), and trunk
(24%). The differential diagnosis, especially early in the course
of the disease, includes herpes gladiatorum, impetigo, subacute
dermatitis, and acne.
First and foremost, athletes should apply warm moist washcloths to the affected area for 10 minutes three times per day.
Several studies have documented pharmacologic options for
tinea corporis gladiatorum. No studies have investigated either
the oral or the topical form of the allylamines. Not surprisingly,
oral antifungal agents clear tinea corporis gladiatorum much
more quickly. Half of the wrestlers, in one study, had negative
cultures after 23 days while using topical clotrimazole twice
daily. However, the same number of wrestlers had negative cultures after only 11 days while taking once-weekly fluconazole.
No clear evidence-based data exists for appropriate return to
competition after experiencing tinea corporis gladiatorum. The
current recommendations for return to NCAA competition
include the use of topical fungicidal agents for at least 72 hours.
In addition, to compete, the athlete must wash with ketoconazole shampoo and cover the lesion with naftifine or terbinafine,
followed by op-site or bioclusive and then tape (Table 18.7).
While little evidence supports the transmission of tinea corporis gladiatorum via mats, headgear, or pads, sharing of equipment should be discouraged. Athletes should practice impeccable
hygiene that includes showering immediately after practice and
competitions, washing with antibacterial soaps or Hibiclens, and
not sharing equipment or towels. Athletes with recurrent disease
should also minimize the amount of skin exposed during skinto-skin contact. Long-sleeved moisture-wicking synthetic clothing also should be used since it allows the athlete’s skin to stay
dry and helps prevent the transmission of tinea corporis gladiatorum among other athletes (Table 18.1).
At-risk athletes should take season-long pharmacological
prevention, which consists of weekly fluconazole (100 mg) or
every other week itraconazole (400 mg in divided doses). Studies
have demonstrated a decrease in prevalence compared to placebo
with both regimens. Clinicians should consider obtaining baseline liver function tests before subjecting the athlete to these
therapies since they last several months.
AT Y P I C A L M YC O BA C T E R IA  S W I M M I N G
POOL GRANULOMA

Caused by Mycobacterium marinum, swimming pool granuloma once caused an epidemic in 290 swimmers from a single

pool. The clinical morphology presents with a myriad of morphologies including papules, nodules, and ulcers distributed
on skin surfaces exposed to the microorganism (most often
the extremities in swimmers). Biopsy and culture of fresh tissue confirms the diagnosis, since the clinical differential diagnosis is vast. The cultures may take several weeks to grow.
Various treatments exist and include combinations of minocycline, clarithromycin, or rifampin. Aquatic athletes need to
attend carefully to abrasions to prevent this swimming pool
granuloma.

PA R A S I T E S  C U T A N E O U S L A R VA
MIGRANS

Ancyclostoma has caused cutaneous larva migrans in sand volleyball players. Infected animals’ feces contain the organisms’
eggs. The larvae that hatch from these eggs penetrate athletes’
skin especially if the stratum corneum possesses any disruption
related to the individual’s sporting activity. The larvae migrate
within the skin and create a linear erythematous plaque that in
athletes happens to occur most often on the lower extremities.
This hookworm may migrate several centimeters per day within
the epidermis. Treatment includes topical thiabendazole for
limited disease or oral thiabendazole for diffuse or recalcitrant
conditions.

P I T FA L L S A N D M Y T H S

The most common pitfall in sports dermatology is to misdiagnose cutaneous infections. Athletic trainers, coaches, and athletes, with heightened awareness, are often concerned about very
small lesions early in the course of disease. As a result, clinicians
are called upon to make accurate diagnoses based on fairly nonspecific morphologic features. Early lesions of tinea corporis,
herpes simplex, and impetigo can easily be confused. Cultures
and direct examination are invaluable tools in making a correct
diagnosis.
Additionally, very small lesions of molluscum contagiosum
(often found beneath protective clothing or tight-fitting uniforms or undergarments) can easily be confused with noninfectious folliculitis or acne. Appropriate therapy, may therefore
be delayed, which results in the spread of the causative organism to other areas of the athlete’s skin or among teammates or
competitors.
Athletes and clinicians often fail to recognize the presence
of verruca in lesions they believe to be calluses. Calluses are
common to sporting activities and there is some evidence to
suggest that viruses that cause warts find refuge in these sportsrelated calluses. Not all thick areas of skin on the hands or feet
of an athlete are calluses; if careful sharp paring of the thick
skin reveals pinpoint black hemorrhages, the callus is or contains a wart.
Lastly, athletes and those entrusted to care for their medical
needs frequently ignore “dry skin” on their feet. This “dry skin”
is frequently KOH positive. Most of the 70% of collegiate and
professional athletes who had KOH positive tinea pedis did not
identify that they had “athlete’s foot.”

Skin Infections in Athletes — 245
SUGGESTED READING

Adams BB. Tinea corporis gladiatorum. A cross-sectional study. J Am
Acad Dermatol 2000;43:1039–1041.
Adams BB. Sports dermatology. Adolesc Med 2001;2:305–322.
Adams BB. Dermatologic disorders of the athlete. Sports Med
2002;32:309–321.
Adams BB. Tinea corporis gladiatorum. J Am Acad Dermatol 2002;
47:286–390.
Adams BB. Sports Dermatology. New York, New York: Springer Science
and Business Media LLC, 2006.
Anderson BJ. The effectiveness of valacyclovir in preventing reactivation of herpes gladiatorum in wrestlers. Clin J Sport Med
1999;9:86–90.
Belongia EA, Goodman JL, Holland EJ et al. An outbreak of herpes
gladiatorum at a high-school wrestling camp. New Engl J Med
1991;325:906–910.
Biolcati G, Alabiso A. Creeping eruption of larva migrans – A
case report in a beach volley athlete. Int J Sports Med 1997;18:
612–613.
Chandrasekar PH, Rolston KVI, Kannangara W et al. Hot tub associated dermatitis due to Pseudomonas aeruginosa. Arch Dermatol
1984;120:1337–1340.

Detandt M, Nolard N. Fungal contamination of the floors of swimming pools particularly subtropical swimming paradises. Mycoses
1995;38:509–513.
Hazen PG, Weil ML. Itraconazole in the prevention and management
of dermatophytosis in competitive wrestlers. J Am Acad Dematol
1997;36:481–482.
Kamihama T, Kimura T, Hosokawa JI et al. Tinea pedis outbreak in
swimming pools in Japan. Pub Health 1997;111:249–253.
Kohl TD, Martin DC, Berger MS. Comparison of topical and oral treatments for tinea gladiatorum. Clin J Sport Med 1999;9:161–166.
Kohl TD, Martin DC, Nemeth R, Hill T, Evans D. Fluconazole for the
prevention and treatment of tinea gladiatorum. Pediatr Infect Dis
J 2000;19:717–722.
Lindenmayer JM, Schoenfeld S, O’Grady P et al. Methicillin-resistant
Staphylococcus aureus in a high school wrestling team and the
surrounding community. Arch Intern Med 1998;158:895–899.
Philpott JA, Woodburne AR, Philpott OS et al. Swimming pool
granuloma. A study of 290 cases. Arch Dermatol 1963;88:
158–161.
Selling B, Kibrick S. An outbreak of herpes simplex among wrestlers
(herpes gladiatorum). N Engl J Med 1964;270:979–982.
Sosin DM, Gunn RA, Ford WL, et al. An outbreak of furunculosis
among high school athletes. Am J Sports Med 1989;17:828–832.

19

SKIN INFECTIONS IN DIABETES
MELLITUS
Nawaf Al-Mutairi

Skin infections are common in diabetic patients. They can
even be the presenting feature of diabetes mellitus. A high
index of suspicion in patients suffering from recurrent common skin infections, or with severe uncommon or rare infections, sometimes helps in detecting diabetes in a person
previously not known to have this common condition. There
can be many factors underlying increased susceptibility to skin
infections in diabetics including poor microcirculation, hypohidrosis, peripheral vascular disease, peripheral neuropathy,
and the decreased immune response seen in diabetics. Some
of these factors may result in poor wound healing for these
patients.
Decreased neutrophil chemotaxis and phagocytosis predisposes diabetic patients to an increased susceptibility of
infections. The incidence of colonization as well as infections
of the skin with bacteria such as Staphylococcus, Streptococcus,
and yeast (Candida albicans) in patients with poor control of
diabetes is increased. Dermatophyte infections are not more
frequent in diabetic than in nondiabetic individuals. Some
of the rare but serious and life-threatening infections of skin
such as necrotizing fasciitis, malignant otitis externa, and
mucormycosis are more common in diabetics and require
special mention.

H I STORY

Before the advent of insulin and antibiotics, bacteria causing
severe or extensive furuncles, carbuncles, ecthyma, cellulitis, and
styes were frequent among diabetic patients. These infections
are still commonly encountered among diabetic patients especially in developing countries where the lifelong management
of underlying diabetes in many patients may not be optimum
because of the cost involved or ignorance.

DIAGNOSIS

Any person presenting with frequent, unusually severe or extensive common bacterial skin infections such as furuncles, carbuncles, cellulitis, ecthyma, erythrasma, or rare but life-threatening
infections such as necrotizing fasciitis, malignant otitis externa,
and mucormycosis should be investigated to rule out diabetes.
Skin signs and symptoms may sometimes be surprisingly misleading even in the presence of serious infections in diabetics.
Bacteriologic culture and sensitivity evaluation of the properly
collected material in common infections, and blood in severe
infections, is of paramount importance in management of
these infections. A simple investigation such as Gram’s stain of
the purulent material may provide an early clue to the etiology.
Gram’s stain is better than KOH examination in demonstrating
corynebacteria causing erythrasma. Material for culture may be
collected via swabbing, injecting saline into the affected area and
then aspirating the material, aspiration of blister fluid, or biopsy.
However, even with all these procedures bacterial culture may
not yield positive results in conditions such as erysipelas and
cellulitis. Streptococcal serology may be helpful retrospectively.
At onset of disease, high titers indicate infection. Serology at
days 1 and 14 are also helpful but early institution of antibiotics
can alter the antibody response. Immunofluorescence identifies
streptococcal group antigens on biopsy specimens. Recurrent
balanitis (infection of the prepuce) or balanoposthitis (infection of the foreskin and glans penis) in males and vaginal discharge (moniliasis) in females due to Candida albicans should
also prompt laboratory investigation for diabetes. Simple KOH
examination of swabs from genitalia will reveal the yeast which
should be budding in active infection.
Cellulitis, erysipelas, and necrotizing fasciitis are primarily
streptococcal diseases. Sometimes pure staphylococcal infection
can cause cellulitis, and mixed infection with both may be present in many cases. Other bacteria such as pseudomonas can also
rarely cause these infections.

EPIDEMIOLOGY

Poor glycemic control is often associated with an increased
incidence of skin infections in diabetics. At least one-third of
persons with diabetes have some cutaneous involvement during the course of this chronic disease. Cutaneous infections are
among the more common skin manifestations of diabetes. The
incidence of skin infections in diabetics shows a close correlation to the patients’ mean blood glucose levels. Skin infections
occur in 20% to 50% of diabetics, but more often in type 2 diabetic patients.
246

C U TA N E O U S I N F E C T I O N S T H AT M AY
B E I N D I C AT I V E O F U N D E R LY I N G
DIABETES MELLITUS

Candida infections
Infections of the mouth (oral thrush, angular cheilitis), nail folds
(paronychia), and genitalia (balanitis/balanoposthitis in males,
and moniliasis/vaginal thrush in females) due to the commonly
present commensal yeast Candida albicans are frequent in diabetics. Candidiasis may be the first presenting clinical feature

Skin Infections in Diabetes Mellitus — 247

Figure 19.1. Candidal paronychia with nail dystrophy affecting
multiple fingers.

Figure 19.2. Paronychia with nail dystrophy.

of diabetes, and it is frequently seen in patients whose diabetes
is not well controlled. A crucial factor is the amount of available glucose in the oral cavity and if this is markedly elevated, as
in diabetes, the normal bacterial flora will not inhibit the yeast.
In the mouth, carbohydrate levels are important. Food debris,
likely to be present in the mouth of the severely ill patient with
inadequate oral hygiene, should not be ignored. High glucose
levels in urine, general tissue fluids, and sweat may make diabetics more susceptible to candidal infections. Phagocytosis is also
impaired in diabetics. Any form of local tissue damage may be
important in the pathogenesis of candidiasis. Increased levels of
glucose in the saliva seem to be responsible for oral candidiasis
in diabetics.

Dermatophyte Fungal Infections
It is traditionally mentioned in most textbooks that the incidence
of superficial dermatophytic fungal infection of the skin is not
increased in diabetic patients. Some of the recent studies, however, have contradicted this. The incidence of superficial dermatophyte fungal infections, especially the moccasin-type tinea
pedis and some other clinical types, has been reported to be
underreported among diabetics.
Angular stomatitis/cheilitis is characterized by redness,
erosions, or fissures at the angles of the mouth. Paronychia
(Figs. 19.1 and 19. 2) produces redness, swelling, pain of proximal and lateral nail folds, and sometimes loss of the cuticle. It
is a very chronic and resistant condition, especially in persons
involved in jobs involving frequent or prolonged contact with
water such as housewives, cooks, chefs, and others. Secondary
bacterial infection with Pseudomonas can result in severe pain
and pus discharge from under the nail fold. Persistent paronychia invariably results in nail dystrophy (Fig. 19.2).
Candida infections of the female genitalia producing curd
white vaginal discharge, soreness, redness, and itching in the
vulva is fairly common in women with diabetes. Intertrigo (erythema and/or maceration of the skin) over inframammary area
in obese female diabetic patients (Fig. 19.3) and web space skin
between the toes (Fig. 19.4) and fingers (Fig. 19.5) (especially the
middle and fourth toes) is also a common occurrence in both

Figure 19.3. Candidal intertrigo of the inframammary area in an
obese diabetic female.

Figure 19.4. Intertrigo of a toe web: a potential source of cellulitis of
the lower limbs.

248 — Nawaf Al-Mutairi

Figure 19.5. Candidal intertrigo of finger webs.

Figure 19.7. Bilateral extensive furunculosis of both legs.

Figure 19.6. Large furuncle affecting the lower limb.

Figure 19.8. Carbuncle: Staphylococcal aureus infection of contiguous
hair follicles in the nape of the neck.

male and female diabetics. Redness, superficial white scaling,
and linear erosions of the foreskin (balanoposthitis) and glans
penis (balanitis), which can cause some discomfort, pain, or
itching in some patients can be the presenting feature of diabetes
in males. Phimosis is a common complication in these patients.
Control of blood sugar and treatment with topical antifungals
usually clears these infections. However, oral ketoconazole is
sometimes required, especially for cases of paronychia. Singledose oral fluconazole 150 mg is an effective and convenient treatment for vaginal candidiasis in women.

Cutaneous Bacterial Infections in Diabetics
Common bacterial infections of the skin in diabetics are usually
caused by Staphylococcus aureus and β-hemolytic streptococci.
They include clinical presentations such as recurrent furuncles,
carbuncles, ecthyma, cellulitis, and erysipelas.
A furuncle (Fig. 19.6) is an acute, usually necrotic, infection
of the hair follicle with S. aureus, which results in an abscess of the
hair follicle. The perifollicular abscess then necroses and destroys
the hair follicle. Clinically this produces an erythematous, warm,

tender, painful nodule centered around a hair follicle, which
forms a pus point on top of the lesions. It is a common infection in normal people but recurrent and extensive furuncles
(Fig. 19.7) in a patient should prompt work-up for the presence
of diabetes. The main defence against staphylococci is ingestion
and killing by phagocytes, a function which may be deficient in
diabetics. Resistance to staphylococcal infection is reduced in
patients with poorly controlled diabetes.
A carbuncle (Fig. 19.8) is a deep infection of a group of contiguous hair follicles with S. aureus, accompanied by intense
inflammatory changes in the surrounding and underlying connective tissues and subcutaneous fat. Carbuncles occur mainly in
men, and usually in middle or old age. They may be seen in the
apparently healthy but are more common in diabetics. The term
“carbuncle” in Latin means “a small, fiery coal”. It aptly describes
the painful, hard, red lump that is the initial stage of infection.
The carbuncle is smooth, dome-shaped, and acutely tender.
It increases in size for a few days, to reach a diameter of 3 to
10 cm or occasionally more. Suppuration begins after some 5 to 7
days, and pus is discharged from the multiple adjacent follicular

Skin Infections in Diabetes Mellitus — 249

orifices. Most lesions occur on the back of the neck (Fig. 19.8), the
shoulders or the hips and thighs. Although usually solitary, these
lesions can be multiple or associated with one or more furuncles.
Constitutional symptoms may accompany, or even precede the
development of skin lesions. Fever may be high, and malaise
and prostration may be extreme if the carbuncle is large or if the
patient’s general condition is poor. The lesion heals slowly to leave
a scar. However, in patients with poor general health, death may
occur from toxemia or from metastatic infection.
A swab of the pus must be taken for culture and sensitivity.
Treatment, however, should not be postponed until bacteriological confirmation is available. Cloxacillin or another penicillinaseresistant antibiotic should be given.
Erysipelas is a bacterial infection of the lower dermis and the
superficial part of subcutaneous tissue resulting in the sudden
appearance of a bright red, edematous, warm, tender swelling
with a well-defined edge, usually on the face or legs. Blistering
and hemorrhage in the superficial skin may result. The patient
can look ill and toxic with constitutional symptoms. Group A
streptococci are usually implicated. Pus and blood cultures are
essential parts of management. Swabs taken from intact overlying skin, saline injection followed by needle aspiration, biopsy,
and even blister fluid may not yield any results. Some organisms
are present in very small numbers.
Blood cultures and swabs from possible entry sites, like
wounds or inflammatory lesions situated distal to the infection
occasionally yield relevant organisms. Streptococcal serology
may be helpful retrospectively. Poor glycemic control predisposes to erysipelas, however, at the same time the infection can
result in hyperglycemia.
Cellulitis refers to the acute, subacute, or chronic inflammation
of subcutaneous tissue. The infectious agent is usually bacterial.
Minor injuries or scratches can introduce the infection. A firm,
red, tender, diffuse swelling without a well-demarcated edge of
the involved part, usually a limb or the face, is produced. It
has been observed many times that features of both cellulitis
and erysipelas can coexist. In such cases, a well-defined edge
is present in one part, and there is diffuse involvement in the
other part of the lesion. Moreover, erysipelas can extend deeper
into the subcutaneous tissue, and cellulitis may spread upward
into the superficial skin, making clinical distinction between
the two conditions impossible. Currently, erysipelas is accepted
as a form of superficial cellulitis by many. Streptococci are usually the pathogens responsible for both conditions. However,
S. aureus alone can also cause cellulitis. Constitutional symptoms are invariably present in both erysipelas and cellulitis.
Exceptions to this rule can be found in some milder cases.
Severe cellulitis can result in bullae (Fig. 19.9), dermal necrosis, myositis, and fasciitis. In one study, cultures of biopsy
specimens, needle aspirates, and samples from probable sites of
entry in 50 patients with cellulitis gave a positive result in only
26% of the cases.

Erythrasma
Erythrasma is a mild, chronic, localized superficial infection of the skin caused by the aerobic coryneform bacterium,
Corynebacterium minutissimum. It is frequently present as normal flora, especially in the toe clefts. A warm, humid climate is
a predisposing factor. A Wood’s lamp examination shows a coral

Figure 19.9. Cellulitis with bullae and superficial necrosis of the skin.

red fluorescence. Erythrasma is a common infection in diabetics.
Erythrasma that is extensive and persistent and involves the axillae, inframammary folds, and large areas of the trunk and groins,
is particularly common in obese, middle-aged women. Gram’s
staining of the scales reveals gram-positive rods and filaments
(Figs. 19.10 and 19.11).
Irregular, sharply demarcated, initially red, but later brown
patches with fine branny scaling are produced (Fig. 19.12). In
colder regions, erythrasma is asymptomatic. In the warmer areas,
however, irritation of lesions in the groins may lead to scratching and lichenification. Pruritus ani can be a symptom in lesions
involving perianal skin. Clinical differential diagnosis includes
tinea versicolor, dermatophytosis, psoriasis, and candidiasis.
Wood’s light examination and bacterial and fungal cultures help
in diagnosis. Topical azole antifungal creams such as clotrimazole or miconazole are helpful in treating this condition. The
antibiotic cream fucidin applied twice a day for 2 weeks is also
effective. Rarely, systemic treatment with erythromycin 500 mg
QID for 2 weeks is required.

L I F E  T H R E AT E N I N G I N F E C T I O N S
IN DIABETICS

Certain skin and soft tissue infections that are potentially lethal
are more common in diabetics than in normal healthy individuals. Two of these are necrotizing fasciitis and malignant external
otitis. Both of these conditions deserve special mention.

250 — Nawaf Al-Mutairi

Figure 19.10. Erythrasma affecting the groins.
Figure 19.12. Erythrasma showing typical fine scaling and mild
erythema.

Necrotizing fasciitis

Figure 19.11. Erythrasma affecting the axilla.

This is a serious, life-threatening infection of the subcutaneous
tissue associated with severe necrosis of underlying tissues (subcutaneous adipose tissue, muscle, fascia, and sometimes, even
bone). The hallmark of this infection is an extensive necrosis accompanying cellulitis. There are two types. One is pure
streptococcal (β-hemolytic Group A streptococci) and mixed
infections type which consists of multiple organisms, and one
is usually an anaerobe. The infections of mixed bacterial origin
are common in diabetics, and include Streptococcus pyogenes,
S. aureus, anaerobic streptococci and Bacteroides. The patient
is usually severely ill and toxic, and mortality of over 45% has
been reported in some case studies. Trauma, infection, diabetes mellitus, and previous surgery are the predisposing factors.
Clinical features appear to be part of a spectrum ranging from
cellulitis to myonecrosis. Erythema, which may become dusky
red, appears within 24 to 48 hours. Bullae that are initially clear
can develop. These later on become hemorrhagic or maroon.
Bullae indicate an already extensive deep soft tissue destruction
such as necrosis of the fascia or muscle. The extent of infection is
variable. In some cases, pathology is restricted to a zone bound
by fascia while in others infection extends to involve muscle
and deep vessels. Swabs from the skin surface are usually negative. The most important step in diagnosis and management
is surgical exploration in which subcutaneous tissues down to
the fascia are found to be necrotic and may contain chains of

Skin Infections in Diabetes Mellitus — 251

gram-positive bacilli. A high index of suspicion and meticulous
physical examination is required to make an early diagnosis. The
diagnosis can be life saving because progression from an indolent presentation starting as a benign infectious process such
as a furuncle to the one resulting in extensive tissue damage,
toxicity, loss of limb, or even death can take place fairly rapidly
among diabetics. Institution of high-dose IV penicillin therapy
with metronidazole and supportive care while awaiting results
of microbiologic work-up is crucial. Surgical debridement of
infected devitalized tissue and surrounding areas is essential
and should not be delayed. High-dose IV antibiotics should be
started empirically, before awaiting the results of culture and
sensitivity. Antibiotics alone, without surgical debridement, are
rarely successful in saving the patient or the affected limb. Even
with optimal care involving surgery and antibiotics, mortality
rate is as high as 20% to 45%. It must be emphasized that 80%
of cases of necrotizing fasciitis begin as a trivial skin lesion such
as a boil, insect bite, or injection site infection. Decubitus ulcers
along with the skin of the perineum and extremities are often
sites where the condition first starts.

Fournier’s Gangrene
These patients are usually diabetic. It is a suddenly erupting and
rapidly progressing infection that involves the fascial planes
of the lower abdominal wall, and extends to the scrotum and
perineum. It can be caused by group A streptococci or multiple
organisms. More commonly, however, it is caused by the latter.
The condition carries a high mortality rate of around 40% despite
surgical intervention or antibiotic use. It has been regarded as a
synergistic necrotizing cellulitis or a subtype of necrotizing fasciitis. The management is similar to that of necrotizing fasciitis.

Malignant otitis externa
It is an invasive infection of the external auditory canal that typically occurs in immunocompromised individuals. The patients
are usually elderly diabetics. Diabetic microangiopathy of the ear
canal causing poor perfusion of the pinna or an increase in the
pH of ear canal cerumen may be responsible. However, no correlation has been found with poor glycemic control. Pseudomonas
aeroginosa is the causative organism in more than 95% of the
cases. The patient presents with a purulent ear discharge and
severe pain. The condition begins as cellulitis in the preaural
area and surrounding skin. It can then progress to chondritis,
osteomyelitis of the skull base, cerebritis, and thrombosis of
the intracranial vessels. A tender pinna and preauricular area, a
swollen external auditory canal, purulent discharge, and granulation tissue at the junction of the cartilaginous and bony parts
are all clinical signs. A high level of clinical suspicion along with
laboratory investigations showing leukocytosis and a markedly
raised ESR are suggestive. CT, MRI, bone scan, and thallium
scan can reveal the extent of bony involvement. Treatment consists of ear canal irrigation, drainage, debridement of devitalized
tissue if needed, along with parenteral or oral quinolones for
6 to 8 weeks, especially if osteomyelitis is present. Resistant
pseudomonas infection requires prolonged treatment with IV
antipseudomonal β-lactam with or without an aminoglycoside.
Correction of acid–base imbalances is also necessary.

Rhinocerebral mucormycosis
Hyperglycemia may permit nonpathogenic organisms to
establish an infection in traumatized skin. Patients with uncontrolled diabetes are predisposed to deep fungal infections.
Rhinocerebral mucormycosis is a rare life-threatening complication of diabetes. It may be a presenting feature of diabetes
in the elderly. Diabetic ketoacidosis is present in most patients
at the time of diagnosis. The causative organism is the fungus
belonging to the class Zygomycetes, which is ubiquitous in
nature, and can be found on decaying vegetation and in the soil.
Hyperglycemia, acidosis, and the increased serum iron levels in
diabetic patients provide favorable growth conditions for these
fungi.
The clinical features include fever, facial cellulitis, periorbital edema, proptosis, blindness, and black eschars in the nasal
mucosa or the palate due to ischemic necrosis of the tissue.
The infection can spread throughout the sinuses and cause cranial nerve palsies, and it can also cause the patient to become
obtunded. Facial numbness from infarction of the fifth cranial
nerve can also be seen.
The diagnosis should be suspected in any poorly controlled
diabetic presenting with sinusitis and purulent nasal discharge,
metabolic acidosis, altered mentation, and/or nasal or palatal
infarction. Endoscopy of the sinuses to look for infarction and
to obtain specimens for culture is recommended. Characteristic
broad nonseptate hyphae with right angle branching are seen
using calcoflour white or methanamine silver stains. CT and
MRI imaging is required to assess sinus involvement and to
evaluate contiguous ocular and intracranial structures. Surgical
debridement and parenteral amphotericin B are the treatments
of choice.

P I T FA L L S A N D M Y T H S

In diabetic patients signs of inflammation may be missing even
in the presence of severe, life-threatening cutaneous infections
like necrotizing fasciitis. Pain may be absent because of peripheral neuropathy. Contrastingly, some diabetic patients with
an underlying bacterial infection can present only with severe
pain and no obvious cutaneous signs. In these cases, bacteria
are present in affected tissues in low numbers. Even with multiple techniques of collecting samples for microbiologic studies the diagnosis can be difficult. The culture positivity is low
in erysipelas and cellulitis. Swab from fissures, erosions, ulcers
or injury sites distal to the site of these infections may yield
relevant organism in some cases. Surface swabs from intact
skin are unhelpful. In the case of facial infections, the pathogen
should be sought in the nose, throat, conjunctiva, and sinuses.
Toe webs must always be examined to look for evidence of
intertrigo (maceration of the skin between toewebs) as that
may be the portal of entry or source of bacteria for cellulitis
on the legs. Deep vein thrombosis of the lower limbs can mimick cellulitis to a great extent. Phlebography, plethysmography,
and Doppler ultrasound helps to decipher between the two. A
simple and inexpensive test is to determine the protein concentration of the edema fluid; levels more than 10g/L indicate
cellulitis whereas levels are usually around 5 g/L in deep vein
thromboses.

252 — Nawaf Al-Mutairi

PRINCIPLES OF THERAPY IN DIABETIC
PA T I E N T S W I T H C U TA N E O U S
INFECTIONS

1. Any patient suffering from recurrent or extensive furuncles,
cellulitis, erysipelas, ecthyma, candidal balanitis/balanoposthitis, vaginal candidiasis, paronychia, and intertrigo should
be investigated for diabetes.
2. Cutaneous signs and symptoms of infection may be absent
even in presence of severe infection due to peripheral neuropathy. A high index of suspicion is required especially in
elderly diabetics.
3. Therapy should not be delayed until the results of culture
studies are available in cases presenting with clinical features suggestive of erysipelas/cellulitis, necrotizing fasciitis,
malignant otitis externa, or Fourniers’ gangrene as these
are all possibly life threatening conditions. IV antibiotics
should be started promptly. High-dose parenteral IV penicillin along with metronidazole in suspected mixed infection
origin cases of necrotizing fasciitis and Fournier’s gangrene
should be started immediately, pending availability of culture results.
4. Surgical debridement is life saving in necrotizing fasciitis
and should not be postponed unnecessarily.
5. Samples for microbiology should be collected from blister
fluid, erosions, ulcers, injury, or inflammatory lesions distal
to the site of cellulitis/erysipelas, necrotizing fasciitis, malignant otitis externa, and Fourniers’. Blood cultures should also
be part of the work-up.
6. In facial infections, samples should be taken from the throat,
nose, conjunctiva, and sinuses. Needle aspiration for collecting samples on the face should be avoided.
7. Measures to control hyperglycemia, management of fluid,
and acid–base balance should be an integral part of the
management, especially in severe infections.

8. Diabetic foot care to prevent detect and treat toe web
intertrigo early can reduce the incidence of cellulitis and
necrotizing fasciitis.
SUGGESTED READING

Ahmed I, Goldstein B. Diabetes mellitus. Clin Dermatol
2006;24(4):237–246.
Al-Mutairi N, Zaki A, Sharma AK, Al-Sheltawi M. Cutaneous manifestations of diabetes mellitus. Study from Farwaniya hospital,
Kuwait. Med Princ Pract 2006;15(6):427–430.
Al-Mutairi N. Skin diseases seen in diabetes mellitus. Bulletin Kuwait
Institute of Medical Specialization 2006;5:30–39.
Ferringer T, Miller F 3rd. Cutaneous manifestations of diabetes mellitus. Dermatol Clin 2002;20(3):483–492.
Mayser P, Hensel J, Thoma W, Podobinska M, Geiger M, Ulbricht H,
Haak T. Prevalence of fungal foot infections in patients with diabetes mellitus type 1 – underestimation of moccasin-type tinea.
Exp Clin Endocrinol Diabetes 2004;112(5):264–268.
Muller LM, Gorter KJ, Hak E, Goudzwaard WL, Schellevis FG,
Hoepelman IM, Rutten GE. Increased risk of infection in
patients with diabetes mellitus type 1 or 2. Clin Infect Dis
2005;41(3):281–8.
Rajagopalan S. Serious infections in elderly patients with diabetes mellitus. Clin Infect Dise 2005;40(7):990–996.
Rich P. Treatment of uncomplicated skin and skin structure infections in the diabetic patient. J Drugs Dermatol 2005;4(6 Suppl):
s26–29.
Saw A, Kwan MK, Sengupta S. Necrotizing fasciitis: a life-threatening
complication of acupuncture in a patient with diabetes mellitus.
Singapore Med J 2004;45(4):180–182.
Tabor CA, Parlette EC. Cutaneous manifestations of diabetes. Signs of
poor glycemic control. Postgrad Med 2006;119(3):38–44.
Tan JS, Joseph WS. Common fungal infections of the feet in patients
with diabetes mellitus. Drugs Aging 2004;21(2):101–112.
Yoga R, Khairul A, Sunita K Suresh C. Bacteriology of diabetic foot
lesions. Med J Malaysia 2006;61 Suppl A:14–16.

PA R T V: I N F E C T I O N S O F S P E C I F I C
S K I N  A S S O C IAT E D B O DY S I T E S

20

INFECTIONS OF THE SCALP
Shannon Harrison, Haydee Knott, and Wilma F. Bergfeld

INTRODUCTION

As an important component of skin, the hair-bearing scalp
represents a unique microenvironment, which is afflicted by
unique infections caused by many organisms such as fungi,
viruses, parasites, and bacteria. Scalp infections affect all ages,
both males and females and all races. This chapter describes the
distinctive features of the hair-bearing scalp and its associated
infections with highlights of current treatment regimes.

H I STORY

Scalp symptoms and conditions are common. Given the significance of scalp hair in today’s society, visible changes in the hair
and scalp such as erythema, scaling, and hair loss can cause considerable psychological distress and affect self-esteem. Although
there are many causes of hair loss not associated with infections,
infections of the scalp can lead to alopecia. Scalp infections are
caused by various pathogenic organisms and were described
years ago in Ancient Egypt.

S C A L P A NAT O M Y

The scalp is comprised of five distinct layers: the skin, the subcutaneous layer, the galea aponeurosis, the loose areolar layer, and
the periosteum. The frontalis and occipitalis muscles merge with
the galea anteriorly and posteriorly respectively, and the temporalis muscle lies deeper under the loose areolar layer laterally.
Important for scalp infections is the density of hair follicles and
sebaceous glands (pilosebaceous units). In individuals without
alopecia, the hair-bearing scalp contains approximately one hundred thousand (100, 000) hair follicles, which provide not only
UV protection, but also considerable thermal insulation, creating an environment, which is warmer, darker, and more moist
than in the non–hair-bearing parts of the body. The follicular
environment supports the growth of microorganisms.
The pilosebaceous unit consists of the hair shaft, the hair follicle, the sebaceous gland, the sensory end organ, and the arrector pili muscle. The hair follicle can be structurally divided into
three components. The inferior component is located below the
insertion of the arrector pili muscle and includes the hair bulb.
The middle component is called the isthmus and corresponds to

Dr. Harrison was funded by the F. C. Florance Bequest through the
Australasian College of Dermatologists in 2008.

the insertion of the arrector pili muscle to the infundibulum and
includes the bulge. The topmost component, or infundibulum,
extends from the skin surface to the opening of the sebaceous
gland. The hair shaft arises from the hair bulb, a rounded structure that contains the hair matrix, or cells, which give rise to the
hair. The infundibulum hosts many normal organisms such as
Malassezia species, Staphylococcus epidermidis, and occasionally
Demodex. When the follicle is overwhelmed with the overgrowth
of organisms, a folliculitis is frequently observed.
The sebaceous glands are unilobular or multilobular structures, which empty into the hair follicle via a short duct. The
sebaceous glands produce an oily substance (sebum) which supplies emollients for the hair and skin. Sebum production peaks
in late adolescence and thereafter declines with age. Sebum production is linked to androgen production, signaling the increase
in circulating androgen levels in puberty and the decrease in
androgen production with increasing age.
The unique anatomical and structural elements of the scalp
reflect the characteristic diseases seen on the scalp. The dense
covering of hair follicles on the scalp provides a warm, dark environment for microorganisms to flourish. Furthermore, due to the
density of hair follicles on the scalp, increased absorption of topical agents occurs via the hair root sheaths. The scalp is associated
usually with a high rate of sebum production, which provides a
rich source of nutrition for microorganisms, particularly when
combined with desquamated skin. The integrity of the scalp epidermis can be disrupted by friction and physical trauma from
the use of combs, brushes, and other grooming tools, as well as
chemicals used during the hair dying, perming, and straightening processes. These processes may create portals for infection
on the scalp. In addition, shared hats, scarves, and hair accessories can introduce infection. The use of some hair products and
occlusive emollients on the scalp can also predispose the hair follicle to infection. Therefore, the scalp is susceptible to a variety of
infections, including superficial mycoses, parasitic and bacterial
infections, and infective scarring processes.

FUNGAL INFECTIONS

Seborrheic dermatitis and pityriasis capitis
Seborrheic dermatitis and pityriasis capitis (dandruff ) are
recognized as two manifestations of a single disease process,
although differing in severity (Table 20.1). Caused by Malassezia
species, previously known as Pityrosporum species, these lipophilic, putative yeasts feed off of the lipids in sebum in patients
with high levels of sebaceous gland activity. Global lifetime prevalence rates of Malassezia verge on 50%. Seborrheic dermatitis most
255

256 — Shannon Harrison, Haydee Knott, and Wilma F. Bergfeld

commonly occurs in adults, between the ages of 15 and 50 years, in
susceptible individuals with the postpubertal increase in androgen
levels and the following rise in sebum production. Seborrheic dermatitis can persist into senescence. Seborrheic dermatitis, commonly known as “cradle cap” is also seen in the infant, likely still
under the influence of circulating maternal androgens.
Immunocompetence is important in limiting the disease
incidence, with approximately 30% to 35% prevalence in immunocompromised adults. Seborrheic dermatitis is associated
with HIV infection where it may cause a generalized dermatitis
requiring therapy with oral ketaconazole. Seborrheic dermatitis
is also increased in patients with neurological conditions such as
Parkinson’s disease, cerebrovascular accidents, and head trauma.
The etiology of these diseases has recently been elucidated in
greater detail. While colonization with Malassezia globosa and
Malassezia restricta (yeasts) occurs in normal scalps, increased
activity of these organisms has been linked to the development of
the disease state. The lipophilic yeast is believed to digest sebaceous
triglycerides, producing free fatty acids. These free fatty acids then
penetrate the stratum corneum, disrupting the skin’s barrier function, leading to inflammatory changes, pruritus, and dryness. It
remains unknown why patients develop one clinical manifestation
versus another, but it is believed to be due to the severity of the
disease, the immune response, and the yeast burden.
Patients with pityriasis capitis (a variant of seborrheic dermatitis) classically experience loosely adherent, small white or grey
flakes, while patients with the more severe seborrheic dermatitis,
experience inflammatory changes of erythema, associated with yellow, greasy scales that collect to form crusts. Telogen effluvium can
also occur in response to scalp inflammation such as severe seborrheic dermatitis. Occasionally, due to the pruritus and scratching,
secondary bacterial infection can occur (Table 20.1). Frequently,
seborrheic dermatitis not only occurs on the scalp, but also involves
other areas of high sebum production including the face, posterior
auricular area, posterior neck, and the body. A Wood’s lamp can
be helpful in confirming the presence of the Malassezia organisms,
which fluoresce orange in active infections. Seborrheic dermatitis
will often demonstrate repeated exacerbations and remissions over
decades, and the treatment protocol needs to be relatively straightforward to ensure high levels of patient compliance.
Treatment consists of mono- or combined topical therapy
using antifungal, keratolytic, or antiproliferative agents (Table 20.1).
Management involves treating the acute exacerbation as well as
continued therapies for prevention and control. Antifungal shampoos (ketoconazole, sulfur, selenium sulfide, pyrithione zinc,
ciclopirox) are widely available and have been shown to be effective. Daily shampooing with an antifungal agent until the condition is under control is helpful. Tar shampoos are antiproliferative
and useful in reducing scale, but are not user friendly, given their
tendency to stain lighter colored hair and be odiferous. If the scale
is thick or severe, the use of keratolytic agents such as salicylic
acid in formulary preparations overnight to the scalp for a short
period will be required to dislodge and remove scale. Tar formulary preparations can also be used as an antiproliferative agent in
more severe cases. Patients with more severe presentations also
require topical corticosteroid to the scalp for a short period to
reduce inflammation and itch. The use of hair conditioners then
can be considered if the topical therapies are drying.
If a secondary bacterial infection is suspected, culture and
appropriate antibiotics should be started. Once the exacerbation

is controlled, regular maintenance of therapies includes use of an
antifungal shampoo every second day or three times per week.
Alternating with another shampoo or another medicated shampoo should be continued to ensure levels of yeast on the scalp
remain under control.

Pityriasis Amiantacea
Pityriasis amiantacea is characterized by thick, closely adherent
overlapping scales on the scalp surrounding the hair shafts. It can
be associated with temporary alopecia, or rarely a scarring alopecia. The etiology is unknown; however, it is believed to possibly involve multiple pathologies including seborrheic dermatitis,
tinea capitis, pyogenic infection, and poor hygiene in addition to
other inflammatory conditions of the scalp such as lichen planus
and psoriasis. It may even be idiopathic.
Management involves removal of the scale with a salicyclic
acid and/or tar preparations left on the scalp overnight or at least
4 to 5 hours before shampooing the hair. This needs to be continued daily until the scale is removed. Antifungal or tar shampoo needs to be continued daily. The underlying condition then
needs to be treated appropriately.

Tinea Capitis
Tinea capitis is a dermatophytosis of the hair follicles of the
scalp and while it is most common in childhood, it may present at any age. Tinea capitis can spread by exposure to infectious
contacts or fomites. There are three genera of dermatophytes:
Microsporum, Trichophyton, and Epidermophyton (Table 20.1).
Epidermophyton does not invade the hair shaft. Both Microsporum
and Trichophyton can infect the hair follicle. Trichophyton tonsurans, an anthrophilic agent, is the most common agent in
North America, Western Europe, and Australia and is increasing
in incidence. Infections in African-American and Latino children are also more likely to be caused by T. tonsurans. In Eastern
Europe, Trichophyton violaceum is the most common etiologic
agent. It should always be remembered that immigrants can be
infected by the organisms endemic to their country of origin.
Tinea capitis infections may be classified according to the
microscopic pattern of fungal invasion: endothrix, ectothrix, and
favus. Ectothrix infection is defined by sporulation around of the
hair shaft, weakening the cuticle and the shaft fractures several
millimeters from the scalp, leading to patchy alopecia with grayishwhite broken hair ends. This is most commonly associated with
Microsporum spp., including Microsporum canis, Microsporum
audouinii, Microsporum distortum, and also Trichophyton ferrugineum. In the United States, M. canis is the most commonly
encountered ectothrix pathogen. Endothrix infection grows
within the hair shaft and the hair breaks at the scalp surface, leading to “black dot” alopecia. Both T. tonsurans and T. violaceum
are endothrix infections (Table 20.1). Favus infections are usually
caused by Trichophyton schoenleinii. Favus is recognizable by firm
yellow crusts of hyphae and skin debris at the follicular orifices.
This type of infection can lead to a scarring alopecia. It is most
common in rural Africa and rural central Asia.
Symptoms of tinea capitis include well-demarcated or irregular alopecia, scaling, pruritus, and broken hair shafts (Table 20.1)
(Fig. 20.1). Clinically, tinea capitis can be inflammatory and noninflammatory. The noninflammatory variant usually presents

Infections of the Scalp — 257

Table 20.1: Fungal Infections of the Scalp
Condition

Organism

Clinical Presentation

Investigations

Treatment

Seborrheic dermatitis/
Pityriasis capitis

Malassezia globosa,
Malassezia restricta

Pruritus, grayish white-toyellow greasy scales with
erythema and crusting
± telogen effluvium

Wood’s light positive;
orange fluorescence
Bacterial cultures if
secondary infection
suspected

Antifungal shampoo
(selenium sulfide, zinc
pyrithione, ketoconazole,
ciclopirox), tar shampoo
Topical keratolytics
(salicylic acid)
Topical antiproliferatives
(tar)
Topical corticosteroids

Tinea capitis

Microsporum canis,
M. audouinii,
M. distortum,
T. ferrugineum

Ectothrix infections
causing white scaling
patchy alopecia
Pruritus

Small spore ectothrix
infections may
fluorescence green
under Wood’s light

Trichophyton tonsurans,
T. violaceum,
T. mentagrophytes,
T. verrucosum

Pruritus
Endothrix infection
causing “black dot” tinea
or inflammatory kerion
±lymphadenopathy

(Endothrix infections
do not)
Scrapings and hair
clippings for culture
and microscopy
Bacterial swab if
secondary infection
suspected

Antifungal shampoo
(selenium sulfide, zinc
pyrithione, ketoconazole,
ciclopirox)
Systemic antifungal agent
(griseofulvin, terbinafinesee text for further
details)
Systemic antibiotic if
secondary bacterial
infection
Cleaning of combs,
brushes, hair accessories
and fomites

Piedra hortae
Trichosporon asahii,
T. asteroides, T. cutaneum,
T. inkin, T. mucoides,
T. ovoides

Gritty adherent black or
beige annular nodules
encircling the hair shaft

Direct hair microcopy
with KOH preparation
and culture

Piedra (Black and white
variants)

Figure 20.1. Scaling dermatitis on the scalp of a child with hair loss of
tinea capitis.
“Photo courtesy of the Cleveland Clinic Department of
Dermatology.”

with oval patches of fine scaling with or without associated alopecia. Black-dot tinea capitis presents as areas of alopecia with
black dots on the scalp surface. Inflammatory tinea capitis is
characterized by a more aggressive presentation, ranging from
pustules to abscess formation and even the development of kerions. Associated lymphadenopathy can be found in the primary

Antifungal shampoo
(selenium sulfide, zinc
pyrithione, ketoconazole,
ciclopirox)
Cutting/shaving hair
Systemic azole antifungal
agent (see text)

Figure 20.2. A boggy mass on the scalp of a child with hair loss is
typical of a kerion.
“Photo courtesy of the Cleveland Clinic Department of
Dermatology.”

nodal basins (Table 20.1). Kerions are boggy, inflammatory scalp
masses (Fig. 20.2) often associated with infection by zoophilic
fungi such as T. mentagrophytes or T. verrucosum, but can also be

258 — Shannon Harrison, Haydee Knott, and Wilma F. Bergfeld

seen with the anthrophilic T.tonsurans infection. If untreated or
inadequately treated, scarring alopecia may result.
Some scalp fungal infections fluoresce under Wood’s
light. Endothrix infections like T. tonsurans do not fluoresce
(Table 20.1). Light-green fluorescence is seen with small spore
ectothrix infections with Microsporum, while Trichophyton
schoenleinii causing favus can also show a duller green fluorescence under Wood’s light. Other ectothrix infections do not
fluoresce. Wood’s light examination may help confirm suspected
infection, but never rules out infection.
The diagnosis of tinea capitis is often clinical. However,
direct microscopy with 20% KOH (potassium hydroxide) of
scalp skin scrapings and infected hair shafts allows the fungal
infection to be visualized. Differentiation between ectothrix and
endothrix infections can also be made. The scale and broken-off
hairs can be obtained by scraping or rubbing the scalp with a
disposable toothbrush or moist gauze. These samples can then
be sent for culture in Sabouraud’s agar to identify the causative
species (Table 20.1). Once tinea capitis is confirmed, the family
members of the patient should also undergo scalp microscopy
and culture to rule out any infected family members or carriers.
Treatment of tinea capitis is currently undergoing extensive
innovation. Griseofulvin has long been the treatment of choice;
however, itraconazole, fluconazole, and terbinafine are also
available (Table 20.1). Only griseofulvin is approved by the U.S.
Food and Drug Administration (FDA) for the treatment of tinea
capitis. Griseofulvin is fungistatic and griseofulvin-resistant
organisms have developed. Doses are 20 to 25 mg/kg daily or 10
to 15 mg/kg daily of the ultra-microsize form for 6 to 8 weeks.
Griseofulvin should be taken with a fatty meal to increase bioavailability and is usually well tolerated. Griseofulvin may cause
gastrointestinal effects including nausea, diarrhea and vomiting, as well as skin rashes, headache, antabuse-like effect, and
photosensitivity. Griseofulvin is a P450 enzyme inducer in the
liver, and results in multiple drug interactions. Given the side
effects and duration of therapy, noncompliance can become an
issue. T.tonsurans appears to be less sensitive to griseofulvin
compared to other species like M. canis.
Terbinafine is an allylamine fungicide, which inhibits synthesis of ergosterol in fungal cells. Terbinafine accumulates in hair
follicles and stratum corneum rapidly. It has less drug interactions
than griseofulvin with a shorter course of therapy. However, it is
not FDA-approved for the treatment of tinea capitis. Treatment
with oral terbinafine using a weight-based protocol (62.5 mg for
patients weighing less than 20 kg, 125 mg for 20–40 kg patients,
and 250 mg for patients greater than 40 kg) for 2 to 4 weeks is
effective if the causative agent is T. tonsurans. Usually longer
therapy is required to eradicate Microsporum species. Side effects
of terbinafine include mild gastrointestinal upset, skin rashes,
abnormal taste, and rarely, abnormal liver function. Reports of
Stevens–Johnson syndrome and toxic epidermal necrolysis also
exist for terbinafine.
In another recent study, itraconazole given in suspension or
capsule form at 5 mg/kg/day for 6 weeks achieved a cure of 88% in
children with tinea capitis caused by M. canis, and the cure rates
were maintained in all subjects when evaluated 12 weeks following the cure. Adverse effects were noted in 6.7% of the children
in the study, with only one child discontinuing the medication as
a result. Itraconazole is an azole antifungal agent and side effects
include gastrointestinal symptoms such as dyspepsia, nausea and

vomiting, skin rashes, dizziness, and headache. It can also rarely
cause abnormal liver function and Stevens–Johnson syndrome,
and has multiple drug interactions.
Fluconazole is another azole antifungal that has been studied
in the treatment of tinea capitis. It also has multiple drug interactions. A study showed in children with tinea capitis using once
weekly fluconazole 8 mg/kg showed that 60 out of 61 children
obtained a mycologic cure. The course duration ranged from
8 to 16 weeks. Side effects of fluconazole include headache, dizziness, nausea, and abnormal taste. Rare cases of Stevens–Johnson
syndrome have been reported. Ketoconazole is associated with
the rare but serious side effect of hepatotoxicity, and is therefore
rarely selected for tinea capitis. Any systemic treatment should
be continued until mycological cure is confirmed by negative
mycological cultures.
In addition to a systemic antifungal agent, an antifungal shampoo such as ketoconazole or selenium sulfide shampoo should be
used on the scalp 2 to 3 times per week to reduce the period of infectivity. Children should not share brushes, combs, hats, or scarves.
Combs, brushes, and other fomites should be cleaned. Unaffected
family members should also use an antifungal shampoo.
The treatment of a kerion has previously involved oral
griseofulvin, an oral antibiotic, and usually oral corticosteroid.
This regimen has been shown to improve itching and scaling
more rapidly than griseofulvin alone. Recently, terbinafine has
also been reported for kerion treatment. Currently, an oral antifungal agent as well as an antifungal shampoo is the treatment of
choice for kerion. Any secondary bacterial infection should be
cultured and treated appropriately.

Piedra
Meaning “stone” in Spanish, piedra represents a group of fungal
infections that present as gritty nodules adherent to the hair shaft.
Piedra can present as white or black variants, depending on the
causative agents. Black piedra is caused by Piedra hortae, an ascomycete fungus. White piedra is caused by different Trichosporon
species: Trichosporon asahii, Trichosporon asteroides, Trichosporon
cutaneum, Trichosporon inkin, Trichosporon mucoides, or Trichosporon ovoides. Each species tends to occupy specific corporeal
niches; while T. inkin infects the genitals, T. asteroides, T. cutaneum, and T. ovoides have been reported to cause scalp infections (Table 20.1). White piedra is less common and occurs in
temperate climates. Black piedra occurs more frequently in the
tropics and subtropics, and mainly affects the scalp. While rare in
the United States, the infection appears to be increasing. This is
largely attributed to the immigrantion of populations of a lower
socioeconomic status. Transmission in humans is uncertain,
although it is believed that close contact is responsible.
Diagnosis of piedra is based on clinical findings and supported
by laboratory testing. The nodules are easily seen, encircling the
hair shaft, and may be black, white, or tan. The shafts may become
weakened by the infection and break at the level of the nodules.
Direct microscopy and KOH mounting demonstrates focal, bulbous concretions on the hair shafts composed of hyphae, asci, and
ascospores in black piedra. White piedra nodules contain hyphae,
blastoconidia, and arthroconidia. Fungal stains and cultures may
further confirm the diagnosis (Table 20.1).
Traditional treatment focused on complete removal or shaving
of the affected hair, and treatment with topical antifungal agents

Infections of the Scalp — 259

Table 20.2: Parasitic Infections of the Scalp
Condition

Organism

Clinical Presentation

Investigations

Treatment

Pediculosis
capitis
(Head Lice)

Pediculosis
humanis capitis

Pruritus and live lice within 2
and 1/2” from the scalp
Nits firmly attached to hair
shafts

Clinical diagnosis
Head lice can be
visualized by dermoscopy
and on microscopy
Bacterial cultures if
secondary infection
suspected

Permethrin 1% cream rinse (See text for
alternatives)
Screen family and close contacts
Cleaning of combs, brushes, hair
accessories and fomites
Antihistamines and topical
corticosteroids may be needed for
pruritus

Demodecidosis

Demodex
follicularum,
D. brevis

Erythema and pustular
folliculitis

Clinical diagnosis
Mites can be seen on skin
biopsy histology

Topical permethrin or topical
metronidazole (see text for alternatives)

Scabies

Sarcoptes
scabiei var.
hominis

Pruritus Erythematous
papules, burrows, and vesicles
in web spaces, volar wrists,
waist, genitals and axillae
Scalp and face involvement in
children
± Secondary bacterial
infection with crusting

Clinical diagnosis
Mites can be visualized
under direct microscopy
Bacterial cultures if
secondary infection
suspected

Permethrin 5% cream (See text for
alternatives)
Screen and treat family and close
contacts
Cleaning of clothes, towels, linens and
fomites
Antihistamines and topical
corticosteroids may be needed for
pruritus

such as ciclopirox, imidazoles, and selenium sulfide. Black piedra
has been treated with terbinafine with good effect, if shaving is not
appropriate. Use of oral azole antifungals for 3 to 4 weeks combined
with an antifungal shampoo for 2 to 3 months has recently been
shown to be an effective treatment and avoids the need for shaving
of the affected hair in white piedra in children (Table 20.1).

PA R A S I T I C I N F E C T I O N S

Pediculosis capitis
Pediculosis capitis is caused by the obligate human parasite Pediculosis humanus capitis or the human head louse
(Table 20.2). The female head louse lives for 30 days and feeds
off the host every 4 to 6 hours. She lays approximately 10 eggs
per day, which hatch 10 to 14 days later. Head lice rarely can
survive without their host; however, in certain climates nits may
survive for 10 days away from the host. This infection is particularly common among children and occurs in all socioeconomic
strata. P. capitis is much more commonly seen among White or
Latino children, due to the difficulty of the lice adhering to the
tightly curled hair of children of African heritage. Girls are more
commonly infected than boys, likely due to their favoring of long
hair and sharing of hair accessories. Transmission is common
through direct contact with fomites that are found on shared
combs, brushes, hats, helmets, bed linens, and clothing.
P. capitis is confined to scalp hair, and pruritus is the
most common symptom. The severity of the pruritus varies
among individuals, depending on the immune hypersensitivity response to the lice’s salivary antigens. The lice load usually is heavier in the occipital and post-auricular regions of the
scalp. Secondary effects are due to itch and scratching, causing
crusting, secondary bacterial infection, and cervical adenitis
(Table 20.2).

The diagnosis is made with clinical recognition of active lice
in the hair. The nits (eggs) are usually more easily seen as white
particles firmly attached to the hair shafts near the scalp skin,
but unlike the concretions of piedra, nits are not completely circumferential. The eggs can sometimes be mistaken for hair casts,
however, hair casts easily slide along the hair and are annular.
The adults measure 3 to 4 mm in size and can therefore be seen
with the naked eye; however, the lice load varies among individuals. In active infection, the lice are attached to the hairs within
2½ inches from the scalp surface. Wet combing with a fine-tooth
comb can assist in visualizing the nits. Dermoscopy can aid in
visualizing the lice or nits. Lice and nits can be identified under
direct microscopy (Table 20.2).
Treatment of P. capitis is almost universally topical
(Table 20.2). A variety of therapies are available, including permethrin, pyrethrin extracts, lindane, malathion, and carbaryl,
which are typically applied twice. The second treatment follows
the first treatment by 7 to 10 days to eliminate any active lice/
nits that survived the initial therapy. Permethrin is a synthetic
pyrethroid with a good safety profile. Permethrin 1% cream
rinse is applied to clean and partially dry hair and is left for
10 minutes. It is then rinsed off and should be repeated in 7
to 10 days time. Resistance to permethrin has been reported.
Pyrethrins plus piperonyl butoxide have also been used to
treat head lice. They are less effective than permethrin and
should not be used in patients with chrysanthemum allergy.
Malathion 0.5% lotion is applied to hair for 8 to 12 hours and is
thought to be safe if used as directed. Malathion is flammable
and accidental ingestion can cause respiratory depression. It is
recommended that malathion only be used in treatment-resistant cases. Lindane 1% shampoo can cause neurotoxicity and
seizures in children and should be avoided if possible. After
topical treatment, the nits need to be removed physically using
a fine-tooth comb daily until the nits and lice are removed.

260 — Shannon Harrison, Haydee Knott, and Wilma F. Bergfeld

Alternate therapies include essential oils as well as petroleum
jelly, mayonnaise (avoid reduced fat varieties), and conditioner,
which are believed to suffocate the lice and nits. These alternative therapies do not appear to be effective and require further
study. Any secondary bacterial infection should be cultured
and treated with the appropriate antibiotics. Antihistamines
and topical steroids are occasionally needed for itch relief.
Family members may also be affected, and should be screened
to prevent reinfection. All clothes and bed linens should also
be washed in hot water and machine dried. Toys should be
washed and dried in a clothes dryer or sealed in plastic bags
for 2 weeks. Carpets and upholstery should be thoroughly vacuumed. Topical drug-resistant strains are emerging, and oral
courses of ivermectin or cotrimoxazole are effective in eradicating these strains. Systemic treatment may also need to be
considered in treatment failures.

Demodecidosis
Demodecidosis is a cutaneous infection caused by an infestation
with demodex mites (Table 20.2). Two species have been implicated in active disease: Demodex folliculorum and Demodex brevis.
Demodecidosis is not limited to the scalp, but may be encountered on the forehead, nose, cheeks, eyelids, as well as more distant locations such as the upper chest and genitals. Demodex
colonization is directly related to areas of high sebum production. As such, there are low rates of colonization in children and
adolescents, with an increasing prevalence among adults.
The demodex mite measures approximately 0.3 to 0.4 mm,
and has a life span of 2 weeks. A strong distinction must be made
between colonization by Demodex spp and active infection, since
colonization rates approach 100% in adults. Therefore, biopsy
specimens containing occasional demodex mites is of no significance, but the finding of more than 5 mites per low power field
or more than 5 per cm2 is believed to be correlated with disease
development. Nevertheless, the ubiquity of the mites among
normal hosts makes pathogenicity controversial. In some conditions, multiplication of the follicle mites and mites in an intradermal location may contribute to disease. Immunocompetent
adults and children can rarely develop infections, but active disease is more common among immunocompromised adults and
children. Case reports have associated demodecidosis with HIV
and leukemia. Demodex mites have been implicated in rosacea
and pustular folliculitis of the scalp. Rarely, severe scalp demodicidosis in children can resemble favus.
A variety of oral and topical agents have demonstrated effectiveness against demodex mites. Lindane, permethrin, metronidazole, crotamiton, benzyl benzoate, and ivermectin have all
shown efficacy (Table 20.2).

Scabies
Scabies is an intensely pruritic skin infestation caused by the
mite, Sarcoptes scabiei var. hominis (Table 20.2). Scabies may
afflict patients of any background, ethnic group, or age. While
scabies usually spares the scalp and face among adults, in children it often involves the scalp. The severe crusted variant
known as Norwegian scabies, commonly involves the scalp, and
is encountered among patients who are immunocompromised
or debilitated.

The scabies mite can survive up to 3 days without a host, so
while direct human contact is the most common mode of transmission, infested bedding or clothing may serve as a reservoir of
infection. The mite moves through the epidermis by secreting
proteases that degrade the stratum corneum on which they feed,
leaving scybala (feces) behind.
Clinically, nocturnal pruritus is characteristic. Scabies is characterized by small papules, vesicles, and burrows over the flexor
aspects of the wrists, the interdigital web spaces of the hands and
feet, axillae, elbows, waist, and genitalia. In children, vesicles and
papules can be seen on the hands and feet, but the scalp and face
can also be involved (Table 20.2). Secondary impetiginization
and eczematization can occur. Patients with Norwegian scabies
typically have crusting on the hands and feet with associated nail
dystrophy, as well as crusting of the head and face. Hair loss can
also be associated with Norwegian scabies.

BACTERIAL INFECTIONS

Folliculitis
Folliculitis can occur in any hair-bearing area of the skin, including the scalp. Folliculitis is inflammation of the hair follicle and
is usually caused by infection. Occlusion, friction, and some
topical agents also predispose to folliculitis. Folliculitis can be
superficial or deep. Superficial folliculitis involves the superior
portion of the hair follicle, and deep folliculitis, the entire follicle or inferior portion of the hair follicle is involved. Superficial
folliculitis is seen as small tender or nontender pustules that can
have associated pruritus and usually heal without scarring. The
clinical presentation of deep folliculitis is different with erythematosus, tender papules, pustules, and nodules, which may
heal with scarring. Folliculitis can be caused by many different
organisms.

Staphylococcal folliculitis
Staphylococcal folliculitis is the most common type of folliculitis
(Table 20.3) (Fig. 20.3). It can be superficial or present as furuncles and carbuncles. A furuncle is a single infective perifollicular abscess, and is less common on the scalp, but can affect the
face and neck. A carbuncle is a deeper infection of a group of
hair follicles and can occur in the scalp and posterior neck. It
can be associated with constitutional symptoms and diabetes
mellitus, obesity, chronic renal impairment, and malnutrition.
Corticosteroid treatment can predispose to infection. Pustules
should be swabbed and sent for culture.
The mainstay of treatment is appropriate oral antistaphylococcal antibiotics and avoidance of overheating, friction,
and occlusion (Table 20.3). In superficial folliculitis, topical
antibiotics and compresses may only be needed. Antibacterial
washes with chlorhexidine or betadine can reduce the bacterial skin load. Surgical incision and drainage may be required
for furuncles and carbuncles. Carrier status of Staphylococcus
aureus in the anterior nares, perineum, and axillae can also
occur in patients with Staphylococcal infections or close family members. Swabs and cultures should be done. Physicians
should always remember that the incidence of methicillinresistant Staphylococcal aureus (MRSA) is increasing in the
community.

Infections of the Scalp — 261

Table 20.3: Bacterial Infections of the Scalp
Condition

Organisms

Clinical Presentation

Investigations

Treatment

Folliculitis

Staphylococcus aureus,
Staphylococcal spp.
MRSA Pseudomonas,
Klebsiella, Aermonas,
Proteus spp

Superficial folliculitis
with erythema and
folliculocentric pustules
Furuncles and carbuncles

Bacterial swab for
microscopy, culture and
sensitivities
MRSA carrier swabs and
cultures

Systemic antibiotics
Anti-bacterial wash
Incision & drainage if
needed for furuncles &
carbuncles

Impetigo

Staphylococcus aureus,
Streptococcal spp.

Erythematous blisters,
crusting and erosions

Bacterial swab for
microscopy, culture and
sensitivities

Systemic antibiotics
Anti bacterial wash

Erysipelas

Streptococcal spp.
Group A

Well demarcated
erythematous painful plaque
± fever and
lymphadenopathy

Bacterial swab for
microscopy, culture and
sensitivities
CBC for leukocytosis.

Systemic antibiotics

Scalp cellulitis

Staphylococcus aureus,
Staphylococcal spp.
Streptococcal spp.
Group A

Poorly demarcated
erythematous, swollen
painful plaque
± fever and
lymphadenopathy

Bacterial swab for
microscopy, culture and
sensitivities
CBC for leukocytosis

Systemic antibiotics

Postoperative
infection

Staphylococcus aureus,
Staphylococcal spp., MRSA,
CA-MRSA, Streptococcal
spp.
Group A

Erythematous, swollen
painful wound ± crusting
± fever and
lymphadenopathy

Bacterial swab for
microscopy, culture and
sensitivities
CBC for leukocytosis

Systemic antibiotics

Infections secondary
to intrauterine fetal
monitoring devices

Staphylococcal spp., MRSA.
Streptococcal spp., mixed
anaerobes and aerobes

Abscess, cellulitis or
osteomyelitis
Rarely meningitis and sepsis

Bacterial swab for
microscopy, culture and
sensitivities

Systemic antibiotics

Eosinophilic pustular folliculitis

Figure 20.3. Inflammatory pustules of the scalp that cultured staphylococcus aureus making the diagnosis of staphylococcal folliculitis.
“Photo courtesy of the Cleveland Clinic Department of
Dermatology.”

It should be remembered that folliculitis can involve not
only the hair follicles of the scalp but other areas of the body as
well. Dermatophyte, Pityrosporum, and candidial infections can
mimic a bacterial folliculitis. Gram-negative bacteria such as
Pseudomonas, Klebsiella, and Proteus can also cause folliculitis.
Pseudomonas folliculitis occurs after using a hot tub or contaminated pool. The folliculocentric lesions occur typically under the
bathing suit, but do not affect scalp hair follicles. Aeromonas hydrophilia may also be responsible for a case of hot tub folliculitis.

Eosinophilic pustular folliculitis (EPF) is a noninfectious folliculitis presenting as red papulopustules. The cause is unknown, but
may be associated with immune dysfunction to certain infectious pathogens. Infancy-associated eosinophilic pustular folliculitis usually starts within the first few weeks of life and affects
particularly the scalp, as well as the face and extremities. Classic
EPF presents as sterile annular papulopustules with peripheral
extension and commonly affects the face, while immunosuppression-associated EPF is mostly HIV-related and also involves
the face, showing more discrete pruritic, erythematous papules.
Histology shows infiltration with eosinophils and lymphocytes
at the follicular isthmus and minimally surrounding the outer
root sheath and sebaceous glands. In infancy-associated EPF,
flame figures may be present in the scalp. Topical corticosteroids
are the first-line treatment and immunosuppression-associated
EPF may require narrow-band UV light therapy.

Impetigo
Impetigo can be primary or secondary and is a superficial
skin infection caused by Staphylococci, Streptococci, or both
(Table 20.3). Primary impetigo presents as erythematous crusting or blisters, particularly on the face, scalp, and extremities.
Secondary impetigo or impetiginization with Staphylococci
presents in skin with impaired barrier function or in traumatized skin. Secondary infection can occur in the scalp affected by

262 — Shannon Harrison, Haydee Knott, and Wilma F. Bergfeld

seborrheic dermatitis, psoriasis, eczema, pediculosis capitis, or
insect bites. Swabs and cultures should be taken and appropriate
oral antibiotic therapy commenced. Antibacterial washes with
chlorhexidine or betadine can reduce the bacterial skin load.
Soaks of aluminum acetate (Burow’s solution) or saline are useful to remove crusting, and the underlying condition in secondary impetigo should also be treated.

Erysipelas and Scalp Cellulitis
Erysipelas is an infection of the upper dermis usually caused by
Group A Streptococci (Table 20.3). The scalp can be involved due
to extension from the face or pinna or due to a scalp wound or
chronic skin condition. Clinically, a well-demarcated erythematous plaque with associated fever is seen. Lymphadenopathy can
be associated. An acute telogen effluvium can follow this infection. Lymphedema predisposes to this infection.
Cellulitis or infection involving the deep dermis and subcutaneous fat can be caused by Streptococcus pyogenes and/
or Staphylcoccus aureus or MRSA (Table 20.3). Entry for the
bacteria can be a scalp wound, scalp surgery, or a chronic skin
condition. Diffuse, poorly demarcated erythema, heat, swelling,
and pain are the hallmarks of cellulitis. Systemic symptoms and
lymphadenopathy can also be associated. Laboratory investigations of cellulitis rarely identify a specific causative organism.
Diagnosis is clinical, with possible identification of the infecting agent on skin swabs and cultures. Blood cultures are recommended in elderly patients with fever and leukocytosis as well as
in immunocompromised patients. For both erysipelas and cellulitis, treatment with systemic antibiotics is required.

Postoperative Scalp Infections
Scalp infection post hair transplant is a surgical risk. Scalp infection
following neurosurgery must also be considered. A recent study
highlighted risk factors for the development of any infection. The
following conditions were found to be risk factors having a scalp
infection following neurosurgery, being >70 years in age, being
male, and having a postoperative cerebrospinal fluid (CSF) leak.
Methicillin-resistant Staphylococcus aureus (MRSA) is a wellknown nosocomial pathogen that can cause soft tissue infections
such as abscesses and cellulitis and should always be considered
as a potential pathogen in scalp infections (Table 20.3). The rate
of community-acquired MRSA (CA-MRSA) infections is on the
rise and should also be kept in mind as a potential pathogen in
cutaneous infections. Culture and antimicrobial sensitivities
should be obtained and appropriate antibiotic therapy should
be instituted. Intravenous vancomycin, or linezolid if vancomycin is contraindicated, is a highly effective treatment option for
MRSA-positive wounds.

IFM devices, cephalohematoma, amnionitis, endometritis, and
a long duration of monitoring have all been implicated in these
infections.
The infection may present as cellulitis, abscess, osteomyelitis
or bacteremia. In the case of cellulitis or abscess, the infection
is usually centered over the area where the electrode had been
placed. Aspiration or placement of a drain may be required if
the abscess does not drain spontaneously. Effective treatment
depends on culture-directed antibiotic therapy. Patients with
minimal infection may improve spontaneously, but most cases
need parenteral antibiotic therapy. If insufficiently treated, osteomyelitis of the occipital bone, meningitis, and sepsis may all
occur as sequelae.
SCALP CONDITIONS WITH PRESUMED
BA C T E R IA L E T I O L O G Y:

Acne miliaris necrotica
The etiology of acne miliaris necrotica is unknown. However,
bacterial infection with Propionibacterium acnes has been suggested. Acne necrotica miliaris is the milder form of the disease,
and acne necrotica varioliformis is the deeper form of the condition, which can cause varicella-like scars. Clinically, tender, itchy,
erythematous papules, which then ulcerate and crust centrally,
occur along the scalp hairline. Biopsy and bacterial swabs and
cultures should be taken. Histology shows a lymphocytic perifollicular infiltrate with plasma cells and lymphocytes invading
the outer root sheath. The outer root sheath also demonstrates
keratinocyte cell necrosis.
Treatment involves topical antibiotics such as 1% clindamycin lotion for the mild form of the disease and an oral antibiotic
such as tetracycline or doxycycline for the more severe condition. Topical and oral steroids are occasionally needed as an
adjunctive therapy.

Folliculitis keloidalis (Acne keloidalis)
Folliculitis keloidalis is a form of scarring alopecia, in which staphylococcal infection is a postulated etiology. Clinically, it presents
as grouped follicular papules, pustules, and hypertrophic scars
at the nape of the neck and occipital scalp. Occasionally, it can
also occur at the vertex and overlap with folliculitis decalvans.
African-American men are commonly affected. Scalp biopsy and
bacterial swabs and cultures should be taken. Biopsy shows hair
follicles with a mixed acute or chronic granulomatous inflammation and hypertrophic scarring with loss of the sebaceous glands.
Treatment is difficult. Antibiotic therapy with cephalosporins,
penicillins or tetracyclines in conjunction with topical and
intralesional corticosteroids is usually required. Carbon dioxide
laser and surgery may be needed in some cases.

Intrauterine fetal monitoring devices
Bacterial infections of the scalp following the placement of
intrauterine fetal monitoring (IFM) devices, which are used
to monitor fetal circulation and oxygenation, are also increasing. Cutaneous infection following placement of IFM devices
is between 0.1% and 5.2%. Sensitive culture techniques have
revealed a diverse microbiology including aerobic, anaerobic,
and mixed aerobic and anaerobic organisms. Use of multiple

Folliculitis Decalvans and Dissecting Cellulitis
of the Scalp
Folliculitis decalvans and dissecting cellulitis of the scalp are neutrophilic-predominant cicatricial alopecias (Fig. 20.4). Inflammatory follicular nodules, pustules, and papules precede areas of
scarring hair loss. Activity is intermittent, but slowly progressive.
In folliculitis decalvans, any area of the scalp can be involved.

Infections of the Scalp — 263

Table 20.4: Unusual Infections of the Scalp
Condition

Organism

Clinical Presentation

Investigations

Treatment

Syphilis

Treponema
pallidum

Diffuse alopecia or motheaten patchy hair loss
Less commonly, gumma,
papulopustular or
noduloulcerative lesions

Skin biopsy with
Warthin-Starry
staining and PCR

Recommended CDC syphilis therapeutic regime
(see text for website details)

Mycobacterial
infection

Mycobacterium
neoaurum.
Mycobacterium spp.

Erythematous indurated
plaque of scarring
alopecia
Skin ulcers and soft tissue
infections

Skin biopsy with
Ziehl-Nelson
staining, culture
and PCR

Antimycobacterial treatment according to species
identified on culture or PCR
Certain mycobacterial species infections require
surgery as treatment
(Management can be reviewed.)

Figure 20.4. Alopecia of the nuchal scalp with inflammatory papules
and scarring of folliculitis decalvans.
“Photo courtesy of the Cleveland Clinic Department of
Dermatology.”

In dissecting cellulitis of the scalp, inflammatory nodules are
accompanied by abscesses and sinus formation. The etiology
for folliculitis decalvans and dissecting cellulitis of the scalp is
not clear, but is believed to be an abnormal host response to
Staphylococcal antigens. They occur more commonly in AfricanAmerican men. Scalp biopsy can confirm the diagnosis and
bacterial swabs and cultures should be taken. Histology shows
keratin plugging of the follicle orifice and many intraluminal
neutrophils, the follicles rupture and there is an interstitial and
perifollicular inflammatory infiltrate with dermal abscess formation. Over time, fibrosis and a chronic inflammatory infiltrate
with granulomas are seen, followed by scarring. In dissecting
cellulitis of the scalp, sinus formation is also seen on histology,
with a deep mixed inflammatory cell infiltrate and foreign body
granulomas.
Treatment consists of prolonged courses of systemic antistaphylococcal antibiotics. Combination treatment with rifampicin and clindamycin can be effective in resistant cases. Fusidic
acid and zinc have also been used. Topical and intralesional corticosteroids are frequently needed. Isotretinoin is now an effective choice for dissecting cellulitis of the scalp. Surgery and hair
removal lasers have also been used for dissecting cellulitis of the
scalp.

Figure 20.5. Grouped pustules on a person with fair skin that already
shows significant alopecia of the scalp. This is early erosive pustular
dermatosis.
“Photo courtesy of the Cleveland Clinic Department of
Dermatology.”

Erosive Pustular Dermatosis of the Scalp
The etiology of erosive pustular dermatosis of the scalp is
unknown. However, abnormal immune responses to infectious
organisms such as Staphylococcus aureus have been suggested. It
is usually seen in chronically sun-damaged scalps of older, balding individuals. Sterile pustules coalescing into lakes with crusting and erosions on the scalp are seen. Scarring alopecia can be
an end result (Fig. 20.5). Histology shows a suppurative folliculitis with adnexal involvement and later, fibrosis and a chronic
inflammatory infiltrate. Treatment involves potent topical steroids, and topical or oral antibiotics with a medicated shampoo.
Isotretinoin has also been used. Topical tacrolimus 0.1% has also
been reported to be effective in erosive pustular dermatosis of
the scalp.

U N U S UA L I N F E C T I O N S

Syphilis Infection
Hair loss can occur in secondary and tertiary syphilis. Syphilis
is caused by the spirochete, Treponema pallidum (Table 20.4).

264 — Shannon Harrison, Haydee Knott, and Wilma F. Bergfeld

Primary syphilis does not cause hair loss unless the primary
chancre involves the scalp. Hair loss in syphilis can present
as a diffuse alopecia mimicking telogen effluvium, but more
classically presents as a “moth-eaten” pattern of hair loss with
irregular patches of scalp hair loss. Other lesions of syphilis
can occur in the scalp including gummata in tertiary syphilis
and a papulopustular or noduloulcerative eruption in secondary syphilis.
Diagnosis of syphilis is based on serological testing. Darkfield microscopy of lesions or tissue identifying the spirochetes
can assist in diagnosis. Scalp biopsy is also helpful for active
scalp lesions, and in the noduloulcerative form spirochetes may
be seen with the Warthin-Starry stain. In cases of diffuse and
moth-eaten alopecia, spirochetes had not been seen previously
and histology showed a sparse perifollicular lymphocytic infiltrate with plasma cells. However, recently Treponema pallidum
has been identified in the peribulbar region in a patient with
patchy nonscarring alopecia due to syphilis infection. The recommended treatment schedule for syphilis from the Centers
for Disease Control and Prevention (CDC) should be followed
(www.cdc.gov/std/syphilis).

topical imiquimod, or physical therapies of cryotherapy or curettage for large lesions. The lesions normally resolve spontaneously,
so treatment is not always necessary.

Herpes viral infections
Herpes zoster can involve the scalp. It is caused by a DNA herpes
virus (VZV) involving the ophthalmic branch of the trigeminal
nerve, and grouped, painful vesicopustules occur in the distribution of the unilateral ophthalmic branch. Crusting, ulceration,
secondary bacterial infection, and hair loss can sometimes occur.
Herpes simplex virus (HSV) can also affect hair follicles and can
mimic bacterial folliculitis. Primary and secondary lesions of
HSV present as grouped, painful vesicopustules on an erythematous base. A Tzank smear of the lesions can clinically corroborate
the diagnosis. Viral culture and/or PCR can confirm the infection. Valacyclovir, acyclovir or famciclovir is the treatment of
choice in herpes zoster. Postherpetic neuralgia is an important
consequence of herpes zoster infection and prompt treatment
is essential. Herpes simplex infection can also be treated with
systemic antivirals. Any secondary bacterial infection should be
treated with appropriate antibiotics.

Mycobacterial infection
Cutaneous mycobacterial infection can cause scalp hair loss.
Mycobacterium neoaurum has been shown to cause an indurated plaque of scarring alopecia in an immunocompetent host
(Table 20.4). Histology showed granulomatous inflammation
and PCR was positive on scalp biopsy for Mycobacterium neoaurum; however, culture was negative. Supportive of the causative
origin of this alopecia, antimycobacterial treatment was instigated and the plaque improved and flattened; however, no hair
growth returned. Other nontuberculosis mycobacteria species
could also infect the scalp, causing soft tissue infections and
skin ulcers. Biopsy, culture, and PCR should be done on any
suspected atypical infection. Treatment is guided by the mycobacterium species identified on culture or PCR.
VIRAL INFECTIONS

Warts
Rarely, viral infections can affect the scalp (Table 20.5). Warts
can occur on the scalp, usually via direct inoculation of the
human papilloma virus (HPV). The peak incidence of warts is
in childhood and warts can occur in immunosuppressed individuals. Warts typically appear as firm hyperkeratotic papules.
They can resolve spontaneously, and treatment depends on the
size and location of the warts. Topical keratolytics and topical
immunotherapy can be used. Curettage under local anesthetic
and cryotherapy are also possible treatment options.

I N F E C T I O N S I N T R A N S P L A N T PA T I E N T S

Transplant patients are at risk for infection from their transplanted
organ, from the surgery itself, from reactivation of latent infections, and from opportunistic infections during the iatrogenic
immunosuppression following their transplant. Success rates
of transplants have improved with increased patient and graft
survival in heart and lung transplant recipients. As a reflection,
clinicians are diagnosing more opportunistic and atypical infections secondary to immunosuppression. These infections frequently involve the skin and scalp.
In transplant patients, the scalp can be affected by all the
organisms that can affect immune competent individuals.
Conditions such as tinea capitis, which are more commonly seen
in children, can be seen in transplant adult patients because of
immunosuppression. Primary invasive cutaneous Microsporum
canis infections have been reported in a transplant recipient
and an HIV-positive patient. Norwegian scabies, which can
involve the scalp, is also more commonly seen in debilitated or
immune-compromised patients. In addition, skin cancers on
sun-damaged scalp can occur in the setting of immunosuppression post transplant. Infections in transplant patients are often
more severe and life threatening. Prophylactic regimens have
been developed to reduce posttransplant infective complications. Any infection in a transplant patient must be diagnosed
and treated early.

Molluscum contagiosum

P I T FA L L S A N D M Y T H S

Molluscum contagiosum caused by a DNA poxvirus can occur
on the face and scalp. Typically, umbilicated skin-colored-topink papules can be identified and rarely can mimic folliculitis
in hair-bearing areas. Giant molluscum has been reported in the
scalp, and diagnosis is through histology on biopsy. Treatment
involves irritant strategies with tape stripping, topical retinoids,

Itchy scalp is a very frequent presenting complaint, and although
it is commonly believed to be a sign of infection, there are noninfective scalp disorders that can produce pruritus. Allergic contact
dermatitis to certain hair dyes and products can occur and cause
pruritus. Pruritus is also an important symptom of inflammatory
scalp conditions such as eczema, seborrhea, irritant dermatitis,

Infections of the Scalp — 265

Table 20.5: Viral Infections of the Scalp
Condition

Organism

Clinical Presentation

Investigations

Treatment

Warts

Human papilloma
virus

Firm, hyperkeratotic
papules

Clinical diagnosis.
Rarely histological
confirmation needed

Observation, topical keratolytics,
immunotherapy, cryotherapy,
curettage

Molluscum

Molluscum
contagiosum DNA pox
virus

Umbilicated skincolored to pink
papules

Clinical diagnosis.
Rarely, histological
confirmation needed

Observation, tape stripping, topical
retinoids, cantharidin, imiquimod,
cryotherapy, curettage

Herpes Zoster

Varicella-Zoster virus

Unilateral grouped
painful erythematous
vesicopustules

Viral swab for microscopy,
culture and PCR.
Tzanck smear

Oral valacyclovir or famciclovir or
acyclovir

Herpes Simplex

Herpes simplex virus

Grouped painful
erythematous
vesicopustules

Viral swab for microscopy,
culture and PCR.
Tzanck smear

Oral valacyclovir or famciclovir or
acyclovir

and psoriasis. Certain forms of cicatricial alopecia such as lichen
planopilaris and discoid lupus erythematosus can also lead to
scalp pruritus. Pruritus of the scalp invariably leads to scratching
and possible secondary bacterial infection. When examining a
scalp for possible infection, it should be remembered that more
than one may be present. It should also be remembered that the
scalp is an area of skin that can easily be forgotten when examining the skin of a patient, and complete skin examination includes
a thorough examination of the scalp.
Importantly, the scalp and its hair follicles can only react to
infectious and/or other pathological processes in a finite number of patterns. These include flaking, erythema, and hair loss.
As such, there can be similarities among the clinical presentations of different conditions and diseases of the scalp, which can
occasionally make accurate diagnosis difficult. Swabs for culture,
hair and skin microscopy, as well as histology can sometimes be
needed to confirm the diagnosis.
A common myth is that only people with poor hygiene habits
develop scalp infections. Another myth is that sleeping with wet
hair can cause fungal scalp infections. These are false beliefs as
infection is usually transmitted through direct head contact with
an infected individual or through sharing of infected fomites
such as brushes, hats, and hair accessories and not through poor
hygiene or sleeping with a wet scalp. Dandruff and seborrheic
dermatitis are also incorrectly believed by some to be from inadequate scalp hygiene or a build up of pollutants or residues from
hair products and the atmosphere. Dandruff and seborrheic dermatitis are caused by resident Malassezia yeasts present in small
numbers on all adult scalps, which under certain influences,
such as hormonal variations and not poor hygiene, can multiply
and cause the clinical picture of itch and scaling. Cradle cap seen
on the scalp of babies was falsely believed to reflect poor parental
care or a serious illness. However, it is caused by the same yeasts
that cause dandruff in adults, which multiply under the influence
of the maternal circulating androgens. Once these hormonal
influences have resolved, the cradle cap often improves.
Normally, scalps are protected by the hair follicles; however,
with aging, the hair follicle density can decrease and can be
affected by androgenetic alopecia (patterned hair loss). Balding
scalps are exposed to UV light, predisposing them to skin cancer.

A skin cancer can either be mimicked by a primary skin infection
or it can be a primary skin cancer that is secondarily infected.
Therefore, an isolated crusted or itchy papule or nodule on a
balding scalp should always be regarded with suspicion and may
require a biopsy as well as bacterial swab and culture to exclude
malignancy.
Hair loss is a common symptom, and usually is not associated with scalp infection. However, infections can cause different types of hair loss including telogen effluvium, and diffuse
or patchy alopecia, and scarring alopecia. Severe inflammatory
conditions of the scalp including seborrheic dermatitis can trigger a telogen effluvium. Inflammatory tinea capitis or kerions
and nontuberculous mycobacteria can also cause scarring hair
loss. Syphilis can cause both a diffuse alopecia and a patchy alopecia, while tinea capitis can cause a patchy or localized nonscarring alopecia. In some cases of hair loss, scalp biopsy and culture,
in addition to microbiological swabs, may be needed to exclude a
possible infective cause of hair loss.
There are many home remedies and natural therapies postulated to cure dry hair, dandruff, head lice, tinea capitis, and hair
loss. Tea-tree oil has been used as a natural antiseptic and antifungal. Apple cider vinegar has been used as a remedy for dandruff. There are many natural products and herbal concoctions
that claim to help hair loss such as aloe vera and saw palmetto,
as well as hair care products containing natural ingredients.
Although natural ingredients such as plant extracts may provide
possible therapeutic activities, there is a lack of clinical trials for
these products.There is a need to understand these chemicals
and possible contaminants, as well as their safety for the community, before they become accepted therapies. In this chapter,
current recommended treatments for scalp infections have been
discussed.

CONCLUSION

The structural and anatomic features of the scalp predispose it to
a variety of infections from fungal, parasitic, bacterial, and viral
organisms. Unusual infections such as syphilitic and mycobacterial infections can also involve the scalp. Interestingly, the scalp

266 — Shannon Harrison, Haydee Knott, and Wilma F. Bergfeld

can also be affected by a set of unique conditions that can mimick a bacterial infection but are not. These conditions are unique
to the scalp and can result in cicatricial alopecia. Clinically,
many of these conditions are recognizable; however, microscopy, culture, and biopsy can assist in diagnosis. Antimicrobial
resistance, newly emerging agents, and the increasing number of
immunosuppressed patients require that clinicians update their
knowledge regarding etiologic agents and treatment protocols.

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21

INFECTIONS OF THE NAIL UNIT
Gérald E. Piérard, Claudine Piérard-Franchimont, and Pascale Quatresooz

The nail unit has probably been the target of infectious processes
since the origin of humanity. However, the causative agents have
changed over time. No information is available on bacterial
infections, but it is likely that few changes have occurred over
the past centuries. By contrast, the nature of onychomycoses has
considerably changed during the 20th century with the progressive spread of Trichophyton rubrum to many parts of the world.
The history of nail infections is also geographically influenced by
geoclimatic conditions as well as by occupational activities, and
cultural habits, and lifestyle habits.

beyond. The intermediate layer, which contains soft keratin, represents almost three quarters of the whole nail thickness. Below
this structure, the ventral layer rich in soft keratin is a few cells
thick and is located firmly at the interface between the nail plate
and the underlying nail bed.
The proximal nailfold consists of a crescentic sheet of tissue
covered with epidermis on its dorsal and undersurface. Its sharp
and angled free margin produces the cuticle. The hyponychium
between the nail underface and pulp epidermis corresponds to
the distal end of the nail structure.
It is also important to distinguish microbial paronychial
infections from onychomycoses.

NAIL UNIT STRUCTURE

M I C R O B I A L PA R O N Y C H I A L I N F E C T I O N S

The nail unit has a unique structure consisting of four distinct
components, namely, the matrix, the nail bed, the nail plate, and
the nailfolds. The matrix is mostly located under the proximal
nailfold and its distal portion, which corresponds to the whitish
lunula.
The nail plate is composed of approximately 25 layers of flattened, cornified onychocytes that are tightly bound together.
This structure is organized as three superimposed layers corresponding to the dorsal and intermediate layers originating from
the matrix and the ventral layer which are both derived from
the nail bed (Fig. 21.1). The dorsal part is a few cell layers thick
containing hard keratin. This structure represents the main barrier to drug and xenobiotic penetration into the nail plate and

The proximal nailfold with its cuticle attached to the nail plate,
the lateral nailfolds, and the ventral hyponychium normally
forms tight closures. They normally prevent infections and xenobiotics from entering the subungual area. Microbial paronychia
is an infectious and inflammatory condition of these periungual
soft tissues. The disorder may correspond to an acute or chronic
infection. Conceptually paronychia is therefore not a primary
disease, but follows some physical or chemical damages. This evidence does not apply to superficial infections, such as impetigo
or herpes simplex affecting the dorsum of the proximal nailfold.

H I STORY

Figure 21.1. Standard microscopy of a normal nail plate showing
3 superimposed structures: the thin dorsal layer (*), the thicker
intermediate layer (**) and the ventral layer (***).
268

Acute Paronychia
Most often, a minor physical trauma under the distal edge of the
nail or in a lateral groove is the cause of acute paronychia. It may
consist of a break in the skin, the inclusion of a splinter, a prick
from a thorn, or a subungual infection following a hematoma.
The bacteria most commonly responsible for acute paronychia
are staphylococci and less commonly β-hemolytic streptococci
and gram-negative enteric bacteria. Paronychia presents as local
erythema, swelling, and throbbing pain. The purulent reaction
often takes several days to localize. A bead of pus is often visible
underneath the nail or in the periungual folds. At this stage, a
topical antibiotic treatment is indicated, combined or not, with
appropriate oral antibiotic therapy. Clinicians should be weary of
response to topical and systemic antibiotics because it may mask
an underlying yeast infection or tumor.
The collected pus tends to create a cleft between the nail
and its underlying proximal attachment. The firmer attachment
of the nail at the site of the lunula often temporarily limits the
spread of the pus. However, the nail matrix is particularly fragile
in early childhood and can be destroyed within a couple of days

Infections of the Nail Unit — 269

by an acute bacterial infection. Distal subungual pyogenic infections may accompany periungual involvement. In some cases,
extension of the infection can involve the finger pulp or the
matrix. In other instances, evacuation of a paronychial abscess
can uncover a narrow sinus. This sinus suggests the presence
of a “collar-stud” abscess communicating with a deep-seated
necrotic zone.
In general, acute paronychia involves only a single nail. The
differential diagnosis should include several conditions including eczema, herpes simplex, psoriasis, Reiter’s disease, and acute
vascular impairment. Bacterial culture and allergy screening are
often indicated.

Chronic Paronychia
Chronic paronychia is a common inflammatory disorder of the
proximal nailfold typically affecting hands that are frequently
exposed to both wet environments and repeated minor traumas
altering the cuticle. The index and middle fingers of the dominant hand are most often affected. In addition, the periungual
skin can be quite vulnerable to harsher surfactants. If the epidermal cover of the cuticle or any other parts of the nailfold is
impaired, these structures will be exposed to an ingress of a variety of xenobiotics including irritants and allergens.
The periungual erythema and swelling form a cushion at
the proximal and lateral nailfolds. With time, the adherence of
the cuticle is weakened and the proximal nailfold retracts and
becomes thicker and rounded. This condition is further prolonged as molecular xenobiotics, foreign particles, and microorganisms lodge beneath the nailfold, and further contribute to the
inflammation and infection. In some cases, pus will arise from
the nailfold. The histological presentation of chronic paronychia
commonly reveals spongiotic dermatitis on the ventral portion
of the proximal nailfold.
The course of chronic paronychia is occasionally accompanied by paroxysmal exacerbations of painful inflammation. In
some instances, episodes can be due to secondary Candida spp.
and bacterial infections or even superinfections, where small
pustules develop between the proximal nailfold and the nail
plate. These microbial abscesses often drain spontaneously and
heal without any treatment in a couple of days. Acute exacerbations of chronic paronychia are not only due to microbes but
also to irritant or allergen xenobiotics penetrating deep into the
proximal nailfold. Contact allergies to foodstuffs, latex, and topical drugs are not uncommon. In addition, fragments of foreign
particles such as hair, foodstuffs, and various other debris can
collect in the proximal nailfold. This multifaceted process often
causes retraction of the nailfold and a persistence of the paronychial process.
In the early stages of paronychia the nail plate is preserved,
but one or both lateral edges may develop surface roughness as
well as yellowish, brownish, or blackish discoloration. This discoloration may further extend over a large portion or even the
totality of the nail plate. This type of chromonychia is believed
to be caused by dihydroxyacetone produced by the microorganisms in the nailfold. By contrast, Pseudomonas spp. tend to produce a greenish hue caused by a pigment called pyocyanin. The
lateral edges of the nail plate become cross-ridged when the disease affects the lateral nailfold. The surface of the nail commonly
becomes rough and friable, and numerous irregular transverse

ridges and grooves appear, due to repeated acute exacerbations.
Eventually, the nail becomes considerably reduced in size because
of swelling in the surrounding soft tissues.
There is some disagreement as to the importance of Candida
spp. colonization or infection in chronic paronychia because
these organisms can behave as commensals or pathogens.
Various factors can damage the area and allow Staphylococcus
aureus and Candida spp. under the cuticle of the nail plate. In
children, the habit of thumb or finger sucking represents the
most common predisposing factor. This condition is potentially
more harmful than occupational hand immersion, as saliva is
more irritating than tap water. Chronic paronychia can also
develop in patients with eczema or psoriasis involving the nailfolds. Chronic paronychia may also develop in association with
ingrown toenails or, more rarely with diabetes or peripheral
vascular impairments. Chronic paronychia can be related to nail
infections caused by Scytalidium spp. In such instances, brown
chromonychia can start at the lateral edges of the nail plate and
spread centrally into the nail. Fusarium spp. can also produce
chronic paronychia.
Syphilitic paronychia can represent a painful chancre.
Pemphigus can alter the nailfold, mimicking chronic paronychia. Psoriasis, Reiter’s disease, and eczema can also involve the
proximal nailfold.

FUNGAL INFECTIONS OF THE NAIL

Onychomycosis is defined as a fungal infection of the nail. It is
not a clinical diagnosis and the presence of the fungus must be
confirmed by laboratory procedures. The common clinical signs
include thickening, discoloration, and splitting of the nail plate,
as well as lifting of the nail plate from the nail bed. The disease
has a high incidence in the general population. The main predisposing factors for onychomycosis include old age, diabetes, HIV
infection, psoriasis, peripheral vascular impairment, peripheral
neuropathies, podiatric abnormalities, certain sporting activities, and traumatic nail disorders.
This condition represents about 50% of all nail disorders. It
has a high occurrence throughout the world and recent epidemiological data indicates a prevalence ranging from 2% to 15%.
Thus, onychomycosis is the most common progressive nail disease by fungi. Some clinicians claim to be able to predict the presence of a fungus in a dystrophic nail. However, it is very difficult.
Dermatophytes are the pathogens most commonly responsible
for primary onychomycoses. Yeasts and nondermatophyte molds
both account for about 5% to 15% of cases. Onychomycosis more
frequently affects the toenails than the fingernails. This is probably explained in part by the fact that the toenail growth rate is
3 times slower than that of fingernails. Different clinical patterns
of onychomycosis due to the way by which fungi invade the nail
have been described. The type of nail invasion depends on both
the nature of the fungus, the host susceptibility and the site at
which the nail is invaded.
Five main categories of onychomycosis have been established.
They are the distal and lateral subungual type, the proximal
subungual type, the white or black superficial type, the midplate type, and the total dystrophic type. There are also mixed
variants of onychomycosis, as well as unusual patterns seen in
onychomycosis relapses.

270 — Gérald E. Piérard, Claudine Piérard-Franchimont, and Pascale Quatresooz

It is not within the scope of this chapter to detail laboratory
procedures, but it is important to stress the necessity of sending suitable specimens to the laboratory. Clippings taken from
affected areas are best, however, this is not always possible. It
may be necessary to scrape or slice off areas of dystrophic nail
with a scalpel blade.
Traditional methods used for the diagnosis of onychomycosis are fungal nail culture on Sabouraud’s dextrose agar and KOH
preparation of nail samples. Although these have been the standard methods used in clinics, the diagnostic accuracy range for
these tests is as low as 50% to 70%, depending on the methods
used to collect and prepare the samples. There is evidence that
histomycology when compared to culture shows higher discriminatory ability and a higher accuracy rate.

(A)

Distal and Lateral Subungual Onychomycosis
Distal and lateral subungual onychomycosis (DLSO) represents
the most common type of onychomycosis. This condition is frequently caused by Trichophyton rubrum, which reaches the nail
through the hyponychium or the lateral nailfolds and invades the
nail bed spreading proximally. The skin of the palms and soles is
the primary site of infection.
In DLSO, the distal and lateral free edges of the nail exhibit subungual hyperkeratosis and eventual onycholysis (Fig. 21.2a, b & c).
In early evolving DLSO, the fungi are confined to the deeper portion of the nail plate (Fig. 21.3). The onycholytic area appears as
opaque, yellow-white areas spreading proximally. Yellow streaks
along the lateral margin of the nail and/or presence of yellow
onycholytic areas in the central portion of the nail represent airfilled tunnels or clumps of dermatophytes named dermatophytomas (Fig. 21.4). As the disease progresses, the nail plate usually
becomes more friable and grossly hyperkeratotic. Various color
changes can also be present in DLSO.
Aspergillus spp., Fusarium spp. and Scopulariopsis brevicaulis
may produce DLSO that involves a single toenail, creating the
diffuse nail invasion associated with paronychia. DLSO due to
Acremonium spp. usually presents as one or a few longitudinal
white streaks extending proximally from the distal margin. In
DLSO due to S. brevicaulis, Alternaria spp. and Scytalidium spp.,
the periungual tissues and the nail plate often show a brown to
black pigmentation.
Sometimes DLSO occurs secondary to posttraumatic onycholysis. The initial space created becomes the potential site for
colonization and infection.

(B)

(C)

Proximal Subungual Onychomycosis
Proximal subungual onychomycosis (PSO) is one of the least
common variants of onychomycosis in the general population,
but it does represent the most common type of onychomycosis among immunocompromised patients (particularly those
infected by HIV where T. rubrum is most likely the etiology).
Fungi most likely target the nail plate through the underface
of the proximal nailfold and the area under the cuticle. The
infection typically spreads to the ventral portion of the nail
plate. PSO presents with or without paronychia. Clinically,
PSO presents as a focal leukonychia appearing from beneath
the proximal nailfold. The affected nail shows a deep, milky-

Figure 21.2. A,B&C. Distal and lateral subungual onychomycosis.
(A) Lateral type; (B) distal onycholytic type;
(C) hyperkeratotic type.

white or yellowish discoloration that overtakes the lunula
(Fig. 21.5a & b). It then spreads to involve the whole nail plate
very rapidly.
Secondary PSO is much more common than the primary
variety, and chronic paronychia is usually the predisposing factor. In chronic paronychia mixed flora of microorganisms can

Infections of the Nail Unit — 271
(A)

Figure 21.3. Deep invasion of the nail plate. Fungi are oriented in
parallel arrays (PAS stain).
(B)

Figure 21.5. A&B. Proximal subungual onychomycosis.
(A) Native aspect of the nail; (B) Aspect of the nail involvement
after scraping the upper portion of the nail plate. The distinction
between this PSO type and a “deep white superficial onychomycosis”
is difficult to establish.

Figure 21.4. Streaky pocket of fungi (black) inside a nail plate as
revealed by image analysis of a histological section.

be isolated from the nailfold area. Candida species, especially
Candida albicans and Candida parapsilosis, are most consistently
found. They are also likely to be the main pathogens. In secondary PSO, the nail plate can be affected centrally or at one or both
lateral edges. The resulting dystrophy then gradually spreads up
the nail. Apart from the cosmetic appearances, the nail bed is
often painful, and sometimes pus can be expressed by applying
pressure to the proximal nailfold.
PSO caused by Aspergillus spp., Fusarium spp. and
Scopulariopsis brevicaulis are typically associated with marked,
painful paronychia. Some patients complain of inflammatory
flares with purulent discharge, especially when Aspergillus is
the cause.

White or Black Superficial Onychomycosis
White superficial onychomycosis (WSO) and black superficial
onychomycosis (BSO) affect the dorsal surface of the nail plate.
The common type of WSO is usually caused by T. interdigitale
that possesses keratolytic enzymes able to metabolize the hard
keratin of the superficial nail plate (Fig. 21.6). Clinically, the nail
shows one or more small white opaque chalky spots that can
easily be scraped off. They may coalesce gradually to cover the
whole nail plate.
In HIV-infected patients, WSO is usually due to T. rubrum.
In these patients, it is not only seen in the toenails but also in the
fingernails. Clinically, the affected nails appears diffusely opaque
and white, with leukonychia often reaching the proximal portion of the nail. A similar clinical picture of “deep WSO” is seen
in children who present with infections due to T. rubrum and
nondermatophyte molds.
The most common species of nondermatophyte molds that
are able to invade the superficial nail plate include Fusarium spp.,

272 — Gérald E. Piérard, Claudine Piérard-Franchimont, and Pascale Quatresooz

Figure 21.6. White superficial onychomycosis with fungal cells confined to the upper portion of the nail plate.

Aspergillus spp., and Acremonium spp. Mold WSO usually affects
a single toenail (mainly the big toe). In some instances, WSO
is complicated by a deeper pattern of nail invasion. This diffuse
and deep nail plate involvement makes it difficult to distinguish
a “deep WSO” from PSO progressing superficially. As seen in the
other types of onychomycosis due to nondermatophyte molds,
paronychia may be associated. However, it usually presents without a pustular discharge.
The uncommon “WSO zebra type” (WSOZ), or superficial
white transverse onychomycosis is characterized by alternating
transversal bands of white and native nail colors. This clinical presentation is probably due to a primary paroxysmal alteration in the
structure of the dorsal aspects of the nail plate. The focal transversal
defect in keratinization allows T. rubrum invasion at these places.
In rare instances, Scytalydium dimidiatum causes BSO with
superficial black patches on the nail plate.

Figure 21.7. Midplate onychomycosis with a parallel pattern of fungal
infiltration.

Figure 21.8. Total dystrophic onychomycosis with fungi present at all
levels of the nail plate.

Midplate onychomycosis
In midplate onychomycosis (MPO), also called endonyx onychomycosis, fungi invade the nail via the free margin of the nailplate. Instead of infecting the nail bed, the fungus penetrates the
mid part of the nail plate where it remains confined (Fig. 21.7).
This rare type of onychomycosis is predominantly caused by
Trichophyton soudanense and Trichophyton violaceum. In midplate onychomycosis the nail plate appears diffusely opaque and
white in the absence of onycholysis and subungual hyperkeratosis. Plantar infection can also be associated.

Total Dystrophic Onychomycosis
Total dystrophic onychomycosis (TDO) rarely occurs as a primary
condition. Most commonly, it represents the endpoint of severely
evolving DSO, PSO, “deep” WSO, and MPO. TDO occurs when
the entire nail plate and nail bed are invaded and dissociated from
the fungal pathogen (Fig. 21.8). Eventually, the nail crumbles
away, leaving a hyperkeratotic bed. The common acquired TDO
type is the expression of a dermatophyte infection.
By contrast, the rare primary type of TDO is usually due to
Candida, and typically affects immunocompromised patients,
such as those suffering from chronic mucocutaneous candidiasis,

iatrogenic immunosuppression, or HIV infection. In the chronic
mucocutaneous type, TDO is associated with paronychia of the
proximal nailfold, and it involves the nail matrix, the nail bed,
and the hyponychium. The nail bed is hyperkeratotic and the nail
plate is considerably thickened and dystrophic in TDO. Several
nails are generally affected, including both fingernails and toenails. In these patients, oral candidiasis is often associated.
In HIV-positive patients and iatrogenic immunocompromised individuals the clinical presentation of Candida onychomycosis is less severe, and only one or a few fingernails are
affected.
Candida albicans is frequently isolated from the subungual area of onycholytic nails and from the proximal nailfold
in chronic paronychia. In both of these conditions, however,
Candida colonization may not represent true infection.

C O M B I N E D VA R I A N T S
OF ONYCHOMYC OSIS

The histological examination of onychomycoses discloses combined variants of onychomycosis associating different patterns

Infections of the Nail Unit — 273

Figure 21.9. Combined variant of onychomycosis.

Figure 21.10. Superficial and deep fungal invasion of a nail plate.

Figure 21.11. Mixed type onychomycosis due to a dermatophyte
(hyphae) and large spores of Scopulariopsis brevicaulis.

Figure 21.12. Fungal conidia and small hyphae trapped in a nail plate
and surviving after antifungal treatment.

of fungal invasions. PSO, WSO, deep WSO, and MPO can be
variably associated in any given nail (Figs. 21.9 and 21.10). These
combined patterns of fungal invasion should not be confused
with mixed onychomycosis, which indicates the presence of differing species of fungi in a single nail (Fig. 21.11).

ONYCHOMYC OSIS REL APSE

Onychomycosis is a challenging infection to treat, with treatment failures and relapses being very common occurrences. The
recurrent onychomycosis clinically is not always the same as in
the primary phase of the disease. The sites of early recurrence
can be inside the nail plate where fungal conidia have survived
the antifungal treatment (Fig. 21.12). In other instances, sites of
recurrence correspond to a site of recontamination from shoes,
fomites, or other environmental structures. In the latter instance,
fungal propagules are found inside cracks in the nail (Fig. 21.13).
A sporodochium can develop in rare instances.

P I T FA L L S A N D M Y T H S

Clinical confusion between noninfectious onychodystrophies
and infections of the nail unit is the main pitfall. Another

Figure 21.13. Critical conidia colonization in cracks dissociating the
distal edge of a nail plate.

important pitfall deals with the identification of the causative
fungus in onychomycosis. Retrieving a fungus at culture does
not mean that it is a pathogen. A myth concerns the extrapolation that in vitro antimicrobial testing correlates with clinical
diseases (such as psoriasis, lichen planus and eczema).

274 — Gérald E. Piérard, Claudine Piérard-Franchimont, and Pascale Quatresooz

CONCLUSION

The nail unit can be infected by a variety of microorganisms. The
unique anatomy of the nail is responsible for specific patterns of
microbial colonization and infection. All conditions merit medical attention because each diagnosis is different, and merits a
specific treatment. In these disorders, clinical assessment must
be combined with culture and histomycology to obtain the correct diagnosis.

SUGGESTED READINGS

Arrese JE, Piérard-Franchimont C, Piérard GE. Fatal hyalohyphomycosis following Fusarium onychomycosis in an immuno-compromised patient. Am J Dermatopathol 1996;18:196–198.
Arrese JE, Piérard-Franchimont C, Piérard GE. Facing up to the
diagnostic uncertainty and management of onychomycoses. Int J
Dermatol 1999;38: 1–6.
Arrese JE, Piérard GE. Treatment failures and relapses in onychomycosis: a stubborn clinical problem. Dermatology 2003;207:
255–260.
Baran R, hay R, Perrin C. Superficial white onychomycosis revisited. J
Eur Acad Dermatol Vener 2004;18:569–571.
Effendy I, Lecha M, Feuilhade de Chauvin M, Di Chiacchio N, Baran
R. Epidemiology and clinical classification of onychomycosis. J
Eur Acad Dermatol Vener 2005;19:S8-S12.
Ghannoum MA, Hajjeh RA, Scher R, et al. A large-scale North
American study of fungal isolates from nails: the frequency of

onychomycosis, fungal distribution, and antifungal susceptibility
patterns. J Am Acad Dermatol 2000;43:641–648.
Gupta AK, Jain HC, Lynde CW, et al. Prevalence and epidemiology
of onychomycosis in patients visiting physicians’s offices: a multicenter Canadian survey of 15,000 patients. J Am Acad Dermatol
2000;43:244–248.
Gupta AK, Lynch LE. Onychomycosis: review of recurrence rates,
poor prognostic factors, and strategies to prevent disease recurrence. Cutis 2004;74:S10–S15.
Gupta AK, Ricci MJ. Diagnosing onychomycosis. Dermatol Clin
2006;24: 365–369.
Haneke E. Surgical anatomy of the nail apparatus. Dermatol Clin
2006;24: 291–296.
Piérard GE, Arrese JE, Pierre S, Bertrand C, Corcuff P, Lévêque JL,
Piérard-Franchimont C. Diagnostic microscopique des onychomycoses. Ann Dermatol Venereol 1994;121:25–29.
Piérard GE, Arrese JE, De Doncker P, et al. Present and potential
diagnostic techniques in onychomycosis. J Am Acad Dermatol
1996;4:273–277.
Piérard GE, Piérard-Franchimont C, Quatresooz P. Fungal thigmotropism in onychomycosis and in a clear hydrogel pad model.
Dermatology, in press.
Piérard GE, Quatresooz P, Arrese JE. Spottlight on nail histomycology.
Dermatol Clin 2006;24: 371–374.
Piérard GE. Spores, sporodochia and fomites in onychomycosis.
Dermatology 2006;213:169–172.
Scher RK, Baran R. Onychomycosis in clinical practice: factors contributing to recurrence. Br J Dermatol 2003;149:S5–S9.
Weinberg JM, Koestenblatt EK, Tutrone WD, Tishler HR, Najarian L.
Comparison of diagnostic methods in the evaluation of onychomycosis. J Am Acad Dermatol 2003;49:103–107.

22

INFECTIONS OF THE MUCOUS
MEMBRANES
Julia S. Lehman, Alison J. Bruce, and Roy S. Rogers, III

H I STORY

Infections involving the mucous membranes have been documented since antiquity. For example, Hippocrates (460–377 B.C.)
referred to condyloma and leprosy in his writings. Genital ulcers
were first proposed to be transmitted sexually in the 1100s A.D.
by Roger of Palermo. Syphilis, one of the most historically significant mucosal infections, was initially described during the
late fifteenth century. Understanding of the pathogenesis of and
recognizing the organisms implicated in these diseases blossomed during the latter half of the 1800s with the development
of new microbiology and histopathology techniques, as well as
the introduction of the Germ Theory paradigm.
The clinical presentation of certain diseases has evolved over
time as a consequence of changing cultural norms. For example, whereas HSV-1 infection historically was limited to the oral
mucosa and HSV-2 to the genitalia, both viral strains are identified frequently in both anatomic locations in recent times due
to changing sexual practices. Moreover, disease epidemiology is
continually changing as a result of medical advances. For example, syphilis has become much less common in the developed
world after the development of penicillin. However, the recent
increase in iatrogenic immunosuppression and other acquired
immunodeficiency states has given rise to a modified set of diseases and disease presentations involving the mucosa. Finally,
the ease of world travel has removed geographic boundaries
that previously limited the spread of many infections, making it
necessary for all practitioners – particularly primary care physicians, dermatologists, dentists, infectious disease specialists,
gynecologists, and urologists – to be familiar with the spectrum
of infectious diseases affecting the mucosa.
Mucosal epithelium, the biologic lining of all orifices of the
human body, is continuously exposed to potentially pathogenic
endogenous and exogenous organisms. Multiple local regulatory
factors contribute to defense against infection of the mucosal
membranes. First, the stratified squamous epithelium of mucosal
membranes offers a physical barrier against invading microbes.
Additional protection is provided by epithelial keratinization at
some sites, such as the gingiva, hard palate, and filiform papillae
of the tongue. Susceptibility to infection increases when mucosal
membranes are disrupted, as is seen with radiation or chemotherapy-related oral mucositis, for example. Second, mucosal
surfaces are colonized by a myriad of native microorganisms
that inhibit invading organisms. The normal flora regulates the
growth of pathogenic organisms by providing competition for
available nutrients, limiting the number of sites to which exotic
organisms may adhere, and releasing antimicrobial substances
(described below). When the normal pattern of flora is altered,

as occurs with antibiotic or corticosteroid usage, mucosal
membranes are rendered more vulnerable to infection. Third,
in many sites, mucous membranes harbor cilia that clear pathogens mechanically. Patients with disturbed ciliary function, such
as those with primary ciliary dyskinesis, for example, are more
likely to develop certain infections. Fourth, salivary and vaginal
secretions not only flush organisms but also alter regional pH
and oxidation–reduction potential, thus selecting which organisms can thrive in the mucosal environment. For example, conditions causing xerostomia, such as Sjögren’s disease, head and
neck irradiation, and medication side effects, predispose the
host to a higher incidence of oral infection. Fifth, mucous epithelial cells intrinsically produce antimicrobial peptides, such
as defensins, histatins, and bacteriocins, which comprise part
of the innate immune system and function as a chemical shield.
Moreover, host epithelial cells secrete cytokines and other mediators that recruit and activate complement, cellular immunity,
and humoral immunity. Thus, host defense of the mucous membranes is achieved by an intricate, multi-tiered system comprised
of locally protective factors and selective activation of innate, cellular, and humoral immunity.
Although mucosal membranes line much of the gastrointestinal, respiratory, and genitourinary tracts, this chapter will
focus on infections that cause disease in the oral cavity and lower
genital tract. Diagnosis of mucosal membrane infections can be
challenging, particularly as mucosal response to insult is often
nonspecific. Optimally, therapeutic decisions are guided by an
accurate diagnosis. In serious or systemic disease, however,
treatment may need to be started empirically. Airway management is another important consideration in infections of the
oropharyngeal mucosa. In addition to treating the underlying
disease and predisposing factors, a variety of therapeutic modalities may be used to alleviate the symptoms of oral infection.
For example, pain may be relieved with the use of topical therapies, such as topical viscous lidocaine, benzocaine-containing
preparations (e.g. Anbesol, Orajel), or analgesic mouthwashes,
such as diphenhydramine elixir. Systemic agents, such as nonsteroidal anti-inflammatory drugs, acetaminophen, and opioid
medications, may be required to achieve adequate analgesia in
select cases.

VIR AL INFECTIONS: DNA VIRUSES

Human herpesviruses
Human herpesvirus (HHV) is a double-stranded DNA virus
with multiple serotypes that have been implicated in the development of mucosal disease in humans (Table 22.1). Pathogenesis
275

276 — Julia S. Lehman, Alison J. Bruce, and Roy S. Rogers, III

Table 22.1: Human Herpesviruses and Associated Disease or Syndrome Potentially Involving Mucous Membranes
Human Herpesvirus
Serotype

Virus Name

Associated Disease or Syndrome Potentially Affecting Mucous Membranes

1

Herpes simplex virus type 1

Primary disease: Acute herpetic gingivostomatitis; ulcerative pharyngotonsillitis;
mononucleosis-like syndrome Recurrent: Herpes labialis; recurrent HSV stomatitis

2

Herpes simplex virus type 2

Primary disease: Genital herpes Recurrent: Genital herpes

3

Varicella-zoster virus

Primary: Varicella (chicken pox) Recurrent: Herpes zoster (shingles); Ramsay Hunt
Syndrome

4

Epstein-Barr virus

Mononucleosis (glandular fever); oral hairy leukoplakia; Burkitt lymphoma;
nasopharyngeal lymphoma; posttransplantation lymphoproliferative disorder

5

Cytomegalovirus virus

Mononucleosis (glandular fever)

6

Roseola virus

Exanthema subitum (roseola infantum)

7

Human herpesvirus 7

Unclear (possible link to roseola infantum)

8

Human herpesvirus 8

Kaposi sarcoma

results from virus-mediated cytopathic change and host
immune-mediated cell damage.
Human herpesvirus 1 and human herpesvirus 2
Herpes simplex virus (HSV)-1 and HSV-2 cause primary and
recurrent mucosal lesions. Seropositivity for HSV-1 ranges from
58% to 90%, while seropositivity for HSV-2 is less frequent in the
general population. HSV-1 is usually isolated from oral herpes
lesions, whereas HSV-2 is found more commonly in genital herpes lesions. Both serotypes may be responsible for either oral
or genital disease, however. HSV is transmitted to oral, nasal,
genital, or conjunctival mucosa via contact with an infected individual. Infection can also result from autoinoculation, dental
work, and contact with fomites. Moreover, HSV can be transmitted vertically from mother to newborn via passage through an
infected birth canal.
After primary infection, HSV travels to the sensory ganglion
innervating the site of inoculation via retrograde intra-axonal
transport. Following a latency period, HSV can undergo antegrade axonal transport, leading to recurrent infection. Recurrent
infection can arise spontaneously or can be precipitated by emotional stress, fatigue, fracture of the facial bones, neurosurgical
axonal injury, or ultraviolet light exposure. Recurrent infection
is seen in 40% of patients infected with HSV-1 but is less common with HSV-2 infection.
C L I N I C A L P R E S E N TAT I O N

Primary HSV infection often occurs during childhood
and is asymptomatic or unrecognized in the vast majority of
infected patients. When symptomatic in children, primary
oral HSV infection most frequently appears as painful, fragile
vesicles on the gingiva and other oral surfaces (acute herpetic
gingivostomatitis). In adolescents, primary HSV infection often
presents as ulcerative pharyngotonsillitis. In adults, primary
oral HSV infection results in painful vesicles and erosions of
the keratinized and nonkeratinized oral mucosa. Pharyngitis,
tonsillitis, dysphagia and associated dehydration, or a mononucleosis-like syndrome may accompany oral herpetic lesions.
Differential diagnosis of primary oral HSV infection is broad and
includes hand-foot-and-mouth disease, herpangina, infectious

Figure 22.1. Primary herpes simplex virus infection of the
genitalia.

mononucleosis, streptococcal stomatitis, acute necrotizing
ulcerative gingivitis, and immunobullous diseases, such as
pemphigus vulgaris and paraneoplastic pemphigus.
Primary genital HSV infection is associated with vesicles
and ulcers on the external genitalia (i.e., labia majora, labia
minora, vaginal vestibule, and introitus in women, and the
glans penis, prepuce, shaft of the penis, and scrotum in men)
(Fig. 22.1). Tender regional lymphadenopathy may accompany
mucosal findings. Because partial immunity develops during
primary infection, recurrent HSV is not usually associated

Infections of the Mucous Membranes — 277

infection include aseptic meningitis, encephalitis, ganglionitis,
and myelitis.
DIAGNOSIS

Figure 22.2. Herpes labialis (herpes simplex virus).

with significant constitutional symptoms. Urethritis and associated dysuria or urinary retention may occur in either sex but
are more commonly seen in women. Herpetic proctitis can
also result from receptive anal intercourse with an infected
individual. The differential diagnosis of HSV infection of the
genitalia includes chancroid, lymphogranuloma venereum,
granuloma inguinale, Behçet’s disease, and immunobullous
disorders.
Lesions of primary herpes simplex develop 5 to 10 days
following exposure, persist for 10 to 14 days, and heal without
scarring. Despite the absence of signs or symptoms of HSV
infection, asymptomatic carriers are contagious, because they
shed infectious viral particles in mucosal secretions.
In most patients, recurrent HSV presents initially with a prodrome of tingling, burning, or itching sensation. Recurrent oral
herpes arises commonly at the cutaneous lip and vermilion border (herpes labialis; Fig. 22.2) but only rarely presents intraorally.
Unlike lesions of primary oral herpes, those of recurrent oral herpes lesions are typically confined to the keratinized mucosa. In
the immunocompetent host, recurrences occur up to 3 to 4 times
each year and last 7 to 10 days. In immunocompromised patients,
however, recurrences are more frequent, last for a longer period,
and may disseminate widely. Recurrent intraoral HSV infection
is frequently confused with recurrent aphthous stomatitis. The
clinical features of the two conditions differ in several respects,
however. Specifically, lesions of recurrent intraoral HSV infection appear as grouped, punched-out ulcers found exclusively
on keratinized mucosa and are reasonably mild in intensity. The
lesions of recurrent aphthous stomatitis, however, are found on
nonkeratinized mucosa, and although they may appear similar
morphologically to those of recurrent intraoral HSV infection,
they often are solitary and can be exquisitely tender.
Epidemiologic and molecular studies have consistently
demonstrated an association between HSV seropositivity and
erythema multiforme (EM), with approximately 36% to 75%
of patients with EM having evidence of previous infection
with HSV. EM is thought to arise as a result of an exuberant
host cytopathic response to circulating immune complexes.
EM is characterized by the appearance of targetoid, erythematous lesions with a dusky center. Mucosal manifestations of
EM are present in 40% of cases and present as a desquamative stomatitis. Frequently involved sites include the buccal
mucosa, palate, and lips. Other nonmucosal sequelae of HSV

Primary and recurrent HSV infections are usually diagnosed
clinically, based on the appearance of characteristic lesions. The
gold standard for detection of all herpesviruses is culture, which
is most useful early in the disease course during the replicative
phase. Once the lesion has crusted over or regressed, however,
viral culture becomes less sensitive because of reduced viral
shedding. Histopathology with hematoxylin and eosin stain
shows ballooning and reticular epidermal degeneration with
characteristic multinucleated keratinocytes. These findings are
nonspecific, as they are also seen with varicella-zoster virus
infection. Tzanck smear is a rapid, inexpensive test that demonstrates multinucleated giant cells with viral inclusions. Even with
optimal technique, however, test sensitivity is about 50% to 65%
and cannot differentiate among various human herpesviruses.
Polymerase chain reaction for the detection of HSV DNA is
being used increasingly because of its high sensitivity. However,
it is significantly more costly than traditional diagnostic modalities. Also, detection of serum antibodies to HSV-1 and HSV-2
with direct immunofluorescence testing or in situ hybridization
is another diagnostic strategy but may be insensitive in early
disease.
T R E AT M E N T

In immunocompetent hosts, initial management of HSV
infection is supportive. As intraoral herpetic infection can lead
to dysphagia, adequate oral intake of fluids should be stressed.
Symptomatic relief can be achieved with mouth rinses containing topical anesthetic agents, such as viscous lidocaine, benzocaine preparations, dental pastes, or a diphenhydramine elixir
with Maalox (1:1). Salicylates, nonsteroidal anti-inflammatory
drugs, and acetaminophen can be used for additional analgesia.
In children, however, salicylates should be avoided because of
the potential to develop Reye’s syndrome. Secondary bacterial
infections, which are uncommon, should be treated with appropriate antibiotics.
When antiviral therapy is indicated in primary HSV infection, acyclovir is the drug of choice. Valacyclovir may be preferred
for its more convenient dosing schedule, however. A randomized controlled trial demonstrated efficacy of oral acyclovir in
childhood acute herpetic gingivostomatitis. Topical acyclovir is
not particularly effective, likely because of poor intraoral drug
absorption. In addition, this medication may contribute to antiviral resistance.
For recurrent herpes simplex, oral antiviral therapy has been
shown to be effective as preventive and suppressive therapy in
immunocompetent patients. Acyclovir, valacyclovir, or famciclovir may be used. Topical use of sunscreen on the lips may
prevent herpes labialis by blocking ultraviolet light, and docosanol 10% cream (Abreva) and topical penciclovir (Denavir)
have been shown to decrease duration of symptoms in herpes
labialis.
In immunocompromised hosts, disease can be severe or disseminated and is more likely to be associated with complications.
Therefore, aggressive antiviral therapy is recommended. Oral
acyclovir can be used as suppressive therapy for HSV infection.
Though not approved by the U.S. Food and Drug Administration
(FDA) for this indication, famciclovir is as effective as highdose acyclovir in the treatment of recurrent herpes labialis in

278 — Julia S. Lehman, Alison J. Bruce, and Roy S. Rogers, III

patients with HIV infection. Intravenous foscarnet may be used
in acyclovir-resistant HSV infection.
Human herpesvirus 3 (varicella-zoster virus)
C L I N I C A L P R E S E N TAT I O N

Varicella infection can cause painful, shallow vesicles and
ulcerations on the palate, buccal mucosa, and pharyngeal mucosa.
These oral lesions are accompanied by the characteristically pruritic eruption of varicella, as well as fever, malaise, and myalgias.
Incubation period is usually 14 to 16 days. Although generally
self-limited in children younger than 10 years, primary varicella
infection in adolescents, adults, and immunocompromised individuals can be severe. Complications include secondary bacterial infection, otitis media, pneumonia, arthritis, uveitis, Reye’s
syndrome (particularly with administration of salicylates in
children), nephritis, and encephalitis. Congenital varicella syndrome (CVS), acquired during the first half of pregnancy, is rare,
because most women of childbearing age have viral immunity.
Recurrent VZV infection (herpes zoster, shingles) is heralded
by the onset of pain, tingling, or pruritus in a dermatomal distribution. One to 2 days later, clustered herpetic lesions arise in
a unilateral dermatomal segment. Oral lesions develop when the
second and third divisions of the trigeminal nerve are involved
and typically affect the palate, buccal mucosa, tongue, and
oropharynx. Usually, lesions resolve within 2 to 3 weeks but can
impart residual chronic pain, known as postherpetic neuralgia.
Other oral complications are rare but include tooth exfoliation
and mandibular necrosis. Ramsay Hunt Syndrome (herpes zoster
of cranial nerves VII and VIII) may involve herpetic lesions on
the anterior two-thirds of the tongue, soft palate, external auditory canal, and pinna. Associated symptoms include facial palsy,
nystagmus, tinnitus, otalgia, ageusia, vertigo, and hearing loss.
Other diseases that mimic oral VZV infection or herpes zoster
include recurrent aphthous stomatitis, acute herpetic gingivostomatitis, erythema multiforme, oral pemphigoid, and pemphigus vulgaris. Unilaterality and dermatomal distribution of
lesions may be helpful in distinguishing herpes zoster from other
conditions.
DIAGNOSIS

Both primary and recurrent VZV infection can be diagnosed
based on clinical findings alone. When the diagnosis is in question, VZV can be differentiated from HSV by culture, PCR, direct
immunofluorescence, or in situ hybridization. Culture and PCR
are insensitive for the presence of varicella-zoster virus, however,
because the organism does not persist in the oropharynx following incubation. As with HSV infection, histopathology of VZVinfected tissue demonstrates ballooning epidermal degeneration
and multinucleated giant cells. Tzanck smear is 75% to 80% sensitive in herpes zoster.
T R E AT M E N T

Topical and systemic analgesics are used for symptomatic
relief. Antiviral therapy is used rarely for primary varicella in
otherwise healthy children, as the disease course is generally
uncomplicated. Also, antiviral therapy is discouraged because of
concerns regarding the development of resistant viral strains and
the cost incurred with therapy. In patients older than 13 years
and immunocompromised individuals, however, oral acyclovir
is indicated because it decreases duration and severity of the
disease.

In the treatment of herpes zoster, narcotic analgesics are
often necessary for pain management. Antiviral drugs of choice
are oral acyclovir or valacyclovir, with the greatest efficacy
achieved when started early in disease course. Antiviral therapy
can shorten disease duration but has not been shown to prevent
postherpetic neuralgia. For disseminated or severe local disease,
systemic acyclovir, famciclovir, and valacyclovir have similar
efficacy and safety profiles. In acyclovir-resistant herpes zoster,
foscarnet or cidofovir are recommended, although these are
both associated with significant toxicity.
Previously a common disease of childhood, varicella is
becoming much less common since the development and distribution of an effective vaccine. Varivax vaccine, the live, attenuated Oka/Merck vaccine, is FDA-approved for children older than
12 months and immunocompromised persons. It is thought to be
70% to 90% effective in preventing infection, and those patients
who do develop varicella following vaccination generally have a
milder course. The ProQuad vaccine, a new quadrivalent vaccine
for measles, mumps, rubella, and varicella, has similar efficacy
to the separate administration of MMR and Varivax vaccines.
When used in adults aged 60 or older, the varicella vaccination
(Zostavax) is effective in reducing the incidence of herpes zoster
and postherpetic neuralgia.
Human herpesvirus 4 (Epstein-Barr virus)
Epstein-Barr virus (EBV) is a ubiquitous organism that is transmitted via oral contact.
C L I N I C A L P R E S E N TAT I O N

Oral findings of EBV-related infectious mononucleosis
include palatal petechiae, oropharyngeal ulceration, erythema
of the posterior oropharynx, exudative tonsillitis, and, in severe
cases, necrotizing gingivitis. These signs are accompanied by
fever, profound malaise, and neck lymphadenopathy. A diffuse
morbilliform exanthem develops in a minority of cases, particularly in children treated with amoxicillin for presumed or concurrent streptococcal pharyngitis. The incubation period ranges
from 5 to 50 days. Differential diagnosis includes streptococcal
pharyngitis, leukemia, syphilis, diphtheria, primary HIV infection, and drug reaction.
Oral hairy leukoplakia presents as an asymptomatic white
patch or hyperkeratotic plaque on the lateral aspect of the
tongue. It can also extend to the dorsal and ventral tongue, buccal mucosa, palate, and tonsils. While usually bilateral in distribution, lesions can also be unilateral. Hypertrophy of the surface
contributes to the development of hair-like projections. Lesions
of oral hairy leukoplakia are fixed and cannot be scraped away
with a tongue depressor. Though intrinsically benign, oral hairy
leukoplakia is only seen in the presence of underlying immunocompromise, as with HIV infection or renal transplantation. In
patients with HIV infection, the presence of oral hairy leukoplakia portends a greater likelihood of developing Pneumocystis
jiroveci (P. carinii) pneumonia.
EBV has been linked to a variety of different cancers,
including Burkitt lymphoma, nasopharyngeal cancer, and posttransplantation lymphoproliferative disorder. In one series of
immunosuppression-related oral lymphomas, EBV was present
universally. Burkitt lymphoma, a form of non–Hodgkin’s lymphoma, has endemic (African) and non-endemic (sporadic)
forms. While EBV infection is strongly linked to endemic Burkitt

Infections of the Mucous Membranes — 279

lymphoma (particularly in African children with concurrent
malarial infection), EBV infection is also identified in about 20%
of nonendemic cases. Burkitt lymphoma is associated with pharyngitis, cervical lymphadenopathy, jaw masses, loosened teeth,
and odontalgia. EBV-related nasopharyngeal cancer, a poorly
differentiated anaplastic carcinoma, is seen predominantly in
Southern China and Northern Africa. A case of posttransplantation EBV-related diffuse, large B-cell lymphoma initially presenting with an oral lesion has been described.
DIAGNOSIS

Diagnosis of EBV-related infectious mononucleosis is clinical but is supported by the presence of the virus-specific IgM
heterophile antibody, detected by the monospot test. Test positivity occurs within 1 to 2 weeks of primary illness. Infectious
mononucleosis is also associated with the presence of large numbers of atypical lymphocytes on differential cell count. Diagnosis
may be confirmed by the presence of other serum viral antigens,
such as those of the viral capsid and membrane.
Oral hairy leukoplakia is diagnosed when EBV is detected in
biopsy specimens of typical oral lesions using in situ hybridization, Southern blotting, direct immunofluorescence testing, or
electron microscopy. EBV-associated lymphomas are diagnosed
by biopsy. The presence of EBV in association with lymphoma
development is demonstrated with serologic tests or in situ
hybridization.
T R E AT M E N T

Infectious mononucleosis typically resolves spontaneously
after approximately 4 weeks and is treated symptomatically.
Bed rest and avoidance of activities that could predispose the
patient to splenic rupture (e.g. contact sports) are recommended.
Acyclovir has not been shown to be effective in limiting duration
or severity of disease, although it reduces subclinical viral shedding. Although co-infection with Streptococcus pyogenes should
be investigated and treated, amoxicillin or ampicillin should be
avoided because of the risk of associated skin eruption.
Oral hairy leukoplakia responds to a 10- to 14-day course of
high-dose acyclovir. Efficacy of topical 0.1% vitamin A acid and
topical podophyllum resin in 25% solution has been reported.
With all therapies, however, recurrence is common upon discontinuation of the medication if the underlying immunosuppression persists. In patients with HIV infection, lesions of hairy
leukoplakia usually regress with antiretroviral therapy.
Burkitt lymphoma may respond initially to chemotherapy
but usually recurs. Nasopharyngeal carcinoma is often diagnosed
after it has metastasized. Treatment is irradiation, although prognosis is poor.
Human herpesvirus 5 (cytomegalovirus)
Although cytomegalovirus (CMV) is ubiquitous, it rarely causes
illness in immunocompetent people. CMV is present in mucosal
secretions and is transmitted via exposure to bodily fluids of an
infected individual. Risk factors for illness from CMV infection
include transplantation, iatrogenic immunosuppression, and
concurrent HIV infection.
C L I N I C A L P R E S E N TAT I O N

Oral manifestations of CMV are rare in immunocompetent hosts. Enlargement of the salivary glands with an accompanying mononucleosis-like syndrome may develop, although
infection is commonly asymptomatic. In immunocompromised

individuals, oral findings include oropharyngeal ulcerations,
gingival hyperplasia, sialadenitis, and necrotizing gingivitis.
Oral lesions may be accompanied by mild hepatitis, thrombocytopenia, or hemolytic anemia. In this patient population, CMV
infection is associated with increased morbidity and mortality.
The incubation period is approximately 4 to 8 weeks. Primary
infection with or reactivation of CMV during the first two trimesters of pregnancy can confer significant teratogenicity to the
developing fetus, including chorioretinitis, intracerebral calcifications, and hepatosplenomegaly. Differential diagnosis for
oral CMV manifestations includes EBV-related mononucleosis,
primary HIV infection, acute herpetic gingivostomatitis, recurrent aphthous stomatitis, mumps, and immunobullous disorders
such as pemphigus vulgaris.
DIAGNOSIS

In otherwise healthy patients, diagnosis is usually based on
clinical findings. In cases in which diagnosis must be established,
enzyme-linked immunosorbent assay (ELISA) can be used to
detect CMV IgM antibodies. Other diagnostic tests include culture with fibroblast media, in situ hybridization, or PCR. On histopathology, the presence of basophilic intranuclear inclusions
and granular cytoplasmic inclusions (“owl eyes”) is specific for
CMV. CMV particles may also be seen on electron microscopy.
T R E AT M E N T

In immunocompetent patients, treatment is limited to
supportive measures. In immunocompromised patients, ganciclovir is the treatment of choice. Foscarnet should be reserved
for resistant disease. Prolonged therapy is often required, as current antiviral therapies suppress but cannot cure viral disease.
Although acyclovir is generally not effective against CMV, resolution of CMV-induced oral lesions with high-dose acyclovir
has been reported. In bone marrow transplant recipients, CMV
prophylaxis with ganciclovir or valganciclovir may be indicated.
Human herpesvirus 6
HHV-6 causes exanthem subitum (roseola infantum) in children and is transmitted via salivary secretions. HHV-6 infection
is very common during the first 2 years of life, and almost all
children are seropositive for HHV-6 by age 4. Following primary
infection, the virus remains latent in salivary glands.
C L I N I C A L P R E S E N TAT I O N

The first signs of exanthema subitum include high fever and
malaise, followed by the eruption of erythematous macules on
the soft palate and uvula (Nagayama spots). A generalized eruption of small, rose-colored macules on the chest, back, and abdomen follows. Lymphadenopathy, diarrhea, and cough may be
associated. Complications are rare but include febrile seizures,
pneumonitis, encephalitis, diarrhea, meningitis, hepatitis, and
bone marrow failure. Co-infection of HHV-6 with HIV is synergistic and can accelerate cytopathic effects. The incubation
period is approximately 7 to 10 days. Differential diagnosis of
exanthema subitum includes measles, rubella, and drug eruption. Some molecular evidence implicates HHV-6 in the development of recurrent aphthous stomatitis, although this remains
to be confirmed.
DIAGNOSIS

In otherwise healthy individuals, diagnosis is usually based
on the presence of classic clinical findings. When the identity
of the etiologic agent is required, immunofluorescence testing

280 — Julia S. Lehman, Alison J. Bruce, and Roy S. Rogers, III

Table 22.2: Mucosal Manifestations of Human Papillomavirus Infection with Commonly Associated HPV Serotypes
Disease

Typical Area of Mucosal Involvement

Most Commonly Associated HPV Serotypes

Squamous papilloma

Palatine, buccal, gingival, or labial mucosa

6, 11

Oral verruca vulgaris

Palatine, buccal, gingival, or labial mucosa

2, 4, 6, 11, 16

Condyloma acuminatum

Anogenital mucosa

6, 10, 11, 16, 18, 33

Focal epithelial hyperplasia

Buccal mucosa; lower lip

11, 13, 32

Cervical intraepithelial neoplasia; cervical cancer

Uterine cervix

16, 18

demonstrates the presence of HHV-6 IgM antibodies or a fourfold
increase in IgG with serial testing in acute disease. A rapid shell
vial assay is sensitive and specific for HHV-6. While specific,
viral culture is insensitive and impractical in clinical practice.
T R E AT M E N T

As exanthema subitum is generally benign and self-limited,
treatment is supportive. In disease complicated by CNS involvement, pneumonia, or hepatitis, ganciclovir and foscarnet are
used but have not been proven effective.

vascular channels and lymphocytes, while later lesions demonstrate numerous mitotic figures, erythrocytes, eosinophilic bodies, and a prominent spindle cell component. PCR or serologic
testing can also identify evidence of an HHV-8 infection. An
HIV test should be performed, and a chest radiograph should be
obtained to screen for pulmonary KS.
T R E AT M E N T

First isolated from salivary secretions in 1989, HHV-7 has not
been definitively linked to disease. Some evidence links HHV-7
to an exanthem subitum-like syndrome, although this has not
been confirmed.

The following treatments for isolated lesions of Kaposi
sarcoma have been reported to be efficacous: surgical excision, cryotherapy, injection of a sclerosing agent, intralesional
interferon, intralesional vinblastine, topica1 retinoids, and local
radiotherapy. For widespread or aggressive disease, systemic
agents, such as liposomal anthracyclines, paclitaxel, antiangiogenic medications, and oral retinoids, may be indicated.
Treatment of underlying immunosuppression is also necessary
to prevent recurrence.

Human herpesvirus 8

Human papillomavirus

HHV-8 is a B-cell lymphotropic human herpesvirus that, unlike
other human herpesviruses, is not present ubiquitously in the
general population. However, HHV-8 is associated with virtually all lesions of Kaposi sarcoma (KS), a low-grade, multicentric
vascular neoplasm. The mechanism of pathogenesis has not been
well established, although HHV-8 infection has been associated
with changes in the host response to cytokines and angiogenesis.
The development of KS in HHV-8-positive individuals is more
frequent in men than in women, thus suggesting a possible role
of hormones in the development of KS. HHV-8 has also been
associated with multiple myeloma, Waldenström’s macroglobulinemia, angiolymphoid hyperplasia with eosinophilia, multicentric Castleman’s disease and primary effusion lymphoma, a
condition characterized by malignant effusions without an identifiable contiguous solid tumor mass.

Human papillomavirus (HPV) is a small, double-stranded DNA
virus and has been associated with several mucosal manifestations, including squamous papilloma, oral verruca vulgaris,
condyloma acuminatum, focal epithelial hyperplasia, cervical
dysplasia and cancer (Table 22.2).

Human herpesvirus 7

C L I N I C A L P R E S E N TAT I O N

Initial lesions of KS are usually found intraorally and appear
as asymptomatic erythematous, violaceous or blue macules,
patches, plaques, ulcers, or nodules. In individuals with darker
skin, lesions may appear brown or black. The hard palate, soft
palate, tongue, and gingiva are involved frequently. In a minority
of cases, intraoral KS is associated with pain, bleeding, or ulceration. Differential diagnosis includes ecchymosis, hemangioma,
lymphangioma, granular cell tumor, and plaques of discoid lupus
erythematosus.
DIAGNOSIS

Diagnosis can be confirmed by typical findings on biopsy.
Early lesions are characterized by the presence of atypical

C L I N I C A L P R E S E N TAT I O N

Commonly described as oral warts, squamous papillomas
(associated with HPV types 6 and 11) and oral verruca vulgaris
(associated with HPV types 2, 4, 6, 11, and 16) are soft, pink, exophytic papules that arise on the lips, tongue, hard and soft palates,
and uvula. Papillomas are pedunculated and persistent, whereas
verrucae are sessile and more likely to resolve spontaneously.
Although usually painless, lesions may be tender at the base.
Condyloma acuminatum (linked to HPV types 6, 10, 11, 16,
18, and 33) appears as multiple soft, sessile, pink or grey papules
on the anogenital mucosa (Fig. 22.3). Rarely, palatal and tongue
lesions arise from autoinoculation, hematogenous spread, or
sexual transmission. Oral lesions are small, white, exophytic
papules, though they can coalesce to form nodules.
Focal epithelial hyperplasia (Heck disease) is seen most
commonly in native Americans, residents of Greenland, Alaska,
South America, and in patients with HIV infection. This disease
presents with multiple tender, pink, soft papules commonly arising on the lower lip and buccal mucosa. HPV types 11, 13 and 32
have been implicated.
Some evidence links oral HPV infection with an increased
risk for oral squamous cell carcinoma. Differential diagnosis for oral HPV lesions includes traumatic fibromas, oral

Infections of the Mucous Membranes — 281

Parvovirus B19
A member of the Parvoviridae family, parvovirus B19 is a
single-stranded DNA virus that is transmitted via inhalation
of aerosolized respiratory droplets or via receipt of contaminated blood products. Frequently, parvovirus B19 infection is
asymptomatic. However, it may be associated with several syndromes, including erythema infectiosum (slapped cheek syndrome; Fifth Disease), Henoch-Schönlein purpura, vasculitis,
glomerulonephritis, aplastic crisis, myocarditis, arthritis, and
papular-purpuric “gloves and socks” syndrome. When transmitted vertically from mother to developing fetus, hydrops
fetalis may result.
C L I N I C A L P R E S E N TAT I O N

Figure 22.3. Condyloma acuminatum (human papillomavirus).

lesions of Cowden disease, fibrous hyperplasia, verruciform
xanthoma, focal dermal hypoplasia syndrome, and squamous
cell carcinoma.
In women, genital infection with high-risk HPV serotypes
(e.g., 16 and 18) confers a higher chance for the development
of squamous intraepithelial lesions of the cervix and, ultimately,
cervical cancer.
DIAGNOSIS

Diagnosis of oral infection by HPV is generally made on
the basis of clinical findings and is confirmed when lesions
turn white with the application of acetic acid (aceto-whitening).
Papanicolaou-stained (Pap) smear is used to screen for high-risk
HPV infection of the cervix. When Pap smear results are abnormal, colposcopy and colposcopy-guided biopsy are performed.
Excisional biopsy may be required in some cases, and HPV serotype can be determined with PCR or in situ hybridization.
T R E AT M E N T

As with cutaneous verrucae, oral HPV lesions can resolve
spontaneously or may require ablative therapy with podophyllum, topical 5-fluorouracil, cryotherapy, laser therapy, electrodessication, or excision. Therapeutic interventions are most
effective if the entire base of the lesion is destroyed, although
recurrences are common regardless of the therapeutic modality
used. To avoid autoinoculation, all lesions should be targeted in a
treated patient. Patients with periungual HPV lesions should be
counseled to avoid nail biting.
In focal epithelial hyperplasia, topical interferon-β and carbon dioxide laser have been used, although lesions may resolve
spontaneously.
For primary prevention of cervical dysplasia and cancer,
highly effective recombinant HPV vaccines containing viruslike particles from high-risk HPV genotypes have been developed. The American Cancer Society recommends routine
vaccination among all females between the ages of 11 and 12
and all females between the ages of 13 and 18 who have not
previously received all three doses of the vaccination. For secondary prevention, the American Cancer Society recommends
regular cervical cancer screening for vaccinated and unvaccinated women starting 3 years after onset of vaginal intercourse
and no later than age 21. Treatment of cervical intraepithelial neoplasms and cervical cancer is based on particular
histopathologic findings and may involve surgical resection,
chemotherapy, or radiotherapy.

In the majority of parvovirus B19-associated syndromes,
mucosal findings are absent. However, oral lesions may develop
in the rare condition, papular-purpuric “gloves and socks” syndrome. These are usually multiple painful, erythematous macules, erosions, or papules on the hard palate. Intraoral petechiae
may also be seen. Rarely, parvovirus B19 infection has been associated with erythema multiforme and erythema nodosum.
DIAGNOSIS

Diagnosis is usually based on the presence of classic clinical findings. PCR is a useful tool in detecting parvovirus B19
DNA. ELISA testing can demonstrate IgM antibodies in acute
infection.
THERAPY

Mucosal involvement is self-limited, so supportive measures
are adequate. No specific antiviral therapy is currently available
for treatment of parvovirus B19. Blood and platelet transfusions
and intravenous immunoglobulin (IVIG) may be required for
hematologic complications.
Molluscum contagiosum
In children, MC lesions in the anogenital region may be a sign of
sexual abuse or may occur from autoinoculation.
C L I N I C A L P R E S E N TAT I O N

Typically a cutaneous pathogen, it rarely causes conjunctival
or oral disease (Fig. 22.4).

RNA Viruses
RNA viral syndromes with frequently implicated viruses and
associated mucosal findings are listed in Table 22.3.
Hand-foot-and-mouth disease
Hand-foot-and-mouth disease is caused by coxsackieviruses
such as coxsackievirus A16 or less commonly, A4, A5, A9, and
A10. Other enteroviruses, such as enterovirus 71, have also been
implicated. Transmitted via saliva and feces, hand-foot-andmouth disease is highly contagious and occurs in outbreaks
among children and young adults.
C L I N I C A L P R E S E N TAT I O N

Oral lesions of hand-foot-and-mouth disease include painful, fragile vesicles, erosions, or ulcerations of the palate, buccal
mucosa, or tongue (Fig. 22.5). Lesions typically arise after 1 to 2
days of flu-like symptoms. Oral lesions are accompanied or followed by the development of papules, vesicles, or ulcers on the
dorsal and ventral surfaces of the hands and feet. Complications

282 — Julia S. Lehman, Alison J. Bruce, and Roy S. Rogers, III

Table 22.3: RNA Viral Syndromes with Frequently Implicated Viruses and Associated Mucosal Findings
Syndrome

Most Commonly Implicated Viruses

Mucosal Findings

Hand-foot-and-mouth
disease

Coxsackieviruses (A16) Enteroviruses (71)

Vesicles, erosions, ulcerations on the palate, buccal mucosa, and
tongue

Herpangina

Coxsackieviruses (group A, types 1–6, 8, 10,
and 22; group B) Echovirus

Small vesicles with an erythematous base on the soft palate and
posterior oropharynx

Measles

Paramyxovirus

Small erythematous macules with white necrotic core (Koplik spots)

Mumps

Paramyxovirus

Swelling of the parotid, submandibular, submental salivary glands;
edema at the opening of Stensen’s duct

Rubella

Togavirus

Petechiae and pinpoint erythematous macules (Forschheimer spots)
on the palate and uvula

Figure 22.4. Molluscum contagiosum.

Figure 22.5. Oral manifestations of hand-foot-and-mouth disease.

are rare but may include meningitis, encephalitis, myocarditis, or pneumonia. The incubation period is 3 to 5 days, and
clinical disease persists for 5 to 10 days. Differential diagnosis
includes herpangina, erythema multiforme, syphilis, EpsteinBarr virus infection, cytomegalovirus infection, varicella, acute
herpetic gingivostomatitis, and recurrent aphthous stomatitis.
Infection during pregnancy may lead to spontaneous abortion
or intrauterine growth retardation.
DIAGNOSIS

Diagnosis is made clinically. In atypical cases, serologic testing may be used. Moreover, virus can be cultured from the saliva
or feces, although this is rarely followed in clinical practice.

T R E AT M E N T

As hand-foot-and-mouth disease is self-limited, symptomatic treatment is usually adequate. In complicated cases, oral
acyclovir may have some efficacy. Low-level laser therapy may
shorten duration of oral lesions.
Herpangina
Herpangina is caused by coxsackievirus group A, types 1–6, 8,
10, and 22 and, less commonly, by coxsackievirus group B and
echovirus. Disease is usually transmitted via the fecal–oral route,
although infection can be acquired via inhalation of respiratory

Infections of the Mucous Membranes — 283

droplets. Herpangina is common in children under the age of
5 years and among school-aged children, particularly during
epidemics in the summer and fall.
C L I N I C A L P R E S E N TAT I O N

Herpangina is associated with the development of small
vesicles on an erythematous base that may be covered with
exudate. Lesions are confined to the soft palate and posterior oropharynx and usually develop after the abrupt onset of
fever. The incubation period lasts for 1 to 2 weeks, and symptoms persist for 4 to 6 days. Differential diagnosis includes
acute herpetic gingivostomatitis, recurrent aphthous stomatitis, streptococcal pharyngitis, hand-foot-and-mouth disease, and erythema multiforme. Unlike the intraoral lesions
of hand-foot-and-mouth disease, those of herpangina do
not involve the anterior oral cavity and can be covered by a
pseudomembrane.
DIAGNOSIS

Diagnosis is usually based on clinical findings. Although
virus can be isolated from oral or fecal culture, laboratory testing
is often not indicated. Serologic testing can be used to confirm
diagnosis when necessary.
T R E AT M E N T

Disease course is usually mild. Conservative therapy is
recommended.
Measles
Measles (rubeola) is caused by a paramyxovirus of the Morbillivirus
genus and is rare in the United States because of widespread vaccination. Measles is transmitted via airborne respiratory droplets
and is highly contagious in unimmunized populations.
C L I N I C A L P R E S E N TAT I O N

Pathognomonic for measles, Koplik spots are the primary
oral manifestation of this disease. Koplik spots are small, bluish
macules with an erythematous background and a white necrotic
core. They generally arise on the buccal mucosa apposing the
first and second molars. This finding precedes the development
of the classic, caudally progressive, maculopapular exanthem of
measles by 1 to 2 days. Other gingival and oral manifestations
of measles include necrotizing stomatitis, ulcerative gingivitis,
and superinfection with candida. Some evidence suggests that
measles virus is associated with recurrent aphthous ulcers, but
this remains to be confirmed. The incubation period ranges from
10 to 12 days. Complications include otitis media, pneumonia,
diarrhea, blindness, croup, acute encephalitis, and subacute
sclerosing panencephalitis. Differential diagnosis of oral manifestations of measles includes recurrent aphthous ulcers, acute
herpetic gingivostomatitis, varicella, exanthem infantum, and
infectious mononucleosis.
DIAGNOSIS

Diagnosis is made based on typical clinical findings or by
the presence of virus-specific IgM antibodies on serologic testing. Alternatively, measles virus RNA may be detected in respiratory secretions of acutely infected individuals using molecular
methods.
T R E AT M E N T

In uncomplicated measles, treatment involves supportive measures, such as hydration and local analgesia. The disease is prevented by administration of the live-attenuated
MMR (Measles, Mumps and Rubella) vaccination series.

Unimmunized individuals are protected via herd immunity
in regions of the world in which vaccination is widespread.
Unimmunized pregnant women should be advised to wait until
after delivery and hospital discharge before receiving the MMR
vaccine.
Mumps
Mumps is caused by a paramyxovirus of the Rubulavirus genus
that, like measles, is transmitted via aerosolized respiratory droplets. Although rare in the United States, an outbreak of cases was
seen as recently as 2006. Mumps most often affects children aged
5 to 15 during winter and spring.
C L I N I C A L P R E S E N TAT I O N

The primary intraoral sign of mumps is localized erythema
and edema at the opening of Stensen’s duct, opposite from the
upper molars on the buccal mucosa. Mumps is characterized
by a 3–5-day prodrome of low-grade fever, chills, and malaise,
swelling of the parotid, submandibular, and submental salivary
glands, and development of a morbilliform eruption. Incubation
period is 2 to 3 weeks. Complications are uncommon but include
myocarditis, pancreatitis, orchitis, meningitis, encephalitis, and
unilateral deafness. Differential diagnosis includes acute suppurative parotitis, parotid enlargement from medications, buccal
cellulitis, sialolithiasis, angioedema, Sjögren syndrome, Mikulicz
syndrome, tuberculosis, syphilis, systemic lupus erythematosus,
Heerfordt syndrome, and salivary gland neoplasms. When contracted in the first trimester of pregnancy, mumps may lead to
spontaneous abortion.
DIAGNOSIS

Mumps is usually a clinical diagnosis. The presence of
mumps-specific IgM antibodies on serologic testing is diagnostic. Moreover, the virus may be isolated with saliva culture.
Elevated serum amylase or lymphocyte percentage in the cell
count differential corroborates the diagnosis.
T R E AT M E N T

Supportive therapy is recommended. Mumps is prevented by
the MMR vaccination, as described earlier.
Rubella
Rubella (German measles) is caused by a togavirus of the
Rubivirus genus and is transmitted via respiratory droplets and
saliva. In the United States, rubella is usually only seen in unimmunized adults and immigrants because of widespread immunization with the MMR vaccine.
C L I N I C A L P R E S E N TAT I O N

The presence of Forschheimer spots, dark red macules on the
palate and uvula, is a nonspecific intraoral sign of rubella present in 20% of cases. A macular eruption develops on the face and
later involves the neck, trunk, and extremities. Lymphadenopathy
of the head and neck, particularly in the suboccipital region, is
frequent. In adults, the eruption is usually preceded by constitutional symptoms. Incubation period is approximately 14 to
21 days. Complications are rare but may include arthralgias,
arthritis, thrombocytopenia, hemolytic anemia, Guillain-Barré
syndrome, and postinfectious encephalopathy. Differential diagnosis includes erythema infectiosum (Fifth Disease), mucocutaneous lymph node syndrome (Kawasaki Disease), measles,
roseola infantum, scarlet fever, streptococcal pharyngitis, infectious mononucleosis, and juvenile rheumatoid arthritis. When

284 — Julia S. Lehman, Alison J. Bruce, and Roy S. Rogers, III

contracted within the first 20 weeks of pregnancy, rubella may
lead to congenital rubella syndrome.

Table 22.4: Viral Organisms That Do Not Usually Cause
Disease of the Oral or Genital Mucous Membranes

DIAGNOSIS

Diagnosis is usually made based on classic physical findings, although serologic testing may demonstrate the presence of
virus-specific IgM immunoglobulin.
T R E AT M E N T

As rubella is usually benign and self-limited, symptomatic
treatment is appropriate. Isolation precautions should be taken
while the patient is infectious to prevent transmission, particularly to pregnant women. Disease prevention is achieved with
widespread administration of the MMR vaccination.

Adenovirus

Ebola Virus

Orthomyxovirus

Arbovirus

Hantavirus

Papovavirus

Calcivirus

Viral hepatidides
(A, B, C, D, E)

Parainfluenza virus

Coronavirus

Influenza virus

Poliovirus

Dengue virus

Norwalk virus

Respiratory syncytial virus

RNA Retroviruses

Human T-lymphotropic virus

Human immunodeficiency virus

Associated with adult T-cell leukemia and lymphoma, the
RNA retrovirus human T-cell lymphotropic virus type 1 is not
typically associated with intraoral manifestations. However,
two cases of HTLV-1-associated acute T-cell leukemia/lymphoma presenting with oral findings have been reported. One
patient had a painful, ulcerated lesion on the hard palate, and
the other developed lymphoproliferative disease at the posterior tongue.
Viral organisms that do not usually cause disease of the oral
or genital mucous membranes include (Table 22.4) adenovirus,
arbovirus, calicivirus, coronavirus, Dengue virus, Ebola virus,
hantavirus, hepatitis A, B, C, D, and E, influenza virus, Norwalk
virus, orthomyxovirus, papovavirus, parainfluenza virus,
paramyxovirus, poliovirus, and respiratory syncytial virus.

Human immunodeficiency virus (HIV) is an RNA retrovirus
that is transmitted by direct exchange of bodily fluids, as with
sexual transmission, transfusion of contaminated blood products, intravenous drug use, vertical transmission from mother to
fetus during pregnancy, or horizontal transmission from mother
to newborn via lactation. Progression from HIV infection to
acquired immunodeficiency syndrome (AIDS) occurs a median
of 11 years after initial infection and predisposes the patient to
opportunistic pathogens.
C L I N I C A L P R E S E N TAT I O N

Oral findings are present in about 55% to 60% of patients
with HIV infection worldwide, and their frequency is inversely
proportional to the patient’s CD4+ T-lymphocyte count.
Nonspecific oral erythema and ulceration may be present at
the time of seroconversion. The most common oral disease
among patients with HIV infection is oropharyngeal candidiasis, which ultimately develops in up to 90% of patients. Other
frequent intraoral findings include KS, disseminated herpes
zoster, oral hairy leukoplakia, perioral or intraoral molluscum
contagiosum, recurrent aphthous ulcers, local or generalized
ulcerative periodontitis, and acute necrotizing ulcerative gingivostomatitis. In the developing world, oral tuberculosis also has
a high prevalence in this patient population. Azidothymidine
(AZT), a thymidine analog used to delay progression of HIV
infection, can cause oral hyperpigmentation. HIV infection is
also associated with an increased prevalence of genital candidiasis. Co-infection with other sexually transmitted infections
with manifestations of the mucosa, such as chlamydia, gonorrhea, chancroid, syphilis, and HPV, is common. In fact, the
ulcerated lesions of chancroid and other causes of genital ulceration are thought to facilitate the acquisition of HIV in exposed
individuals.
DIAGNOSIS

Since ELISA is very sensitive for the presence of HIV-specific
antibodies, it is used for screening. Reactive tests are repeated. If
two ELISA tests are reactive, then Western blot is utilized, as it
has a very high specificity. A positive Western blot test confirms
diagnosis.
T R E AT M E N T

Treatment of mucosal manifestations of HIV infection
should be tailored to the particular disease process. Moreover,
pharmacotherapy of the underlying HIV infection is necessary
to avoid recurrence.

FUNGAL INFECTIONS

Superficial Mycoses
Candida spp.
Candida spp., saprophytic dimorphic yeast, are the most frequent
colonizing fungal organisms of the oral and genital mucosa and
can function as opportunistic pathogens. Risk factors for candidal infection are numerous and include previous infection of
the mucosa, antibiotic use, diabetes mellitus, and other endocrine
disorders, malnutrition, various primary immune deficiencies,
neutropenia, denture usage, usage of immunosuppressive medications (such as topical corticosteroids, corticosteroid inhalers,
systemic corticosteroids, chemotherapy agents, and others),
xerostomia, certain nutritional deficiencies, and malignancy.
Candida spp. bind to mucosal surfaces and degrade epidermal keratin, which permits invasion. Although both the yeast
and mold forms of Candida albicans may be present in infection, branching mycelia predominate. Engulfment of these large
mycelia by host phagocytes is difficult. Moreover, Candida spp.
are capable of undergoing phenotype switching, a phenomenon
that can contribute to increased organism virulence and to the
development of drug resistance. Candida spp. are responsible for
a range of mucosal disease syndromes, which are described subsequently (Table 22.5).
C L I N I C A L F E AT U R E S

Acute pseudomembranous candidiasis (thrush) from
Candida is common in neonates, young children, chronically ill
adults, and the elderly. Thrush presents with thick, creamy white,

Infections of the Mucous Membranes — 285

Table 22.5: Syndromes and Physical Findings Associated
with Infection with Candida Spp
Syndrome

Physical Findings

Acute pseudomembranous
candidiasis

White patches and plaques with an
erythematous base

Denture stomatitis

Erythema and edema of the hard
palate

Acute atrophic candidiasis
(candidal glossitis)

Tender erythematous atrophy of
dorsal tongue and palate

Angular cheilitis

Linear erythema and fissures at the
commissures

Oral leukoplakia (candida
leukoplakia, hyperplastic
candidiasis)

Persistent, tender oral lesions

Median rhomboid glossitis

Rhomboid-shaped region of
atrophy on the dorsal tongue

Figure 22.6. Acute pseudomembranous candidiasis of the buccal
mucosa.

Candidal infection of the tongue Findings of median rhomboid
and nonspecific inflammation of glossitis with tender erythema of
the palate (CIT-NIP)
the hard palate
Chronic mucocutaneous
candidiasis

Chronic candidal infection of skin,
mucous membranes, and nails

Systemic candidiasis

Candidemia, fever, myalgias

cheese-like patches and plaques on the mucosa, which often have
an erythematous or ulcerated base (Fig. 22.6). A pseudomembrane may develop in severe cases. These plaques can be
removed with scraping, but a bleeding surface often remains. In
most otherwise healthy patients, infection remains confined to
the mucosa.
Denture stomatitis results from contact between the palate and a dental appliance that has been colonized by Candida
(usually C. albicans). Denture stomatitis is characterized by
asymptomatic or painful erythema and edema of the hard palate (Fig. 22.7). The combination of appliance colonization, local
tissue trauma, and presence of a moist, occluded local environment contributes to pathogenesis.
Acute atrophic candidiasis (candidal glossitis) presents with
tender, smooth, erythematous lesions of the dorsal tongue and
palate. Atrophy results from the loss of filiform papillae, a feature that distinguishes lesions of acute atrophic candidiasis
from those of local trauma or nonspecific inflammation. Use of
inhaled corticosteroids predisposes the patient to this condition
in a dose-dependent fashion.
Candidal infection can cause angular cheilitis (perlèche), a
condition associated with linear erythema and commissural fissuring. Risk factors for this condition include situations in which
the oral commissures are chronically moist, as with denture
usage and the edentulous state. Nutrient deficiencies and hematologic dyscrasias may also be associated with angular cheilitis.
These predisposing factors must be addressed before antifungal
therapy can be maximally effective. Infection may be polymicrobial and bacterial pathogens such as Staphylococcus aureus often
coexist. Therefore, synchronous antibacterial therapy may be
necessary.

Figure 22.7. Denture stomatitis (Candida).

Candida has been found to be a risk factor for oral leukoplakia, also known as candida leukoplakia or hyperplastic
candidiasis. Oral leukoplakia is characterized by the presence
of persistent, tender, speckled, white oral lesions that are not
removed easily with mechanical scraping. Histopathology reveals
epithelial hyperplasia, which is associated with cytologic atypia
or malignant conversion in 3% to 6% of patients.
Median rhomboid glossitis appears as painless atrophy in a
distinctive rhomboid pattern at the central portion of the tongue.
This condition was previously attributed to the congenital persistence of the tuberculum impar. However, it is now thought that
chronic oral candidiasis contributes to pathogenesis, because
candidal hyphae are often seen in intralesional focal neutrophilic
microabscesses, and antifungal therapy frequently leads to cure.
Although median rhomboid glossitis intrinsically is benign, the
concern for HIV infection or AIDS arises when the condition
is accompanied by erythema and pain at the hard palate. This
phenomenon is seen in a condition known as CIT-NIP (candidal infection of the tongue and nonspecific inflammation of
the palate). Although occasionally confused with the presence of
a lingual thyroid, median rhomboid glossitis differs morphologically in several respects. Specifically, median rhomboid glossitis
is located anterior to the foramen cecum and is generally macular, whereas lingual thyroid is present posterior to the foramen
cecum and is raised.

286 — Julia S. Lehman, Alison J. Bruce, and Roy S. Rogers, III

Genital candidiasis is typically seen in people during their
sexually active years. Vulvovaginal candidiasis is a common
cause of vaginitis and presents with thick, white vaginal discharge, localized pruritus, and dysuria. C. albicans causes 93%
to 98% of vulvovaginal candidiasis in healthy women, although
Candida glabrata and other non-albicans species are causative
more frequently in patients with recurrent disease. In men, candida may infect the coronal sulcus, prepuce, or perimeatal area
and is characterized by localized pruritus, pain, and erythema.
Disease may also be asymptomatic in either sex.
Differential diagnosis of mucosal candidiasis includes chronic
cheek bite keratosis, morsicatio buccarum, chemical and thermal
burns, oral hairy leukoplakia, lichen planus, syphilis, hereditary
benign intraepithelial dyskeratosis, and white sponge nevus.
DIAGNOSIS

In most uncomplicated cases, diagnosis is made clinically.
Round or oval yeast forms, hyphae, or pseudohyphae are seen on
KOH preparation and culture. Isolation of candida alone cannot
confirm candidiasis, however, since candida is often part of the
normal mucosal flora. Colposcopy may have a role in the diagnosis of chronic vulvar candidiasis.
T R E AT M E N T

Treatment of localized Candida typically involves the use
of topical nystatin, topical imidazoles (such as clotrimazole in
an oral troche or cream), or oral imidazoles. For candidiasis
confined to the mouth, duration of treatment should be at least
twice as long as it takes for the signs and symptoms to resolve.
In immunocompromised patients, early treatment is crucial to
avoid dissemination. Moreover, management of underlying predisposing factors is necessary to avoid recurrence.

DIAGNOSIS

CMC is diagnosed clinically in patients with recurrent or persistent candidal infections. Reversible causes for cell-mediated
immune deficiency should be sought.
T R E AT M E N T

Acute flares are treated with topical or systemic antifungal
agents, depending on the severity of the infection. Long-term
prophylaxis with antifungal therapy is also indicated, as most
patients with CMC experience recurrent infection upon discontinuation of antifungal medications. Immunomodulatory therapy is being investigated.

Deep Mycoses ( Table 22.6 )
Deep mycotic infections with frequently implicated fungal organisms and associated mucosal findings are listed in Table 22.6.

Non-Endemic Mycoses
Disseminated candidiasis
Disseminated candidiasis, or candidemia, is seen exclusively
in immunocompromised individuals and can arise from proliferation or migration of Candida from colonized gastrointestinal or urinary tracts, oral mucosa, heart valves or central
venous catheters. Although Candida albicans is the most common nosocomial fungal infection, other Candida species are
common in some immunocompromised populations. Systemic
candidiasis causes significant morbidity and mortality and, in
patients with HIV, its presence is a strong predictor of HIV progression rate.
C L I N I C A L P R E S E N TAT I O N

Subcutaneous Mycoses
Chronic mucocutaneous candidiasis
Chronic mucocutaneous candidiasis (CMC) results from a
diverse group of congenital or acquired conditions that render
patients unable to clear Candida spp. Recent research revealed
that CMC is associated with deficits in the production of type 1
cytokines (such as IL-2 and IL-12) and overproduction of type 2
cytokines (IL-6 and IL-10) in response to Candida. These alterations in cytokine response to infection appear to be specific to
Candida and are due to upstream immune defects.
Primary CMC results from a variety of primary immunodeficiencies, all of which disrupt host response to candidal
infection. Primary CMC may arise as a spontaneous mutation
or through autosomal dominant or autosomal recessive inheritance. Secondary CMC is associated with HIV infection, corticosteroid usage, and denture usage.

Disseminated candidiasis may be associated with nonspecific oral lesions and classically presents with the triad of fever,
skin eruption, and myalgias. Potentially life-threatening complications include esophageal rupture, Candida pneumonia, and
widespread dissemination.
DIAGNOSIS

The consistent presence of C. albicans or other Candida spp.
in blood cultures in the immunocompromised patient is suggestive of systemic infection. Histologic examination of skin lesions
is relatively sensitive and may offer identification of the offending organism before blood culture results are available.
T R E AT M E N T

Although amphotericin B used to be the drug of choice
in disseminated candidiasis, fluconazole and other systemic
azoles are now preferred because of their more favorable side
effect profile. However, azole-resistant Candida has emerged
in HIV patients. Underlying immunosuppression should be
addressed.

C L I N I C A L P R E S E N TAT I O N

CMC is characterized by chronic candidal infection of the
skin, mucous membranes, and nails. Painful, hyperkeratotic vegetating lesions that are exacerbated by the consumption of acidic
or spicy foods develop in the mouth. When the esophagus is
involved, dysphagia may result. Infections tend to remain superficial, although deep or disseminated disease may follow. When
inherited in an autosomal recessive manner, primary CMC has
been associated with endocrine and inflammatory disorders. In
cases of adult-onset CMC, concomitant presence of thymoma
has been reported.

Mucormycosis (zygomycosis)
Mucormycosis is a rare condition caused by Rhizopus and Mucor
spp., which are found commonly in the soil and on moldy bread.
Application of contaminated medical tape and bandages over
facial wounds has also been implicated in disease transmission. Mucormycosis is seen in patients with diabetes mellitus
(particularly those in diabetic ketoacidosis), burns, uremia,
malnutrition, neutropenia, iatrogenic immunosuppression, or
liver cirrhosis. Since iron is a growth stimulant for the causative

Infections of the Mucous Membranes — 287

Table 22.6: Deep Mycoses with Mucosal Manifestations and the Appearance of Pathogenic Organism upon Histopathologic
Examination
Systemic Mycosis

Mucosal Findings

Appearance of Organism on Histopathology

Disseminated candidiasis

Nonspecific oral lesions

Round or oval yeast cells; hyphae; pseudohyphae

Mucormycosis

Ulcer with black, necrotic eschar; hard palate perforation

Broad, nonseptate, right-angled hyphae

Aspergillosis

Single ulcer with grey exudate or surrounding eschar; hard
palate perforation

Hyphae with septae branching at 45 degrees

Histoplasmosis

Tender, nonhealing ulcers; granulomatous lesions

Yeast within monocytes, histocytes, or neutrophils

Blastomycosis

Ulcer with verrucous surface vegetating plaque;
granulomatous edema

Broad-based budding yeast

Cryptococcosis

Ulcer with vegetating surface; granulomatous nodule

Encapsulated narrow-based budding yeast

Paracoccidioidomycosis

Painful, destructive, granulomatous lesions (mulberry
lesions); hard palate perforation

Budding yeast in “ship’s steering wheel” or
“Mickey Mouse” forms

Coccidioidomycosis

Ulcerative tongue lesion resembling squamous cell
carcinoma (very rare)

Spherules and loose endospores

agents of mucormycosis, this condition can also arise in patients
with iron overload states, such as hemochromatosis.
C L I N I C A L P R E S E N TAT I O N

Mucormycosis is a highly destructive infection that erodes
arteries of the nasal membranes, upper and lower respiratory
tracts, gastrointestinal system, and central nervous system,
leading to thrombosis, ischemia, and necrosis. Tissue necrosis appears as an ulcer surrounded by a black, necrotic eschar.
Resultant perforation of the palate has also been reported.
Disseminated disease typically starts with orbital cellulitis with
or without proptosis and may result in cranial nerve palsy. Other
associated symptoms include low-grade fever, malaise, epistaxis,
sinus pressure, and retro-orbital headache. Associated mortality
is high. Differential diagnosis includes lethal midline granuloma,
tuberculosis, squamous cell carcinoma, anthrax, aspergillosis,
nasopharyngeal carcinoma, syphilis, Wegener’s granulomatosis,
and systemic mycoses.
DIAGNOSIS

Histopathology and smear examination demonstrate the
presence of broad, right-angled hyphae (Fig. 22.8) and tissue
necrosis. Culture is necessary to identify the involved species.
Serum ferritin, total iron-binding capacity, and glucose and electrolyte levels should also be checked. Computed tomography can
aid in diagnostic confirmation, delineation of disease extent, and
surgical planning.
THERAPY

Effective treatment of mucormycosis often requires surgical
debridement and systemic antibiotic therapy with amphotericin B.
Because of the nephrotoxicity associated with amphotericin B,
particular caution must be used in patients with poorly controlled
diabetes mellitus. Although most azoles and echinocandins are
not effective in this disease, posaconazole, a new azole, has been
shown to have in vitro and in vivo efficacy. Predisposing factors
must also be controlled.
Cryptococcosis
Cryptococcosis, caused by the encapsulated yeast Cryptococcus
neoformans, generally is acquired via the respiratory tract and

Figure 22.8. Broad, sharply-angled hyphae of Mucor spp.

classically occurs by inhalation of aerosolized bird feces. While
C. neoformans var neoformans affects immunocompromised
patients, C. neoformans var gattii may cause disease in healthy
individuals.
C L I N I C A L P R E S E N TAT I O N

Oral findings in cryptococcosis are uncommon and typically represent manifestations of disseminated disease. Mucosal
cryptococcosis appears as erythematous papules that evolve
into ulcerative lesions. Reported sites of intraoral involvement
include the tongue, palate, gingiva, and sites of previous tooth
extraction. Diseases mimicking mucosal manifestations of cryptococcosis include squamous cell carcinoma, chancroid, lethal
midline granuloma, tuberculosis, syphilis, traumatic ulcer, and
other systemic fungal infections.
DIAGNOSIS

The diagnosis of cryptococcosis is supported by the presence of encapsulated, narrow-budding yeast on histopathology
(Fig. 22.9). Special stains, such as methenamine silver periodic
acid-Schiff, Mayer mucicarmine or Masson-Fontan silver stains,
often are required to visualize the organism and its distinctive
capsule. Diagnosis may be confirmed by in situ hybridization or
isolation of the organism on fungal culture.

288 — Julia S. Lehman, Alison J. Bruce, and Roy S. Rogers, III

Figure 22.10. Oral histoplasmosis.
Figure 22.9. Narrow-budding, encapsulated organisms of
Cryptococcus spp. (mucin stain).

THERAPY

In symptomatic cryptococcosis, fluconazole is considered
the first-line therapy. In severe disease, amphotericin B may be
required. Patients with HIV infection may require lifelong suppressive therapy.

voriconazole is now preferred. Caspofungin can also be used
in refractory cases or in patients who do not tolerate azoles or
amphotericin. Consistent hand washing and the use of laminar
airflow or high-efficiency particulate air (HEPA) filtration can
limit the dissemination of airborne Aspergillus organisms.

Endemic Mycoses
Histoplasmosis

Aspergillosis
Aspergillis spp. are ubiquitous airborne fungi that can spread on
the hands of health-care providers and via ventilation systems,
particularly in hospitals during times of renovation. The most
common cause of invasive aspergillosis is Aspergillus fumigatus.
Risk factors include leukopenia, lymphoma, iatrogenic immunosuppression, and HIV infection.
C L I N I C A L P R E S E N TAT I O N

Primary intraoral aspergillosis is extremely rare but has
been reported. When present intraorally, primary aspergillosis
appears as an isolated ulcer covered with a grayish exudate on
the gingiva, hard palate, soft palate, and dorsum of the tongue.
In disseminated aspergillosis, mucosal lesions are present in
about 10% of cases. Intraoral lesions of disseminated aspergillosis develop as a result of hemorrhagic necrosis and appear as
ulcerated eschars on the palate and posterior tongue. Hard palate perforation from invasive aspergillosis has been reported in
several patients with acute leukemia. Disseminated aspergillosis
can be life threatening. Differential diagnosis of mucosal lesions
includes mucormycosis, lethal midline granuloma, nasopharyngeal carcinoma, Wegener’s granulomatosis, tuberculosis, syphilis, and other systemic mycoses.
DIAGNOSIS

On tissue histology, Aspergillus spp. can be visualized as
hyphae with septae branching at 45 degrees with Gomori methenamine silver stain. Cultures are often negative and, when positive, might represent colonization. Other diagnostic methods,
such as PCR and ELISA, have been developed.
THERAPY

Surgical debridement may be useful in primary intraoral
aspergillosis. In disseminated aspergillosis, empiric treatment
often must be instituted while diagnostic work-up is pending, since early treatment is required for reduction in mortality. Although amphotericin B used to be the drug of choice,

Histoplasma capsulatum, the causative agent in histoplasmosis, is
endemic to the Mississippi and Ohio River Valleys of the United
States, as well as parts of Africa and Australia. It can be found in
soil contaminated by bat or bird feces. Human disease can result
from the inhalation of airborne spores or more rarely, the direct
inoculation of organisms into the skin or mucous membranes.
The sporulated organism converts to a yeast form and replicates
at body temperature.
C L I N I C A L P R E S E N TAT I O N

Histoplasmosis can cause oral lesions as part of primary or
disseminated disease. Oral histoplasmosis can present with one
or multiple tender, nonhealing, friable ulcers or as nodular, verrucous, or granulomatous lesions (Fig. 22.10). These are found
on the tongue, palate, and buccal mucosa. Reactivation of latent
histoplasmosis of the oropharynx following radiation therapy
for laryngeal squamous cell carcinoma has been documented.
Histoplasmosis may also cause macroglossia via tongue infiltration. Differential diagnosis of oral findings includes squamous
cell carcinoma, lethal midline granuloma, mucocutaneous leishmaniasis, CMV infection, Wegener’s granulomatosis, lymphoma,
tuberculosis, sarcoidosis, and other deep mycoses.
DIAGNOSIS

The diagnosis of oral histoplasmosis can be confirmed by
visualizing yeast within phagocytes with the use of routine and
special stains, such as periodic acid-Schiff and methenamine silver nitrate stains on histopathology. In situ hybridization is also
an effective mode of diagnosis. Serologic tests can demonstrate
the presence of organism-specific antibodies, although false negatives can occur in immunocompromised individuals. Serum
and urine antigen tests may also be helpful. As the organism is
fastidious, fungal culture is often insensitive.
THERAPY

Cutaneous lesions may be self-limited, so treatment is
warranted only if disease is prolonged or systemic. Although

Infections of the Mucous Membranes — 289

Table 22.7. Fungal Organisms That Do Not Usually Cause
Disease of the Oral and Genital Mucous Membranes

Figure 22.11. Blastomycosis.

amphotericin B used to be the preferred agent for complicated
histoplasmosis, systemic azole derivatives are now the treatment
of choice.
Blastomycosis
Blastomycosis, caused by the thermal dimorphic fungus
Blastomyces dermatitidis, occurs in parts of North America and
Africa. Blastomycosis is not as closely linked as the other systemic endemic mycoses with immunocompromise.
C L I N I C A L P R E S E N TAT I O N

As with other systemic endemic mycoses, oral lesions associated with blastomycosis can be the first clue to the presence of
systemic disease. Lesions of oral blastomycosis usually take one
of three morphologies: (1) painless solitary ulcers with a verrucous surface and thin, raised edges, (2) vegetating plaques, or
(3) granulomatous edema. Blastomycosis can also infiltrate the
nasal mucosa or the larynx (Fig. 22.11), mimicking squamous
cell carcinoma or the tongue, resulting in macroglossia. Other
areas of potential disease involvement include the genitourinary tract, central nervous system, skin, and bone. Diseases
that mimic oral blastomycosis include tuberculosis, squamous
cell carcinoma, sarcoidosis, Wegener’s granulomatosis, syphilis, and other deep mycoses. One group reported a case of oral
blastomycosis with secondary bacterial infection that mimicked
actinomycosis because the infection eroded through from the
mandible to the oral cavity.
DIAGNOSIS

Presumptive diagnosis can be made by the demonstration of
broad-based budding yeasts with doubly refractile cell walls on
direct examination of the sputum or histopathology. Diagnosis is
confirmed by in situ hybridization and tissue culture.

Dermatophytes

Malassezia furfur

Exophiala werneckii

Piedraia hortai

Fonsecaea pedrosoi

Pseudallescheria boydii

Fonsecaea compacta

Trichosporon beigelii

Madurella grisea

Sporothrix schenckii

Madurella mycetomatis

Wangiella dermatitidis

America and primarily affects men, with a male-to-female
ratio of 15:1. Although inhalation is the most common route
of infection, direct inoculation can occur when contaminated
twigs are used to clean teeth, as is the practice in some areas of
rural Brazil.
C L I N I C A L P R E S E N TAT I O N

Oral findings are present in about half of all patients with
paracoccidioidomycosis. Paracoccidioidomycosis causes painful, destructive, granulomatous lesions (mulberry lesions), which
can be found on the tongue, lips, gingiva, hard palate, buccal
mucosa, and, less commonly, nasal mucosa. These lesions can
lead to dysphagia and dysphonia. Other previously documented
presentations of paracoccidioidomycosis include squamous cell
carcinoma–like lesions and hard palate perforation. Associated
cervical lymphadenopathy is common. Differential diagnosis
includes mucocutaneous leishmaniasis, actinomycosis, lymphoma, squamous cell carcinoma, Wegener’s granulomatosis,
necrotizing sialometaplasia, sarcoidosis, and other systemic
fungal infections.
DIAGNOSIS

Tissue biopsy is the gold standard for diagnosis. Multiple
budding yeast in “Mickey Mouse” or “ship’s steering wheel”
forms, as well as granuloma formation, can be seen with Gomori
methenamine silver (GMS) stain. A small study of patients
with biopsy-demonstrated oral paracoccidioidomycosis found
that cytology obtained through direct smear was positive in all
infected patients. A subsequent trial found that cytology from
direct smear had a sensitivity of 68% and a specificity of 92%.
Therefore, cytology may be a reasonable first test for oral paracoccidioidomycosis, but biopsy should be performed if cytology
is unrevealing and the clinical index of suspicion remains high.
THERAPY

Slow-acting sulfonamides are the preferred treatment option
in paracoccidioidomycosis. Other reasonable pharmacologic
options include fluconazole, terbinafine, and amphotericin B.

THERAPY

Blastomycosis is treated with azole derivatives and amphotericin B. In immunocompromised individuals, early and aggressive treatment with amphotericin B is indicated.
Paracoccidioidomycosis
Paracoccidioidomycosis (formerly South American blastomycosis) is a systemic endemic mycosis caused by the dimorphic
fungus, Paracoccidioides brasiliensis. Paracoccidioides brasiliensis is found in the soil in countries of Central and South

Coccidioidomycosis
Coccidioidomycosis is a systemic mycosis caused by Coccidioides
immitis, which is endemic to the southwestern United States.
Although not usually associated with mucosal lesions, one case of
coccidioidomycosis of the tongue has been reported. The tongue
lesion resembled squamous cell carcinoma and responded to
systemic antifungal medication.
Fungal organisms that do not usually cause disease of
the oral or genital mucous membranes include (Table 22.7)

290 — Julia S. Lehman, Alison J. Bruce, and Roy S. Rogers, III

Table 22.8: Sexually Transmitted Bacterial Infections with the Associated Disease Syndrome and Characteristic Mucosal
Lesions
Organism

Disease Syndrome

Lesions

Chlamydia trachomatis
Types A-C

Trachoma (conjunctivitis)

Injection of the bulbar conjuntivae, ulceration and scarring of the cornea, ocular
discharge, pre-auricular lymphadenopathy

Types D-K

Cervicitis, urethritis,
epididymitis, pharyngitis

Oral mucosa: Diffuse erythema and small pustules in the tonsillar area Genital
mucosa: Purulent vaginal or urethral discharge, dysuria, dyspareunia

Types L1-L3

Lymphogranuloma
venereum

Phase 1: Small, painless papule or ulceration Phase 2: Lymphadenopathy, buboe
formation Phase 3: Chronic ulceration and stricture

Neisseria gonorrheae

Cervicitis, urethritis,
vaginitis, pharyngitis

Oral mucosa: Erythema of posterior oropharynx, painful oral ulcers with
pseudomembranes, necrosis of gingivae and intradental papillae Genital mucosa:
Purulent vaginal or urethral discharge, dysuria, dyspareunia Conjunctiva: Erythema
of bulbar conjunctiva, profuse purulent discharge

Trichomonas vaginalis

Trichomoniasis

Mucosal petechiae, overlying exudate, dysuria, profuse vaginal discharge, urethral
discharge, dysuria, dyspareunia

Haemophilis ducreyi

Chancroid

Tender ulcerated lesions with grey or purulent base, lymphadenopathy

Calymmato-bacterium
granulomatis

Granuloma inguinale
(Donovaniasis)

Erythematous, moist papule at site of inoculation that enlarges and spreads along
body folds; no significant lymphadenopathy

Treponema pallidum

Syphilis

See Table 22.9.

dermatophytes, Exophiala werneckii, Fonsecaea pedrosoi or
compacta, Madurella grisea or mycetomatis, Malessezia furfur,
Piedraia hortai, Pseudallescheria boydii, Trichosporon beigelii,
Sporothrix schenckii, and Wangiella dermatitidis.

BACTERIAL INFECTIONS

A range of bacterial species cause disease of the mucous membranes. These will be categorized as (1) sexually transmitted
bacterial organisms, (2) spirochetes, (3) mycobacteria, and
(4) other.

Sexually Transmitted Infections of Bacterial Origin
( Table 22.8 )
Sexually transmitted bacterial infections with frequently implicated bacterial organisms and associated mucosal findings are
listed in Table 22.8.
Chlamydia
Chlamydia trachomatis, an obligate intracellular organism
transmitted via sexual activity, has multiple immunoptypes
that can impart one of three diseases to the host. Specifically,
C. trachomatis immunotypes A-C cause trachoma (conjunctivits), D-K infect the genital tracts and other mucosal membranes and L1-L3 cause lymphogranuloma venereum (LGV).
In the United States, C. trachomatis is the commonest pathogen responsible for urethritis and cervicitis in young adults
and, when associated with pelvic inflammatory disease, is
a leading cause of infertility in women. LGV is rare in the
United States. For a more detailed discussion of Chlamydia
see chapter 24.

T R E AT M E N T

The treatment of choice for uncomplicated chlamydial infection is azithromycin or doxycycline. Sexual partners
should also be treated to prevent reinfection. LGV is treated
with tetracycline, doxycycline, or erythromycin. Some authors
have reported azithromycin to be effective, although definitive evidence is lacking. Buboes may be aspirated for symptomatic relief. Strictures and fistulas may require operative
intervention.
Gonorrhea
Gonorrhea is a sexually transmitted infection caused by the gramnegative diplococci of Neisseria gonorrheae. From 1981-1991, it
was the most frequently reported sexually transmitted infection
in the United States and is currently second in frequency only
to Chlamydia. For a more detailed discussion of Gonorrhea, see
chapter 24.
T R E AT M E N T

Symptoms are often self-limited but can be transmitted to
others if left untreated. Given the high prevalence of co-infection
with Chlamydia, treatment strategies should cover both organisms. The drug of choice for gonorrhea is intramuscular ceftriaxone. Ciprofloxacin and levofloxacin are alternative antimicrobial
agents, although resistance to fluoroquinolones is rising. The use
of chlorhexidine as a vaginal lubricant was shown to prevent transmission of gonorrhea in one study.
Chancroid
Chancroid, a sexually transmitted infection caused by the small
gram-negative rod, Haemophilus ducreyi, is the commonest cause of genital ulceration worldwide. It is only rarely seen
in the developed world, where it is generally associated with
prostitution, crack cocaine use, and travel to an area with high

Infections of the Mucous Membranes — 291

prevalence of chancroid. Chancroid may be associated with HIV
infection and other sexually transmitted infections. The male to
female ratio is 3:1. For a more detailed discussion of Chancroid,
see chapter 24.
T R E AT M E N T

Antimicrobial therapy consists of erythromycin, azithromycin,
ciprofloxacin, ceftriaxone, or spectinomycin. Resistance is
emerging against penicillins, aminoglycosides, trimethoprim-sulfamethoxazole, and tetracycline, however. When
possible, in vitro antimicrobial susceptibility testing should
guide therapy. Treatment failure is commonest in patients
with HIV infection. Since rupture of buboes may cause
chronic ulceration, aspiration or incision and drainage may
be indicated.

Table 22.9: Mucosal Lesions of Syphilis, by Disease Phase
Organism

Disease Syndrome

Treponema
pallidum

Early stage

Mucosal Lesions

Primary phase

Solitary, painless ulcers
(chancres)

Secondary phase

Mucous patches, snailtrack ulcers, macular and
papular syphilides, oral hairy
leukoplakia-like lesions,
pseudomembranous lesions,
condyloma lata

Early latent phase

(No physical signs of disease)

Spirochetes

Late stage

Spirochetes are long, helically coiled cells with flagella that run
between the cell membrane and cell wall. These flagella permit
active movement of the organism. The two phyla of spirochetes
that cause disease in the mucosal membranes of humans are
Treponema and Borrelia.

Late latent phase

(No physical signs of disease)

Tertiary phase

Destructive granulomas
(gummas), syphilitic
leukoplakia, interstitial
glossitis, syphilitic sialadenitis

Syphilis

Congenital

Syphilis is a systemic disease caused by the spirochete, Treponema
pallidum. Although the incidence of syphilis decreased significantly in the mid-20th century with the introduction of penicillin, changing sexual practices, availability of crack cocaine,
and increased prevalence of HIV infection have led to a resurgence in the United States and Europe. Syphilis can be acquired
via maternal transmission to the fetus (i.e. congenital syphilis)
or via mucosal contact with an infected individual. Syphilis is
extremely infectious, with reported transmission rates ranging
from 18 to 80%. Mucosal findings can be seen in almost every
stage of syphilis (Table 22.9).
C L I N I C A L P R E S E N TAT I O N

Syphilis is characterized by an early stage (involving primary,
secondary, and early latent phases) and a late stage (involving
late latent and tertiary phases). The patient is highly infectious in
early syphilis but becomes less contagious once late syphilis has
developed due to reduced spirochetemia.
Primary syphilis is marked by the development of a relatively
painless solitary ulcer (chancre) at the site of inoculation.
Classically, this primary lesion begins as a dome-shaped papule
and erodes into a punched out, clean ulcer with distinct edges
and a firm, granular base. Lesions are covered with a grey, serous
exudate. Although primary syphilis affects the genital mucosa in
the vast majority of cases, oral manifestations may be the presenting sign of primary syphilis in about 10% of cases. The most
frequent anatomic sites for primary oral syphilis are the lips,
tongue, and tonsillar fauces, depending on the method of disease transmission. Primary oral chancres are commonest on
the upper lip in men and the lower lip in women. These lesions
are associated with regional, nontender lymphadenopathy and
appear approximately 3 weeks following inoculation. Ulcers of
primary syphilis resolve spontaneously without residual scarring in 2 weeks. Without treatment, 25% of patients will develop
secondary syphilis from persistent spirochetemia, while others
develop latent syphilis, a phase characterized by the absence of
physical signs of disease despite continued infectivity.

High arched palate,
Hutchinson’s teeth, Mulberry
molars, mucous patches,
rhagades at commissures

Secondary syphilis presents with constitutional symptoms
and a widespread maculopapular eruption involving the palms
and soles. Mucosal manifestations are common in secondary
syphilis, occurring in at least 30% of patients. Mucous patches,
shallow gray-white necrotic patches surrounded by erythema,
are the most frequent intraoral sign of secondary syphilis. Other
mucosal manifestations of secondary syphilis include macular syphilides (erythematous, oval macules), papular syphilides
(painless, grayish nodules), snail-track ulcers (confluent mucous
patches), oral hairy leukoplakia-like lesions, and rarely, condyloma lata (slightly exophytic, papillated lesions at the commissures and genital mucosa). Mucocutaneous manifestations
of secondary syphilis usually resolve spontaneously after 3 to
12 weeks.
Tertiary syphilis develops in about one-third of patients
with untreated secondary syphilis and may arise after a prolonged latency period. Tertiary syphilis is characterized by the
widespread development of localized, destructive granulomas
(gummas) that develop as a consequence of endarteritis obliterans. Oral gummas arise on the tongue, soft palate, and hard
palate and may contribute to scarring and palatal perforation.
Another oral finding of tertiary syphilis is syphilitic leukoplakia,
which may be associated with increased risk for squamous cell
carcinoma. Atrophic glossitis, chronic interstitial glossitis, and
syphilitic sialadenitis also develop occasionally.
Rarely, syphilis is associated with erythema multiforme-like
lesions. Congenital syphilis can predispose the child to multiple
intraoral abnormalities, including a high arched palate, mucous
patches, Hutchinson’s incisors, Mulberry molars, and commissural rhagades.

292 — Julia S. Lehman, Alison J. Bruce, and Roy S. Rogers, III

Because of the diversity of mucosal manifestations associated with syphilis, differential diagnosis is broad.
DIAGNOSIS

In primary and secondary syphilis, definitive diagnosis can
be made by dark-field microscopy and direct fluorescent antibody tests on lesional exudate and tissue. Screening can be performed with the nontreponemal tests, including the Venereal
Disease Research Laboratory (VDRL) and Rapid Plasma Reagin
(RPR) tests. These become reactive within a week of primary
infection and can be used to monitor disease response to therapy. Nontreponemal tests should revert to being negative within
1 year after adequate antimicrobial therapy. Diagnostic specificity is enhanced with treponemal tests, including the Treponema
pallidum hemagglutination assay (TPHA), T. pallidum phytohemagglutination assay (TPPA), microhemagglutination assay for
antibody to T. pallidum (MHA-TP), and fluorescent treponemal
antibody absorbed assay (FTA-Abs). Treponemal tests remain
positive indefinitely. Patients with syphilis should also be tested
for other sexually transmitted infections, including HIV.
T R E AT M E N T

Treponema pallidum is one of only two main pathogens
(along with S. pyogenes) that remain uniformly susceptible to
penicillin, making this agent the drug of choice. In patients
with a true penicillin allergy, the preferred second-line therapy
is doxycycline. Ceftriaxone and azithromycin may also have a
role in treatment. Treatment failure has been reported in patients
with concurrent HIV infection, although this might represent
re-infection. Jarisch-Herxheimer reaction, a transient febrile
reaction following antibiotic treatment in syphilis, is rare.

Mycobacteria
Mycobacteria are facultative anaerobes that resemble bacteria
but lack rigid cell walls. Several species have been implicated in
diseases with oral manifestations.
Tuberculosis
Tuberculosis, caused by Mycobacterium tuberculosis, is uncommon in the United States but is widespread in many parts of the
developing world. In the United States, tuberculosis is seen most
commonly in immigrants, homeless individuals, alcoholics, and
immunocompromised patients.
C L I N I C A L P R E S E N TAT I O N

Oral manifestations of tuberculosis are unusual but may result
from dissemination of pulmonary tuberculosis or, rarely, from
primary oral inoculation. Nonhealing, granulomatous ulcers
covered by a grey-yellow exudate develop on the dorsum of the
tongue, palate, or, less commonly, buccal mucosa, and lips. Ulcers
are usually accompanied by cervical lymphadenopathy with or
without overlying skin breakdown (scrofula). Macroglossia may
result from granulomatous infiltration of the tongue. Differential
diagnosis of intraoral tuberculosis includes sarcoidosis, Wegener’s
granulomatosis, mucormycosis, squamous cell carcinoma, lethal
midline granuloma, systemic mycoses, actinomycosis, eosinophilic ulcer, Crohn’s disease, and traumatic ulcer.
DIAGNOSIS

A tuberculin skin test is usually placed as part of the preliminary evaluation. Results may be false positive if the patient
has ever been exposed to M. tuberculosis and has been treated

successfully or if the patient has been immunized previously
with the Bacille Calmette-Guérin (BCG) vaccine. False-negative
results may occur if the patient is immunocompromised (a phenomenon known as anergy) or has recently been immunized
with a live virus vaccine. In patients with positive tuberculin
skin tests or with a high pretest probability for tuberculosis, chest
radiography and sputum culture should be obtained. Acid-fast
bacilli may be seen on tissue biopsy. Definitive diagnosis requires
identification of M. tuberculosis on culture.
T R E AT M E N T

The American Thoracic Society has developed a treatment
algorithm for pulmonary tuberculosis. In the United States, initial therapy for active tuberculosis includes isoniazid, rifampin,
ethambutol, and pyrazinamide for 2 months. In some cases,
directly observed therapy is important to ensure patient adherence. Smear and culture should be repeated following 2 months
of treatment, and results should guide further therapy. Close
patient contacts or exposed health-care workers may need to
undergo tuberculin skin testing and, if positive, chest radiography and 9 months of isoniazid prophylaxis.
Mycobacterium avium intracellulare
Oral lesions associated with disseminated Mycobacterium avium
intracellulare (MAI) in a patient with AIDS has been reported.
Lesions appeared as granulomatous masses on the hard palate
and gingivae.
Leprosy (Hansen disease)
Mycobacterium lepra, the etiologic agent in leprosy, is an obligate
intracellular bacillus that grows optimally at a temperature less
than 37°C. Leprosy is a chronic systemic granulomatous disease
that can affect the mucosa as well as skin, peripheral nerves, and
other tissues. Several forms of the disease exist, including tuberculoid (paucibacillary), lepromatous (multibacillary), borderline,
and indeterminate leprosy. The form the disease takes in each
individual is dependent on the host’s immunologic response to
infection. A predominantly cell-mediated immune response generally leads to tuberculoid leprosy, whereas a humoral response
results in lepromatous leprosy, for example.
C L I N I C A L P R E S E N TAT I O N

Oral lesions are usually seen only with lepromatous leprosy and are present in 20% to 60% of cases. Nodules arise on
oral surfaces and ultimately become necrotic and ulcerate. This
can be highly destructive to the involved tissue and result in
disfigurement (Fig. 22.12). Mucosal findings are rare in other
forms of leprosy, although papules, erythema, and ulcers have
been observed in borderline leprosy. Leprosy develops after an
incubation period of many years. Differential diagnosis includes
aspergillosis, Wegener’s granulomatosis, sarcoidosis, syphilis,
lethal midline granuloma, noma, lymphoma, mucormycosis,
and squamous cell carcinoma.
DIAGNOSIS

The diagnosis of leprosy can be made clinically. One study
found that in the appropriate clinical scenario, the presence of
one of the following three signs had a 97% sensitivity for diagnosis: (1) hypopigmented or erythematous patches with definite
loss of sensation, (2) thickened peripheral nerves, or (3) acid-fast
bacilli on skin smears or biopsy material. Visualization of
an inflamed nerve on skin biopsy in a patient with signs or

Infections of the Mucous Membranes — 293

dorsal tongue papillae (“strawberry tongue”). After the eruption
subsides, desquamation may persist for several weeks.
Rarely, balanitis or penile pyoderma may result from streptococcal infection in children via autoinoculation or in adults
via oral sex.
DIAGNOSIS

Streptococcal pharyngitis can be diagnosed with the rapid
antigen detection test and confirmed by isolation of the organism
on throat culture. Serum antistreptolysin O (ASO) antibodies are
usually elevated with recent streptococcal infection, but it is not
necessary to check ASO antibody levels in uncomplicated acute
disease. Scarlet fever is often diagnosed clinically and confirmed
by demonstrating acute pharyngeal infection with S. pyogenes.
T R E AT M E N T

Figure 22.12. Leprosy.

symptoms of leprosy is confirmatory. Lepromin testing assesses
delayed-type hypersensitivity to antigens of M. lepra, and a
positive test indicates brisk cell-mediated immunity (i.e., most
consistent with the tuberculoid form).
T R E AT M E N T

For lepromatous (multibacillary) leprosy, a regimen consisting of rifampin, dapsone, and clofazimine is recommended.
Rifampin and dapsone without clofazimine should be sufficient
for tuberculoid (paucibacillary) cases.

The treatment of choice for streptococcal pharyngitis is a
10-day course of penicillin. The goal of antimicrobial therapy in
streptococcal pharyngitis is to prevent suppurative and certain
nonsuppurative complications, such as acute rheumatic fever.
The incidence of acute poststreptococcal glomerulonephritis is
not affected by antibiotic therapy.
Staphylococcus
Staphylococcus spp. are gram-positive organisms that are found in
clusters on Gram’s stain. S. aureus is a colonizing organism of the
nasopharynx and posterior oropharynx and only rarely causes
intraoral infection. Intraoral staphylococcal infections occur
more commonly in patients with hematologic malignancies.
C L I N I C A L P R E S E N TAT I O N

Other Mucosal Infections of Bacterial Origin
Streptococcus
Streptococcus spp., gram-positive cocci that appear in pairs or
chains on Gram stain, can be found as part of the normal oral
flora or as a pathogen. Streptococcus viridans, an important contributor to the normal oral flora, competes with invading bacteria for mucosal adherence sites and secretes bacteriocins. In
certain situations of mucosal disruption or host immunocompromise, however, S. viridians can migrate from the oral mucosa
and cause bacterial endocarditis or sepsis. S. mutans is associated with the development of dental caries, and its presence in
the mouth is a predictor of future caries. Group A Streptococcus
pyogenes contains the virulence factor M protein and is the most
common cause of acute bacterial pharyngitis.
C L I N I C A L P R E S E N TAT I O N

Streptococcal pharyngitis presents with an intensely sore
throat, tender anterior cervical lymphadenopathy, and fever.
Intraoral findings include petechiae of the soft palate, tonsillar
hypertrophy, and tonsillar exudate. Cough and nasal congestion
are usually absent, and indeed, their presence lowers the pretest
probability of the pharyngitis being attributable to S. pyogenes
significantly. Streptococcal pharyngitis has been associated
with suppurative (i.e. tonsillar exudate, peritonsillar cellulitis or
abscess, sinusitis, streptococcal bacteremia) and nonsuppurative
(i.e., acute rheumatic fever, acute poststreptococcal glomerulonephritis) postinfectious sequelae. Incubation period for the
primary disease is 2 to 4 days.
Scarlet fever results from pyrogenic exotoxin release from
Group A β-hemolytic streptococcus (S. pyogenes) and presents
with high fever, diffuse scarletiniform rash, and erythema of the

Intraoral abscesses, as well as staphylococcal mucositis and
parotitis, may arise rarely as a result of S. aureus infection and are
accompanied by regional lymphadenopathy. Staphylococcus has
also been implicated in angular cheilitis. When the oral cavity is
infected with phage group 2 S. aureus, the release of epidermolytic
toxins A and B can cause staphylococcal scalded skin syndrome.
DIAGNOSIS

Culture is used to identify the organism and determine antibiotic susceptibility patterns of the pathogenic organism.
T R E AT M E N T

Systemic antistaphylococcal antibiotics hasten resolution of
intraoral staphylococcal infections. Although only about 5% of
S. aureus isolates from the oral cavity were methicillin resistant
in one recent study, antibiotic selection is best guided by antimicrobial susceptibility testing. Incision and drainage are often
necessary to treat abscesses.
Diphtheria
Diphtheria is a rare upper respiratory syndrome that results from
production of an exotoxin by Corynebacterium diphtheriae. The
organism is highly contagious and is transmitted via respiratory
droplets or direct mucosal contact with an infected individual. In
the United State s, the incidence of disease has declined since the
introduction of the diphtheria vaccine in the 1940s.
C L I N I C A L P R E S E N TAT I O N

The three phases of upper respiratory infection include
(1) catarrhal, (2) paroxysmal, and (3) convalescent phases,
with the last phase causing paroxysmal coughing for weeks to
months after acute infection. Intraoral manifestations of diphtheria include the development of an adherent white or grey
pseudomembrane that coats the posterior oropharynx and bleeds

294 — Julia S. Lehman, Alison J. Bruce, and Roy S. Rogers, III

when removed. Diffuse mucosal edema, pharyngeal ulceration,
and necrosis may develop in severe disease. If oral lesions and
edema extend into the airway, obstruction can result. Paralysis of
the soft palate and posterior pharyngeal wall may occur as a consequence of the neurotoxic effects of the C. diphtheriae exotoxin.
Nasal discharge often accompanies oropharyngeal signs of diphtheria and is associated with the presence of white patches on
the nasal septal mucosa. Anterior cervical lymphadenopathy and
acute lymphadenitis may accompany intraoral findings. Rarely,
the genital mucosa may become infected and cause vulvovaginitis. Previously vaccinated individuals should have a less severe
but still prolonged disease course. The presence of the characteristic pharyngeal pseudomembrane on clinical examination
differentiates diphtheria from other causes of upper respiratory
infection and cough.
DIAGNOSIS

Although organisms may be demonstrated on culture and
PCR and fluorescent antibody tests are available, laboratory tests
are relatively insensitive for C. diphtheriae. Therefore, diphtheria
is usually diagnosed clinically and is treated empirically.
T R E AT M E N T

Airway protection is the first goal of therapy in severe disease.
Erythromycin, azithromycin, and clarithromycin are equally
effective in routine cases. Trimethoprim–sulfamethoxazole may
be used as an alternative agent. Prevention is achieved by widespread administration of the diphtheria, tetanus, and acellular
pertussis (DTaP) vaccine to infants and children (5 total doses),
as well as the adult tetanus and diphtheria (Td) booster every 10
years. The new tetanus, diphtheria, and acellular pertussis (Tdap)
vaccine can substitute for one booster dose of Td.

coccobacillus, Klebsiella rhinoscleromatis. K. rhinoscleromatis
is transmitted via inhalation of respiratory droplets. Although
endemic in parts of Africa, Central America, and India, rhinoscleroma is relatively rare in the United States. Women are more
commonly affected than men, and disease arises in the second
and third decades of life.
C L I N I C A L P R E S E N TAT I O N

The first symptom associated with rhinoscleroma is rhinitis
that evolves into a purulent rhinorrhea. Subsequently, proliferative granulomas erupt in the nasopharynx. Ultimately, these
lesions may ulcerate and undergo sclerosis and fibrosis, leading
to scarring and, occasionally, stenosis of the nasal passages.
Symptoms include rhinorrhea, nasal obstruction, and
epistaxis. Although the nasal cavity is involved in almost every
case of rhinoscleroma, lesions may also develop in the larynx,
oral cavity, sinuses, or soft tissue of the lip. Rarely, rhinoscleroma can cause upper airway obstruction. Differential diagnosis
includes mucosal leishmaniasis, leprosy, lethal midline granuloma, Wegener’s granulomatosis, tuberculosis, mucormycosis,
and aspergillosis.
DIAGNOSIS

Subepithelial Mikulicz cells may be visualized with cytology or on biopsy with periodic acid-Schiff, Giemsa, Gram, or
silver stain. Radiographic imaging of the head with CT or magnetic resonance (MR) imaging delineates the extent of disease
involvement.
T R E AT M E N T

Tetracycline, ciprofloxacin, oral rifampicin, and topical
rifampicin have been shown to be effective in the treatment of
rhinoscleroma. Surgical intervention or laser ablation may also
be indicated.

Actinomycosis
Actinomyces spp. are anaerobic or facultative gram-positive rods
commonly found in the oral mucosa. Typically, actinomycosis is
caused by A. israelii, an organism present in the tonsillar crypts
and dental calculi.
C L I N I C A L P R E S E N TAT I O N

At the site of inoculation, yellow purulent material (“sulfur
granules,” or colonies of Actinomyces) drains from abscesses
or sinuses. Generally, Actinomyces infects the head and neck
(cervicofacial actinomycosis), with the tongue, lips, and buccal
mucosa being involved infrequently. Infiltration of the tongue by
A. israelii can rarely lead to macroglossia. Isolated involvement
of the gingiva has also been reported. In severe cases, disease
may extend to involve the mandibular or maxillary facial bones.
Differential diagnosis includes nocardiosis, staphylococcal infection, tuberculosis, or systemic mycoses.
DIAGNOSIS

Isolation of Actinomyces israelii by culture is diagnostic in the
appropriate clinical setting. A. israelii may also be visualized on
histopathologic examination.
T R E AT M E N T

Penicillin is the treatment of choice, while erythromycin or
doxycycline are used in patients allergic to penicillin. Surgical
debridement may also be required.
Rhinoscleroma
Rhinoscleroma, a chronic granulomatous condition of the nose
and upper respiratory tract, is caused by the gram-negative

Acute Necrotizing Ulcerative Gingivitis
Also known as “trench mouth,” acute necrotizing ulcerative
gingivitis (ANUG) is an intraoral infection seen in young people with poor oral hygiene. Implicated organisms include the
spirochete Borrelia vincentii and other bacteria such as Bacillus
vicentii, Bacteroides spp., and Selenomonas spp. Risk factors
include psychological stress, smoking, poor oral hygiene,
malnutrition, physical debilitation, and immunocompromise.
C L I N I C A L P R E S E N TAT I O N

ANUG can present with the sudden onset of fiery red, painful, “punched-out” ulceration at the interdental papillary tips.
Ulcers may be covered with a friable grey or yellow pseudomembrane. The disease progresses to involve the interpapillary, lingual,
and facial gingiva. Ensuing necrosis may cause substantial tissue
destruction. Intraoral findings may be accompanied by constitutional symptoms, such as fever, chills, and malaise. Moreover,
patients have a characteristic fetid odor (fetor oris) to their breath.
DIAGNOSIS

ANUG is diagnosed clinically. Although various sets of diagnostic criteria have been established, most require a history of
gum soreness and bleeding and the presence of blunting, ulceration, and necrosis of the interdental papillae. Foul-smelling
breath and pseudomembranous, hemorrhagic ulcerations are
supportive findings.
T R E AT M E N T

ANUG is treated with local irrigation and debridement, combined with simultaneous administration of systemic antibiotics,

Infections of the Mucous Membranes — 295

such as metronidazole or penicillin. Treatment of predisposing
factors is necessary for cure.
Noma (cancrum oris, gangrenous stomatitis)
Noma is a destructive disease of the hard and soft tissues of the
face associated with multiple organisms, such as Fusobacterium
necrophorum, Borrelia vincentii, Prevotella intermedia, Tannerella
forsynthesis, Porphyromonas gingivalis, Bacillus fusiformis, and
Treponema denticola. Noma typically affects children younger
than 4 years living in developing countries, particularly in subSaharan Africa. This condition is associated with malnutrition,
overcrowded living conditions, contaminated water supplies,
and extreme poverty.
C L I N I C A L P R E S E N TAT I O N

Noma starts as ulcerative gingivitis or stomatitis, with
gangrenous ulcers that are covered with whitish brown fibrin
on the cheeks and lips. The disease progresses rapidly, and
the sloughing of necrotic tissues exposes the underlying facial
bones and teeth. Associated signs include failure to thrive,
salivation, fever, halitosis, anemia, and leukocytosis. Severe
disfigurement often results. If left untreated, this disease is
associated with a 70% to 90% mortality rate. Differential diagnosis includes lethal midline granuloma, leprosy, squamous
cell carcinoma, leukemia, mucormycosis, and aspergillosis.
DIAGNOSIS

Diagnosis is made clinically. Although demonstration of
implicated organisms on Gram’s stain or tissue culture may be
supportive, this is not usually practical.
T R E AT M E N T

Medical therapy should include reversal of dehydration and
electrolyte imbalances, as well as administration of antibiotics,
such as penicillin or metronidazole. Following the acute phase,
surgical debridement and repair may be indicated.
Anthrax
Human anthrax is caused by the gram-positive curved bacillus, Bacillus anthracis. Depending on the route of acquisition,
anthrax spores may cause cutaneous, intestinal, or respiratory
anthrax. In the agricultural setting, anthrax usually results from
contact with B. anthracis spores on the skin or mucosa. Ingestion
of spores, as may occur with the consumption of undercooked
herbivore meat in endemic areas, can lead to anthrax of the gastrointestinal tract. Oral anthrax is rare but has been reported. In
an outbreak in Northern Thailand, 24 of 52 people who developed anthrax following consumption of undercooked cattle and
water buffalo had intraoral manifestations. Anthrax has been
of heightened interest in recent years because of the concern
regarding its use in bioterrorism, particularly after the outbreaks of inhalation anthrax associated with terrorism in 2001.
Inhalation anthrax has not been associated with lesions of the
mucous membranes.
C L I N I C A L P R E S E N TAT I O N

Mucosal lesions of anthrax resemble those of cutaneous
anthrax and arise at the tonsils, hard palate, and posterior oropharynx. These friable, ulcerated lesions undergo necrosis, resulting
in black eschars. Mucosal lesions are almost always associated
with regional lymphadenopathy. Symptoms include neck swelling, sore throat, hoarseness, and dysphagia. The patient may be
otherwise asymptomatic or may have associated symptoms and

signs of gastroenteritis, shock, or sepsis. Differential diagnosis
includes pyogenic granuloma, Wegener’s granulomatosis, syphilis, mucormycosis, and aspergillosis.
DIAGNOSIS

Diagnosis of mucosal anthrax is made by Gram’s stain and
culture of a lesional smear. The presence of serum antibodies and
consistent epidemiologic data are supportive findings.
T R E AT M E N T

Penicillin is the drug of choice in anthrax, although doxycycline and fluoroquinolones can also be used. Airway management is critical when significant oropharyngeal edema is
present.
Bacterial vaginosis
The normal flora of the vagina is dominated by lactobacilli,
organisms that acidify the vaginal environment with the production of lactic acid. Bacterial vaginosis results when the lactobacillus population is depleted. Gardnerella (Haemophilus) vaginalis,
a small gram-negative or gram-variable unencapsulated, nonmotile rod that is present in the normal flora of the vagina, is among
the organisms that proliferate pathologically in this condition.
Though no evidence clearly demonstrates that bacterial vaginosis is transmitted sexually, risk factors for bacterial vaginosis
include recent change of sexual partner, frequent douching, and
having a female sexual partner.
C L I N I C A L P R E S E N TAT I O N

Bacterial vaginosis can cause a stringy, gray-white, vaginal
discharge that has a distinctive fishy odor. Some patients report
an increase in the volume of vaginal discharge. Disease can also
be asymptomatic.
DIAGNOSIS

Bacterial vaginosis is a clinical diagnosis. Amsel’s criteria
for diagnosis includes the presence of three of the following:
(1) visualization of “clue cells” (vaginal squamous epithelial cells
with coccobacilli adherent to the cell periphery) on wet prep,
(2) positive amine odor test (addition of 10% potassium hydroxide to wet preparation leads to generation of the distinctive
amine odor), (3) thin, watery, vaginal discharge, and (4) vaginal
pH greater than 4.5. Vaginal culture is not useful, as bacterial
vaginosis is due to a polymicrobial overgrowth of organisms
usually present in the normal flora.
T R E AT M E N T

Oral metronidazole is the standard treatment for bacterial
vaginosis. Women should be advised to avoid alcohol while
using this medication because of its disulfiram-like effect.
Metronidazole gel and clindamycin cream have similar efficacy
as oral metronidazole. Treatment is particularly important in
pregnant women, as bacterial vaginosis has been correlated with
an increased incidence of preterm labor.
Pseudomonas aeruginosa
Even though Pseudomonas aeruginosa thrives in moist environments, infection in the non-respiratory oral and genital mucosa
is rare. Necrotizing stomatitis caused by Pseudomonas aeruginosa
has been described previously in a case series of three patients.
Each of these patients were immunocompromised. Authors
proposed that these oral lesions represent a mucosal variant of
ecthyma gangrenosum.

296 — Julia S. Lehman, Alison J. Bruce, and Roy S. Rogers, III

Table 22.10: Bacterial Organisms That Do Not Usually
Cause Disease of the Oral and Genital Mucous Membranes
Aeromonas hydrophila

Klebsiella pneumonia

Bacillus cereus

Legionella pneumophila

Borderella pertussis

Listeria monocytogenes

Borrelia burgdorferi

Pseudomonas aeruginosa

Brucella spp.

Rickettsia spp.

Campylobacter spp.

Salmonella spp.

Clostridium perfringens

Shigella spp.

Escherichia coli

Vibrio spp.

Helicobacter pylori

Yersinia spp.

Hemophilus influenza

Mycoplasma pneumoniae
Typically a respiratory pathogen, Mycoplasma pneumoniae has
also been implicated in the development of erythematous vesicles of the oral and genital mucosa, stomatitis, erythema multiforme, and severe erythema multiforme (Stevens-Johnson
syndrome). Patients with oropharyngeal involvement from M.
pneumoniae infection generally have a concurrent infection of
the lower respiratory tract.
Tetanus
Tetanus is caused by the tetanospasmin toxin of Clostridium tetani, an anaerobic, gram-positive bacillus. Infection results in trismus (lockjaw, risus sardonicus) and generalized muscle spasms,
followed by apnea and, ultimately, death. A previous report of
a patient who developed tetanus without a clear source documented complete disease resolution following dental extraction
and gingival debridement. The authors concluded that the source
of infection was periodontal.
Bacterial organisms that do not usually cause disease of the oral
or genital mucous membranes include (Table 22.10) Aeromonas
hydrophila, Bacillus cereus, Bordetella pertussis, Borrelia burgdorferi, Brucella spp., Campylobacter spp., Clostridium perfringens, Escherichia coli, Helicobacter pylori, Hemophilus influenza,
Klebsiella pneumonia, Legionella pneumophila, Listeria monocytogenes, Pseudomonas aeruginosa, Rickettsia spp., Salmonella spp.,
Shigella spp., Vibrio spp., and Yersinia spp.

Protozoa
Trichomoniasis
Trichomoniasis results from infection with the sexually transmitted intracellular protozoan, Trichomonas vaginalis. Epidemiologic
risk factors include harboring other sexually transmitted infections, engaging in sexual activity with a new partner or engaging
in sexual activity more frequently than once weekly, and having more than three sexual partners in the preceding month.
Trichomoniasis commonly causes vaginitis and urethritis, while
oral disease is uncommon.

C L I N I C A L P R E S E N TAT I O N

Oral trichomoniasis can present as generalized mucosal
inflammation covered with an overlying exudate. Trichomonas
vaginitis is symptomatic in most women. Specifically, patients
describe dyspareunia, labial pruritus, dysuria, and copious, yellow or green, frothy, odiferous vaginal discharge. On clinical
examination, petechiae may be present on the vulva and cervix
(strawberry cervix). In men, trichomoniasis is usually asymptomatic, although there may be some irritation of the urethra,
penile pruritus, or first-void urethral discharge. In both sexes,
the involved mucosal surfaces may develop erythematous puncta
resulting from local vasodilation and an overlying layer of exudate. Incubation period is 5 to 28 days.
DIAGNOSIS

Trichomonas vaginalis is a highly motile rod that can be seen as
a pear-shaped, unicellular organism with two pairs of anterior flagella on wet mount saline preparation. This finding is nonspecific
for T. vaginalis, however, as other motile trichomonads frequently
are present in the mouth or gastrointestinal tract (i.e. T. tenax and
T. hominis, respectively). With trichomonal cervicitis, vaginal pH
is typically greater than 4.5 (normal vaginal pH: 4.0).
T R E AT M E N T

The treatment of choice is oral metronidazole, although
tinidazole may be used for metronidazole-resistant trichomoniasis. Sexual partners must also be treated.
Leishmaniasis
Leishmaniasis occurs as a result of infection with the protozoan parasite, Leishmania spp. The vector is the female sandfly Phlebotomus in Old World leishmaniasis and Lutzomyia in
New World leishmaniasis. Although the patient often reports a
recent history of travel to an endemic area, the latency period
from infection to the development of clinical manifestations may
extend for years.
Leishmaniasis is classified as cutaneous (CL), mucocutaneous
(MCL), or visceral (VL). Mucosal lesions are almost exclusively
seen in mucocutaneous leishmaniasis, which is caused by L. braziliensis. Oral lesions in association with L. amazonensis infection
also have been documented. Finally, a recent case report describes
oral ulcers in a patient with visceral leishmaniasis, although the
particular species of Leishmaniasis was not reported.
C L I N I C A L P R E S E N TAT I O N

Mucosal findings are accompanied by cutaneous signs of
leishmaniasis and typically include nonspecific erythematous
regions of induration that can become eroded or ulcerated
(Fig. 22.13). Mucocutaneous leishmaniasis has a predilection
for the nasal septum and larynx, although involvement of the
tongue, soft palate, and hard palate may also occur. Nasal septum
perforation and significant facial disfigurement may ensue if the
patient remains untreated. Differential diagnosis includes paracoccidioidomycosis, histoplasmosis, syphilis, leprosy, Wegener’s
granulomatosis, tuberculosis, mucormycosis, rhinoscleroma,
aspergillosis, systemic mycoses, and nasopharyngeal carcinoma.
DIAGNOSIS

The preferred method of diagnosis is examination of a dermal thin smear obtained from the border of an active lesion.
This demonstrates the presence of amastigotes. Organisms also
can be isolated with culture. Histopathology reveals a nonspecific granulomatous reaction, and organisms may be seen with

Infections of the Mucous Membranes — 297

Table 22.11: Protozoal Organisms That Do Not Usually
Cause Disease of the Oral and Genital Mucous Membranes
Plasmodium Falciparum
Trypanosoma spp.

symptoms suggestive of mucosal disease. Another common pitfall
is to mistake normal clinical findings for pathology. The importance of routine mucosal examination as a means to gain familiarity with normal mucosal anatomy cannot be overemphasized.
Even when a thorough examination is performed, accurate
diagnosis of mucosal infections can be challenging, because
similarly appearing lesions may result from a variety of insults
to these tissues. Therefore, the practitioner should obtain a complete patient history, including constitutional symptoms, travel
history, sexual practices, and environmental exposures. This
is particularly important in diagnostically challenging cases.
Finally, the index of suspicion for atypical disease presentations
or unusual opportunistic infections must be raised when evaluating immunocompromised patients.
SUGGESTED READINGS

Figure 22.13. Leishmaniasis.

Giemsa stain. Serology and PCR can also be used to confirm
diagnosis. A high index of suspicion is required in geographic
regions in which leishmaniasis is not endemic.
T R E AT M E N T

Pentavalent antimonies are the standard treatment of mucocutaneous leishmaniasis, although amphotericin B is the drug
of choice for advanced disease. Early therapy can lead to an
excellent cure rate. A recent study found that itraconazole is not
an effective pharmacologic alternative. Disease is prevented in
endemic areas with use of netting impregnated with permethrin,
protective clothing, and insect repellent.
Protozoal organisms that do not usually cause disease of
the oral or genital mucous membranes include (Table 22.11)
Plasmodium falciparum and Trypanosoma spp.

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PA R T V I : S P E C I A L D I S E A S E
C AT E G O R I E S

23

INFECTION S IN SKIN SU RGERY
Jean-Michel Amici, Anne-Marie Rogues, and Alain Taïeb

H I STORY

Dermatologic surgery has grown in popularity and stature
during the past few decades. Skin surgery is routinely performed
by dermatologists and plastic surgeons, mostly using local anaesthesia. Types of skin surgery include, skin biopsy (punch biopsy,
shave biopsy, incisional biopsy, and excisional biopsy), excision
of the skin lesion, curettage, and cautery, flap, skin grafting, and
Mohs microscopically controlled excision (for cancers at high
risk of local recurrence). It is common to remove benign tumors.
It is even more common to remove malignant tumors such as
basal cell carcinoma (BCC), squamous cell carcinoma (SCC),
or melanoma. Skin cancer is the most common malignancy in
humans and its incidence, especially that of BCC, has increased
over the last decades and is still increasing. Left untreated, these
lesions may become locally destructive (BCC) and others (SCC
and mostly melanoma) have a potential for metastasis. The primary treatment of cutaneous neoplasms is surgical excision, and
dermatologists have expanded their practice to include surgical
procedures in response to the epidemic of cutaneous tumors
related to an increased elderly population worldwide. Besides the
treatment of tumors, dermatologic surgery is used for cosmetic
purposes, and in emergency cases to drain abscesses or inflamed
cysts.
A survey of the American Society for Dermatologic Surgery
found that members performed about 3.9 million procedures
a year. Of these procedures, skin cancer surgery was the most
common with 1.4 million operations. Surgery performed by
dermatologists on an outpatient basis under local anesthesia is
less costly than other more complex options and has become the
treatment of choice for many cutaneous malignancies.
This chapter focuses on infections within the context of conventional excisional surgery excluding facial resurfacing, liposuction, and other cosmetic surgical procedures.
Thus, we will first review the description, frequency, and risk
factors for skin infections following dermatologic surgery. And
in the second part, we will discuss management and prevention.

E P I DE M IOL O G Y OF SK I N SU RG E RY
INFECTIONS

Definition and Classification
Infection after skin surgery is a surgical site infection (SSI)
defined by the Centers for Disease Control and Prevention
(CDC) as any surgical wound that produces a suppuration
within 30 days of the procedure, even in the absence of a positive culture. Inflammation without suppuration is not sufficient

to classify the wound as infected. The CDC wound classification
correlates four degrees of contamination of wounds with subsequent infection rates (Table 23.1).
Most dermatological procedures are considered “clean” or
“clean-contaminated.” The Mohs extirpation of cutaneous tumors
is more correctly classified as a clean-contaminated procedure.
As a consequence, acceptable rates of wound infection for “clean”
procedures are thought to range between 1% and 4% or between
5% and 10% for “clean-contaminated” procedures.
A literature search for the incidence of infections in skin surgery produced a very limited number of relevant publications,
and studies that have looked at postoperative wound infection
rates in dermatologic surgery indicate a lower rate of infection
than expected in the CDC classification. Indeed, the frequency
of SSI in skin surgery reported in different studies varies between
0.7% and 7.6%. This wide range is explained by different types of
wound and patient categories.
One of the first studies was conducted by Whitaker and
colleagues, who found an overall infection rate of 0.7% while
performing over 3,900 clinic-based dermatologic surgical procedures including Mohs surgery, simple excisions, flaps, grafts,
scalp reductions, and hair transplantations. Dettenkofer et al.
followed a cohort of 995 patients undergoing surgical procedures in a German university hospital. They reported an infection rate of 7.6% after surgery for BCC. In this study, none of
the 163 patients with malignant melanoma acquired an infection
after surgery. Regarding Mohs surgery, Futoryan and Grande
reported an overall infection rate of 2.4% in 520 cases. Two large
prospective studies that reported data on dermatologic surgery proceeding without Mohs micrographic surgery (MMS)
in outpatients showed an overall incidence of infections of 1.5%
and 1.9%.
In a prospective study assessing the incidence of various
complications associated with MMS based on 1,358 procedures for skin cancers, the complication rate was 1.6% with only
one wound infection. In the Australian Mohs database which
includes 2,673 patients, a total of 11.7% of cases had recipientsite complication, and infection accounted for only 3.5% of all
complications (graft hypertrophy: 42.3%, partial graft failure:
27.2%, and graft contraction: 15.3%).
The total incidence of anesthetic, hemorrhagic, and infectious complications in 3,788 surgical procedures performed by a
French dermatologist was 5.6% including 2.1% for wound infections. The first signs of clinical infection following procedure
appeared a mean of 6.3 days (1–12 days) later.
By far, the most common pathogen isolated in SSIs is
Staphylococcus aureus. Streptococcal species, Pseudomonas aeruginosa and coliform bacteria, are also occasionally encountered,
303

304 — Jean-Michel Amici, Anne-Marie Rogues, and Alain Taïeb

Table 23.1: Wound Status and Infection Rate
Wound Status

Class

Infection Rate %

Clean

I

Elective incision on
non-inflamed tissues
using strict aseptic
technique

1–4

Cleancontaminated

II

Surgery in
contaminated areas
(axilla, perineum,
mucosal areas)

5–10

Contaminated

III

Major breaks in sterile
technique, obviously
inflamed skin

6–25

Infected

IV

Frank purulence
(Abscess)

>25

grafts maximize blood supply and minimize ischemia, which can
lead to the development of devitalized tissue and the potential
for wound infection. In our experience, the incidence of wound
infections was higher for excisions with a reconstructive procedure. However, no difference was found in the incidence of
infectious complications between two types of simple excision
surgical procedures with an overall scar of less than 2 cm or an
overall scar greater than 2 cm.
In Mohs surgery, the mean area of the infected defects was
twice that of the noninfected group, and procedures performed
on the ear were found to have a higher rate of wound infections.
Longer procedure duration led to a greater risk of infectious
complications which was consistent with other reported surgery
practices.
TYPE OF LESION

especially in selected anatomic sites, such as the perioral area or
ear. Pseudomonas aeruginosa is known to colonize the auricular canal, and thereby as a result there is a relatively high risk of
infection for any wound that involves the auricular cartilage.

Risk factors
Multiple factors play a role in increasing the risk of surgical
wound infections. They can be classified into three categories:
intrinsic factors that relate to host defenses, an independent category related to the nature of the surgical procedure, and extrinsic
factors that are aimed at decreasing the opportunity for bacterial
contamination.
Intrinsic factors related to the patient
Aspects of the patients’ health may affect a propensity to wound
infection. Many preexisting, sometimes coexistent, conditions
have been identified in the literature as risk factors for SSIs.
These include diabetes mellitus, obesity, smoking, renal failure,
malnutrition, corticosteroid use and other immunosuppressant
medications, and an immunocompromised status. However, in
dermatologic surgery such risk factors have rarely been significantly linked with SSIs.
Smoking may be an important risk factor in undesired outcomes of cutaneous surgery. In a retrospective study that evaluated the effects of cigarette smoking on tissue survival in wounds
repaired after Mohs extirpations (916 flaps and full-thickness
grafts performed during a 10-year period), heavy smokers (1 or
more packs per day) developed tissue necrosis at a rate that was
approximately 3-fold higher than that of controls.
Factors related to the nature of the surgical procedure
T Y P E O F P R O C E D U R E A N D R E PA I R

Regarding the surgical technique, flap surgery has a significantly higher infection incidence than elliptical excision and
closure. There is some evidence that more complicated procedures (flaps or skin grafts) are associated with increased infection rates, independent of the size of the excision. However, this
should be mitigated by the notion that well-designed flaps and

In an Australian general practice study the histological
subtypes, basal cell carcinoma (BCC) (11.4%) and squamous
cell carcinoma (SCC) (13.5%), and prevalence of diabetes were
independently correlated with wound infection. Those findings
were consistent with a study conducted in a specialist dermatology clinic, which suggested that oncologic surgery (excision for
skin cancer) is associated with a higher risk of infection. In a
recent study concerning 1,400 Mohs procedures, the difference
in infection rate between SCC and BCC was statistically significant. It was 2.7% for SCC versus 1.4% for BCC.
L O C AT I O N

Some anatomical areas with moist conditions and increased
resident microbial counts, such as the ear or facial region, have
a higher risk of developing a wound infection. The study of
Futuroyan et al. clearly shows that the infection rate for MMS
performed on the ear is significantly higher than on non-ear anatomic sites. In this study, wound infections on the ear occurred in
6 out of 48 patients with an infection rate of 12.5%. Furthermore,
there was a significantly higher risk of wound infection when
cartilage was involved. The rate was 28.5% versus the 5.9% found
in cases where the tumor-free tissue was above the level of the
cartilage. This rate is higher than the recent study reported by
Campbell, who mentioned a rate of infection of 5.5% in 144 excisions of BCC and SCCs of the auricular area or that of Kaplan
and Cook who had no cases of suppurative chondritis in 337
patients who underwent cartilage procedures.
In a French multicenter study reported by our group, the
infection rate for procedures performed on the nose or nostril
was higher than that found for other anatomical locations whatever the size of the excision. In another study the higher risk of
infection for nasal or auricular areas was found to be independent of the type of lesion being excised (benign vs. malignant)
or of the complexity of the surgery (skin grafts and local flaps).
Other body locations reported to be at a higher risk for wound
infection following dermatologic surgery included the lip and
the axilla.
Extremities are believed to be at a higher risk of wound infection. Surgery below the knee (n = 448) had an infection incidence
of 6.9% (31/448). Multivariate generalized linear modeling conducted on data provided by a prospective study on minor skin
excisions in Australian general practice also confirmed increased
infectious risk for legs, feet, and thighs (15%).
BLEEDING DURING PROCEDURE

A prospective multivariate analysis of 3,788 surgical skin
procedures showed that hemorrhagic complication is an

Infections in Skin Surgery — 305

independent factor for SSIs. The control of hemorrhagic complications is an important challenge to prevent SSIs. Maintaining
good hemostasis and eliminating “dead space” via the appropriate use of sutures, the use of pressure dressing, and occlusion are
significant surgical considerations to help minimize postoperative morbidity.

MANAGEMENT AND PREVENTION

Management of infection after skin surgery
In cases of suspicion of a postoperative wound infection, the
wound should be examined in a sterile facility under local
anesthesia if required. Some or all sutures are removed and,
after the wound is sampled for culture, the wound is washed to
remove all debris. The wound can either be packed with sterile
gauze or allowed to remain open to heal by second intention.
Empirical antibiotics are begun, based on the presumed causal
pathogen, and can be adjusted based on the culture susceptibility profiles.
In our experience, most infections after skin surgery were
minor superficial suppurations requiring additional antibiotic
treatment, in 18 of 79 cases. However, cases of serious infectious
complications after dermatologic surgery have been reported:
such as toxic shock syndrome and necrotizing fasciitis following
excision of a malignant melanoma. Disastrous outcomes such as
suppurative chondritis are fortunately exceedingly rare following
incisions or manipulation of auricular cartilage.

Aseptic technique
Little is known about the sterile conditions required for this type
of surgery and the optimal resources needed are unclear.
The surgical hand scrub serves to remove transient flora and
soil from the fingernails and hands. For minor or short-lived
procedures, the literature does not support the need for a formal
surgical hand scrub, but it is recommended before more lengthy
or invasive procedures.
Surgical gloves provide a second line of defense against
potential contamination from the hand flora of the surgical
team. In dermatologic surgery, gloves become perforated in
approximately 11% of procedures, and the wearer recognizes
that a perforation has occurred in only 17% of these cases. In
this manner, the aseptic barrier between the surgeon’s hand and
the patient’s wound can be unknowingly breached for extended
periods of time. The risk of glove perforation in dermatologic
surgery is lower than in other specialties and double gloving
provides additional protection from perforation but may limit
sensitivity and dexterity.
A recent study evaluating infection rates in 1,400 surgical
procedures revealed no statistical difference in infection rates
when sterile or nonsterile gloves were used for MMS before
reconstruction. However, it was a retrospective study and the
surgeons involved used sterile gloves for all reconstructions.
Recently, in a prospective study, with 3,491 dermatologic surgical procedures, there was a significantly higher risk of infectious
complications when no sterile gloves were worn for excisions
with a reconstructive procedure, even after controlling other factors, and irrespective of the place where the surgery was performed (private office or hospital setting).

Gowns serve as personal protection but there is no scientific
data to show that wearing a sterile gown versus not wearing one
affects the incidence of SSIs in skin surgery. Sterile gowns may be
considered optional for minor surgical procedures. Face masks
were originally designed to limit contamination of the surgical
site from microorganisms expelled by operators. They not only
protect the surgical wound from airborne contamination but
also serve to protect the wearer’s mouth and nose from unexpected splashes of blood and bodily fluids. All devices that enter
the sterile field must be sterile. Instruments should be steam
autoclaved. Sterile drapes serve to protect the surgical site from
microorganisms present on the surrounding nonsterile surfaces.
There is no published evidence that dermatologic surgical
procedures are riskier when carried out in a private office as
opposed to a hospital setting. Hospital theatres are not required
for most dermatologic surgery procedures. Further studies have
shown that dermatologic surgery can be safely performed in outpatient settings without a significant risk of infection. The data
from Cook and Perone confirm that office-based dermatologic
surgery involving Mohs surgery and reconstruction is very safe
when performed by properly trained physicians. A controlled
trial study is needed to confirm that the risk factor for dermatologic surgery procedures carried out in private office as opposed
to hospital setting is not different irrespective of the procedure
or the type of patients. However, there are sufficient grounds to
approach surgery on certain locations or certain patient types
with appropriate caution. Kaplan’s experience has suggested that
the frequency of inflammatory and infectious complications
associated with the manipulation of auricular skin and cartilage
during reconstructive procedures is minimal when sterile, gentle
operative techniques are used.

Surgical site care
Surgical site preparation is a major goal to lower the resident bacterial count as much as possible and limit rebound growth with
minimal skin irritation. A preoperative shower with an antiseptic
soap has been shown to decrease wound infection rates and may
be considered for procedures with large surgical fields. At the
time of the surgery, after a thorough cleansing, it is necessary to
apply an antiseptic solution appropriate for the location. Heavily
colonized areas such as the umbilicus or nasal vestibule should
receive close attention. Similar to cardiac surgery, where intranasal mupirocin treatment decreases the rate of Staphylococcus
aureus surgical site infection, this strategy could be effective in
skin surgery. Administration of intranasal mupirocin before surgery is cost saving because health care-associated infections are
very expensive.
Hair removal is only indicated if the hair will obscure the
surgical field or hinder proper surgical technique. Shaving with a
razor in particular should be avoided, because it causes abrasions
that compromise skin integrity and allow bacteria to flourish.
Wound dressing is an important part of surgical site care.
No single dressing is suitable for all types of wounds. Dressings
should perform one or more of the following functions: maintain a moist environment at the wound, absorb excess exudates
without leakage to the surface of the dressing, provide thermal
insulation and mechanical protection, provide bacterial protection, be nonadherent to the wound and easily removed without
trauma, be nontoxic, nonallergic, nonsensitizing, and sterile.

306 — Jean-Michel Amici, Anne-Marie Rogues, and Alain Taïeb

Figure 23.1. Intranasal dressing.

Wound dressing and tape, with or without pressure to encourage hemostasis, are important to help prevent wound infections.
Pressure dressings help prevent postoperative hematoma formation. We recommend the use of an intranasal dressing during
surgery of the nasal sidewall because this area is particularly susceptible to hemorrhage and infection. Packing done with tulle
gauze has three advantages: it acts as a support block to improve
the compressive nature of the external dressing, it acts as a nostril conformator and finally, it physically limits colonization of
the wound by endonostril bacteria (Fig. 23.1).
Guidelines for managing surgical wounds that are primarily
closed (i.e., those with the skin edges re-approximated at the end
of the procedure) include instructing the patients to keep their
wound dry and covered for 24 to 48 hours. This allows a degree
of epithelialization to take place and seals the edges of the wound
from bacterial contamination. However, if the dressing becomes
soaked with blood or wound exudates before then, a change of
dressing is necessary.

Antibiotic prophylaxis
The usage of wound infection prophylaxis in dermatologic surgery varies greatly from surgeon to surgeon, with some studies
reporting a widespread usage of antibiotics. Some Mohs surgeons
use prophylactic antibiotics in up to 77% of cases. Antibiotic
wound infection prophylaxis for dermatologic surgery can be
topical (including within the wound itself) and systemic.
In a prospective randomized controlled trial, Dixon et al.
demonstrated a lack of efficacy of topical mupirocin in preventing wound infections in skin cancer surgery. A controlled study
has compared the incidence of suppurative chondritis after
auricular surgery in patients who have received gentamicin
ointment versus petrolatum during second-intention healing of
auricular wounds after Mohs surgery. There was no statistically
significant difference between the two groups of patients in terms
of postoperative auricular suppurative chondritis but the data
demonstrates a disproportionate number of cases of inflammatory chondritis in patients who used gentamicin ointment. This
study, however, was not powered sufficiently to obtain statistical

significance. Regarding inflammatory chondritis, Smack and
colleagues noted similar observations in their comparisons of
bacitracin and petrolatum. They randomized 922 postsurgical
patients into two groups receiving topical therapy and prospectively evaluated infection rates. Overall infection rates in both
groups were less than 2% and they were not statistically significant. In addition, several adverse events have been related to
topical antibiotic administration, including contact dermatitis,
anaphylaxis, and Stevens-Johnson syndrome. We agree that
the use of topical antibiotics in dermatologic surgery should
be considered only in contaminated or infected class III or IV
wounds.
The literature suggests that in the majority of dermatologic surgery procedures, systemic antibiotic prophylaxis is not
needed because the overall incidence of infection is low and
infections are not severe. During prolonged Mohs procedures,
delayed repairs, grafts, takedowns of interpolation flaps, or any
procedure that breaches a mucosal surface, the evidence is less
clear, and decisions should be made on a case-by-case basis.
Additional studies may help clarify the most appropriate indications, and the appropriate patient populations.
It is important to distinguish between antibiotic prophylaxis
for wound infection and antibiotic prophylaxis for bacterial
endocarditis. The guidelines pertaining to prescription of prophylactic antibiotics to prevent endocarditis during dermatologic surgery appears clear. Manipulation of clinically infected
skin is associated with a high incidence (>35%) of bacteremia
with organisms known to cause endocarditis. Although, few
studies have investigated bacteremia associated with dermatologic surgery procedures, those that do exist seem to indicate
that the incidence of bacteremia following dermatologic surgery
is low. The bacteremia generally occurs within the first 15 minutes of the procedure and is short lived, with growing organisms
not commonly causing endocarditis. The British Society for
Dermatological Surgery, in agreement with the British Society
for Antimicrobial Chemotherapy, states that antibiotic prophylaxis for endocarditis is not required for routine dermatological
surgery procedures (such as punches, shaves, curettage and simple excisions) even in the presence of a preexisting heart lesion.
In clean-contaminated skin surgery, antibiotic prophylaxis may
be considered in patients with a cardiac lesion because a wound
infection may result in bacteremia and subsequent endocarditis.
In contaminated, dirty and/or infected classes of wounds the risk
of wound infection is even higher. Elective skin surgery should
be postponed if possible until the wound infection is treated with
therapeutic antibiotics.

P I T FA L L S A N D M Y T H S

– Before surgery procedure, detect an already infected tumor
and in particular do no forget to scratch the scabs that often
cover ulcerated carcinomas (Fig. 23.1). In this case surgery
should be delayed and wound infection should be treated
with antibiotics.
– In the nasal area take special care because of the high incidence
of infection.
– Remember that bleeding needs to be controlled in order to
prevent infection because of the strong association between
hemorrhagic and infectious complications.

Infections in Skin Surgery — 307

– Standard precautions have to be applied and no touch technique should be used.
– Do not believe that nonsterile gloves are sufficient to perform
all procedures. For reconstruction, use systematically sterilized gloves because they are protective against infection
occurrence.
– Systematic antibiotic prophylaxis is not necessary because no
significant advantage has been reported for the prevention
of SSIs.

CONCLUSION

The incidence of infection in skin surgery is low in the vast
majority of dermatologic surgery cases. Major determinants
of infection are the type of procedure, location, bleeding and
intrinsic factors related to the patient. Good operative techniques, including meticulous hemostasis, can reduce the risk of
SSIs. Nevertheless, excisions followed by a reconstructive procedure or performed on some anatomical sites such as the nose
may require more strict infection control protocols. Further
studies are needed to establish optimal guidelines for these kinds
of surgery.

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24

VENEREAL DISEASES
Travis Vandergriff, Mandy Harting, and Ted Rosen

INTRODUCTION

Because many of the most common sexually transmitted diseases
(STDs) present with prominent and characteristic skin lesions,
dermatologists have historically played a key role in their diagnosis and treatment. Dermatologists continue to contribute in
both diagnostic and therapeutic endeavors, often working closely
with gynecologists, urologists, infectious disease specialists, and
family physicians, and others. Despite improved public awareness and continued diagnostic and therapeutic advances, STDs
remain a major source of morbidity and mortality throughout
the world. The urgency with which the health-care profession
addresses STDs will intensify along with a better understanding of the full impact they have on public health. It has recently
become apparent, for example, that the genital ulcers associated
with many of the common STDs facilitate the transmission of
the human immunodeficiency virus (HIV) and that some STDs
(notably herpes progenitalis) may adversely affect the course of
HIV infection. Moreover, recent Centers for Disease Control and
Prevention (CDC) estimates place the direct health-care costs
for STDs at well over $13 billion annually in the United States
alone (http://www.cdc.gov/std/stats04/trends2004.htm, accessed
May, 2007). The long- and short-term physical and mental health
consequences of STDs are indeed extensive, and it is critical that
health-care providers remain apprised of current trends in epidemiology, diagnosis, and management of these diseases. The present chapter focuses on the cutaneous manifestations and current
diagnostic and therapeutic recommendations for STDs including syphilis, chancroid, lymphogranuloma venereum, granuloma inguinale, gonorrhea, and genital bite wounds. Scabies,
pubic lice, genital herpes, and anogenital warts are covered in
more detail elsewhere in this book. However, as the latter are
commonly transmitted through sexual contact, these disorders
will be briefly summarized herein as well.

H I STORY

The origin of syphilis is controversial, but current evidence
seems to support the so-called “Columbian theory,” which holds
that the disease originated in the New World and was imported
to Europe by Spanish soldiers returning from exploratory voyages led by Christopher Columbus in the late 15th century. Bony
changes characteristic of syphilis, including tibial remodeling
and gummatous destruction, have been identified by anthropologists in North and South American skeletal remains dating back
more than 8000 years, but no such changes have been identified
in skeletons from pre-Columbian Europe. A major epidemic

of syphilis swept across Europe in the late 15th and early 16th
centuries, and the disease became known as the “great pox” to
distinguish it from smallpox. The disease was a source of public
embarrassment, and the British and Germans began calling it
morbus gallicus, or the “French disease.” The Russians labeled the
disease “Polish sickness” while the Poles impugned the Germans
with the term “German sickness,” and the Japanese knew the disease by the name of “Chinese ulcer.” The disease was later called
lues venerea, or “venereal pest,” but the disease’s most well-known
name originated from an epic poem written in 1530 by Girolamo
Fracastoro, an Italian physician and poet. In his “Syphilis sive
morbus gallicus” (translated: Syphilis, or the French disease),
Fracastoro relates the tale of Syphilis, a shepherd afflicted with
the first case of the disease as a punishment for offending the god
Apollo. Controversy surrounding the disease again resurfaced
in Alabama in 1972 as the infamous Tuskegee Syphilis Study
was exposed. This study, in which African-American men with
syphilis were intentionally denied treatment so that the natural
history of the disease could be studied, ran from 1932 to 1972
and marks a gloomy chapter in the history of modern medicine.
The study ultimately led to the development of informed consent
protocol and patient rights advocacy.
Chancroid was recognized as a clinical entity distinct from
syphilis in the mid 19th century. The term “chancre” was already
used popularly to describe the ulcer caused by primary syphilis,
and in the 1850s the term “soft chancre” was applied to the ulcer
of chancroid. This designation stems from an important distinction: while the syphilitic chancre has an indurated, almost cartilaginous peripheral consistency, the ulcer of chancroid is soft
and fleshy. Through the years, the ulcer was also known as ulcus
molle (soft ulcer) and chancre mou (soft chancre). In 1889, the
causative bacillus was identified by Augusto Ducrey, an Italian
dermatologist who made the discovery after a series of experimental autoinoculations with ulcer material gathered from
patients. Clinical descriptions of lymphogranuloma venereum
(LGV) date back to the early 19th century, but it was in 1913
that the disease was recognized and described as a unique entity
by the French dermatologists Joseph Durand, Maurice Nicolas,
and Joseph Favre. In 1925, the German dermatologist Wilhelm
Frei developed the Frei test for LGV by intradermally injecting
antigens prepared from causative Chlamydia species cultured in
chick embryos. Because the test lacks specificity it is no longer
used today, but Frei’s name continues to be linked to LGV. The
disease has also been known as tropical bubo, climatic bubo,
Frei’s disease, and Durand-Nicolas-Favre disease.
Kenneth McLeod, a Scottish professor of surgery, first
described granuloma inguinale as “serpiginous ulcer” while seeing patients in Madras in 1882. In 1905, the Irish physician Charles
309

310 — Travis Vandergriff, Mandy Harting, and Ted Rosen

Donovan described the presence of intracellular microorganisms
in ulcer debris. Visualization of these so-called “Donovan bodies” still constitutes an important aspect of diagnosis today. In
honor of Dr. Donovan, the disease was designated donovanosis in 1950, and is today known as both donovanosis and GI.
Gonorrhea, recognized since ancient times, was named by the
Greek physician Galen in the second century. He created the
term gonorrhea, literally meaning “flow of seed,” after mistakenly
identifying the purulent urethral discharge commonly associated with the disease as involuntary flow of semen. For centuries, physicians believed gonorrhea and syphilis to be the same
disease. In 1530, Paracelsus declared gonorrhea to be an early
stage of syphilis, and it was not until the late 19th century that
the two diseases were clinically distinguished. In 1879, Albert
Neisser first identified the gonococcus after examining the purulent urethral exudates of patients with gonorrhea. The bacterium
was later determined to be the causative agent of the disease.
Scabies has been described by physicians for more than 2500
years and has been referred to in the biblical Old Testament and
the writings of Aristotle and Galen. In 1687, the Italian physician Giovan Cosimo Bonomo, in collaboration with a colleague
Diacinto Cestoni, isolated the mite from a patient with widespread pruritic papules, identified the mite as the cause of the
disease, and published illustrations of the ectoparasite. This significant discovery marked the first microorganism specifically
linked to an infectious disease.

Syphilis
A founder of modern medicine, Sir William Osler once stated
that “syphilis simulates every other disease. It is the only disease necessary to know.” Indeed, the protean manifestations of
syphilis have puzzled physicians for centuries and have earned
the disease its designation as “the great imitator.” Syphilis continues to be the subject of contemporary research, and our current
understanding of the disease stems from an interesting and welldocumented history.
Epidemiology
Syphilis continues to be one of the world’s most common STDs
with a worldwide incidence in excess of 12 million cases yearly.
The disease is most prevalent in developing countries, where up
to 10% of the population has been infected. In the United States,
syphilis is historically most common in the South and among
young, sexually active African-Americans. Reported cases of
syphilis in the United States declined through the 1990s to reach
an all-time low in 2000. Since that time, however, the number of
reported cases of syphilis has been steadily rising by more than
10% per year and currently stands at an estimated 3 cases per
100,000 population. The recent resurgence of syphilis can be
almost completely attributed to cases in men. Since 2000, the
incidence of syphilis in men has risen by more than 70%, and the
vast majority of these cases occur in men who have sex with men
(MSM). Similar alarming trends have been observed in Europe
and in Canada. In the United Kingdom, for example, the number
of reported cases since 2000 has risen three-fold in women and
25-fold in MSM. One theory suggests that the recent dramatic
increase in syphilis among MSM is due to an increase in risky
sexual behavior as patients have become less fearful of HIV with

the advent of highly active antiretroviral therapy (HAART). The
current epidemic of syphilis among MSM now appears to be the
dominant obstacle to overcome if syphilis is ever to be eliminated
as a major public health concern.
Clinical presentation and diagnosis
Syphilis is caused by the spirochete Treponema pallidum and is
transmitted through direct sexual contact, as well as transplacentally. Although the clinical manifestations of syphilis have
traditionally been divided into three distinct stages, these stages
may have significant overlap and serve mostly to simplify our
understanding of the disease and classify its presenting signs and
symptoms.
The first stage, called primary syphilis, is characterized by the
chancre, a lesion that develops at the site of inoculation 14 to 21
days after exposure. The chancre begins as a red, painless papule 0.5 to 2 cm in diameter and eventually ulcerates, creating a
clean base with indurated, rolled borders and a characteristic
“punched-out” appearance (Fig. 24.1). The remarkably painless ulcer may have a slight yellow or gray exudate and may be
accompanied by moderate bilateral inguinal adenopathy. When
the chancre appears on the penis or scrotum in men or on the
vulva or at the vaginal introitus in women, the ulcer is usually
readily apparent, and the diagnosis may be made in the primary
stage. However, when occurring in the vaginal canal, rectum, or
oropharynx, it may go unnoticed by the patient. Occult chancres
are common in women and MSM, and in such cases the diagnosis
is not typically made until later stages. Regardless of its location,
the chancre may last from 3 to 6 weeks and resolves spontaneously without treatment. In untreated patients, the treponemes
proliferate and migrate through the lymphatic channels to the
bloodstream where they are disseminated throughout the body.
Metastatic accumulations of treponemes create the lesions characteristic of the second stage of syphilis.
Secondary syphilis is characterized by many different signs
and symptoms, some of which are fairly generic and some of
which are quite distinct. It is the litany of possible manifestations
of secondary syphilis that have earned the disease its designation
as “the great imitator.” Because the lesions of secondary syphilis
appear 4 to 10 weeks after the development of the primary chancre,

Figure 24.1. Solitary, indurated, “punched-out” erosion (chancre).

Venereal Diseases — 311

Figure 24.2 . Asymptomatic palmar macules (secondary syphilis).

Figure 24.3 . Oral erosion (mucous patch) of secondary syphilis.

there is some potential for overlap between the two stages. In
the modern era, patients who have a persistent chancre during
clinically obvious secondary syphilis should be highly suspect of
being HIV co-infected. More than 90% of patients with secondary
syphilis have skin or mucous membrane involvement. Typically,
patients first develop a transient macular erythema on the trunk,
which spreads to the shoulders and extremities, sparing the face,
palms, and soles. Patients later develop a papulosquamous eruption with a characteristic copper hue. The typically asymptomatic eruption classically involves the palms and soles and may
also manifest as shallow erosions on oral mucous membranes.
This creates the so-called “mucous patches” (Figs. 24.2 and 24.3).
When the eruption involves the scalp, a non-cicatricial, patchy
or “moth-eaten” alopecia results. Another characteristic lesion of
secondary syphilis is condyloma latum, a smooth, moist, whitegray flat papule occurring in aggregates in intertriginous areas.
Condyloma lata often have eroded surfaces oozing a spirocheterich drainage, making them the most infectious of all lesions of
secondary syphilis. Additionally, patients often have generalized
symptoms associated with secondary syphilis and may present

with diffuse lymphadenopathy, low-grade fever, malaise, fatigue,
myalgias, arthralgias, and weight loss. The signs and symptoms
of secondary syphilis also eventually resolve without treatment.
Untreated patients enter a stage of latency in which treponemes
continue to proliferate while the patient remains asymptomatic.
From the latent state, one-third of untreated patients will
ultimately go on to develop late sequelae or tertiary syphilis. This
stage begins 3 to 15 years after the initial infection, and complications are responsible for most of the mortality associated with
syphilis. Cardiovascular complications include stenosis of the
coronary artery, ostia, and aortic root aneurysm, leading to aortic insufficiency. The nervous system is commonly involved in
tertiary syphilis, and patients may present with seizures, blindness, altered mental status, focal neurologic deficits, tabes dorsalis, dementia, or psychosis. Persons co-infected with HIV are
at increased risk of developing tertiary neurosyphilis. Another
characteristic lesion of tertiary syphilis is the gumma, a necrotic
granulomatous ulcer with indurated dusky-red serpiginous borders. Gummas occur in hard and soft tissues including skin,
cartilage, bone, and brain, and they are often locally destructive.
In its primary stage, syphilis must be distinguished from
other causes of genital ulcers, including chancroid, genital herpes, lymphogranuloma venereum, granuloma inguinale, neoplasms, fixed drug eruptions, bullous diseases, and Behçet’s
disease. A definitive diagnosis of syphilis can be made in the primary stage by identifying treponemes on dark-field microscopy
of the ulcer exudate. When performed properly, this technique
has very few false-negative results and no false-positive results.
Alternatively, the exudate may be tested with direct fluorescent
antibody (DFA) assays. Serologic tests may also be used in primary syphilis, but results must be interpreted cautiously. The
nontreponemal tests include the rapid plasma reagin (RPR) and
the venereal disease research laboratory (VDRL) test, both of
which measure antibody to cardiolipin and both of which are
equally valid. The treponemal tests, including the fluorescent
treponemal antibody absorption test (FTA-ABS) and the microhemagglutination assay for Treponema pallidum antibodies
(MHA-TP), measure antibodies to specific treponemal proteins.
Within 1 week of chancre development, the nontreponemal tests
are positive in approximately 85% of patients with primary syphilis but usually yield titers lower than 1:16. Additionally, falsepositive results are possible in cases of autoimmune disease,
collagen vascular disease, HIV, tuberculosis, pregnancy, rickettsial infection, and bacterial endocarditis. The treponemal tests
are positive in 90% of patients with primary syphilis. However,
the majority of patients with reactive treponemal assays will continue to have reactive assays for life unless the disease is treated
early in the primary stage. Therefore, the specific treponemal
assays are of limited use in making a diagnosis of infection, but
a negative result may exclude the diagnosis or confirm a falsepositive result on nontreponemal tests.
The cutaneous findings of secondary syphilis must be distinguished from primary HIV infection, pityriasis rosea, erythema
multiforme, lichen planus, drug eruptions, scabies, and psoriasis
among many other diagnoses. In the second stage, serologic tests
become more reliable with both treponemal and nontreponemal
assays, virtually always yielding positive results. Nontreponemal
assays are positive in high titers and often exceed 1:64. A fourfold increase in titer presumptively diagnoses active infection.
Additionally, dark-field microscopy may identify spirochetes in

312 — Travis Vandergriff, Mandy Harting, and Ted Rosen

the exudates from lesions of secondary syphilis. Although it is
not necessary for diagnosis, histopathologic evaluation of biopsied tissue reveals a polymorphous cellular infiltrate typically
rich in plasma cells, macrophages, and lymphocytes. A positive
result on VDRL testing of cerebrospinal fluid is highly specific
for tertiary neurosyphilis.
Treatment
As with other STDs, practitioners should review current recommendations from the Centers for Disease Control and Prevention
(CDC) when treating patients with syphilis. Parenterally administered penicillin G remains the preferred drug for treating syphilis in all stages. For adults with primary or secondary syphilis, a
single intramuscular (IM) dose of 2.4 million units of benzathine
penicillin G is the recommended treatment and has been used
for more than 50 years to achieve clinical resolution. Children
with acquired primary or secondary syphilis should be evaluated for sexual abuse and treated with benzathine penicillin G
in a single IM dose of 50,000 units/kg, up to the adult dose of
2.4 million units. Pregnant women with syphilis should be treated
with the adult dose of benzathine penicillin G, and pregnant
patients allergic to penicillin should be desensitized and treated
with penicillin. Non-pregnant patients with penicillin allergy
may be treated with doxycycline (100 mg orally twice daily for
14 days) or tetracycline (500 mg orally four times daily for 14
days). Although azithromycin administered in a single oral dose
of 2 g may be effective, treatment failure has been reported and
justifies caution when using this drug. Similarly, single-dose ceftriaxone remains an unproven alternative to single-dose penicillin for syphilis management.
In the absence of active lesions, as occurs in the latent stage,
patients are not contagious to sexual contacts. Therefore, treatment of latent syphilis does not reduce transmission of syphilis
to others but benefits the patient by preventing late sequelae.
The treatment of latent syphilis may require a different dosing
protocol. Patients with latent syphilis who acquired the infection within the past year are considered to have “early latent
syphilis” and should be treated with 2.4 million units of benzathine penicillin G in a single IM dose. Patients with latent
syphilis of greater than 1 year duration or of unknown duration
should be treated with a total of 7.2 million units of benzathine
penicillin G, administered in 3 IM doses of 2.4 million units
separated by 1 week intervals. All patients with tertiary syphilis should be treated with this same regimen. Pregnant patients
with penicillin allergy and latent syphilis should be desensitized and treated with penicillin. Non-pregnant patients with
penicillin allergy and early latent syphilis should be treated
with the alternative regimens appropriate for primary and
secondary syphilis, while patients with late latent syphilis
should receive either doxycycline (100 mg orally twice daily
for 28 days) or tetracycline (500 mg orally four times daily for
28 days).
All patients should be warned about a possible JarischHerxheimer reaction, an acute febrile reaction occurring within
12 hours of initial treatment. Antipyretic treatment has not been
shown to prevent this reaction. Sex partners of patients diagnosed
with syphilis should be clinically and serologically evaluated for
syphilis and appropriately treated if necessary. Furthermore, persons who have been exposed within the last 90 days preceding

the diagnosis of syphilis in a sex partner may have false-negative
seroreactivity and should be treated for a presumptive diagnosis
of syphilis. Because of the high risk of co-infection, patients diagnosed with syphilis should always be evaluated for other STDs,
including HIV. Treatment failure may occur with any regimen,
and patients should be clinically and serologically reexamined
6 and 12 months after initial treatment. Patients with persistent
clinical signs or symptoms or a sustained four-fold increase in
nontreponemal titers should be retreated and reevaluated for
HIV infection.

Chancroid
In addition to syphilis, chancroid is a major cause of genital ulcer
disease worldwide. While the two diseases share some common
features, important differences exist in their epidemiology, clinical presentation, diagnosis, and treatment.
Epidemiology
Because of global irregularities in diagnostic accuracy and
reporting practices, the exact incidence of chancroid is unknown.
However, some experts suspect that its worldwide incidence may
surpass that of syphilis. Chancroid constitutes a major proportion of genital ulcer disease worldwide, especially in areas of
chronic endemicity. In parts of sub-Saharan Africa, chancroid
is the most common cause of genital ulcer disease, and in India
more than half of all genital ulcers are caused by chancroid. Other
endemic locales include the Caribbean basin and southern Asia.
In the United States and other developed countries, chancroid
occurs in discrete and sporadic outbreaks in restricted geographic areas. In the United States, most reported cases occur in
New York, South Carolina, and Texas, and the number of cases
has been steadily declining from nearly 5,000 in 1987 to just
143 in 1999. Most recent CDC statistics suggest that chancroid
is becoming exceedingly rare in the United States. Many of the
prior outbreaks affected mostly African-American and Hispanic
heterosexuals with a male to female ratio ranging from 3:1 to
25:1. Commercial sex workers appear to be important vectors
of transmission, and outbreaks have also been associated with
crack cocaine use.
Clinical presentation and diagnosis
Chancroid is caused by Haemophilus ducreyi, a gram-negative
facultative anaerobic coccobacillus. The bacterium enters the
skin through epidermal microabrasions created during intercourse. Four to 7 days later, a tender erythematous papule or
pustule develops at the site of inoculation, although this incubation period may be longer in patients with concomitant HIV
infection. Within days, the papule or pustule erodes and forms a
deep, painful ulceration with central necrosis. The ulcer is characteristically tender, soft, and friable with ragged undermined
margins. There is often a foul-smelling yellow or gray exudate
and surrounding erythema. The ulcer occurs in men most commonly on the prepuce and shaft of the penis, while ulcers in
women tend to occur on the labia and fourchette. Extragenital
chancroid is rare. One-half of patients go on to develop painful
unilateral or bilateral inguinal lymphadenopathy within one to
two weeks (Fig. 24.4). Affected lymph nodes may become matted
or fluctuant, eventually rupturing and forming suppurative sinus

Venereal Diseases — 313

Figure 24.4 . Several painful ulcerations and marked adenopathy
of chancroid.

Figure 24.5. Ruptured inguinal lymph nodes of late chancroid.

tracts (Fig. 24.5). Because of the propensity of chancroidal ulcers
to autoinoculate adjacent skin, multiple opposing ulcerations or
“kissing lesions” are not uncommon. Untreated infections typically resolve spontaneously within 3 months, but potential complications include phimosis, local tissue destruction, and fistulae
formation.
Less common clinical presentations of chancroid have also
been described. In transient chancroid, the ulcer resolves in 4 to
6 days and suppurative inguinal adenopathy develops weeks
later. Follicular chancroid is characterized by ulcerations of the
pilar apparatus in hair-bearing areas. In giant chancroid, multiple
small ulcerations coalesce to form a single ulcer with the potential for severe local destruction of tissue. Finally, phagedenic
chancroid results in widespread necrosis and soft tissue destruction of the genitals and perineum.
Laboratory techniques for the diagnosis of chancroid are
imperfect and not uniformly available. Gram’s stain of the ulcer
debris may show the classic “school of fish” pattern of pleomorphic gram-negative coccobacilli in parallel chains or clusters.
A definitive diagnosis requires the isolation of H. ducreyi on

gonococcal culture media with high humidity and low oxygen
tension. However, even in experienced laboratories the sensitivity of this technique is less than 80%. Nucleic acid amplification
tests developed for research laboratories are the most sensitive
and specific diagnostic assays but are not commercially available for routine diagnosis. Because of the suboptimal diagnostic
modalities available to physicians, the diagnosis of chancroid is,
in practice, largely clinical. According to CDC recommendations,
a likely diagnosis of chancroid can be made if all of the following
criteria are met: (a) the patient has one or more painful genital
ulcers; (b) the patient has no evidence of T. pallidum infection
by dark-field examination of ulcer exudate or by a serologic test
for syphilis performed at least 7 days after onset of ulcers; (c) the
clinical presentation, appearance of genital ulcers and, if present,
regional lymphadenopathy are typical for chancroid; and (d) a
test (viral culture-PCR) for HSV performed on the ulcer exudate
is negative.
Treatment
Current recommendations made by the CDC direct physicians
to treat patients with chancroid with one of the following medications: azithromycin (1 g orally in a single dose), ceftriaxone
(a single 250 mg IM dose), ciprofloxacin (500 mg orally twice
daily for 3 days), or erythromycin (500 mg orally three times daily
for 7 days). Both azithromycin and ceftriaxone offer the benefit of
single-dose therapy, eliminating potential problems of medication
noncompliance.
Patients diagnosed with chancroid should be tested for other
STDs, including syphilis and HIV. In the United States, up to
10% of patients with chancroid also have concomitant syphilis.
Patients should also be clinically reexamined 3 to 7 days after
beginning treatment. Failure to observe objective improvement
in the ulcer within 1 week of appropriate therapy suggests unsuccessful treatment. In these cases the treating physician must
consider whether the diagnosis of chancroid is correct, or if the
patient has another, confounding concomitant STD including
HIV, or if the specific H. ducreyi isolate is resistant to the chosen medication. Suppurative lymph nodes heal more slowly than
primary ulcers and usually require needle aspiration or surgical
drainage to allow for complete resolution.

Lymphogranuloma venereum
Included in the differential diagnosis of genital ulcer disease is
lymphogranuloma venereum (LGV), a disease that has recently
received considerable and renewed attention in the literature due
to its reappearance in developed countries around the world.
Epidemiology
Lymphogranuloma venereum (LGV) is caused by Chlamydia
trachomatis serovars L1, L2, or L3 and has classically been a
disease of tropical and subtropical climates. Areas of endemicity include India, Southeast Asia, South America, sub-Saharan
Africa, and the Caribbean basin. Even in these areas, LGV is
a relatively uncommon cause of genital ulcers, accounting for
less than 10% of cases. In 2003, the first cases of LGV in Europe
were documented in the Netherlands. Since then, outbreaks
have been reported in Belgium, Germany, France, the United
Kingdom, Sweden, and the United States, with virtually all cases

314 — Travis Vandergriff, Mandy Harting, and Ted Rosen

occurring in MSM and presenting as proctitis rather than as genital ulcers. In 2004, 27 cases of LGV were reported to the CDC.
Gene amplification techniques have identified the L2b strain of
C. trachomatis as the common variant in recent outbreaks in
industrialized countries. Additionally, these techniques have
also determined that the L2b strain has been present in the
United States since 1981. LGV has been underdiagnosed in the
United States in past decades, and recent cases probably represent the discovery of a slow but ongoing epidemic rather than
a new outbreak.
Clinical presentation and diagnosis
LGV classically presents in three stages. First, after an incubation period of 3 to 30 days, a small painless papule or herpetiform ulcer develops at the site of inoculation. The primary ulcer
resolves without treatment after 2 to 6 weeks and most often
goes unnoticed by the patient. The second stage of the disease
is known as the inguinal syndrome, and it is at this stage that
most patients present for medical evaluation. LGV is predominantly a disease of the lymphatic tissue, and in the second stage,
the nodes draining the site of inoculation enlarge and develop
necrotic abscesses (Fig. 24.6). Painful, enlarged regional lymph
nodes may develop into fluctuant buboes, which ultimately rupture in one-third of patients. In men, adenopathy often involves
the inguinal and femoral nodes. Prominent unilateral or bilateral
inflammation of these nodes around the inguinal ligament create
the so-called “groove sign,” a finding considered to be pathognomonic for LGV. In women, however, only 20% to 30% of
patients develop inguinal adenopathy. More commonly, the deep
iliac and perirectal nodes are involved as they drain the vaginal
canal, cervix, rectum, and urethra. Systemic symptoms including fever, malaise, and arthralgia may be present in the second
stage. Rare systemic complications have also been reported
during the second stage and include pneumonitis, hepatitis,
aseptic meningitis, and ocular inflammatory disease. The third
stage is known as the genitoanorectal stage and tends to affect
mostly women and MSM. The continued presence of bacteria
in regional lymphatic channels leads to chronic inflammation,
resulting in lymphedema, ulceration, scarring, strictures, and

fistulae formation. Patients develop proctocolitis, perirectal
abscesses, and lymphorroids. They may present with complaints
of purulent or mucoid anal discharge, rectal bleeding, constipation, or tenesmus. Genital elephantiasis also occurs and is known
as “esthiomene” in women and as “saxophone penis” in men.
Nearly all cases of LGV recently diagnosed in Europe and the
United States have presented in the second and third stages with
signs and symptoms of proctocolitis rather than genital ulcers or
inguinal lymphadenopathy.
The diagnosis of LGV is based primarily on clinical findings,
nonspecific laboratory techniques, and the exclusion of other
diagnoses. The U.S. Food and Drug Administration (FDA) has
approved the use of nucleic acid amplification tests for genital
and lymph node specimens. These tests are nonspecific chlamydial assays and are not currently approved for use on rectal specimens. The CDC has recently announced that clinicians with
patients whose symptoms are suggestive of LGV may send rectal
swabs to CDC laboratories to be tested with LGV-specific genotyping techniques that are not commercially available. In the
absence of specific testing, the CDC recommends that patients
with likely LGV based on clinical findings be treated for this
presumptive diagnosis.
Treatment
Doxycycline is the preferred treatment of LGV and should
be orally administered at a dose of 100 mg twice daily for
21 days. Alternatively, patients may receive erythromycin
500 mg orally four times daily for 21 days. Pregnant and lactating women should receive erythromycin rather than doxycycline. Although treatment cures infection, tissue scarring due
to chronic inflammation may not be reversible. Furthermore,
buboes may require needle aspiration or surgical drainage to
achieve resolution. Patients diagnosed with LGV should be
evaluated for other STDs including HIV. In one series, 84% of
patients with LGV in the United States had concomitant HIV
infection.

Granuloma inguinale
Like LGV, granuloma inguinale (GI) is a cause of genital ulcer
disease, which infrequently occurs outside of endemic areas.
Nonetheless, cases are reported in industrialized countries, and
clinicians should be aware of this diagnosis when differentiating
genital ulcers.
Epidemiology

Figure 24.6. Painful, bilateral adenopathy without an erosive
lesion (LGV).

The causative agent of GI is the intracellular gram-negative rod
Klebsiella granulomatis (formerly known as Donovania granulomatis and Calymmatobacterium granulomatis). The disease is
endemic in India, Southeast Asia, South Africa, the Caribbean
basin, Brazil, Papua New Guinea, and aboriginal Australia. The
largest epidemic occurred in an area of Papua New Guinea from
1922 to 1952, where 10,000 cases were documented among a
population of 15,000 people. Aggressive public health campaigns have dramatically reduced the incidence of GI in northern Australia. Less than ten cases are reported annually in the
United States, and most of these are related to international
travel. Men are infected two to six times more often than women,
and infection rates peak in the third decade of life.

Venereal Diseases — 315

safety pin–shaped rods located within mononuclear cells and
are the actual infecting bacteria engulfed by macrophages and
monocytes.
Treatment

Figure 24.7. Friable deep ulcer typifies donovanosis.

Few studies have been conducted to determine optimal treatment for GI, but the traditionally preferred treatment is with
doxycycline (100 mg orally twice daily for at least 3 weeks or
until lesions have healed). However, there is now a relatively high
risk of therapeutic failure when utilizing tetracycline derivatives
in the management of GI, especially in cases encountered in
North America. Alternative medications include trimethoprim–
sulfamethoxazole (one 160 mg/800 mg tablet orally twice daily
for at least 3 weeks), ciprofloxacin (750 mg orally twice daily for
at least 3 weeks), erythromycin (500 mg orally four times daily
for at least 3 weeks), or azithromycin (1 g orally once weekly for
at least 3 weeks). TMP-SMX is probably the best alternative drug
and may actually be the drug of choice for current American
cases. Treatment should continue for at least 3 weeks or until all
lesions have healed.

Clinical presentation and diagnosis
The exact incubation period of GI is unknown and may last
up to 1 year, but most patients develop clinical evidence of the
disease within 2 to 6 weeks of exposure to K. granulomatis.
Ulcerogranulomatous disease, the most common presentation,
begins as single or multiple subcutaneous nodules that develop
at the site of inoculation. These nodules enlarge and erode,
becoming painless ulcers with clean bases and sharply demarcated rolled margins. The ulcer bases are classically described
as “beefy red” and consist of friable granulation tissue, which
bleeds readily when touched (Fig. 24.7). Ulcers occur most commonly on the coronal sulcus in men and on the labia minora in
women. However, 6% of ulcers are extragenital and have been
reported to occur on the oropharynx, nose, neck, and chest. True
inguinal lymphadenopathy does not develop in the absence of
bacterial superinfection. Rather, subcutaneous edema and granulomas lead to inguinal enlargement in 10% of patients. These
pseudobuboes may ulcerate or form abscesses. Less common
clinical presentations of GI include hypertrophic or verrucous
ulcers, necrotic ulcers, and cicatricial GI, which is characterized
by extensive fibrosis and sclerosis. Constitutional symptoms are
not typically associated with GI, but severe local complications
have been reported and include genital elephantiasis, urethral
and vaginal stenosis, and autoamputation of the penis. Untreated
lesions have no tendency to resolve and can be quite destructive
as they progress. Additionally, squamous cell carcinoma develops in 0.25% of cases and involvement of the cervix can lead to
fatal hemorrhage during childbirth.
The differential diagnosis of GI includes other causes of
genital ulcers, such as syphilis, chancroid, LGV, genital herpes,
carcinoma, and amebiasis. K. granulomatis is difficult to isolate
on culture media. Therefore, routine clinical diagnosis of GI is
made by visualizing Donovan bodies in a crush preparation of
granulation tissue obtained from the ulcer base. The tissue is
obtained by scraping or punch biopsy. It is then stained with
Wright’s, Giemsa, Warthin-Starry, or other stains. These stains
reveal the fine cytological detail that is necessary for diagnosis.
Ultrathin tissue samples may be optimal for disclosing the characteristic Donovon bodies. Donovan bodies appear as bipolar

Gonorrhea
Gonorrhea remains an extremely common STD in the United
States and worldwide, and while most cases produce signs
and symptoms restricted to the urogenital tract, prominent
cutaneous manifestations may develop in local infection
sites (e.g., Bartholin’s or Skene’s glands) or when the infection
disseminates.
Epidemiology
Gonorrhea, caused by the gram-negative intracellular diplococcus Neisseria gonorrhoeae, is quite common, with an estimated
worldwide incidence of 60 million cases annually. In the United
States alone, more than 600,000 new cases occur each year. The
disease incidence peaked in the 1960s and 1970s and declined
steadily through the late 1990s. However, since 1997, the incidence has again been on the rise, with an increase of 7% from
1997 to 2001. The disease is especially prevalent in AfricanAmericans, Hispanic adolescents, prisoners, commercial sex
workers, MSM, and patients with HIV. In one study, 15% of
MSM presenting to an STD clinic had evidence of gonorrheal
infections, with the pharynx being the most common site.
Clinical presentation and diagnosis
After an incubation period of 1 day to 2 weeks, patients infected
with N. gonorrhoeae may develop signs and symptoms of inflammation at the site of primary inoculation. Common presenting
complaints include pharyngitis, urethritis, intense burning or
painful dysuria, profuse, purulent urethral discharge, and pelvic
pain. (Fig. 24.8) However, up to one-half of patients will have
completely asymptomatic infections. Occasionally, primary
cutaneous lesions develop. If the inoculation is from sexual contact, a genital pustule or tender furuncle may appear. In cases of
traumatic inoculation, abscesses or pustules may also occur. The
primary lesions of the skin are uncommon and tend to go unnoticed. The most prominent cutaneous manifestations occur when
the gonococcal infection disseminates widely. Disseminated

316 — Travis Vandergriff, Mandy Harting, and Ted Rosen

In symptomatic male patients, a Gram’s stain of the urethral
discharge is virtually always positive and diagnostic of gonorrhea.
However, Gram’s stains of oropharyngeal, rectal, or endocervical specimens lack the appropriate sensitivity and specificity for
diagnosis. In cases of DGI, blood cultures and specimens from
pustules rarely yield positive results. Culture or gene amplification techniques are recommended for diagnosis in these cases.
Therefore, the diagnosis of DGI should be made based on clinical findings and isolation of N. gonorrhoeae from the primary
site of infection. Culture of N. gonorrhoeae offers the additional
benefit of determining antimicrobial susceptibility and allowing
for appropriate therapy.
Treatment

Figure 24.8 . Profuse purulent gonococcal urethral discharge.

Figure 24.9. Distal hemorrhagic bulla (gonococcemia).

gonoccocal infection (DGI) develops in 1% to 3% of cases and
usually occurs in young healthy patients with asymptomatic genital, rectal, or oropharyngeal infection. Other risk factors for the
development of DGI include hereditary defects in the terminal
complement pathway and hypocomplementemia due to lupus
erythematosus.
Two distinct clinical presentations exist and may occur concomitantly in cases of DGI. The septic arthritis syndrome is
characterized by fever and inflammation of one or more joints
with pain, swelling, erythema, and decreased range of motion.
The tenosynovitis-arthritis-dermatitis syndrome occurs in 60%
of cases of DGI. Patients develop tenderness and erythema over
tendons and their bony insertion sites. Additionally, a migratory
arthralgia or arthritis involving appendicular joints occurs and
typically affects less than three joints. The characteristic skin
lesions of DGI begin as erythematous macules and progress to
form tender necrotic pustules or hemorrhagic bullae (Fig. 24.9).
The pustules usually occur on the dorsal aspect of distal extremities near the joints of the wrists, hands, and ankles. These pustules
result from bacterial embolization followed by microabscess formation. Typically, there is a paucity of lesions present.

Due to the ongoing development of drug resistance in strains of
N. gonorrhoeae, the CDC has made frequent updates to its recommendations for therapy of gonorrhea. Currently, only cephalosporins are recommended for first-line therapy of gonorrhea.
High levels of fluoroquinolone resistance have eliminated these
drugs from the treatment algorithm. Patients with uncomplicated infections of the urethra, rectum, or cervix may be treated
with ceftriaxone (125 mg IM in a single dose) or cefixime (400
mg orally in a single dose). Patients with cephalosporin allergy
should be treated with spectinomycin (2 g IM in a single dose).
The management of DGI requires more aggressive treatment.
Patients should be hospitalized and monitored for complications
such as bacterial endocarditis, meningitis, or perihepatitis. These
cases should be managed with parenteral antibiotics. The recommended regimen is with ceftriaxone (1 g IM or IV every 24 hours)
and alternatives include cefotaxime (1 g IV every 8 hours) and
ceftizoxime (1 g every 8 hours). Treatment with IV antibiotics
should continue for 24 to 48 hours after clinical improvement
begins, at which point the patient may be switched to cefotaxime
(400 mg orally twice daily) for a total of at least 1 week of antibiotic therapy. Cephalosporin allergic patients should receive
spectinomycin (2 g IM every 12 hours) for the same duration of
therapy. Patients diagnosed with gonorrhea should be evaluated
for other STDs including chlamydia, syphilis, and HIV.

Genital Bite Wounds
Without a doubt, genital bite wounds and resultant complications
are underreported and underdiagnosed. Patients with genital
bite wounds often seek medical care late in the course of disease,
if at all, and presentation is delayed because of patient embarrassment and attempts at self-treatment. The subject receives
very little attention in the medical literature, and consequently
clinicians have few resources for diagnostic or therapeutic
recommendations.
Traumatic orogenital contact occurs frequently and is not
restricted to any demographic group. The exact incidence of genital bite wounds is unknown, but it is estimated that more than
1% of emergency center visits are related to bite injuries. The
clinical presentation of a patient with a genital wound is dependent on the amount of time that has elapsed since the injury
and the severity of the injury. Patients may present with painful, superficially to deeply necrotic laceration or ulceration of the
external genitalia (Fig. 24.10). Although most genital wounds
are superficial, the loose subcutaneous tissue of the perineum

Venereal Diseases — 317

Figure 24.10 . Rapidly progressive, painful necrosis due to Eikenella
Corrodens.

facilitates the spread of microorganisms and creates the potential
for severe complications including rapidly advancing cellulitis,
balanoposthitis, Fournier’s gangrene, abscess formation, lymphangitis, and sepsis. The most important complication of genital bite wounds is the risk of infection with oropharyngeal flora.
Infections are nearly always polymicrobial and often involve
Eikenella corrodens and various oral anaerobes. Patients presenting later in the course of disease usually have some form of
advanced complication. Particularly, aggressive orogenital contact can also result in disfigurement and may ultimately lead to
sexual dysfunction, urethral strictures, and fistulae formation.
Additionally, transmission of diseases such as syphilis, viral hepatitis, tetanus, tuberculosis, and HIV has been reported to occur
through human bites.
Wounds should be cultured for both aerobic and anaerobic
bacteria. If a genital ulcer is present, additional assessment with
dark-field microscopy and viral culture is warranted. Genital
wounds should be cleansed by copious irrigation with a bactericidal and virucidal solution such as 1% povidone-iodine.
Because of the high risk of infection, genital bite wounds should
not be closed primarily. There are no standardized or evidencebased recommendations for treatment of genital bite wounds
in the medical literature. However, empiric antibiotic therapy
should cover for potential pathogens such as gram-positive
cocci and gram-negative rods, especially Eikenella corrodens. No
guidelines have been established, but successful treatment has
been reported with amoxicillin-clavulanic acid (500 mg/125 mg
twice daily for 14 days). Alternatives may include second generation cephalosporins (e.g. cefuroxime) or combination therapy
with dicloxacillin and penicillin. Antibiotic therapy should ultimately be adjusted according to antimicrobial sensitivity results
obtained from wound cultures whenever feasible.

Scabies
To this day, scabies maintains a worldwide distribution but is
most prevalent in areas of endemicity including India, South
Africa, Brazil, Central America, and aboriginal Australia. While
estimates place the global incidence at 300 million cases annually,

Figure 24.11. Pruritic nodules on glans typifies scabies.

or 5% of the world population, scabies may affect up to one-half
of the population in isolated areas of endemicity. The disease
is caused by the mite Sarcoptes scabiei var hominis, an obligate
human ectoparasite transmitted by direct skin-to-skin contact.
The prolonged and intimate contact that occurs during sexual
activity makes it an especially important mode of transmission
as dislodged mites use heat and odor as guides to find new hosts.
General risk factors for transmission include low socioeconomic
status, poor nutrition, and poor hygiene. Risk factors specific to
sexual transmission include multiple sexual partners and MSM.
The female mites lay eggs in the stratum granulosum, and the
hatched larvae later dig burrows while enzymatically digesting
the skin and consuming the debris for nutrition. A host hypersensitivity response to mite saliva, eggs, and feces leads to sensitization and ultimately pruritus, a clinical hallmark of scabies
infection. The pruritus classically worsens at night and spares the
head and neck in adults. Physical examination of the patient may
reveal erythematous papules or the pathognomonic scabietic
burrows, which prominently involve the interdigital spaces, the
flexural aspect of the wrists, the umbilicus, the glans and shaft
of the penis, and the nipple-areolar zone (Fig. 24.11). While the
common form of infection involves only 10 to 15 mites per host,
other clinical variants of scabies may involve many more mites.
Immunocompromised or malnourished patients are especially
susceptible to crusted or Norwegian scabies with more than one
million mites infecting the host. In this variant, heavily crusted
and often fissured pruritic patches are characteristic. Fissures
may predispose to eventual bacterial septicemia.
The diagnosis of scabies is unequivocal when the clinician
visualizes the mite, its eggs, or its feces. The so-called “scabies
preparation” is performed by coating a blade in mineral oil
and scraping a suspected burrow. The debris is transferred to a
slide and microscopically examined for evidence of mite infection. Alternatively, dermoscopy of burrows is equally as sensitive but less specific for identifying the presence of mites, eggs,
or feces. Patients diagnosed with scabies should be treated with
5% permethrin cream applied to the entire body from the neck
down and thoroughly washed after 8 to 14 hours. Alternatively,
patients may receive a dose of ivermectin (200 mcg/kg orally

318 — Travis Vandergriff, Mandy Harting, and Ted Rosen

once and repeated in two weeks). Although topical lindane may
also be used, the potential for neurotoxicity (even without abuse,
such as over-zealous application or ingestion) restricts its place
to second- or third-line therapy. There are no standard recommendations for treatment of crusted scabies, but some recommend combination therapy with a topical scabicide and oral
ivermectin. All patients with scabies should wash clothing and
bed sheets in hot water. Fumigation of the home environment is
not necessary.

Pubic Lice
Public lice, like the other ectoparasites, have infested human
hosts for millennia. Paleoarcheologists have discovered pubic
lice in mummified human remains dating back 2000 years in
both Europe and South America. Today the pubic louse has a
worldwide distribution and is most common in MSM, patients
aged 15 to 25, and in patients of lower socioeconomic status. The
pubic louse is almost always transmitted by sexual contact. There
is a 95% transmission rate when an individual has sexual contacts with an infected person.
Because pubic lice is not a reportable disease, the exact incidence of the disease is not known, but some estimates place
the number at 3 million cases (or 1% of the population) in the
United States annually. The pubic or crab louse, Pthirus pubis,
is a one mm ectoparasite visible to the naked eye. The louse
attaches to hair of the pubis and adjacent areas, including the
abdomen, buttocks, thigh, and perineum. (Fig. 24.12) The lice
are capable of migrating up to 10 cm daily, and are thus occasionally found in the hair of the chest and eyelashes. Rarely is
the face or scalp involved with infestation by the pubic louse.
Infested patients may be asymptomatic or complain of pruritus
or erythema. Physical examination reveals the lice and their nits
attached to coarse pubic hairs. The lice are usually abundant, and
the diagnosis of pediculosis pubis is made when the lice are visually identified. Additionally, maculae ceruleae, or blue-gray macules due to deep dermal hemosiderin, can be observed at sites
of louse bites. Rarely, patients develop pediculid, which is an id
reaction to pediculosis that resembles a viral exanthem.

Figure 24.12. Pubic louse attached to pubic hair.

The CDC recommends that patients with pubic lice be treated
with 1% permethrin cream applied to affected areas and rinsed
away after 10 minutes. Alternative treatment regimens include
0.5% malathion lotion applied to affected areas and washed away
after 8 to 12 hours. Patients preferring oral therapy can receive
ivermectin (250 mcg/kg orally once, repeated in 2 weeks).
Clinicians should remind patients using topical treatment to
apply the medication to all perineal areas as well as the pubis.
Pediculocides should not be applied near the eyes. Patients with
eyelash involvement should apply an occlusive eyelid ointment
or petroleum jelly to the eyelid margins twice daily for 10 days.
Alternatively, ophthalmologic pilocarpine preparations may
prove to be selectively neurotoxic to the lice while safe for use
around the human host’s eye. Finally, bed sheets and clothing
should be washed in hot water, but household fumigation is not
necessary.

Genital Herpes
Genital herpes is a chronic and life-long viral infection, which
has become the most prevalent cause of genital ulcer disease in
the United States and other developed countries. The disease is
caused by the herpes simplex virus (HSV), an enveloped double-stranded DNA virus. There are two variants of HSV, named
HSV-1 and HSV-2, and both are capable of causing genital herpes. Traditionally, HSV-1 is associated with labial herpes and
HSV-2 is associated with genital herpes infections. While historically most cases of genital herpes are due to HSV-2, HSV-1
is emerging as an important cause of genital herpes and now is
responsible for up to 30% of cases.
Genital herpes is one of the most common STDs, and
approximately less than 20% of Americans above the age of
12 nationwide are currently infected with HSV-2 based on
recent seroprevalence studies. In densely populated urban areas
and inner cities, the prevalence exceeds 50%. Risk factors for the
acquisition of genital herpes include multiple sex partners, lower
socioeconomic status, African-American or Hispanic ethnicity, and female gender. The virus is transmitted through direct
contact with an infected person. The most efficient transmission
occurs with symptomatic lesions shedding high viral loads, but
transmission can also occur in asymptomatic patients continually shedding the virus in smaller numbers. In fact, more than
70% of genital herpes infections are transmitted by patients
unaware of their own infection and resultant asymptomatic
shedding status.
After a postexposure incubation period of 2 days to 2 weeks,
primary genital herpes develops and is characterized by widespread vesicles on the genitalia accompanied by regional lymphadenopathy and dysuria. The vesicles resolve without treatment
and the virus migrates to the sensory nerve ganglia where it
remains for the lifetime of the patient. During times of dormancy, the patient is asymptomatic but continues to shed the
virus at unpredictable intervals. Reactivation of the virus leads
to overt recurrent outbreaks. The outbreaks tend to begin with
a 3- to 4-day prodrome of pruritus, pain, tingling, and burning. Small edematous grouped papules appear on the genitalia
and progress to thin-walled vesicles and ulcers. The vesicles and
ulcers form soft crusts, which eventually dry and heal over, and
the virus resumes a period of latency. Patients with HSV-1 infection average one recurrence annually, while patients with HSV-2

Venereal Diseases — 319

infection have four or more recurrences each year. Triggers for
viral reactivation include sunlight, emotional stress, extremes
of temperature, concurrent infections, menstruation, and skin
trauma (as in sexual contact).
The clinical diagnosis of genital herpes lacks sensitivity and
specificity, so specific laboratory analyses are required for the
diagnosis. Because the prognosis differs between HSV-1 and
HSV-2, the identification of the exact viral type responsible
for infection is an important aspect of diagnosis. Specimens
from genital ulcers may be cultured or tested with gene amplification assays to determine the presence of HSV-1 or HSV-2.
Additionally, type-specific serologic assays can be used to test for
antibodies to HSV-1 and HSV-2. Because HSV-2 is almost exclusively acquired through sexual contact, the presence of antibodies to HSV-2 is diagnostic of genital herpes. However, because
HSV-1 may cause either labial or genital herpes, the presence
of antibodies to HSV-1 should be interpreted more cautiously.
Current serologic assays demonstrate well in excess of 90% sensitivity and specificity. However, they may be subject to some
delay in seroconversion following initial contact. Currently,
there is no serological test that can determine when the disease
was acquired.
The first episode of genital herpes should be treated with
acyclovir (400 mg orally three times daily for 7 to 10 days, or
200 mg orally five times daily for 7 to 10 days), valacyclovir
(1 g orally twice daily for 7 to 10 days), or famciclovir (250 mg
orally three times daily for 7 to 10 days). In patients with frequent recurrences, suppressive therapy reduces outbreaks and
improves quality of life. These patients should be treated with
acyclovir (400 mg orally twice daily), valacyclovir (500 mg to 1 g
orally once daily), or famciclovir (250 mg orally twice daily). In
the past, patients with infrequent outbreaks may have preferred
episodic treatment; however, more recent data suggests that due
to asymptomatic shedding, chronic suppressive therapy may be
recommended to all infected patients to decrease transmission to
their susceptible sexual partners. In the only small head-to-head
comparison, valacyclovir outperformed famciclovir in terms of
efficiency of suppression.

Anogenital Warts
Anogenital warts, or condyloma accuminata, are caused by
the human papilloma virus (HPV). There are more than 100
serotypes of HPV, and 30 types are capable of infecting the
anogenital region. Genital HPV infection is very common,
and infections are usually self-limited and may be completely
asymptomatic. It is estimated that 75% of adults of reproductive age have been infected at least once with sexually transmitted HPV, and there are more than 5 million new infections
annually in the United States alone. Most infections go unnoticed by the patient and ultimately resolve without treatment.
In fact, only about 1% of adults have clinical evidence of anogenital warts.
HPV types 6 and 11 are the most common causes of anogenital warts, although many more types are capable of causing
condylomata. Other serotypes, most notably types 16, 18, 31, and
45 are associated with anogenital dysplasia and squamous cell
carcinoma. In fact, nearly all cervical neoplasia and anogenital
carcinomas are related to HPV infection. Anogenital warts are
not considered to have malignant potential, but HPV types 6 and

Figure 24.13. Large cauliflower-like, verrucous mass (venereal warts).

11 have been associated with the Buschke-Lowenstein tumor, a
slow-growing but locally destructive verrucous carcinoma.
Anogenital warts appear as fleshy verrucous papules, either
individual or coalesced into clusters. They may also have a filiform or pedunculated appearance, and confluent warts can form
large cauliflower-like lesions of the anogenital zone (Fig. 24.13).
Although the warts occur most often on the fourchette in women
and on the glans or subprepuce in men, they may appear anywhere where sexual contact has been made. The diagnosis of
condyloma is made by clinical inspection and identification of
the warts. Histopathological evaluation of biopsied lesions can
confirm the diagnosis, revealing papillomatosis and koilocytes.
Serologic testing is not recommended for use in the routine diagnosis of anogenital warts.
Untreated genital warts resolve because of cell-mediated
immunity in less than one-third of patients. Treatment is recommended to prevent an increase in the size and number of
warts and to reduce the likelihood of transmission to sex partners. Treatment options are many, and the chosen regimen
should be based on patient preferences and available resources.
For warts of the external genitalia, the CDC recommends the
use of 0.5% podofilox solution (Condylox) or imiquimod 5%
cream (Aldara). Condylox is applied twice daily to warts for 3
days, followed by 4 days of no therapy, with up to four cycles of
repetition as necessary. Aldara is applied once daily to warts for
3 weeks at a time, and up to 16 weeks total. Physicians can also
apply podophyllin 10% resin or trichloracetic acid 80% solution to the warts in the office setting. Alternatively, the clinician
may use cryotherapy, curettage, electrodessication, or excision
to destroy the warts. For warts of the vaginal canal, anus, or
urethral meatus, the CDC recommends destruction with liquid
nitrogen cryotherapy. Use of these options is discussed in detail
elsewhere in this text.

P I T FA L L S A N D M Y T H S

Syphilis
Because syphilis has been considered the prototypical STD for
centuries, public awareness is higher than with other STDs.

320 — Travis Vandergriff, Mandy Harting, and Ted Rosen

However, with increased public awareness comes a significant
amount of misinformation, and the advances in telecommunications and Internet technology have only facilitated dissemination
of this misinformation. Practitioners should anticipate some of
the common misconceptions their patients may hold regarding
syphilis. First, it is common for patients to believe that syphilis
has been eradicated. The recent global increases in incidence and
the surge of new cases in MSM disprove this belief. Additionally,
patients may assume that if they were infected with syphilis they
would be aware of the infection. While it is true that most chancres in heterosexual men occur on the penis or scrotum and are
readily apparent, women and MSM often have occult chancres
and present at later stages of the disease. Finally, patients may
believe that having syphilis once provides lasting immunity
against future infection. In fact, no immunity is developed after
infection by T. pallidum and patients are subject to future reinfection. The specific treponemal antibodies measured in the
FTA-ABS and MHA-TP assays provide no protective immunity.

Chancroid
Because of the dramatic decline in reported cases of chancroid
in the United States in recent years, both patients and physicians
may believe the disease to have been eliminated. However, sporadic outbreaks continue to occur, and the disease remains quite
common worldwide. Just as patients may believe that a prior case
of syphilis offers protective immunity to future infection, they
may also believe repeat infection with chancroid to be impossible. Neither natural nor experimental infection with chancroid
appears to protect against future infections. However, repeated
experimental inoculation in a swine model has led to a moderate
degree of humoral immunity and diminished severity of future
infections. While these results are not immediately applicable to
human patients, researchers hope to eventually develop a vaccine that may confer at least partial resistance to infection with
H. ducreyi. This is especially likely since a putative etiopathogenic factor has been recently characterized (cytolethal distending factor).

Lymphogranuloma Venereum
Because LGV is endemic to tropical climates and was heretofore underrecognized in the United States, both physicians and
patients may be unaware of LGV as a cause of genital ulcers and
proctocolitis. Physicians should consider LGV when differentiating possible causes of genital ulcers, lymphadenopathy, and
proctocolitis, especially in MSM and patients with HIV.

Granuloma Inguinale
Like LGV, GI is a very rare source of genital ulcers in the United
States. Many clinicians may not consider the diagnosis routinely.
However, with the ease of international travel, GI is certainly a
diagnostic possibility both in the United States and abroad.

Gonorrhea
The common symptoms of gonorrhea, including urethritis and
urethral discharge, are well known among the public. Some
patients may describe their symptoms as “the clap,” a slang term

referring to gonorrhea and originating from the Old French
clapoir (venereal sore) and clapier (brothel). However, the potentially fatal complications of DGI are not well known and the
disease may be underrecognized. Furthermore, patients with
DGI typically do not have symptoms of primary infections, so
physicians must complete comprehensive histories and physical
examinations in patients with widespread pustular and necrotic
eruptions or septic arthritis to ensure proper diagnosis and
management.

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25

L I F E  T H R E AT E N I N G S K I N I N F E C T I O N S :
S K I N S I G N S O F I M P O R TA N T B A C T E R I A L
INFECTIOUS DISEASES
Lisa A. Drage

An important group of bacterial infectious diseases are
life-threatening conditions that require immediate intervention and treatment. Appropriate diagnosis and management
of this group of severe bacterial infections can be expedited by
recognition of their distinctive cutaneous findings. The clinical
manifestations, diagnosis, and management of meningococcal
disease, Rocky Mountain spotted fever (RMSF), Staphylococcal
toxic shock syndrome, and Streptococcal toxic shock syndrome
will be highlighted herein with emphasis being placed on their
cutaneous signs.

H I STORY

Reports of illnesses resembling meningococcal disease date
back to the 1500s. The description reported by Vieusseux
in 1805 is considered the first identification of the disease,
and the causative organism was first isolated by Weichselbaum
in 1887. Today, meningococcal disease remains a feared
cause of significant morbidity and mortality throughout the
world.
Rocky Mountain spotted fever (RMSF) was first described
in Boise, Idaho, by Marshall Wood, an Army Physician in 1896.
More than 100 years have elapsed since Howard T. Ricketts first
identified the pathogen and demonstrated its transmission by
Montana ticks. Four years after his classic investigation, Ricketts
died at the age of 40 of epidemic typhus while investigating that
disease in Mexico City.
Toxic Shock Syndrome (TSS) was first described in 1978
by Todd and associates as a complication of infection by
Staphylococcus aureus. An early association was made between
TSS and concomitant tampon usage in menstruating women.
The sudden increase in TSS in the early 1980s was temporally
related to the introduction of these super absorbent tampons,
which were subsequently withdrawn from the market. A case
definition of Staphylococcal TSS was first published in 1982.
Severe invasive Group A Streptococcal infections reemerged
in the mid-1980s after a period of low streptococcal morbidity
and mortality in the mid-20th century. Prominent media coverage of the dramatic outbreaks of “flesh-eating bacteria” in the
1990s raised public awareness of the potential serious nature of
these infections.

** The author has no conflict of interest to disclose. There were no funding
sources for this work.

322

MENINGOCOCCAL DISEASE

Acute meningococcemia and meningococcal meningitis are
caused by Neisseria meningitidis, a distinctive encapsulated
gram-negative diplococcus. Ten percent to twenty percent of
healthy people are nasopharyngeal carriers of this organism and
the percentage of carriers increases in crowded conditions, such
as military settings or college dormitories. Most often, nasopharyngeal colonization imparts protective antibodies and immunity to the disease. Factors that increase colonization such as
crowding, viral upper respiratory infection, and active or passive
smoking are associated with an increased risk of transmission
of meningococcal disease. Meningococcal disease is not highly
contagious, and transmission is via direct contact with large
droplet respiratory secretions or saliva, so very close contact is
needed. The disease occurs most commonly in people who lack
protective antibodies and have newly acquired N. meningitidis.
Although the highest rate of meningococcal disease occurs during the late winter and spring months in patients younger than 5
years, more than half of cases occur in people aged 18 or older.
Students newly arrived to college who live in dormitories have a
moderately increased risk for meningococcal disease.
The mortality rate of meningococcal disease ranges from
10% to 14%. Substantial sequelae occur in 11% to 19% of survivors and include neurologic damage, hearing loss, and limb loss
associated with disseminated intravascular coagulation (purpura fulminans). Improved patient outcomes depend heavily on
early recognition and prompt use of appropriate antibiotics and
supportive measures. Recognition of the skin findings associated
with meningococcal disease can aid in early diagnosis.

Clinical Manifestations
Invasive meningococcal disease is infamous for its rapidly evolving, dramatic signs and symptoms; yet it begins with nonspecific findings of fever, headache, nausea, vomiting, and myalgias.
Altered consciousness, severe headache, and nuchal rigidity signal
meningitis. Children are often markedly lethargic. Skin lesions
are a common and early sign that offers an important clue to this
rapidly progressive disease. The majority of patients with meningococcemia present with a rash. Classically, the rash appears as
petechiae scattered over the trunk and extremities and quickly
evolves into purpura with distinctive gun metal gray centers and
geographic or angular borders (Fig. 25.1). However, the initial
skin findings may be macular, papular, or urticarial. A thorough
skin examination is important as some patients present with only
a few petechiae or purpura. Clusters of petechiae may occur at

Life-Threatening Skin Infections — 323

Figure 25.1. Meningococcemia. Widespread purpura with gun metal
grey centers and geographic borders.

sites of pressure such as the site of a blood pressure cuff or elastic
bands of the socks. Adults with meningococcal disease are less
likely than children to have the classic skin findings. Fulminant
meningococcal disease (Waterhouse-Friderichsen syndrome) can
be complicated by purpura fulminans – generalized ecchymoses
and hemorrhagic bullae that are cutaneous manifestations of disseminated intravascular coagulation. This dramatic scenario may
be accompanied by ischemia of the digits or limbs with resultant
necrosis or autoamputation and death.

Diagnosis
Meningococcal disease should be suspected in an acutely ill
patient, especially a child or young adult, presenting with a petechial eruption in the setting of fever, headache, and myalgias.
While the gold standard of diagnosis is Gram’s stain and culture of the blood or cerebrospinal fluid, microbiologic testing of
skin lesions can help with a definitive diagnosis. Gram’s stain of
smears from active skin lesions may demonstrate the characteristic gram-negative diplococcus in up to 70% of cases. Gram’s
stain and culture of a biopsy from an active skin lesion may be
positive for N. Meningitidis even after the blood and CSF fluid
have been rendered sterile by antibiotics. PCR techniques may
also be helpful in diagnosing the disease.

Management
Early treatment is the highest priority in any suspected case of
meningococcal disease. Appropriate antibiotic therapy should
not be forestalled while awaiting transfer or hospitalization of
a patient. Prehospital antibiotic treatment is advocated. Initial
empiric therapy is based on the most common bacteria causing
meningitis or sepsis based on the patient’s age, clinical setting, and
local patterns of antimicrobial susceptibility. After the results of
cultures and susceptibility testing are available, antimicrobial therapy should be modified for optimal treatment. Adjunctive dexamethasone therapy may be instituted in carefully selected patients
with meningitis. Aggressive supportive care and monitoring in an
intensive care setting is necessary with an emphasis on restoration
of circulation, correction of DIC, and prevention of hypoxia.
Chemoprophylaxis with rifampin (non-pregnant adults and
children) or ciprofloxacin (non-pregnant adults) or intramuscular ceftriaxone is offered to close contacts of documented cases
(household members, childcare contacts and hospital personnel

with secretion exposure). In the United States, most cases of
invasive meningococcal disease are caused by serogroups B, C,
and Y, each of which accounts for approximately one-third of
cases. While there is no current vaccine for serogroup B, a new
meningococcal conjugate vaccine A, C, Y, and W-135 (Menactra,
Sanofi Pasteur) is available and currently recommended for
children aged 11 to 12, teens entering high school, and college
freshman in dormitories. Vaccination is also recommended for
outbreak or epidemic settings, patients with a terminal complement pathway deficiency, patients with anatomic or functional
asplenia, travelers to hyperendemic areas (sub-Saharan Africa,
or Saudi Arabia), and military recruits.
Since catastrophic outbreaks occur in college, school, and
day-care settings, meningococcal infections can cause community panic. Prevention of meningococcal disease by vaccination
is the best control strategy. Institution of new vaccine recommendations may help to minimize the disease; however, there
is still no vaccine available to prevent the most common cause
of meningococcal disease in young children, serogroup B. This
situation makes prompt recognition and treatment of patients
with suspected meningococcal disease essential in preventing
mortality and associated morbidities.

R O C K Y M O U N TA I N S P O T T E D F E V E R

Rocky Mountain spotted fever (RMSF) is a tick-borne zoonoses
caused by Rickettsia rickettsii, an obligate intracellular coccobacillus. This organism is maintained in a natural cycle involving mammals and ixodid (hard-bodied) ticks. Transmission to
humans occurs through the bite of infected ticks. The most common tick vectors include Dermacentor variabilis (American dog
tick) in the eastern, central, and pacific coastal United States and
Dermacentor andersoni (Rocky Mountain wood tick) in the western United States. Other tick species such as Rhipicephalus sanguineus (Brown dog tick) and Amblyomma Cajennense (Cayenne
tick) cause RMSF in Arizona and Texas, respectively.
From an epidemiologic standpoint, the term Rocky Mountain
spotted fever is deceiving. While first described in the Bitter
Root valley of Montana, most cases are currently centered in the
south-eastern and south-central United States. More than half of
RMSF cases are from five states: North Carolina, South Carolina,
Tennessee, Oklahoma, and Arkansas. The disease, however, has
been reported in all states of the contiguous United States except
Vermont and Maine and due to modern travel patterns, the disease could be encountered in patents from any of the 50 states.
Rocky Mountain spotted fever is a seasonal disease reflecting the activity levels of the vectors, reservoirs, and humans that
increase exposure to the disease. Most cases occur during the spring
and summer months when ticks are most active and human–tick
contacts are most likely to occur. Ninety percent of cases occur
between April and September. Outdoor workers, recreationalists,
and young children are most frequently affected by RMSF. In the
past, young children were the most common victims, but recent
surveillance data has shown that adults aged 40 to 64 had the highest reported incidence of RMSF. Mortality rates range from 5% in
treated cases to 20% in untreated cases. Outcomes thus depend
heavily on prompt recognition of the disease and early initiation of
specific antibiotic therapy. The skin manifestations of RMSF may
be a helpful clue to making a life-saving diagnosis.

324 — Lisa A. Drage

Figure 25.2. Rocky Mountain Spotted Fever. Although the rash demonstrates centripetal spread, it may be generalized when first viewed.
(From Mayo Clinic Proceedings with permission)

Clinical manifestations
Fever, chills, malaise, myalgia, and severe headaches are the most
common initial features of Rocky Mountain spotted fever and
resemble the nonspecific findings of other infectious diseases.
Nausea, vomiting, and abdominal pain may be striking symptoms seen in a subset of patients with RMSF. Most patients visit
a physician during the first 2 to 4 days of the illness, before the
development of the petechial (spotted) rash that is the hallmark
of the disease. This presents a formidable challenge to the physician who must diagnose the disease early in the clinical course
when antibiotic treatment is most effective.
The dermatologic findings provide clues that lead to consideration of the diagnosis and can help “rule out” other exanthemata. Classically, the rash of RMSF begins on day 4 of the illness
(range: 1–15 days) on the wrists and ankles. It then spreads to the
palms and soles and subsequently involves the proximal extremities and trunk (Fig. 25.2). This classic centripetal spread is a
hallmark of RMSF. However, most patients do not discern this
pattern and health-care providers may first see the patient when
the rash has generalized (Fig. 25.2). Initially the exanthem presents with small pink or red macules that blanch with pressure
and evolves into petechia and purpura. Periorbital and peripheral edema and conjunctivitis may also be present. Calf pain and
tenderness has been reported in the literature. Gangrenous areas
may develop on the fingers, toes, ears, scrotum, and vulvar areas.
Involvement of the scrotum and vulva has been heralded as a
diagnostic clue, albeit a late one. The classic rash is absent in up
to 20% of RMSF patients. In addition, the skin finding may be
difficult to appreciate in patients with deeply pigmented skin or
late development in the disease course. Rocky Mountain “spotless” fever is a recognized presentation that is associated with a
higher fatality rate.

Diagnosis
During the early stages of RMSF, rapid laboratory confirmation
is not available to guide acute therapeutic decisions. Diagnosis is
based on the recognition of the epidemiologic clues and clinical
findings of: fever, headache, and rash in a person with a known
or potential exposure to a tick bite. A history of tick bite, travel
to an endemic area, or recent outdoor activity should be sought

from the patient. Similar illness in a family member, coworker,
or even a family pet may provide an important clue. Household
clusters of disease have been reported and dogs may develop
RMSF alongside human family members. Unfortunately, the
“classic” triad of fever, rash, and a history of a tick bite is elicited
in only 60% to 70% of patients on initial examination.
Laboratory clues to the disease may include a left-shift in the
WBC, thrombocytopenia, elevated hepatic transaminases, and
hyponatremia. Although serologic tests are confirmatory, they
are not helpful in guiding immediate therapeutic decisions. Early
in the course of the disease, the serologic tests will be negative
and it is only after 2 to 3 weeks when the acute and convalescent
serum samples can be compared for a rising IgG and IgM level
(a four-fold or greater increase in antibody titer) that the diagnosis of RMSF is confirmed. Direct immunofluorescence testing of a skin biopsy can be helpful in the acute setting; however,
while 100% specific, it is only 70% sensitive and is not widely
or immediately available. Immunohistochemical (IHC) staining
may also be used to document presence of the organism in a skin
biopsy or other tissue. Polymerase chain reaction (PCR ) testing
of a skin biopsy is a rapid method for evaluation of RMSF but is
only available in limited venues (Centers for Disease Control and
Prevention [CDC], certain state public health laboratories, a few
research and commercial labs) and has a low sensitivity. Rickettsia
rickettsii, an obligate intracellular coccobacillus, may only be
isolated using cell culture techniques in laboratories equipped
to handle Biosafety Level-3 agents; thus culture is rarely used for
diagnosis. Owing to sensitivity or time issues surrounding these
complex diagnostic tests, they are used primarily in a confirmatory role and the initial treatment decisions for RMSF are based
primarily on clinical and epidemiologic evidence.

Management
Early treatment is of the highest priority in a suspected case of
Rocky Mountain spotted fever. Empiric antibiotic treatment
should be initiated when clinical and epidemiologic clues even
suggest RMSF. Doxycycline (oral or intravenous) is the drug
of choice for adults and children with Rocky Mountain spotted fever. The American Academy of Pediatrics Committee on
Infectious Diseases has endorsed the use of doxycycline for treatment of presumed or confirmed cases of RMSF in children of all
ages given the life-threatening nature of the disease and the negligible risk for tooth staining with a limited course of treatment.
Chloramphenicol is typically the preferred treatment for RMSF
during pregnancy; however, the use of tetracycline might be warranted during pregnancy in life-threatening situations where the
clinical suspicion of RMSF is high. Supportive care may be needed
for severely ill patients. Of importance, typical “broad-spectrum”
antibiotic coverage will not treat RMSF. Empiric treatment should
be initiated when clinical and epidemiologic clues even suggest
RMSF. Failure to consider the diagnosis of RMSF and institute
early effective antibiotic treatment can be a fatal error.

S TA P H Y L O C O C C A L T O X I C S H O C K
SYNDROME

Staphylococcal toxic shock syndrome (TSS) is caused by
infection or colonization with the common skin pathogen,

Life-Threatening Skin Infections — 325

Staphylococcus aureus. A toxin-mediated disease; menstrual
toxic shock syndrome is caused by the superantigen exotoxin
toxic shock syndrome toxin-1 (TSST-1). In this multisystem disease, superantigens overactivate the human immune system to
release various cytokines that cause the clinical features of TSS
such as fever, capillary leak, and rash.
Nowadays, nonmenstrual toxic shock syndrome is more common than menstrual TSS and can occur in anyone, male or female,
young or old. Nonmenstrual toxic shock syndrome settings
include post-influenza, postpartum, postsurgical, nasal packing or stent use, barrier contraceptive use, localized infections
(cellulitis, burns, abscess, hidradenitis suppurativa, wounds),
and postviral upper respiratory infection. Nonmenstrual TSS is
mediated by TSST-1 (50%) or by staphylococcal exotoxin B or C
(up to 50%). The mortality rate for menstrual TSS has dropped to
5%, but remains higher for nonmenstrual cases, possibly because
of the delay in making a definitive diagnosis.
With the emergence of community-acquired methicillinresistant S. aureus (CA-MRSA), an increase in high toxinproducing strains capable of causing TSS is occurring. In
addition, “new” clinical patterns such as purpura fulminans and
necrotizing fasciitis in association with S. aureus are emerging.

Clinical Manifestations
The prodromal features of staphylococcal TSS include fever,
malaise, myalgias, nausea, vomiting, diarrhea, and prominent confusion. The cutaneous signs can be quite striking and
typically include a “sunburn-like” diffuse or patchy macular
erythroderma with perineal accentuation. A scarlatiniform
eruption with flexural accentuation may also be present.
Desquamation follows in 5 to 14 days and is prominent on the
hands, feet, and perineal areas (Fig. 25.3). As it occurs during
the convalescent phase, it is generally not a helpful skin sign in
the acute stage of the illness. Conjunctiva injection, mucosal
hyperemia (oral and genital), and strawberry tongue are helpful clinical clues, especially in deeply pigmented patients in
whom the erythroderma may be subtle or overlooked. Less
common findings include edema of the hands and feet, petechia, and the late loss of hair and nails. Purpura fulminans,
most commonly associated with meningococcal disease, has
been reported in association with CA-MRSA and toxic shock
syndrome. Necrotizing fasciitis in association with CA-MRSA

is an emerging clinical entity requiring urgent surgical and
medical therapy.

Diagnosis
Formal diagnostic criteria for TSS have been developed and
include fever, desquamative erythroderma, and hypotension
within a setting of multiple organ system involvement. The multisystem involvement (three or more systems) may include gastrointestinal, hepatic, musculoskeletal, renal, cardiopulmonary,
CNS, metabolic findings, and mucosal hyperemia. TSS is a diagnosis of exclusion and other causes of sepsis must be “ruled out.”
Milder cases of TSS do occur and may not fulfill all of the criteria
of the case definition. Severe sepsis associated with CA-MRSA
may or may not present with the emblematic desquamating
erythroderma of “classical” TSS and may not fulfil the diagnostic
criteria for TSS.
As a toxin-mediated disease, Staphylococcus aureus is rarely
isolated from TSS blood cultures. A thorough search to identify
the potential sources of infection includes a close examination
of the skin surface to identify any wounds or abscesses. The classic signs of localized infection at a wound or surgical site such
as erythema, tenderness, and purulence may be absent, making
clinical diagnosis challenging. Cultures must be obtained from
all mucous membranes (vaginal, oropharyngeal, and conjunctival) as well as from blood and urine. All wounds and surgical sites should be cultured and considered possible sources of
infection even without signs of local infection. Toxins may be
identified by antibody reactivity or PCR.

Management
Treatment of staphylococcal TSS includes the identification and
removal of the source of the Staphylococcus aureus, initiation of
effective anti-staphylococcal antibiotic coverage, and supportive
care. Examples of removal of the source of infection may include
incision and drainage of an access, surgical debridement of a
wound site, or the removal of nasal packing or tampon. With the
emergence of CA-MRSA, initial treatment of an infection should
be based on the antibiotic resistance patterns in the community.
Vancomycin is included for empirical coverage of severe
infections. Additional therapies to consider include intravenous immunoglobulin to neutralize circulating toxins and clindamycin, which may help reduce the actual toxin production.
Aggressive management of the hypovolemia associated with capillary leak, vasodilation and fluid loss is a mainstay of therapy.
Patients may require vast amounts of fluid replacement.
Primary prevention of TSS is via education about the early
signs and symptoms of TSS, risk factors, and limited use of
high-absorbency tampons. Up to 30% of women diagnosed with
menstrual TSS relapse during subsequent menses. Tampons and
barrier contraceptives should be avoided in women who do not
have documented seroconversion after the acute illness.

STREPTO CO CCAL TOXIC SHO CK
SYNDROME
Figure 25.3. Staphylococcal Toxic Shock Syndrome. Desquamative
erythroderma in the groin and perineal area.

Streptococcal toxic shock syndrome (STSS) is caused by infection with Group A β-hemolytic streptococcus (Streptococcus

326 — Lisa A. Drage

pyogenes), the same organism that causes strep throat and simple
skin infections. However, the strains leading to STSS possess
virulence properties that lead to severe and life-threatening disease. STSS is typically encountered in the setting of invasive soft
tissue infection. Cellulitis, necrotizing fasciitis, or myonecrosis
is present in 80% of cases. However, it is also seen in association with streptococcal pharyngitis, pneumonia, septic arthritis,
endophthalmitis, peritonitis, meningitis, and sinusitis. Cases
have been encountered where there is no obvious evidence of
a strep infection but only a history of blunt trauma or muscle
strain – hematogenous spread from a pharyngeal source to the
site of muscle or soft tissue injury has been hypothesized. Most
cases of STSS occur sporadically with only occasional clusters reported in nursing homes, health-care workers, or family
members.
In cases associated with a soft tissue infection, a portal of
entry is often discernible such as surgical excision, laceration,
burn site, varicella lesion, childbirth trauma, decubitus ulcer, or
an insect bite. Comorbidities such as diabetes mellitus, peripheral arterial disease, obesity, alcohol abuse, human immunodeficiency virus (HIV), or recent varicella-zoster virus (VZV) may
be present, but many patients are healthy, immunocompetent,
and are in the 20- to 50-year age range. The mortality for STSS
has been reported as 30% to 60% despite aggressive modern
treatments.
Special features of the streptococcal bacterium make the
syndrome more deadly. M-1 and M-3 surface proteins increase
adherence to tissue, possess antiphagocytic properties that blunt
the immune response, and induce capillary leak. Streptococcal
pyrogenic exotoxins function as superantigens. They bypass and
amplify the conventional immune response, interacting nonspecifically with T-cells to activate a large segment of the T-cell population and trigger a massive cytokine release. The cytokines cause
the fever, hypotension, rash, and tissue injury of the toxic shock
syndrome. Host factors, such as lack of past exposure to virulent
bacteria and possession of specific HLA class II haplotypes that
determine the magnitude of the cytokine response, predispose
to invasive Group A streptococcal disease. Interplay between the
bacterial virulence factors and host factors allow this severe and
life-threatening form of streptococcal infection to develop.

Clinical Manifestation
Streptococcal toxic shock syndrome often occurs in a young,
previously healthy person who seeks medical care because of the
abrupt onset of fever, hypotension, and skin findings accompanied by severe, localized pain. Pain is the most common initial
symptom and is typically localized to an extremity and is disproportionate to the examination findings. The pain may be so
out of proportion to the clinical signs that physicians may suspect that the patient is displaying malingering or drug-seeking
behavior. Twenty percent of patients have an influenza-like prodrome with fever, chills, myalgias, nausea, vomiting, and diarrhea. While fever is the most common presenting sign of STSS,
confusion is present in over half of patients and may manifest
as combativeness. In 80% of patients, STSS is accompanied by
clinical signs of soft tissue infection, which in 70% of patients,
will progress to necrotizing fasciitis or myositis.
The initial skin signs of STSS may be subtle, and a thorough
examination of the skin is needed to look for portals of entry and

Figure 25.4. Streptococcal Toxic Shock Syndrome. Necrotizing
fasciitis. Dusky, violaceous erythema, edema and tenderness. A bulla
developed between the first and second finger webspace.

evidence of a soft tissue infection such as tenderness, localized
swelling, or erythema. The disease progresses at an alarming rate
with the development of red/purple discoloration, dusky blue
pigment, and distinctive violaceous vesicles or bullae. These areominous signs of necrotizing fasciitis or myonecrosis (Fig. 25.4).
The evolving area may also develop decreased sensation. The
crepitance noted in a patient with a polymicrobial or anerobic
infection is not prominent in patients with streptococcal necrotizing fasciitis. Desquamating erythroderma is noted in only
10% of patients with STSS.

Diagnosis
A clinical case definition for STSS is established and includes the
isolation of Group A Streptococcus from a normally sterile site,
hypotension, and multisystem involvement. Involvement of two
or more organ systems is required and may include a generalized
erythematous rash that may desquamate, soft tissue necrosis,
renal impairment, coagulopathy, liver involvement, and acute
respiratory distress syndrome. An intraoperative Gram’s stain,
culture, and biopsy are helpful in making a definitive diagnosis. The presence of gram-positive cocci in pairs and/or in chains
supports the diagnosis of streptococcus. As opposed to staphylococcal toxic shock syndrome, 60% of patients with STSS will
have bacteremia and positive blood cultures. Magnetic resonance imaging, muscle compartment pressure monitoring, and
creatine kinase levels can be used to help diagnose, monitor, and
predict necrotizing fasciitis or myonecrosis.

Management
The management of STSS in association with necrotizing fasciitis or myonecrosis relies on both surgical and medical intervention. Early surgical involvement with aggressive exploration
and debridement of soft tissue infection is the standard of care.
While small retrospective studies have shown successful medical management with high-dose IV immunoglobulin and antibiotics in patients too unstable for aggressive surgical treatment,
early surgical consultation and action is the mainstay of therapy.
Early surgical exploration facilitates the definitive diagnosis
through acquisition of Gram stains, tissue cultures, and biopsies.

Life-Threatening Skin Infections — 327

A series of surgical reexplorations with repeated debridements
or amputation may be necessary to remove necrotic tissue.
Empiric treatment includes broad-spectrum antibiotic coverage
until the results of cultures and sensitivities return, intravenous
immunoglobulin to help neutralize circulating toxins, and clindamycin to decrease toxin synthesis. Aggressive supportive care
is necessary and extensive reconstructive surgery and rehabilitation is part of a long-term rehabilitation plan.

P I T FA L L S A N D M Y T H S

Meningococcal Disease
• Misdiagnosing meningococcal disease as “viral exanthem” in
a child
• Failing to recognize the signs and symptoms of meningococcus in an adult (especially a college-age student)
• Failing to identify risk factors for meningococcal disease:
patients with a terminal complement pathway deficiency,
patients with anatomic or functional asplenia, military
recruits, travelers to hyperendemic areas (sub-Saharan Africa,
or Saudi Arabia), and college-age students in dormitory
settings
• Failing to recognize the early skin signs of meningococcal
disease
• Neglecting to perform a complete skin examination and
missing the key clue in patients who present with only a few
petechiae
• Delaying initiation of antibiotic treatment while awaiting
blood culture, imaging tests, or transfer to a hospital
• Failing to treat upon clinical suspicion
Rocky Mountain Spotted Fever
• Failing to obtain a history that elicits exposure to ticks, tick
habitats, or concurrent illness in household pets or family
members
• Discounting the diagnosis when there is no history of a tick
bite
• Waiting for the petechial rash (“spots”) to develop on the
palms/soles before making a diagnosis
• Failing to consider RMSF in the differential diagnosis of a
generalized petechial rash
• Excluding the diagnosis of RMSF because of geography
• Misdiagnosing as gastroenteritis due to significant nausea
and vomiting
• Failing to treat upon clinical suspicion
• Failing to treat with an appropriate antimicrobial agent
(doxycycline)
• Failing to use doxycycline in children suspected of having
RMSF
Staphylococcal Toxic Shock Syndrome
• Failing to recognize the disease in men
• Failing to recognize “nonmenstrual” cases
• Missing the early skin signs of the disease, thus delaying
diagnosis and treatment
• Waiting for desquamation, a late skin finding
• Not identifying and treating/removing the source of
infection
• Overlooking the erythroderma in dark-skinned patients

•
•

Failing to recognize the high recurrence rate in menstrual
staphylococcal TSS
Decreasing the level of vigilance for cases of staphylococcal TSS

Streptococcal Toxic Shock Syndrome
• Failing to recognize the early skin signs of the disease
• Overlooking “portals of entry” for the streptococcal
pathogen
• Misdiagnosing as gout or a musculoskeletal disease
• Ascribing the patient’s severe pain (out of proportion to the
exam findings) to “drug-seeking” behavior or malingering
• Difficulty in differentiating cellulitis from necrotizing
fasciitis
• Failing to involve surgical consultation early in the disease
course
• Delaying surgical intervention or relying on medical management when surgical treatment is the mainstay of effective
therapy

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Index

abscesses, 17, 189. See also carbuncles;
furuncles
acanthamebiasis, in HIV infection, 193–194
Acanthamoeba spp., 121
Acanthaster planci (crown of thorns) starfish,
173
acellular pertussis (DTaP) vaccination, 294
acetaminophen, for HSV 1 and 2 infections,
277
Acinetobacter baumannii, 189
Ackerman, A. Bernard, 6
acne miliaris necrotica, 262
Acquired Immune Deficiency Syndrome
(AIDS). See also HIV-related skin
infections; Kaposi’s sarcoma (KS)
acid-fast bacilli in, 72
anergy, presence of, in, 4
coccidioidomycosis and, 144
cryptococcus with, 111
cutaneous tuberculosis with, 73
diabetes and, 8
disseminated histoplasmosis (DH) and,
104
esophageal infections with, 221
historical background, of, 185
Mycobacterium avium intracellulare with,
292
pbmycosis with, 108
progressive vaccinia and, 23
pulmonary tuberculosis in, 60
systemic tropical mycoses and, 96
tuberculosis and, 60
Acremonium spp., 113, 270–272
actinias, reactions to, 169–171
Actinomadura madurae grains, 97, 156
Actinomyces, 3
Actinomyces israelii, 294
actinomycosis, 294
acute disseminated miliary tuberculosis
(tuberculosis cutis miliaris acuta
generalisata), 67
acute exanthem, 145
of HIV infection
cytomegalovirus, 187
Epstein-Barr virus, 187
herpes simplex virus (types 1 and 2),
186
human herpes virus 8, 188–189
pox virus, 187
varicella-zoster virus, 186–187
acute febrile neutrophilic dermatosis (Sweet’s
syndrome), 146

acute infections, primary signs of, 8
acute miliary cutaneous tuberculosis, 60, 74
acute necrotizing ulcerative gingivitis,
294–295
acute paronychial infections, 268–269
acyclovir
for congenital herpes simplex, 30
for genital herpes, 319
for hand-foot-and-mouth disease, 282
for herpes simplex virus, 200, 277
for herpes virus B, 34
for herpes zoster, 31
for HSV-1/HSV-2, 29
oral, for HSV, 186
for oral hairy leukoplakia, 187, 279
for suspected neonatal HSV, 225
for varicella zoster virus, 31, 201
for VZV, 187
Aedes aegypti mosquito, 92, 95, 151, 152
African Americans
and lepromatous leprosy, 77
and pediculosis, 230
and pseudofolliculitis barbae, 216
and tinea capitis, 43
agent formulary for topical therapy, 11
albendazole
for cysticercosis, 129
for echinococcosis, 129
for enterobiasis, 128
for filariasis, 124
for loiasis, 124
for mansonelliasis, 128
for onchocercosis, 176
for trichinellosis, 128
Alcyonidrium gelatinosum bryozoans, 175
Alcyonidrium hirsutum bryozoans, 175
Alcyonidrium topsenti bryozoans, 175
algae/Bryozoans and aquatic dermatoses
algae, 174
Bryozoans, 175
protothecosis, 174–175
allopurinol, for Old World CL, 144
allylamine, for tinea unguium
(onychomycosis), 52
Almeida, Floriano de, 151
Alternaria spp., 113, 270
aluminum acetate (Burrow’s solution), for
impetigo, 261–262
Amblyomma americanum (lone star tick), 215
Amblyomma Cajennense (Cayenne tick), 323
American Society for Dermatologic Surgery
survey, 303

American Thoracic Society, 292
American trypanosomiasis, 123
amikacin with tetracycline, for
protothecosis, 175
aminoglycosides
for ecthyma gangrenosum, 215
for nocardiosis, 198
amitriptyline for post-herpetic neuralgia, 31
amorolfine
nail lacquers, for tinea unguium, 219
topical, for tinea unguium, 236
amoxicillin
complications from, 33, 278–279
for genital bite wounds, 317
for Lyme disease, 215
for perianal streptococcal dermatitis, 212
amphotericin B
for candidiasis, 191
for chromoblastomycoses, 156
for coccidioidomycosis, 148
for cryptococcosis, 112
for cutaneous cryptococcus, 191
for entomophthoromycosis, 111
with 5-fluorocytosine
for aspergillosis/cryptococcosis/
candidiasis, 114
for histoplasmosis, 192
IV, for protothecosis, 175
for leishmaniasis, 297
liposomal, for mucormycosis, 110
for mycetoma, 157
for Old World CL PVA failures, 143
for paracoccidioidomycosis, 109
intravenous, 159
for penicilliosis, 193
for rhinosporidiosis, 104
for sporotrichosis, 102
amyloidosis (primary) and Hansen’s
disease, 78
Anaerobic streptococci, 250
Anaplasma phagocytophilum, 215
Ancylostoma braziliensis (hookworm of dogs
and cats), 125, 127, 176
Ancylostoma caninum, 125, 176
Anemonia sulcata actinia, 168–170
anergic leishmaniasis, 151
angular cheilitis (perleche), 221
anogenital disease
bowenoid papulosis, 26
condyloma acuminatum, 26
verrucous carcinoma, 26–27
anogenital warts, 319
329

330 — Index

anopheline (malaria-carrying) mosquitos, 95
anthrax, 295
Anthraxin test, 4
antibiotics. See individual antibiotics
anticonvulsants. See carbamazepine;
gabapentin; pregabalin
antifungal medications. See also fluconazole;
griseofulvin; itraconazole;
ketoconazole; terbinafine
for pityriasis versicolor (PV), 52–53
for seborrheic dermatitis/pityriasis
capitis, 256
for tinea capitis, 51
for tinea corporis/cruris/faciei, 50–51
for tinea pedis/manuum, 47–50
for tinea unguium (onychomycosis),
51–52
antifungal shampoos, 51, 217, 218, 256, 258
antihistamines
for folliculitis, 189
for mite symptom control, 231
for pediculosis capitis itch control, 260
antimalarials, for ENL treatment, 84
anti-retroviral therapy
for acute exanthem, 186
for hairy leukoplakia, 279
for KS, 34
Aphrodite aculeata polychaete, 176
Apophysomyces elegans, 109
aquatic dermatoses from biotic organisms
from algae/Bryozoans
algae, 174
Bryozoans, 175
protothecosis, 174–175
from aquatic bacteria
erysipeloid, 179
mycobacterium marinum, 178–179
from aquatic worms
cercariae, 175
contact with bait, 176
leeches, 176
nematodes, 176–177
onchocercosis, 175–176
polychaetes, 176
from arthropods, 174
from coelenterates, 167–172
actinia reactions, 169–171
jellyfish reactions, 168–169
physaliae/corals/hydroid reactions,
172
sea bather’s eruptions, 171–172
from echinoderms
sea urchins, 172–173
starfish, 173–174
from fish, 177–178
historical background, 167
from mollusks, 174
from sponges, 174
aquatic worms and aquatic dermatoses
cercariae, 175
contact with bait, 176
leeches, 176
nematodes, 176–177
onchocercosis, 175–176
polychaetes, 176

arboviruses. See arthropod-borne infections
Argentinian hemorrhagic fever, 153
Aristotle
on contagiousness of phthisis, 59
on parasites, 117
arthropod-borne infections. See also Chagas’
disease; Dengue fever; ectoparasite
infestation; mouse-borne diseases;
sandfly-borne diseases; tick-borne
diseases; Yellow fever
diagnosis, 93–94
epidemiology, 93
general information, 92
historical background, 92–93
pitfalls and myths, 95
therapy, 94–95
arthropods, lesions from, 174
Asians
and lepromatous leprosy, 77
syphilis rates in pregnant women, 222
aspergillosis, 7, 47, 109, 192, 206, 207
clinical presentation, 288
diagnosis, 288
at hospital sites, 206
invasive, in AIDS, 192
in mucormycosis, 287
in transplant patients, 264
treatment, 288
Aspergillus spp., 270–272
asymmetry (as sign of acute infection), 8
athletes, skin infections in
atypical mycobacteria (swimming pool
granuloma), 244
bacterial infections
folliculitis, 239
furunculosis, 238–239
gram negative hot tub folliculitis, 240
green foot, 240
hot foot syndrome, 240
impetigo, 238
pitted keratolysis, 239–240
tropical ulcers, 240
fungal infections
tinea corporis gladiatorum, 243–244
tinea pedis, 243
historical background, 238
parasites (cutaneous larvae migrans), 244
viral infections
herpes simplex
activation, 240
skin-to-skin transmission, 240–241
molluscum contagiosum, 241–242
verruca, 242
atopic dermatitis, 21, 114, 193, 225
atovaquone, for tularemia, 95
atypical mycobacterioses, 6
classification, 88–89
Mycobacterium avium complex, 89
Mycobacterium chelonaeMycobacterium abscessus
complex, 89
Mycobacterium fortuitum complex, 89
Mycobacterium kansasii, 88
Mycobacterium marinum, 67, 88
Mycobacterium scrofulaceum, 64, 74, 89

clinical presentation, 89–90
diagnosis, 90
historical background, 88
pitfalls and myths, 90–91
therapy, 90
autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy
(APECED) syndrome, 222
Ayurveda, 59
azidothymidine (AZT), for HIV, 185, 284
azithromycin
for bacillary angiomatosis, 189–190,
198
for cat-scratch disease, 215
for chancroid, 313
for diphtheria, 294
for granuloma inguinale, 315
for syphilis, 312
for tularemia, 95
azoles
for coccidioidomycosis, 148, 192
for Old World CL, 143
for pityriasis versicolor, 53
for tinea unguium (onychomycosis), 52
topical, for erythrasma, 249
B. dermatitides, 7
babesiosis, 92
bacillary angiomatosis (BA)
in HIV, 189–190
in transplant recipients, 197–198
Bacillus anthracis, 295
Bacillus Calmette-Guerin (BCG), 60, 67
vaccinations of against TB, 4, 62, 65,
72–73
bacillus Calmette-Guerin (BCG)
vaccinations, 4
Bacillus vincentii, 294
bacterial infections in athletes
folliculitis, 239
furunculosis, 238–239
gram negative hot tub folliculitis, 240
green foot, 240
hot foot syndrome, 240
impetigo, 238
pitted keratolysis, 239–240
tropical ulcers, 240
bacterial infections in elderly patients
cellulitis/erysipelas, 234
herpes zoster, 235
impetigo/folliculitis/furunculosis,
234–235
necrotizing fascitis, 235
bacterial infections of the scalp
eosinophilic pustular folliculitis, 261
erysipelas/scalp cellulitis, 262
folliculitis, 260
impetigo, 261–262
staphylococcal folliculitis, 260–261
bacterial infections related to HIV
bacillary angiomatosis, 189–190
folliculitis, 189
impetigo, abscesses, cellulitis, necrotizing
fascitis, 189
mycobacterial infections, 189

Index — 331

bacterial infections related to mucous
membranes
actinomycosis, 294
acute necrotizing ulcerative gingivitis,
294–295
anthrax, 295
bacterial vaginosis, 295
diphtheria, 293–294
mycoplasma pneumoniae, 296
noma (cancrum oris/gangrenous
stomatitis), 295
pseudomonas aeruginosa, 295
rhinoscleroma, 294
staphylococcus, 293
streptococcus, 293
tetanus, 296
bacterial uSSSIs. See uncomplicated skin and
skin structure infections (uSSSIs)
bacterial vaginosis, 295
bacterial/viral disease in transplant recipients
bacillary angiomatosis, 197
B-hemolytic streptococcus, 196–197
gram-negative bacilli (GNB), 197
historical background, 195
necrotizing fascitis, 197
nocardiosis, 198
Staphylococcus aureus, 195–196
vibrio vulnificus, 197
Bacteroides, 250
Baker-Rosenbach’s erysipeloid, 179
Balamuthia mandrillaris, 121
Barmah Forest virus (BFV), 152–153
Bartonella, 4, 197
Bartonella henselae, 189, 197, 215
Bartonella quintana, 92, 189, 197
basal cell carcinoma (BCC), 303
Basidiobolus haptosporus, 110
Basidiobolus ranarum, 110
Bayle, Gaspard Laurent, 59
Bazin, Ernest, 69. See also erythema
induratum of Bazin
bedbugs, 232
benzathine penicillin
for endemic treponematoses, 216
for scarlet fever, 212
for syphilis, 190, 312
congenital, 223
benznidazole
for American trypanosomiasis, 123
for Chagas’ disease, 160
benzocaine preparations, for HSV, 277
benzoyl peroxide, 20, 21
benzyl benzoate
for demodicidosis, 260
for scabies, 193, 260
betadine, for impetigo, 261–262
bifonazole
for pityriasis versicolor, 53
with urea, for tinea unguium
(onychomycosis), 219
Bipolaris, 113
black piedra, 154, 258
black superficial onychomycosis (BSO),
271–272
black-dot tinea capitis, 257

Blastomyces dermatitidis, 105
blastomycosis. See also
chromoblastomycosis; North
American blastomycosis;
paracoccidioidomycosis (South
American blastomycosis)
chromomycosis (see
chromoblastomycosis)
clinical presentation, 289
diagnosis, 289
differentiation from
lupus vulgaris, 63, 74
warty tuberculosis, 65
in HIV infection, 193
keloidal blastomycosis, 102, 157
in mucous membrane infections, 289
oral itraconazole for, 47
bleomycin injections, for verrucae vulgaris/
condyloma acuminatum, 203
blister beetles, 232
blistering dactylitis, in children, 212
Bolivian hemorrhagic fever, 153
borderline lepromatous (BL) disease, 79, 83
borderline tuberculoid (BT) leprosy, 78, 83
Borrelia, 4
Borrelia burgdorferi, 215
Borrelia vincentii, 294
bowenoid papulosis, 26
breasts, tuberculosis of, 72
British Society for Antimicrobial
Chemotherapy, 306
British Society for Dermatological
Surgery, 306
Brucella, 3
Brugia malayi, 123
Brugia timori, 123
bryozoans and dermatitis, 175
bullous impetigo, 195, 211
Bunostomum phlebotomum, 125
Burkitt lymphoma, 187, 279
Buruli ulcer, 7
Burulin intradermal reaction, 4
Butcher’s warts, 26
butenafine
for tinea corporis/cruris/faciei, 50
for tinea pedis/manuum, 47
C. immitis, 7
C. neoformans, 7
Calymmatobacterium granulomatis, 314
Calymmatobacterium granulomatis Gramnegative rod, 151, 190
CA-MRSA. See community-acquired
methicillin resistant Staphylococcus
aureus (CA-MRSA)
cancer patients and skin infections
cutaneous infections
bacterial infections, 207
fungal infections, 207
viral infections, 207
diagnosis, 206
epidemiology, 206
historical background, 206
malignant infections
angiosarcoma, 209

breast cancer, inflammatory, 208–209
cancers metastatic to skin, 210
keratoacanthoma, 209–210
lethal midline granuloma, 209
leukemia cutis, 208
lymphoma, 208
squamous cell cancer, 209
Stewart-Treves syndrome, 209
verrucous carcinoma, 209
therapy principles for cutaneous
infections, 208
Candida, 3
Candida albicans, 191, 235, 246, 271, 272, 286
Candida dubliniensis, 191
Candida glabrata, 191
Candida krusei, 191
Candida parapsilosis, 191, 271
Candida tropicalis, 191
candidal onychomycosis, 221, 236
candidiasis
in children, 220–221
in diabetes mellitus, 246–247
in elderly patients, 235–236
in HIV infection, 191
Candidin test, 4
Capnocytophaga, cat and dog bites from, 19
Capnocytophaga canimorsus, 19, 112
carbamazepine, for post-herpetic neuralgia, 31
carbapenems (newer generation), for MRSA
strains, 20
carbaryl, for pediculosis capitis, 259
carbuncles, 17. See also furuncles
in diabetes mellitus, 248–249
in folliculitis, 234, 260
S. aureus as causative, 19
treatment of, 20
carpal tunnel syndrome and Hansen’s
disease, 78
cat and dog bites, Pasteurella spp. as
causative, 19
caterpillars and moths, 232
cat-scratch disease, 6, 92, 215
Caucasians, and lepromatous leprosy, 77
cefixime, for gonorrhea, 315–316
cefoperazone sodium, for necrotizing
fascitis, 213
ceftriaxone
for chancroid, 313
for erysipeloid, 214
for gonorrhea, 315–316
intramuscular, for meningococcal
disease, 323
for nocardiosis, 198
for syphilis, 190
cefuroxime
for genital bite wounds, 317
for Lyme disease, 215
cellulitis, 17–18
in diabetes mellitus, 249
in elderly patients, 234
in HIV, 189
of lower extremity, pitfalls and myths, 21
S. aureus/S. pyogenes as causative, 19
in scalp infections, 262
treatment of, 20

332 — Index

Centers for Disease Control and Prevention
on arthropod-borne diseases
risk factors, 93
treatment, 94–95
on treatment for cutaneous TB, 73
cephalopods, dermatoses from, 174
cephalosporin
for cellulitis/erysipelas, 234
for erysipelas, 20
for folliculitis keloidalis, 262
for genital bite wounds, 317
for gonorrhea, 316
for S. aureus, 196
cercarial dermatitis (swimmer’s itch), 130,
175
Cercopithecus aethiops (green monkeys), 153
Cerqueira, Alexandre, 150
cestodes, 128–130
coenurosis, 129–130
cysticercosis, 129
echinococcosis, 129
sparganosis, 129
Chagas, Carlos, 159
Chagas’ disease, 123. See also American
trypanosomiasis
diagnosis, 160
treatment, 160
chancroid, 309, 312–313
chemical peels, for pseudofolliculitis barbae,
216
chemotherapy
for Burkitt lymphoma, 279
for cervical intraepithelial neoplasms, 281
for chromomycosis, 100
for cutaneous tuberculosis, 73
for KS, 34, 202
pre-bone marrow transplant, 264
skin infections after, 206
candidiasis, 221
ecthyma gangrenosum, 214
oral mucositis, 275
chickenpox, 30, 186, 200, 235
Chironex fleckeri jellyfish, 169
Chiropsalmus quadrigatus jellyfish, 169
Chlamydia, 4
Chlamydia trachomatis, 191, 313
chloramphenicol, for Rocky Mountain
spotted fever, 324
chlorhexidine
for impetigo, 261–262
for S. aureus in transplant recipients, 196
for skin colonization issues, 21
chromoblastomycosis, 6, 7, 98–100
differentiation from warty tuberculosis,
65
genera differences, 99–100
treatment, 100
chronic granulomatous disease, 74
chronic hepatitis C virus (HCV), 37
chronic mucocutaneous candidiasis (CMC),
221–222
chronic paronychial infections, 269
chronic traumatic lymphedema of the hands,
from sea urchins, 173
Chrysops spp3, 124

ciclopirox
for piedra, 259
for tinea corporis/cruris/faciei, 50
for tinea pedis/manuum, 47, 47–50, 236
for tinea unguium (onychomycosis), 219,
236
topical, for pityriasis versicolor, 53
(topical), for white piedra, 154
ciclopirox olamine (1%), for tinea pedis/
manuum, 47
ciclopirox shampoo, 256
cidofovir
for condyloma acuminata, 188
for herpes simplex virus, 200
cimetidine, for verrucae vulgaris/condyloma
acuminatum, 203
ciprofloxacin
for cat-scratch disease, 215
for chancroid, 313
for erysipeloid, 214
for granuloma inguinale, 315
for rhinoscleroma, 294
Cladophialophora carrionii, 98–99
cladosporiosis. See chromoblastomycosis
Cladosporium carrionii dematieous fungus,
156
clarithromycin
for atypical mycobacteria, 244
for atypical mycobacterioses, 90
for bacillary angiomatous, 189–190
for diphtheria, 294
clindamycin
for acne miliaris necrotica, 262, 262
for bacterial vaginosis, 295
for erythrasma, 214
for necrotizing fascitis, 213
oral, for nasal carriage issues, 21
for perianal streptococcal dermatitis, 212
for pitted keratolysis, 214
with rifampicin, for scalp cellulitis, 263
topical, 20
for tularemia, 95
clofazimine
for leprosy, 293
for lobomycosis, 103, 158
for multibacillary disease, 84
clotrimazole
for erythrasma, 249
for pityriasis versicolor, 53
for tinea corporis/cruris/faciei, 50
for tinea pedis/manuum, 47
for tinea unguium (onychomycosis), 219
cloxacillin, for carbuncles, 249
cnidocytes (of coelenterates), 167–168
Coccidioides immitis, 104
Coccidioidin test, 4
coccidioidomycosis and the skin
acute exanthem, 145
diagnosis, 144–145
disseminated infection, 147
epidemiology, 144
erythema multiforme-like eruptions,
145–146
erythema nodosum, 145
historical background, 144

in HIV infection, 192
interstitial granulomatous dermatitis,
146–147
pitfalls and myths, 148
primary cutaneous coccidioidomycosis,
147–148
serologic testing, 148
Sweet’s syndrome, 146
treatment, 148
coelenterates
and aquatic dermatoses, 167–172
actinia reactions, 169–171
jellyfish reactions, 168–169
physaliae/corals/hydroid reactions,
172
sea bather’s eruptions, 171–172
description of actions, 167–168
coenurosis, 129–130
colchicine, for ENL treatment, 84
color (as sign of acute infection), 8
Colorado tick fever, 92
common warts (verruca vulgaris), 25,
203, 280
community-acquired methicillin resistant
Staphylococcus aureus (CA-MRSA),
19, 211, 238, 262
S. aureus colonization from, 21
treatment of, 20
complement fixation (CF) test, 4
complications
measles/rubeola, 36
Condylactis aurantiaca actinia, 170
condyloma acuminatum (genital warts), 203
clinical manifestations, 26
preventative therapies, 26
treatment, 26
congenital cytomegalovirus, 33
congenital HSV, 30
congenital indifference to pain and Hansen’s
disease, 78
cytomegalovirus, 224
neonatal HSV, 224–225
parvovirus B19, 225
rubella, 223–224
syphilis, 222–223
varicella zoster, 225
congenital rubella syndrome, 37
conidiobolomycosis, 110
Conidiobolus coronatus, 110
Conidiobolus incongruens, 111
Conus aulicus shell, 174
Conus geographus shell, 174
Conus gloria maris shell, 174
corals, reactions to, 172
corticosteroids
for folliculitis, 189
for folliculitis keloidalis, 262
for scalp cellulitis, 263
for tinea capitis, 217
for trichinellosis, 128
Corynebacterium diphtheriae, 293
Corynebacterium minutissimum, 214, 249
co-trimoxazole, for entomophthoromycosis,
111
cowpox, 24

Index — 333

Coxsackie A-16. See hand, foot, and mouth
disease
creatinine phosphokinase, for differentiation
of necrotizing fascitis, 8, 213
crotamiton
for demodicidosis, 260
for scabies, 260
crusted (ecthymatous) zoster, 186
cryotherapy
for anogenital warts, 319
for chromoblastomycoses, 156
for condyloma acuminata, 188
for genital warts, 319
for KS, 202
for lobomycosis, 103
for molluscum contagiosum, 187
for Old World CL, 143
for verruca, 228
for verrucae vulgaris/condyloma
acuminatum, 203, 228
cryptococcal meningitis, 47, 111
cryptococcosis, 96, 111–112, 187
clinical presentation, 287
diagnosis, 112, 287–288
in HIV infection, 191
treatment, 112, 114, 288
vs. molluscum contagiosum, 187
Cryptococcus, 4
Culex mosquito, 152
Cunnigham, D. D., 135
Cunninghmaella bertholletiae, 109
curettage
for anogenital warts, 319
for genital warts, 319
for molluscum contagiosum, 23, 187
for verrucae vulgaris/condyloma
acuminatum, 203
Curvularia, 113
cutaneous infections (possibly) indicative of
underlying cancer
fungal infections
aspergillosis, 207
Rhizopus/Mucor spp/saprophytes, 207
S. Aureus of streptococcal cellulitis, 207
therapy principles, 208
viral infections
herpes simplex, 207
herpes zoster, 207
warts, 207
cutaneous larva migrans, 124–125
cutaneous pneumocystosis, 187
cutaneous tuberculosis
classification, 62
clinical features
acute disseminated miliary
tuberculosis, 60, 67
erythema induratum of Bazin, 69–70
erythema nodosum, 70, 75
lichen scrofulosorum, 68–69
lichen scrofulosorum (LS), 75
lupus vulgaris, 60, 62–64, 74
orificial tuberculosis, 60, 67–68, 74–75
papulonecrotic tuberculids, 68, 75
primary inoculation tuberculosis, 67
scrofuloderma, 60, 64

tuberculids, 68
tuberculosis gumma, 68, 74
tuberculosis verrucosa cutis, 60, 65, 74
tuberculous chancre, 60
diagnosis, 61–62, 73–74
general information, 59–60
histopathology, 70–71
historical background, 59
HIV with, 59, 72
pathogenesis, 60–61
pitfalls and myths of, 73–75
systemic involvement, 71–72
treatments, 73
Cyclops, 124–125, 129
cyclosporine, with fluconazole, 47
cysticercosis, 129
cytomegalovirus (CMV), 33
in children, 224
diagnosis, 33
in HIV infection, 187
in mucous membrane infections, 279
in transplantation recipients, 201–202
treatment, 33
da Fonseca Filho, Olympia, 151
Dakin’s solution, for skin colonization issues,
21
dapsone
for leprosy, 293
for multibacillary disease, 84
for Old World CL, 144
for paucibacillary disease, 84
daptomycin, for MRSA strains, 20
Dasypus novemcinctus, 106
DEET (N,N-diethyl-3-methylbenzamide)
mosquito repellant, 95
for deterrence of sandflies, 137
for prevention of cercarial dermatitis, 130
Demodex brevis mite, 260
Demodex folliculorum mite, 260
demodicidosis, 193, 260
demodicidosis (of the scalp), 260
Dengue fever, 92, 95, 151–152
cutaneous features, 151–152
treatment, 152
dental pastes, for HSV, 277
depilatory creams, for pseudofolliculitis
barbae, 216
Dermacentor andersoni (Rocky Mountain
wood tick), 323
Dermacentor variabilis (American dog tick),
323
dermatophyte onychomycosis (of fingernails/
toenails), 47, 47, 52
dermatophytosis, 42, 53, 191, 249, 256. See
also tinea capitis
dermatoses, aquatic (from biotic organisms)
from algae/Bryozoans
algae, 174
Bryozoans, 175
protothecosis, 174–175
from aquatic bacteria
erysipeloid, 179
mycobacterium marinum, 178–179
from aquatic worms

cercariae, 175
contact with bait, 176
leeches, 176
nematodes, 176–177
onchocercosis, 175–176
polychaetes, 176
from arthropods, 174
from coelenterates, 167–172
actinia reactions, 169–171
jellyfish reactions, 168–169
physaliae/corals/hydroid reactions,
172
sea bather’s eruptions, 171–172
from echinoderms
sea urchins, 172–173
starfish, 173–174
from fish, 177–178
from mollusks, 174
desert infections, Eastern hemisphere
Old World cutaneous leishmaniasis,
117–118
clinical presentation, 138–140
diagnosis, 140–141
epidemiology, 135–136
historical background, 135
patient follow-up, 144
prevention, 137–138
transmission (sandfly vector/
Leishmania lifecycle), 136–137
treatment, 141–144
desert infections, Western hemisphere
coccidioidomycosis and the skin
acute exanthem, 145
diagnosis, 144–145
disseminated infection, 147
epidemiology, 144
erythema multiforme-like eruptions,
145–146
erythema nodosum, 145
historical background, 144
interstitial granulomatous dermatitis,
146–147
pitfalls and myths, 148
primary cutaneous
coccidioidomycosis, 147–148
serologic testing, 148
Sweet’s syndrome, 146
treatment, 148
desipramine, for post-herpetic neuralgia, 31
Dharmendra lepromin antigen, 4
diabetes mellitus, skin infections
cutaneous infections
candida, 246–247
carbuncles, 248–249
cellulitis, 249
erysipelas, 249
erythrasma, 249
furuncles, 248
dermatophyte fungal infections, 247–248
diagnosis, 246
epidemiology, 246
historical background, 246
life threatening infections
Fournier’s gangrene, 251
malignant otitis externa, 251

334 — Index

diabetes mellitus, skin infections (cont.)
necrotizing fascitis, 250
rhinocerebral mucormycosis, 251
predisposition to, 8
S. aureus colonization from, 21
terbinafine for, 47
therapy for, 252
diabetic ketoacidosis, 110, 251, 286
diabetic neuropathy and Hansen’s disease, 78
diaper dermatitis (monilial diaper
dermatitis), 221
Dick’s test, 4
diethylcarbamazine (DEC)
for filariasis, 124
for loiasis, 124
for onchocerciasis, 124
diffuse cutaneous leishmaniasis, 4
diloxanide, for enteric amebiasis, 121
diphenhydramine elixir with Maalox, for
HSV, 277
diphtheria, 293–294
diphtheria vaccination, 294
directly observed therapy (DOTS), 73, 292
dissecting cellulitis (of the scalp), 262–263
disseminated herpes-zoster, 186
disseminated histoplasmosis (DH), 104
disseminated infection, 147
distal subungual onychomycosis, 236
distal/lateral subungual onychomycosis, 270
DNA microarray technology (DNA chip
technology), 6
DNA viruses. See also herpes virus, various
presentations
hepadnaviruses, 35 (See also hepatitis B)
human papillomavirus (HPV)
anogenital disease
bowenoid papulosis, 26
condyloma acuminatum, 26
verrucous carcinoma, 26–27
nongenital cutaneous diseases
Butcher’s warts, 26
common warts (verruca
vulgaris), 25
epidermodysplasia verruciformis
(EV), 25–26
flat warts (verrucae plana), 25
palmoplantar warts (myrmecia),
25
nongenital mucosal disease
oral focal hyperplasia (Heck
disease), 27
in mucous membrane infections
cytomegalovirus, 279
Epstein-Barr virus, 278–279
HSV-1 and HSV-2, 276–278
human papilloma virus, 280–281
Kaposi’s sarcoma, 280
molluscum contagiosum, 281
parvovirus B19, 281
roseola infantum, 279–280
varicella zoster (HSV-3), 278
parvoviruses, 34–35
pox viruses
cowpox, 24

Molluscum Contagiosum (MCV), 23
monkey pox, 24
smallpox, 23
docosanol (10%) cream, for herpes labialis,
277
Donovan, C., 135
Donovania granulomatis, 314
doxycycline
for acne miliaris necrotica, 262
for actinomycosis, 294
for anthrax, 295
for atypical mycobacterioses, 90
for bacillary angiomatosis, 189–190, 198
for cat-scratch disease, 215
for ehrlichiosis, 215
for endemic treponematoses, 216
for granuloma inguinale, 191, 315
for Lyme disease, 215
for Lyme disease/rickettsial diseases, 95
for lymphogranuloma venereum, 191,
314
for Rocky Mountain spotted fever, 324
for syphilis, 312
for tick-borne disease, 95
for vibrio vulnificus, 197
dracunculiasis, 124–125
Dracunculus medinensis, 124–125
Dyptera Order of insects (vectors), 161
Ebola virus, 153, 284
EBV-associated large cell lymphoma, 187
echinococcosis, 129
Echinococcosis granulosus, 129
Echinococcosis multilocularis, 129
Echinococcosis vogeli, 129
echinoderms and aquatic dermatoses
from fish, 177–178
sea urchins, 172–173
starfish, 173–174
econazole
for tinea corporis/cruris/faciei, 50
for tinea pedis/manuum, 47
ecthyma, 18, 24, 229
in children, 211
diagnosis, 20
S. aureus/S. pyogenes causative for,
19, 197
similarity to mucormycosis, 109
in varicella zoster virus, 186, 200
ecthyma gangrenosum, 109, 197, 214–215,
295
ecthymatous (crusted) zoster, 186
ectoparasite infestation, 92
Edwardsiella lineata anemone, 171–172
eflornithine
for pseudofolliculitis barbae, 216
for trypanosomiasis, 123
Ehrlichia chaffeensis, 215
ehrlichiosis, 92
Eikenella corrodens, 317
elderly people, skin infections in
bacterial infections
cellulitis/erysipelas, 234
herpes zoster, 235

impetigo/folliculitis/furunculosis,
234–235
necrotizing fascitis, 235
fungal infections
candidiasis, 235–236
onychomycosis, 236
tinea pedis/manum, 236–237
historical background, 233–234
Electra pilosa bryozoan, 175
electric razor shaving, for pseudofolliculitis
barbae, 216
electrocautery
for Butcher’s warts, 26
for common warts, 25
for condyloma acuminata, 26, 188
for genital warts, 319
for lupus nodules, 73
for oral florid papillomatosis, 281
electrodesiccation
for anogenital warts, 319
for molluscum contagiosum, 187
for oral florid papillomatosis, 281
emetine hydrochloride, for enteric amebiasis,
121
endemic treponematoses, in children,
215–216
Entamoeba histolytica, 121
enteric amebiasis, 121
Enterobacteriaceae, 19
enterobiasis, 128
Enterovirus 71. See hand, foot, and mouth
disease
Enteroviruses
hand, foot, and mouth disease, 35–36,
281–282
hepatovirus/hepatitis A, 36
herpangina, 36, 276, 282–283
Entomophthorales (Zygomycosis), 109–110
entomophthoromycosis, 110–111
eosinophilic pustular folliculitis (EPF), 216,
261
epidermodysplasia verruciformis (EV),
25–26, 228
epithelioid cell granulomas, 74
Epstein-Barr virus (EBV)
clinical manifestations, 32
in HIV infection, 187
lethal midline granuloma association, 209
in mucous membrane infections, 278–279
in transplantation recipients, 201
treatment, 33
equine encephalitis, 92
erosion (as sign of acute infection), 8
erosive pustular dermatosis (of the scalp), 263
erysipelas, 18
in diabetes mellitus, 249
in elderly patients, 234
pitfalls and myths of, 21
S. pyogenes as causative, 19
in scalp infections, 262
treatment of, 20
erysipeloid (Baker-Rosenbach’s
erysipeloid), 179
in children, 214

Index — 335

Erysipelothrix rhusiopathiae, 179, 214
erythema induratum of Bazin, 69–70
erythema infectiosum. See parvovirus B19
erythema multiforme-like eruptions,
145–146
erythema nodosum (EN), 70, 75, 145
erythema nodosum leprosum (ENL), 81
erythrasma
in children, 214
clindamycin for, 214
from Corynebacterium minutissimum, 214
in diabetes mellitus, 249
Whitfield’s ointment for, 214
erythromycin
for actinomycosis, 294
for bacillary angiomatosis, 189–190, 198
for cat-scratch disease, 215
for chancroid, 313
for diphtheria, 294
for endemic treponematoses, 216
for erythrasma, 249
for granuloma inguinale, 315
for pitted keratolysis, 214
for scarlet fever, 212
erythromycin-clindamycin double disk
testing, 20
ethambutol
for cutaneous TB treatment, 73
for pulmonary tuberculosis, 292
Exophiala, 113
Exophiala jeanselmei, 113
extrapulmonary paragonimiasis, 131
extrapulmonary tuberculosis, 5, 59
famciclovir
for congenital herpes simplex, 30
for genital herpes, 319
for herpes simplex virus, 200, 277
for herpes zoster, 31, 264
for HSV-1/HSV-2, 250
for varicella zoster virus, 31, 201
for VZV, 187
Fasciola gigantica, 127, 130
Fasciola hepatica, 127, 130
fascioliasis, 130
fetal toxoplasmosis, 222
Fibula nolitangere touch me not
sponge, 174
filariasis, 123–124, 150
Filoviridae virus, 153
fingernail onychomycosis, 51
Finsen, Niels, 59
fish and aquatic dermatoses, 177–178
5-fluorocytosine
with amphotericin B
for aspergillosis/cryptococcosis/
candidiasis, 114
for chromoblastomycoses, 156
5-fluorouracil injectable gel
for condyloma acuminata, 188
for oral florid papillomatosis, 281
flat warts (verrucae plana), 25
treatment, 25
Flaviviridae genus, 151, 152

flaviviruses. See Dengue fever; hepatitis C
virus
flea-borne diseases, 231–232
fluconazole
for Balamuthia mandrillaris, 122
for coccidioidomycosis, 192
for cryptococcosis, 112
for cutaneous cryptococcus, 191
for entomophthoromycosis, 111
with 5-fluorocytosine, for candidiasis/
cryptococcosis, 114
for pityriasis versicolor, 53
for sporotrichosis, 102
for tinea capitis, 217, 258
fluconazole (oral)
adverse effects, 47
for candidiasis, 191
for cryptococcal meningitis, 47
for dermatophyte fungal infections, 248
for old world leishmaniasis, 120, 143
for onychomycosis, 191
for oropharyngeal/esophageal
candidiasis, 47
for pityriasis versicolor, 53
for tinea capitis, 51
for tinea corporis/cruris/faciei, 50–51
for tinea unguium (onychomycosis), 52
for vaginal candidiasis, 47, 248
flucytosine
for Balamuthia mandrillaris, 122
for cryptococcosis, 112
Fluorescent In Situ Hybridization (FISH), 5
fluoroquinolones
for anthrax, 295
for CA-MRSA, 20
for cellulitis/erysipelas, 234
for malignant otitis externa, 251
for nocardiosis, 198
follicular zoster, 186
folliculitis, 17
in AIDS/HIV, 186, 189
in athletes, 239
carbuncles in, 234
in elderly patients, 234–235
eosinophilic pustular folliculitis, 261
in HIV, 189
hot tub folliculitis, 19, 240
pitfalls and myths of, 21
in scalp infections, 260
eosinophilic pustular (EPF), 261
staphylococcal, 260–261
therapies for, 20
folliculitis decalvans, 262–263
folliculitis keloidalis (acne keloidalis), 262
Fonsecaea compacta dematiaceus fungus,
98–99, 156
Fonsecaea pedrosoi dematiaceus fungus,
98–99, 156
Fonseca’s disease. See chromoblastomycosis
foscarnet
for CMV, 187
for herpes simplex virus, 200
for HSV (in acyclovir-resistant patients),
186

Foshay test, 4
Fournier’s gangrene, 8
in diabetes mellitus, 251
treatment, 252
free living amebas, 121–122
Frei’s test, 4
fulminant meningococcal disease
(Waterhouse-Friderichsen
syndrome), 323
fungal infections (common)
diagnostic procedures, 43–44
epidemiology, 42–43
historical background, 42
pitfalls and myths, 53
therapy, 44 (See also antifungal
medications)
fungal infections (deep)
general information, 96
historical background, 96
opportunistic cutaneous infections, 114
pitfalls and myths, 114–116
subcutaneous mycosis
chromomycosis, 98–100
mycetoma, 97–98
rhinosporidiosis, 103–104
sporotrichosis, 100–102, 193
systemic mycosis
blastomycosis (North American),
105–106, 193
cryptococcosis, 111–112, 192
entomophthoromycosis, 110–111
histoplasmosis, 104–105
hyalohyphomycosis, 113–114
mucormycosis, 109–110
paracoccidioidomycosis (S.A.
blastomycosis), 106–109, 192
chronic form (adult type), 107–108
residual/sequel form, 108–109
phaeohyphomycosis, 112–113
zygomycosis, 109
fungal infections in athletes
tinea corporis gladiatorum, 243–244
tinea pedis, 243
fungal infections in children, 216–221
candidiasis, 220–221
piedra, 220
tinea capitis, 217–218
tinea cruris, 218
tinea faceii, 218
tinea imbricata (tokelau), 219
tinea incognito, 218
tinea nigra, 220
tinea unguium (onychomycosis),
218–219
fungal infections in elderly patients
candidiasis, 235–236
onychomycosis, 236
tinea pedis/manum, 236–237
fungal infections in mucous membrane
infections
chronic mucocutaneous candidiasis, 286
endemic mycoses, 288–290
blastomycosis, 289
coccidioidomycosis, 289–290

336 — Index

fungal infections in mucous membrane
infections (cont.)
histoplasmosis, 288–289
paracoccidioidomycosis, 289
nonendemic mycoses, 286–288
aspergillosis, 288
disseminated candidiasis, 286
mucormycosis, 286–287
superficial mycoses/Candida spp., 284–286
fungal infections of HIV infection
aspergillosis, 192
blastomycosis/sporotrichosis, 193
candidiasis, 191
coccidiomycosis, 192
cryptococcus, 191
dermatophytosis, 191
histoplasmosis, 191–192
paracoccidiomycosis, 192
penicilliosis, 192–193
pneumocystosis, 191
fungal infections of the nail unit, 269–273
combined variants of onychomycosis,
272–273
distal/lateral subungual onychomycosis,
270
mid-plate onychomycosis, 272
proximal subungual onychomycosis, 270
relapse of onychomycosis, 273
total dystrophic onychomycosis, 272
white/black superficial onychomycosis,
271–272
fungal infections of the scalp
piedra, 258–259
pityriasis amiantacea, 256
pityriasis capitis, 255–256
seborrheic dermatitis, 255–256
tinea capitis, 256–258
fungating granulomas, 67
fungi
dematieous fungi
Cladosporium carrionii, 156
Fonsecaea compacta, 156
Fonsecaea pedrosoi, 156
Phialophora verrucosa, 156
Rhinocladiella aquaspersa, 98–99, 156
dimorphic fungi
Paracoccidioides brasiliensis, 106–109,
158–159
Sporothrix schenckii, 155, 155
Hortaea werneckii, 154
Lacazia loboi, 102, 157
furuncles, 17. See also carbuncles
in diabetes mellitus, 248
S. aureus as causative, 19
treatment, 20
furunculosis
in athletes, 238–239
in elderly patients, 234–235
in mycobacterium fortuitum complex, 89
Fusarium spp., 113, 270, 271–272
fusidic acid, for scalp cellulitis, 263
gabapentin
for herpes zoster, 235
for post-herpetic neuralgia, 31

Galen, on treatment of ulcerations, 59
ganciclovir (oral), for CMV, 187, 202
Gardnerella (Haemophilus) vaginalis, 295
genital bite wounds, 316–317
genital herpes, 318–319
in AIDS patients, 186
from HSV-2, 27, 276
genital ulcers, 3, 275
genital warts (condyloma acuminatum), 203
clinical manifestations, 26
preventative therapies, 26
treatment, 26
gentamicin antibiotic ointment, for Old
World CL, 143–143
Germ Theory paradigm, 275
gingival stomatitis, 27
gingivitis, acute necrotizing ulcerative,
294–295
Glucantime® (meglumine antimonate), for
Old World CL, 143
glycopeptides, for cellulitis/erysipelas, 234
gnathostomiasis, 126–127
Gnathostomiasis americanum, 126
Gnathostomiasis binucleatum, 126
Gnathostomiasis doloresi, 126
Gnathostomiasis miyasaki, 126
Gnathostomiasis procyonis, 126
Gnathostomiasis spinigerum, 126
Gnathostomiasis turgidum, 126
gonococcal infection, 3
gonorrhea, 315–316
clinical presentation/diagnosis,
315–316, 320
epidemiology, 315
historical background, 310
with HIV, 284
treatment, 316
gram-negative bacteria (in children)
cat-scratch disease, 215
ecthyma gangrenosum, 214–215
ehrlichiosis, 215
gram-positive bacteria (in children)
blistering dactylitis, 212
ecthyma, 211
erysipeloid, 214
erythrasma, 214
impetigo, 211
necrotizing fascitis, 213
orbital/periorbital cellulitis, 213
perianal streptococcal dermatitis, 212
pitted keratolysis, 214
scarlet fever, 212
trichomycosis axillaris, 214
granuloma annulare, 78
granuloma annulare vs. Hansen’s disease
lesions, 78
granulomas
from Aphrodite aculeata (“sea mouse”), 176
candidal, 222
categories, 6
epithelioid, 74, 83
fungating, 67
lymphocytes in, 61
necrotizing, 141
pelvic/peritoneal, 128

pyogenic granulomata, 189, 197
from sea urchins, 173, 180
tuberculoid, 6, 7, 62, 70
granulomatous diseases, 2
entomophthorales infections, 111
fish tank/swimming pool granulomas, 88,
178, 244
granuloma inguinale (donovanosis), 3, 6,
190–191
granulomatous dermatitis, 114
granulomatous meningo-encephalitis,
121
interstitial granulomatous dermatitis,
146–147
lethal midline granulomas, 122, 209, 287
lymphogranuloma venereum (LGV),
191
Majocchi’s disease, 191, 234
mycetoma, 97–98
pbmycosis, 106
Wegner’s granulomatosis, 164
green foot, in athletes, 240
griseofulvin (oral), 47
for tinea capitis, 51, 217, 258
for tinea imbricata (tokelau), 219
group A b-hemolytic streptococci (GABHS)
blistering dactylitis from, 212
ecthyma from, 211
impetigo from, 211
perianal streptococcal dermatitis from,
212
scarlet fever from, 212
gyrate erythema, 78
H. capsulatum, 7
Haemagogus, 152
Haemophilus ducreyi, 312, 313
Haemophilus influenza, 19, 213
hair-cutting (treatment)
for black piedra, 154
for white piedra, 154
HA-MRSA. See hospital associated
methicillin resistant Staphylococcus
aureus
hand, foot, and mouth disease, 35–36,
283–284
Hansen, Gerhard Henrik Armauer, 76
Hansen’s disease (leprosy). See also
borderline lepromatous (BL) disease;
borderline tuberculoid (BT) leprosy;
lepromatous leprosy (LL)
clinical findings/classification criteria
Ridley-Jopling (classification), 78–80,
83
WHO (classification), 76, 80
epidemiology/microbiology/
transmission, 76–77
historical background, 76
hypersensitivity reactions, 80–82
immunology/pathogenicity, 77
laboratory tests, 82–83
pathology, 83–84
pitfalls/myths about, 86–87
treatment/therapy, 84–86
Hapalochlaena maculosa octopus, 174

Index — 337

helminths, 123–131
cestodes, 128–130
coenurosis, 129–130
cysticercosis, 129
echinococcosis, 129
sparganosis, 129
nematodes, 123–128
cutaneous larva migrans, 124–125
dracunculiasis, 124–125
enterobiasis, 128
filariasis, 123–124
gnathostomiasis, 126–127
loiasis, 124
mansonelliasis, 128
onchocerciasis, 124
trichinellosis, 127–128
trematodes, 130–131
fascioliasis, 130
paragonimiasis, 131
schistosomiasis, 130
b-hemolytic Group A streptococci, 250
hemorrhagic fevers, 92, 151, 153. See also
South American hemorrhagic fevers
hepatitis A virus (HAV), 36
hepatitis B virus (HBV), 35
clinical manifestations, 35
diagnosis, 35
treatment, 35
hepatitis C virus (HCV), 37
clinical manifestations, 37
treatment, 37
Hermodice carunculata polychaetes, 176
herpangina, 36, 276, 282–283
herpes labialis, 27, 240, 276
herpes simplex virus (HSV)
in athletes
activation, 240
skin-to-skin transmission, 240–241
chronic ulcerative, 30
generalized acute mucocutaneous, 30
in immunosuppressed patients, 29–30
in scalp infections, 264
systemic, 30
herpes simplex virus 1 (HSV-1)
clinical manifestations, 27
diagnosis, 27
in HIV infection, 186
in mucous membrane infections, 276–278
in transplantation recipients, 199–200
treatments, 29
viral properties, 27
herpes simplex virus 2 (HSV-2)
clinical manifestations, 29
in HIV infection, 186
in mucous membrane infections, 276–278
in transplantation recipients, 199–200
treatments, 29
viral properties, 29
herpes virus, various presentations of
chickenpox, 30
congenital HSV, 30
cytomegalovirus (HHV-5), 33
Epstein-Barr virus (HHV-4), 31–32
human herpes virus 7, 33
in-utero infections

congenital varicella syndrome, 30
infantile zoster, 31
neonatal varicella, 31
Kaposi sarcoma (HHV-8), 33–34
roseola infantum (HHV-6), 33
treatment, 30
varicella zoster (HHV-3), 30
zoster (shingles), 31–32
herpes virus B (herpes simiae), 34
herpes zoster virus (HSV), 3, 30, 207
in AIDS patients, 186
diagnosis, 31
in elderly patients, 235
pediatric manifestations
eczema herpeticum, 225–226
gingivostomatitis, 225
herpes gladiatorum, 226–227
herpetic whitlow, 226
in scalp infections, 264
treatment, 31
vaccination for, 31, 235
herpetic folliculitis, in AIDS patients, 186
herpetic whitlow, 186, 226
HHV 4. See Epstein-Barr virus (EBV)
HHV-8. See Kaposi’s sarcoma (KS)
highly active antiretroviral therapy
(HAART)
causative for varicella zoster virus, 186
for folliculitis, 189
for HIV, 185, 310
for oral hairy leukoplakia, 187
for penicilliosis, 193
Hippocrates, 275
histoid leprosy, 80
Histoplasma, 3
Histoplasma capsulatum, 104
Histoplasmin test, 4
histoplasmosis, 104–105
diagnosis, 104
in HIV infection, 191–192
in mucous membrane infections,
288–289
oral itraconazole for, 47
treatment, 104–105
vs. molluscum contagiosum, 187
historical background
of AIDS, 185
of arthropod-borne infections, 92–93
of athlete skin infections, 238
of atypical mycobacterioses, 88
of bacterial/viral disease in transplant
recipients, 195
of cancer patients and skin infections,
206
of common bacterial infections, 18–19
of common fungal infections, 42
of cutaneous tuberculosis, 59
of HIV-related skin infections, 185
of Kaposi sarcoma, 185
of life-threatening skin infections, 322
management principles, 8
of mucous membrane infections, 275
of Old World cutaneous leishmaniasis,
135
of parasitology, 117

of pediatric skin infections, 211
of sexually transmitted diseases, 309–310
of skin surgery-related infections, 303
History of Animals (Aristotle), 117
HIV-related skin infections. See also sexually
transmitted diseases (STDs) and HIV
skin infections
acute exanthem
cytomegalovirus, 187
Epstein-Barr virus, 187
herpes simplex virus (types 1
and 2), 186
human herpes virus 8, 188–189
pox virus, 187
varicella-zoster virus, 186–187
bacterial infections
bacillary angiomatosis, 189–190
folliculitis, 189
impetigo, abscesses, cellulitis,
necrotizing fascitis, 189
mycobacterial infections, 189
co-infections
cutaneous lesions of histoplasmosis,
104
cutaneous tuberculosis, 59, 72
with Mycobacterium leprae, 83
diagnosis, 38
fungal infections
aspergillosis, 192
blastomycosis/sporotrichosis, 193
candidiasis, 191
coccidiomycosis, 192
cryptococcus, 191
dermatophytosis, 191
histoplasmosis, 191–192
paracoccidiomycosis, 192
penicilliosis, 192–193
pneumocystosis, 191
historical background, 185
mucous membrane infections, 284
parasitic/ectoparasitic infections
acanthamebiasis, 193–194
demodicidosis, 193
leishmaniasis, 194
scabies, 193
from sexually transmitted diseases
(STDs)
granuloma inguinale (donovanosis),
190–191
lymphogranuloma venereum (LGV),
191
syphilis, 190
HLA-DQ1 association with lepromatous
leprosy, 77
Horta, Parreiras, 151
Hortaea werneckii fungus, 154
hospital associated methicillin resistant
Staphylococcus aureus
(HA-MRSA), 19
hospital gangrene. See necrotizing fascitis
hot-tub folliculitis, 19, 20, 240, 261
human African trypanosomiasis (sleeping
sickness), 122–123
human granulocytic anaplasmosis (HGA),
215

338 — Index

human herpes virus 3 (HHV-3). See varicella
zoster virus
human herpes virus 4 (HHV-4). See EpsteinBarr virus
human herpes virus 5 (HHV-5). See
cytomegalovirus
human herpes virus 6 (HHV-6). See roseola
infantum
human herpes virus 7 (HHV-7), 33
human herpes virus 8 (HHV-8). See Kaposi’s
sarcoma
human monocytic ehrlichiosis (HME), 215
human papillomavirus (HPV)
anogenital disease
bowenoid papulosis, 26
condyloma acuminatum, 26, 188
verrucous carcinoma, 26–27
in HIV infection, 187–188
low risk/high risk subtypes, 188
in mucous membrane infections, 280–281
nongenital cutaneous diseases
Butcher’s warts, 26
common warts (verruca vulgaris), 25
epidermodysplasia verruciformis
(EV), 25–26
flat warts (verrucae plana), 25
palmoplantar warts (myrmecia), 25
nongenital mucosal disease
oral focal hyperplasia (Heck disease),
27
in transplantation recipients, 203
Hutchinson, Jonathan, 59
hyalohyphomycosis, 113–114
causative agents, 113
treatment, 113–114
hydroids, reactions to, 172
hyperbaric oxygenation, 9
hyperglycemia control for diabetes skin
infections, 249, 251, 252
hyper-IgE syndrome, 222
hyperimmune globulin, for South American
hemorrhagic fevers, 153
IgG immunoglobulin, 9
IL-8 cytokine association with lepromatous
leprosy, 77
IL-12 cytokine association with lepromatous
leprosy, 77
imidazoles
for localized Candida, 286
for piedra, 259
imipenem, for nocardiosis, 198
imiquimod (topical)
for condyloma acuminata, 188
for molluscum contagiosum, 187
for Old World CL, 144
for verrucae vulgaris/condyloma
acuminatum, 203
immune reconstitution inflammatory
syndrome (IRIS), 186
immunoglobulin (IV)
for staphylococcal TSS, 325
for streptococcal TSS, 326
impetigo, 18
in athletes, 238

in children, 211
diagnosis, 20
in elderly patients, 234–235
in HIV, 189
S. aureus/S. pyogenes causative for, 19
in scalp infections, 261–262
treatment, 20
In Situ Hybridization (ISH), 5
Indians, and lepromatous leprosy, 77
Indo-Aryans, 59
induration (as sign of acute infection), 8
infections diseases, diagnostic techniques
culture, 3
intradermal reactions, 3–4
molecular biology, 5–6
sample collection, 2
serology, 4–5
skin biopsy, 6–7
smears, 2–3
infestations of children, 230–232
bedbugs, 232
blister beetles, 232
caterpillars and moths, 232
fleas, 231–232
mites, 230–231
papular urticaria, 231
pediculosis, 230
scorpions, 231
spiders, 231
stinging insects, 232
insect repellants. See DEET (N,N-diethyl-3methylbenzamide) mosquito repellant
interferon a
for condyloma acuminata, 188
for hepatitis B, 35
for KS, 34
interstitial granulomatous dermatitis,
146–147
intradermal reactions, 3–4
intraepidermal abscesses (in
chromomycosis), 99
intralesional interferon
for KS, 280
for verrucae vulgaris/condyloma
acuminatum, 203
intralesional vinblastine, for KS, 34, 280
in-utero herpes infections
congenital varicella syndrome, 30
infantile zoster, 31
neonatal varicella, 31
isoniazid
for cutaneous TB treatment, 73
for pulmonary tuberculosis, 292
isotretinoin
for erosive pustular dermatosis of
scalp, 263
for scalp cellulitis, 263
Ito Reenstierna test, 4
itraconazole
for candidiasis, 191
for coccidioidomycosis, 192
for cutaneous cryptococcus, 191
for entomophthoromycosis, 111
for histoplasmosis, 192
for hyalohyphomycosis, 113

for lobomycosis, 158
for mycetoma, 157
for Old World CL, 143
for onychomycosis, 191
for paracoccidioidomycosis, 109, 159
for protothecosis, 175
for tinea capitis, 217, 258
itraconazole (oral), 47
adverse effects, 47
for North American blastomycosis,
105–106
for penicilliosis, 193
for pityriasis versicolor, 53
for sporotrichosis, 102
for tinea capitis, 51, 51
for tinea corporis/cruris/faciei, 50–51
for tinea pedis/manuum, 47–50
for tinea unguium (onychomycosis), 52,
236
for toenail onychomycosis, 52
itraconazole (topical), for tinea nigra, 154–155
ivermectin
for demodicidosis, 260
with doxycycline for onchocerciasis, 124
for filariasis, 124
for gnathostomiasis, 127
for loiasis, 124
for mansonelliasis, 128
for onchocerciasis, 124
for onchocercosis, 176
for scabies, 193, 260, 317–318
Ixodes pacificus, 215
Ixodes scapularis, 215
jellyfish, reactions to, 168–169
Jones, Joseph, 8
Jorge Lobo’s disease. See keloidal
blastomycosis
K. rhinoscleromatis, 7, 7
Kaposi’s sarcoma (KS), 5, 33–34
clinical manifestations, 33
diagnosis, 34
historical background, 185
in HIV infection, 188–189
in mucous membrane infections, 280
in transplantation recipients, 202
treatment, 34
Katayama syndrome, 130
keloidal blastomycosis, 102, 157
ketoconazole
for entomophthoromycosis, 111
for Old World CL, 143
for paracoccidioidomycosis, 109
for pityriasis versicolor, 53
for tinea capitis, 51, 258
for tinea corporis/cruris/faciei, 50
for tinea pedis/manuum, 47
ketoconazole (oral), 47
adverse effects, 47
for dermatophyte fungal infections, 248
for North American blastomycosis,
105–106
for pityriasis versicolor, 53
for protothecosis, 175

Index — 339

ketoconazole (shampoo), 256
for tinea capitis, 217, 218
for tinea corporis gladiatorum, 244
ketoconazole (topical)
for tinea nigra, 154–155
for tinea pedis/manuum, 47–50, 236
for white piedra, 154
Klebsiella pneumoniae, 19
Koch, Robert, 59
KOH preparations, 2–3
L. loboi (lobomycosis), 3, 7
Lacazia loboi fungus, 102, 157
Laennec, Rene, 59
larva currens, 126
larva migrans cutanea, 176–177
laser treatment
for Bowenoid papulosis, 26
for condyloma acuminata, 188
for folliculitis keloidalis, 262
for oral florid papillomatosis, 281
for pseudofolliculitis barbae, 216
for rhinoscleroma, 294
for verrucae vulgaris/condyloma
acuminatum, 203, 228
Lassa fever, 153
Latruncula magnifica red sponge, 174
Laws of Manu, 59
Leão, Arêa, 151
leeches, reactions to, 176
Legionella, 4
Leishman, W. B., 135
Leishmania aethiopica, 117–118
Leishmania amazonensis, 119, 161
Leishmania braziliensis (viannia), 117, 120,
150, 160–161
Leishmania chagasi, 119
Leishmania donovani, 117, 119
Leishmania guyanensis, 161
Leishmania infantum, 117–118, 119
Leishmania major, 117–118
Leishmania mexicana, 117
Leishmania panamensis, 120
Leishmania peruviana, 117
Leishmania tropica, 117
leishmaniasis, 92, 117–121. See also anergic
leishmaniasis; mucocutaneous/
tegmental leishmaniasis; Old World
cutaneous leishmaniasis
classifications
cutaneous leishmaniasis, 117
diffuse cutaneous, 4
lupus leishmaniasis, 74
mucocutaneous leishmaniasis, 119
new world leishmaniasis, 118–121
old World leishmaniasis, 117–118
clinical manifestations, 161, 296
diagnosis, 120
in HIV infection, 194
in Texas, borne by sandflies, 92
treatment, 120–121
vacuolated histiocytes with
lymphoplasmacytic infiltrate
in, 6
visceral, 4

Leishmanin test (Montenegro test), 4
lepromatous leprosy (LL), 4, 7, 77, 79
histopathology, 83
HLA-DQ1 association, 77
Lucio’s phenomenon in, 82
oral lesions in, 292
resemblance to disseminated
coccidioidomycosis, 147
Lepromin test, 4
leprosy. See Hansen’s disease
Leptospira, 4
Letterer-Siwe syndrome, 74
lichen scrofulosorum (LS), 68–69, 75
lidocaine (topical)
for herpes zoster, 235
for HSV, 277
for oral infections, 275, 277
for post-herpetic neuralgia, 31
life-threatening skin infections
historical background, 322
meningococcal disease, 322–323
Rocky Mountain spotted fever, 92,
323–324
staphylococcal toxic shock syndrome,
324–325
streptococcal toxic shock syndrome,
325–327
ligase based method (of PCR), 5
lindane
for demodicidosis, 260
for pediculosis capitis, 259
for scabies, 260
topical, for scabies, 317–318
linear streaking along lymphatics (as sign of
acute infection), 8
linezolid
for impetigo/folliculitis/furunculosis,
235–234
for MRSA strains, 20
for nocardiosis, 198
for S. aureus, 196
Linuche unguiculata jellyfish, 171–172
Loa loa, 124
Lobo, Jorge, 102, 151
lobomycosis, 102–103, 151
diagnosis, 103
treatment, 103
loiasis, 124
lower extremity cellulitis, pitfalls and
myths, 21
Lucio’s phenomenon, 82, 84, 85
lupoid rosacea, 74
lupus leishmaniasis, 74
lupus vulgaris, 59, 62–64, 74, 78
Lutz, Adolpho, 151
Lutzomyia genera, 117
Lyme disease, 92, 95, 215
lymphadenopathy (as sign of acute
infection), 8
lymphogranuloma venereum (LGV), 309,
313–314
Lyngbya majuscola seaweed, 174
macrolides
for atypical mycobacterioses, 90

for Balamuthia mandrillaris, 122
for perianal streptococcal dermatitis, 212
Madurella mycetomatis grains, 156
Majocchi’s granuloma, 191
malaria, 92, 93, 95, 150
Malassezia globosa yeast, 256
Malassezia restricta yeast, 256
malathion
for pediculosis capitis, 259
for public lice, 318
malignant otitis externa, 251
malignant skin infections
angiosarcoma, 209
breast cancer, inflammatory, 208–209
cancers metastatic to skin, 210
keratoacanthoma, 209–210
lethal midline granuloma, 209
leukemia cutis, 208
lymphoma, 208
squamous cell cancer, 209
Stewart-Treves syndrome, 209
verrucous carcinoma, 209
management principles
clinical diagnosis, 8
historical background, 8
laboratory diagnosis, 8
myths/pitfalls, 9–13
treatment, 8–9
Mansonella ozzardi, 128
Mansonella perstans, 128
Mansonella streptocerca, 128
mansonelliasis, 128
Mantoux test, 4
maprotiline, for post-herpetic neuralgia,
31
Marburg/Ebola virus, 153
Masters of the Salerno School of Medicine,
59
Mastomys natalensis rodent, 153
measles/rubeola, 36–37
clinical manifestations, 36
diagnosis, 37
in mucous membrane infections, 283
ProQuad vaccine for, 278
treatment, 37
mebendazole
for dracunculiasis, 125
for enterobiasis, 128
for trichinellosis, 128
melarsoprol, for trypanosomiasis, 123
Meleney’s ulcer, 8
meningococcal conjugate
vaccine A, C, Y, W-135, 323
meningococcal disease
clinical manifestations, 322–323
diagnosis, 323
management, 323
pitfalls and myths, 327
meningoencephalitis, 152, 152
methicillin, introduction of, 19
methicillin resistant Staphylococcus aureus
(MRSA), 19, 20, 189, 195, 238, 262
methicillin sensitive Staphylococcus aureus
(MSSA), 19, 195
N-methylglucamine, for leishmaniasis, 164

340 — Index

methylprednisolone, for post-herpetic
neuralgia, 31
metronidazole
for acute necrotizing ulcerative
gingivitis, 295
for bacterial vaginosis, 295
for demodicidosis, 260
for dracunculiasis, 125
IV/oral, for enteric amebiasis, 121
for noma, 295
for trichomoniasis, 296
miconazole
for erythrasma, 249
for hyalohyphomycosis, 113
for pityriasis versicolor, 53
for tinea corporis/cruris/faciei, 50
for tinea pedis/manuum, 47
topical, for tinea nigra, 154–155
miconazole nitrate 1%, for tinea pedis/
manuum, 47
microbial paronychial infections, 268
Microciona prolifera sponge, 174
Micrococcus (Kytococcus) sedentarius, 214
Micrococcus spp., 189
Microsporum audouinii, 256
Microsporum canis, 256
Microsporum distortum, 256
mid-plate onychomycosis, 272
Miller’s nodules (Paravaccinia)
clinical manifestations, 24
diagnosis, 24
treatment, 24
miltefosine, for Old World CL, 144
minocycline. See also ROM therapy
for atypical mycobacteria, 244
for mycobacterium marinum, 179
for nocardiosis, 198
Mitsuda lepromin antigen, 4
MMR (measles, mumps, rubella)
vaccination, 283
Moh’s surgery, 303, 305
molecular biology, 5–6
molluscum contagiosum virus (MCV),
7, 23
in athletes, 241–242
in children, 228–229
clinical manifestations, 23
in HIV infection, 187
in mucous membrane infections, 281
in transplantation recipients, 202–203
treatment, 23
mollusks and aquatic dermatoses, 174
monkeypox, in children, 229
Montenegro, João, 151
Montenegro test (Leishmanin test), 4
Mosquito Magnet (mosquito trap), 95
mosquito vectors
of Barmah Forest virus, 153
of mucocutaneous/tegmental
leishmaniasis, 161
of West Nile virus, 152
of Yellow fever, 152
moths and caterpillars, 232
mouse-borne diseases, 92

mouth rinses with topical anesthetic agents,
for HSV 1/2 infections, 277
MRSA. See methicillin resistant
Staphylococcus aureus
mucocutaneous/tegmental leishmaniasis,
160–164
clinical manifestations, 161–164
diagnosis, 164
mosquito vectors, 161
transmission, 161
treatment, 164
Mucorales (Zygomycosis), 109
mucormycosis, 7, 109–110. See also
rhinocerebral mucormycosis
clinical patterns, 109, 287
diagnosis, 287
treatment, 110, 287
mucous membrane infections
bacterial infections, other
actinomycosis, 294
acute necrotizing ulcerative gingivitis,
294–295
anthrax, 295
bacterial vaginosis, 295
diphtheria, 293–294
mycoplasma pneumoniae, 296
noma (cancrum oris/gangrenous
stomatitis), 295
pseudomonas aeruginosa, 295
rhinoscleroma, 294
staphylococcus, 293
streptococcus, 293
tetanus, 296
DNA viruses
Epstein-Barr virus, 278–279
human papilloma virus,
280–281
human simplex 1 and 2,
276–278
Kaposi’s sarcoma, 280
molluscum contagiosum, 281
parvovirus B19, 281
roseola infantum, 279–280
varicella zoster, 278
fungal infections
chronic mucocutaneous candidiasis,
286
endemic mycoses, 288–290
blastomycosis, 289
coccidioidomycosis, 289–290
histoplasmosis, 288–289
paracoccidioidomycosis, 289
nonendemic mycoses, 286–288
aspergillosis, 288
disseminated candidiasis, 286
mucormycosis, 286–287
superficial mycoses/Candida spp.,
284–286
historical background, 275
mycobacterial infections
leprosy, 292–293
mycobacterium avium intracellulare,
292
tuberculosis, 292

protozoa
leishmaniasis, 296–297
trichomoniasis, 296
RNA retroviruses, 284
HIV, 284
human T-lymphotropic virus, 284
RNA viruses, 281–284
hand-foot-and-mouth disease, 281–282
herpangina, 282–283
measles, 283
mumps, 283
rubella, 283–284
sexually transmitted bacterial infections
spirochetes, 291
syphilis, 291–292
mumps
in mucous membrane infections, 283
ProQuad vaccine for, 278
mupirocin (topical)
for folliculitis, 20, 239
for impetigo, 20, 211
for nasal carriage, 21
for S. aureus in transplant recipients, 196
mycetoma, 97–98, 156–157
Mycobacterium abscessus, 3
Mycobacterium africanum, 60
Mycobacterium avium complex, 89, 292
Mycobacterium avium-intracellulare
lymphadenitis, 64, 74
Mycobacterium bovis, 60, 64. See also
scrofuloderma
Mycobacterium chelonae, 3
Mycobacterium chelonae-Mycobacterium
abscessus complex, 89
Mycobacterium fortuitum, 3
Mycobacterium fortuitum complex, 89
Mycobacterium kansasii, 4, 88
Mycobacterium leprae, 3, 4, 5, 7, 60, 76,
292–293. See also Hansen’s disease
Mycobacterium marinum, 7, 67, 88, 173,
178–179
Mycobacterium microti, 60
Mycobacterium scrofulaceum, 4, 64, 74, 89
Mycobacterium tuberculosis, 3, 4, 6, 7, 60, 61.
See also cutaneous tuberculosis
causative for tuberculosis, 292
classification, 62
diagnosis, 61–62
histopathology, 70–71
HIV and, 72
PCR for, 189
Mycobacterium ulcerans, 3–5, 7
mycoplasma pneumoniae, 296
Mycosel anaerobes, 3
Naegleria spp., 121
naftifine hydrochloride 1%, for tinea pedis/
manuum, 47
nail unit infections
fungal infections, 269–273
combined variants of onychomycosis,
272–273
distal/lateral subungual
onychomycosis, 270

Index — 341

mid-plate onychomycosis, 272
proximal subungual onychomycosis,
270
relapse of onychomycosis, 273
total dystrophic onychomycosis,
272
white/black superficial
onychomycosis, 271–272
historical background, 268
paronychial infections
acute, 268–269
chronic, 269
microbial, 268
pitfalls and myths, 273
structure of nail unit, 268
necrosis (as sign of acute infection), 8
necrosis lipoidica vs. Hansen’s disease
lesions, 78
necrotizing fascitis, 8
in children, 213
in diabetes mellitus, 250
differentiation of via creatinine
phosphokinase, 8
in elderly patients, 235
in HIV, 189
HIV infection and, 189
medication for
cefoperazone sodium, 213
clindamycin for, 213
creatinine phosphokinase, 213
in transplant recipients, 197
Neisseria gonorrhoeae, 2, 315, 316
Neisseria meningitidis, 4, 322, 322
nematocysts of coelenterates, 168
nematodes, 123–128
and aquatic dermatoses, 176–177
cutaneous larva migrans, 124–125
dracunculiasis, 124–125
enterobiasis, 128
filariasis, 123–124
gnathostomiasis, 126–127
loiasis, 124
mansonelliasis, 128
onchocerciasis, 124
trichinellosis, 127–128
new world leishmaniasis, 118–121
nifurtimox
for American trypanosomiasis, 123
for Chagas’ disease, 160
N-methylglucamine, for leishmaniasis, 164
nocardia, 2, 198, 264
Nocardia asteroides, 198
Nocardia brasiliensis, 97, 156
nocturnal pruritus, 260
noma (cancrum oris/gangrenous
stomatitis), 295
non-bullous impetigo, 211
nongenital cutaneous diseases
Butcher’s warts, 26
common warts (verruca vulgaris), 25
epidermodysplasia verruciformis (EV),
25–26
flat warts (verrucae plana), 25
palmoplantar warts (myrmecia), 25

nonsteroidal anti-inflammatory drugs
(NSAIDs)
association with gangrene, 8
for ENL treatment, 84
for HSV 1 and 2 infections, 277
for HSV infection, 277
for multibacillary/paucibacillary
disease, 84
North American blastomycosis, 6, 105–106
diagnosis, 105
treatment, 105–106
Nucleic Acid Sequence-based Amplification
(NASBA), 5
nucleoside reverse transcriptase inhibitors
(NRTIs), 38
Occult amigdalitis paracoccidioica, 107
Ochlerotatus mosquito, 152, 153
Octopus vulgaris, 174
olamine (topical)
for tinea pedis/manuum, 47
for white piedra, 154
Old World cutaneous leishmaniasis (CL),
117–118
clinical presentation, 138–140
diagnosis, 140–141
epidemiology, 135–136
historical background, 135
patient follow-up, 144
prevention, 137–138
transmission: sandfly vector/Leishmania
lifecycle, 136–137
treatment, 141–144
Onchocerca skin test, 4
Onchocerca volvulus, 124, 175
onchocerciasis, 123, 124, 175–176
onychomycosis. See also tinea unguium
dermatophyte onychomycosis, 47, 52
distal subungual onychomycosis, 236
distal/lateral subungual, 270
mid-plate, 272
proximal subungual, 270
relapse of, 273
total dystrophic, 272
white/black superficial, 271–272
opiates, for herpes zoster, 235
oral hairy leukoplakia (OHL), 187
orbital cellulitis, 213, 287
orf virus, 81.10
organomegaly, 130
orificial tuberculosis, 67–68, 74–75
oropharyngeal candida (thrush), 221
oropharyngeal/esophageal candidiasis, 47
otitis externa (malignant), 246, 251–252
oxygen therapy, for Dengue fever, 152
P. braziliensis (South American
blastomycosis). See
paracoccidioidomycosis
Paecilomyces spp., 113
PAIR ((percutaneous aspiration, infusion
of scolicidal agents, respiration))
procedure, 129
palmoplantar warts (myrmecia), 25

Panstrongylus megistus parasite, 160
papular urticaria, 231
papulonecrotic tuberculids, 68, 75
Paracentrotus lividus sea anemone, 172
paracoccidioidomycosis (South American
blastomycosis), 6, 106–109, 158–159
acute/subacute form (childhood/juvenile
type), 106–107
chronic form (adult type), 107–108
clinical manifestations, 106, 158
diagnosis, 108, 158–159
discovery of, 151
in HIV infection, 192
in mucous membrane infections,
289–290
residual/sequel form, 108–109
treatment, 108–109, 159
paragonimiasis, 131. See also
extrapulmonary paragonimiasis;
scrotal paragonimiasis
Paragonimiasis westermani, 131
Paramyxoviridae virus, 153
parasitic infections of the scalp
demodicidosis, 260
pediculosis capitis, 259–260
scabies, 260
parasitology
helminths, 123–131
cestodes, 128–130
nematodes, 123–128
trematodes, 130–131
historical background, 117
pitfalls and myths, 131
protozoa
enteric amebiasis, 121
free living amebas, 121–122
leishmaniasis, 117 (see also
leishmaniasis)
trypanosomiasis, 122–123
parenteral penicillin, for congenital syphilis,
223
Parinaud’s oculoglandular syndrome, 215
PARK2 promoter region, association with
Hansen’s disease, 77
paromomycin (topical), for Old World CL,
143
paronychial infections of the nail unit
acute, 268–269
chronic, 269
microbial, 268
parvovirus B19, 35
clinical manifestations, 34
diagnosis, 35
in mucous membrane infections, 281
treatment, 35
paucibacillary disease treatment guidelines
(WHO), 84
pbmycosis. See paracoccidioidomycosis
(South American blastomycosis)
PCR. See polymerase chain reaction (PCR)
pediatric infestations, 230–232
bedbugs, 232
blister beetles, 232
caterpillars and moths, 232

342 — Index

pediatric infestations (cont.)
fleas, 231–232
mites, 230–231
papular urticaria, 231
pediculosis, 230
scorpions, 231
spiders, 231
stinging insects, 232
pediatric periorbital cellulitis, 19
pediatric skin infections
clinical infections
angular cheilitis (perleche), 221
chronic mucocutaneous candidiasis
(CMC), 221–222
chronic paronychia, 221
congenital candidiasis, 221
diaper dermatitis (monilial diaper
dermatitis), 221
invasive fungal dermatitis, 221
oropharyngeal candida (thrush), 221
spontaneous intestinal perforation, 221
systemic candidiasis, 221
congenital infections, 222–225
cytomegalovirus, 224
neonatal HSV, 225
parvovirus B19, 225
rubella, 223–224
syphilis, 222–223
varicella zoster, 225
eosinophilic pustula folliculitis, 216
fungal infections, 216–221
dermatophytes
candidiasis, 220–221
piedra, 220
tinea capitis, 217–218
tinea cruris, 218
tinea faceii, 218
tinea imbricata (tokelau), 219
tinea incognito, 218
tinea nigra, 220
tinea unguium (onychomycosis),
218–219
gram-negative bacteria, 214–215
cat-scratch disease, 215
ecthyma gangrenosum, 214–215
ehrlichiosis, 215
gram-positive bacteria, 211–214
blistering dactylitis, 212
ecthyma, 211
erysipeloid, 214
erythrasma, 214
impetigo, 211
necrotizing fascitis, 213
orbital/periorbital cellulitis, 213
perianal streptococcal dermatitis, 212
pitted keratolysis, 214
scarlet fever, 212
trichomycosis axillaris, 214
historical background, 211
infestations, 230–232
bedbugs, 232
blister beetles, 232
caterpillars and moths, 232
fleas, 231–232
mites, 230–231

papular urticaria, 231
pediculosis, 230
scorpions, 231
spiders, 231
stinging insects, 232
pseudofolliculitis barbae, 216
spirochetes, 215–216
endemic treponematoses, 215–216
Lyme disease, 215
viral diseases
HSV manifestations
eczema herpeticum, 225–226
gingivostomatitis, 225
herpes gladiatorum, 226–227
herpetic whitlow, 226
molluscum and poxviridae, 228–229
monkeypox, 229
vaccinia and variola, 229–230
verruca, 227–228
pediatric streptococcal dermatitis, 212
pediculosis, 154, 230
pediculosis capitis (of the scalp), 259–260
Pediculosis humanus capitis parasite, 259
pediculosis pubis, 318
Pedroso and Lane’s mycosis. See
chromoblastomycosis
peginterferon a for hepatitis C virus, 37
pegylated interferon + ribavirin for hepatitis
C virus, 37
Pelagia noctiluca jellyfish, 168
Pelodera strongyloides, 125
penciclovir, for herpes labialis, 277
penicillin
for actinomycosis, 294
for acute necrotizing ulcerative
gingivitis, 295
for anthrax, 295
anti-pseudomonal, for ecthyma
gangrenosum, 215
for cellulitis/erysipelas, 234
for erysipeloid, 214
for folliculitis keloidalis, 262
for impetigo/folliculitis/furunculosis,
235–234
introduction of, 18
with metronidazole
for Fournier’s gangrene, 252
for necrotizing fascitis, 252
for noma, 295
for perianal streptococcal dermatitis, 212
for S. pyogenes caused erysipelas, 20
for scarlet fever, 212
for streptococcal pharyngitis, 293
penicillin G, for syphilis, 223, 312
penicilliosis, in HIV infection, 192–193
Penicillium marneffei infection, 187
Penicillium spp., 113, 187
pentamidine
for Balamuthia mandrillaris, 122
for enteric amebiasis, 121
for trypanosomiasis, 123
pentavalent antimonials, for leishmaniasis,
164, 297
Pentostam® (sodium stibogluconate), for Old
World CL, 121, 143, 164

pentoxifylline, for ENL treatment, 84
perianal streptococcal dermatitis, in
children, 212
periorbital cellulitis, in children, 213
peripheral neuropathies, from Hansen’s
disease, 76
perleche (angular cheilitis), 221
permethrin (topical)
for demodicidosis, 260
for pediculosis capitis, 259
for public lice, 318
for scabies, 193, 260
phaeohyphomycosis, 112–113
Phialophora verrucosa, 98–99, 113, 156
phlebotominae insects (vectors), 161
Phlebotomus papatasi, 136
Phlebotomus sandfly, 117, 136–137.
See also Old World cutaneous
leishmaniasis (CL)
Phlebotomus sergenti, 136
photodynamic therapy, for Old World CL,
144
Physalia physalis physaliae (Portuguese manof-war), 172
Physalia utriculus physaliae, 172
physaliae, reactions to, 172
picornaviruses
Enteroviruses
hand, foot, and mouth disease, 35–36
hepatovirus: hepatitis A, 36
herpangina, 36
Piedra hortae, 258
piedra nigra, 151, 220
Piedraia hortai, 151
pilocarpine preparations
for leprosy diagnosis, 79
for pubic lice, 318
Pirquet test, 4
pitfalls and myths
of arthropod-borne infections, 95
of athletic skin infections, 244
of atypical mycobacterioses, 90–91
of cancer-related skin infections, 208
of common fungal infections, 53
of cutaneous tuberculosis, 73–75
of deep fungal infections, 114–116
of diabetic skin infections, 251
of elderly patient skin infections, 237
of erysipelas, 21
of folliculitis, 21
of Hansen’s disease, 86–87
of HIV-related skin infections, 90–91
of lower extremity cellulitis, 21
of marine biotic agents, 179–181
of meningococcal disease, 327
of mucous membrane infections, 297
of nail unit infections, 273
of parasitology, 131
of pediatric skin infections, 232
of Rocky Mountain spotted fever, 327
of scalp infections, 264–265
of sexually transmitted disease, 319–320
of skin infections, 9–13
of staphylococcal toxic shock syndrome,
327

Index — 343

of surgical skin infections, 306–307
of tropical infections, 164–165
of viral skin infections, 38
pitted keratolysis
in athletes, 239–240
in children, 214
pityriasis amiantacea (of the scalp), 256
pityriasis capitis (of the scalp), 255–256
pityriasis lichenoides et varioliformis acuta
(PLEVA), 74
pityriasis versicolor (PV), antifungal
medications for, 52–53
PLEVA. See pityriasis lichenoides et
varioliformis acuta (PLEVA)
Pliny the Elder, on tuberculosis, 59
Pneumocystis carinii pneumonia, 185
pneumocystosis
cutaneous, 187
in HIV infection, 191
podophyllin (topical)
for molluscum contagiosum, 187
for oral hairy leukoplakia, 187
podophyllotoxin solution (or resin)
for anogenital warts, 319
for condyloma acuminata, 188
for oral florid papillomatosis, 281
for oral hairy leukoplakia, 279
for verrucae vulgaris/condyloma
acuminatum, 203
polychaetes, dermatitis from, 176
polymerase chain reaction (PCR), 5, 7, 38
posaconazole, 110, 287
potassium iodide (KI)
for entomophthoromycosis, 111
for sporotrichosis, 102
povidone iodine shampoo, for tinea
capitis, 51
pox viruses
Molluscum Contagiosum (MCV), 23
orthopox
cowpox, 24
monkey pox, 24
smallpox, 23
vaccinia, 24
parapox
Miller’s nodules (Paravaccinia), 24
orf, 24
PPD-Y intradermal reaction, 4
praziquantel
for cysticercosis, 129
for fasciolasis, 130
for paragonimiasis, 131
pregabalin, for post-herpetic neuralgia, 31
primary cutaneous coccidioidomycosis,
147–148
primary inoculation tuberculosis
(tuberculosus chancre), 67
progressive hypertrophic familial neuropathy
and Hansen’s disease, 78
Propionibacterium acnes, 262
ProQuad vaccine, for measles/mumps/
varicella, 278
Prototheca green seaweed mutant, 174
Prototheca wickerhamii, 174
protothecosis infection, 174–175

protozoa. See also individual Leishmania
species
Chagas’ disease, 159–160
enteric amebiasis, 121
free living amebas, 121–122
leishmaniasis, 117. See also leishmaniasis
mucocutaneous/tegmental leishmaniasis,
160–164
in mucous membrane infections
leishmaniasis, 296–297
trichomoniasis, 296
trypanosomiasis, 122–123
American trypanosomiasis, 123
human African trypanosomiasis,
122–123
proximal subungual onychomycosis (PSO),
236, 270
Pseudallescheria boydii, 113
pseudoepitheliomatous hyperplasia (in
chromomycosis), 99, 114
pseudolymphoma of the skin, 74
Pseudomonas aeruginosa, 19, 189, 214–215,
251, 295, 303
psoriasis
guttate psoriasis, 211, 212
impetigo infections from, 261
mimicking of
by lupus vulgaris, 74
by onychomycosis, 53
nail dystrophy from, 236
pityriasis amiantacea from, 256
vs. Hansen’s disease lesions, 78
pubic lice, 318
Public Health Service (PHS) paucibacillary
disease treatment guidelines, 84
pulmonary tuberculosis, 5
pustulation (as sign of acute infection), 8
pyrazinamide
for cutaneous TB treatment, 73
for pulmonary tuberculosis, 292
pyrethrin extracts, for pediculosis capitis,
259
pyrithione zinc shampoo, 256
quinine, for tularemia, 95
quinolones
for atypical mycobacterioses, 90
for cellulitis/erysipelas, 234
quinupristin/dalfopristin, for MRSA
strains, 20
Rabello, Francisco, 151
ravuconazole, for mucormycosis, 110
recalcitrant cutaneous dermatophyte, 47
“reinfection” tuberculosis, 60
relapsing fever, 92
repellants for insects. See DEET (N,Ndiethyl-3-methylbenzamide)
mosquito repellant
retapamulin ointment, for impetigo, 20
retinoids (topical)
for Bowenoid papulosis, 26
for KS, 34
for molluscum contagiosum, 229, 264
for pseudofolliculitis barbae, 216

for verrucae vulgaris/condyloma
acuminatum, 203, 228
Rhabdoviridae virus, 153
rhinocerebral mucormycosis, 251
Rhinocladiella aquaspersa dematieous
fungus, 98–99, 156
rhinophycomycosis, 110
rhinoscleroma, 294
rhinosporidiosis, 103–104
Rhinosporidium seeberi, 103
Rhipicephalus sanguineus (Brown dog tick),
323
Rhizomucor pusillus, 109
Rhizopodiformis, 109
Rhizopus arrhizus (oryzae), 109
Rhizopus microsporus var., 109
Rhodnius prolixus parasite, 160
ribavirin
for chronic HCV, 37
for South American hemorrhagic fevers,
153
Rickettsia rickettsii, 323
rickettsial disease, 92, 95, 311
Ridley-Jopling classification of Hansen’s
disease, 78–80, 83
rifampicin
for CA-MRSA, 20
with clindamycin, for scalp cellulitis, 263
for cutaneous TB treatment, 73
for multibacillary disease, 84
for nasal carriage issues, 21
for Old World CL, 144
for paucibacillary disease, 84
for rhinoscleroma, 294
rifampin
for actinomycetoma management, 98
for atypical mycobacteria, 244
for cat-scratch disease, 215
for cutaneous tuberculosis, 73
for ehrlichiosis, 215
for leprosy, 293
for meningococcal disease, 323
for multibacillary disease, 84
for pulmonary tuberculosis, 292
Rig Veda, 59
RNA retroviruses in mucous membrane
infections
HIV, 284
human T-lymphotropic virus, 284
RNA viruses
flaviviruses: hepatitis C, 37
in mucous membrane infections, 281–284
hand-foot-and-mouth disease,
281–282
herpangina, 282–283
measles, 283
mumps, 283
rubella, 283–284
paramyxoviruses: rubeola/measles, 36–37
picornaviruses
enteroviruses
hand, foot, and mouth disease,
35–36
hepatovirus: hepatitis A, 36
herpangina, 36

344 — Index

RNA viruses (cont.)
retroviruses: HIV, 37–38
togaviruses: rubella (German
measles), 37
Rocky Mountain spotted fever (RMSF), 92,
323–324
clinical manifestations, 324
diagnosis, 324
historical background, 322
management, 324
Roger of Palermo, 275
Rokintansky, Carl, 59
ROM therapy (rifampin 600 mg, ofloxacin
400 mg, minocycline 100 mg), 84
roseola infantum (HHV 6), 33
bone marrow transplant patients and,
33
clinical manifestations, 33
diagnosis, 33
HIV and, 33
in mucous membrane infections, 279–280
treatment, 33
rubella (German measles), 37
clinical manifestations, 37
congenital, 223–224
diagnosis, 37
treatment, 37
rubeola (measles), 36–37
clinical manifestations, 36
diagnosis, 37
in mucous membrane infections, 283
ProQuad vaccine for, 278
treatment, 37
Rudolph, Max, 151
Saksenaea vasiformis, 109
salicylates, 277, 278
salicylic acid
for Butcher’s warts, 26
for common warts, 25
for tinea nigra, 154–155
for verruca, 228
for verruca vulgaris/condyloma
acuminatum, 25, 203
sandfly-borne diseases, 92, 136–137,
137. See also Old World cutaneous
leishmaniasis
Sappinia diploidea, 121
sarcoidal granulomas, 6
Sarcoptes scabiei var. hominis, 260, 317
scabies, 317–318
causative agents, 193
diagnosis, 2
in HIV infection, 193
vs. onchocerciasis, 124
scalp infections
bacterial infections
eosinophilic pustular folliculitis, 261
erysipelas/scalp cellulitis, 262
folliculitis, 260
impetigo, 261–262
staphylococcal folliculitis, 260–261
fungal infections
piedra, 258–259
pityriasis amiantacea, 256

pityriasis capitis, 255–256
seborrheic dermatitis, 255–256
historical background, 255
from intrauterine fetal monitoring
devices, 262
parasitic infections
demodicidosis, 260
pediculosis capitis, 259–260
scabies, 260
pitfalls and myths, 264–265
postoperative infections, 262
with presumed bacterial etiology
acne miliaris necrotica, 262
dissecting cellulitis, 262–263
erosive pustular dermatosis, 263
folliculitis decalvans, 262–263
folliculitis keloidalis (acne keloidalis),
262
scalp anatomy, 255
in transplant patients, 264
unusual infections
mycobacterial infection, 264
syphilis, 263–264
viral infections
herpes viral infections, 264
molluscum contagiosum, 264
warts, 264
Scedosporium apiospermum, 113
Schistosoma hematobium, 130
Schistosoma japonicum, 130
Schistosoma mansoni, 130
schistosomal dermatitis. See cercarial
dermatitis (swimmer’s itch)
schistosomiasis, 130, 150
Scopulariopsis brevicaulis, 219, 236, 270, 271
Scopulariopsis spp., 113
scorpions, 231
Scrofulin intradermal reaction, 4
scrofuloderma, 59, 64, 74
scrotal paragonimiasis, 131
Scytalidium dimidiatum, 272
sea bather’s eruption, 171–172
sea urchins, reactions to, 172–173
seborrheic dermatitis, 255–256
secondary syphilis, 74
selenium sulfide
for piedra, 259
for tinea capitis, 51, 217
selenium sulfide shampoos, 51, 217, 256
sexually transmitted diseases (STDs) and
HIV skin infections
anogenital warts, 319
chancroid, 309, 312–313
genital bite wounds, 316–317
genital herpes, 318–319
gonorrhea, 310, 315–316
granuloma inguinale (donovanosis),
190–191, 309, 314–315
historical background, 309–310
lymphogranuloma venereum (LGV), 191,
309, 313–314
pubic lice, 318
scabies, 317–318
syphilis, 190, 309, 310–312 (see also
syphilis)

Silva, Flaviano, 151
skin surgical site infections (SSIs)
definition/classification, 303–304
historical background, 303
intrinsic risk factors, 304
management/prevention
antibiotic prophylaxis, 306
aseptic technique, 305
surgical site care, 305–306
procedure-related risk factors
bleeding during procedure, 304–305
location, 304
type of lesion, 304
type of procedure and repair, 304
“Slapped Cheeks.” See parvovirus B19
sleeping sickness. See human African
trypanosomiasis (sleeping sickness)
smallpox virus
clinical manifestations, 23
vaccination for, 23, 229
sodium stibogluconate (Pentostam®), for
leishmaniasis, 121, 143, 164
South American blastomycosis
(P. braziliensis). See
paracoccidioidomycosis (South
American blastomycosis)
South American hemorrhagic fevers, 153
sparganosis, 129
spectinomycin, for gonorrhea, 315–316
Spherulin test, 4
spiders, 231
spirochetes (in children)
endemic treponematoses, 215–216
Lyme disease, 215
Spirometra spp., 129
sponges and aquatic dermatoses, 174
Sporothrix schenckii dimorphic fungus, 155
sporotrichosis, 6, 64, 100–102
cutaneous forms, 100–101
diagnosis, 101–102, 155
extra-cutaneous forms, 101
treatment, 102
zoonotic transmission, 155
Sporotrichum, 7
squamous cell carcinoma (SCC)
anogenital, 187
from chronic sun exposure, 203
differentiation from tuberculosis, 65
epidermoid, 99
lesion excision, 303
oral, 280
PS as suggestive of, 114
subungual, 209
squamous cell carcinoma in situ (SCCIS),
203
staphylococcal scalded skin syndrome
(SSSS), 196, 212–213
staphylococcal scarlet fever, 196
staphylococcal toxic shock syndrome, 19,
324–325
clinical manifestations, 325
diagnosis, 325
historical background, 322
management, 325
pitfalls and myths, 327

Index — 345

staphylococcus, 293
Staphylococcus aureus, 18
blistering dactylitis from, 212
carbuncles caused by, 19
cellulitis from, 249
conditions predisposing to colonization,
21
ecthyma caused by, 19
folliculitis from, 189, 234
furunculosis from, 234
impetigo from, 19, 211, 234, 238
orbital/periorbital cellulitis from, 213
perianal streptococcal dermatitis from,
212
SSSS from, 212
staphylococcal TSS from, 322, 325
surgical skin infections from, 303
in transplant recipients, 195–196
Staphylococcus epidermis, 189, 212
Staphylococcus pneumoniae, 196, 213
starfish, reactions to, 173
Steven-Johnson syndrome, 45, 185, 258
Stichodactyla gigantea anemone, 170
stinging insects, 232
streptococcal toxic shock syndrome, 19,
325–327
clinical manifestations, 326
diagnosis, 326
historical background, 322
management, 326–327
pitfalls and myths, 327
Streptococcus aureus, 250, 262
Streptococcus mutans, 293
streptococcus pharyngitis, 293
Streptococcus pyogenes, 18, 250, 262, 293,
325–326
ecthyma caused by, 19
erysipelas caused by, 19
impetigo caused by, 19
orbital/periorbital cellulitis from, 213
Streptococcus viridians, 293
Streptomyces somaliensis, 97
streptomycin
for actinomycetomas, 98
for tularemia, 95
Strongyloides stercoralis, 125, 126
subcutaneous phaeohyphomycosis, 113
subcutaneous/deep mycoses
chromoblastomycosis, 98–100, 156 (see
also chromoblastomycosis)
lobomycosis, 151, 157 (see also
lobomycosis)
mycetoma, 97–98, 156–157
paracoccidioidomycosis, 158–159 (see
also paracoccidioidomycosis)
rhinosporidiosis, 103–104
sporotrichosis, 100–102, 155–156 (see
also sporotrichosis)
subungual proximal superficial
onychomycosis, 191
sulconazole nitrate 1%, for tinea pedis/
manuum, 47
sulfadiazine
for Balamuthia mandrillaris, 122
for congenital toxoplasmosis, 222

sulfamethoxazole-trimethoprim (SMZTMP), for paracoccidioidomycosis,
108, 159
sulfur preparations, for scabies, 260
sulfur shampoos, 256
sunscreen
on lips, for herpes labialis, 240, 277
for warts, 203
superficial mycoses
black piedra, 154
piedra nigra, 151
tinea nigra, 154–155
white piedra, 153–154
suppurative granulomas, 6
suppurative/granulomatous inflammatory
infiltrate (in chromomycosis), 99
suramin, for trypanosomiasis, 123
surgical excision
for anogenital warts, 319
for chromoblastomycoses, 156
for coenurosis, 130
for condyloma acuminata, 188
for echinococcosis, 129
for genital warts, 319
for KS, 202
for lobomycosis, 103
for mucormycosis, 110
for oral florid papillomatosis, 281
for protothecosis, 175
for rhinosporidiosis, 104
of solitary KS lesions, 34
Sweet’s syndrome (acute febrile neutrophilic
dermatosis), 146
swimmers itch. See cercarial dermatitis
sympathetic nerve blockade, for postherpetic neuralgia, 31
syphilis, 190, 275, 309, 310–312
clinical manifestations, 310
and secondary/tertiary hair loss,
263–264
systemic corticosteroids
for candidal infection, 284
for Lucio’s phenomenon, 85
for Sweet’s syndrome, 146
systemic mycosis
blastomycosis (North American),
105–106
chronic form (adult type), 107–108
cryptococcosis, 111–112
entomophthoromycosis, 110–111
histoplasmosis, 104–105
hyalohyphomycosis, 113–114
mucormycosis, 109–110
paracoccidioidomycosis (S.A.
blastomycosis), 106–109
chronic form (adult type), 107–108
residual/sequel form, 108–109
phaeohyphomycosis, 112–113
residual/sequel form, 108–109
zygomycosis, 109
T. pallidum, 3, 216, 292, 313, 320
tacrolimus (topical), for erosive pustular
dermatosis of scalp, 263
Taenia crassiceps, 129

Taenia multiceps, 129
Taenia serialis, 129
tar shampoos, 256, 256
Tedania anhelans sponge, 174
Tedania ignis fire sponge, 174
tegmental leishmaniasis. See
mucocutaneous/tegmental
leishmaniasis
teicoplanin, for MRSA strains, 20
telogen effluvium, 256
tenderness (as sign of acute infection), 8
terbinafine (oral)
for adult dermatophyte onychomycosis,
47
adverse effects, 47
for black piedra, 259
for diabetes mellitus, 47
for entomophthoromycosis, 111
mycological cure rates in dermatophyte
onychomycosis, 52
for onychomycosis, 191, 236
for sporotrichosis, 102
for tinea capitis, 51, 51, 217, 258
for tinea corporis/cruris/faciei, 50–51
for tinea imbricata (tokelau), 219
for tinea pedis/manuum, 47–50
for tinea unguium, 52, 191, 236, 237
for transplant patients, 47
terbinafine (solution, cream, gel, spray), for
pityriasis versicolor, 53
tertiary syphilis, 74
tetanus, 294, 296, 317
tetanus, diphtheria, acellular (DTaP) vaccine,
294
tetanus vaccination, 294
tetracyclines
for acne miliaris necrotica, 262
for atypical mycobacterioses, 90
for CA-MRSA, 20
for endemic treponematoses, 216
for folliculitis keloidalis, 262
for rhinoscleroma, 294
for syphilis, 312
thermocoagulation, for condyloma
acuminata, 188
ThermoMed™ device, for Old World CL,
142–143
thrush (oropharyngeal candida)
in children, 221
in elderly people, 235
tick-borne diseases, 92
tigecycline, for MRSA strains, 20
Tilbury, William, 59
tinea capitis. See also dermatophytosis
antifungal medications for, 51
black-dot tinea capitis, 257
in children, 217–218
oral vs. topical medication, 45
of the scalp, 256–258
Tinea corporis, 191
tinea corporis/cruris/faciei, 50–51, 78
tinea cruris, in children, 218
tinea imbricata (tokelau), in children, 219
tinea incognita, 2, 218
tinea nigra, 154–155, 220

346 — Index

tinea pedis/manuum, 47–50, 236–237
Tinea rubrum, 191
tinea unguium, 42, 51–52
antifungal medications for, 51–52
in children, 218–219
in elderly patients, 236
mimicking by other conditions, 53
North American prevalence, 42
oral vs. topical therapy, 45
subtypes of, 236
white onychomycosis, 2
tinidazole
for enteric amebiasis, 121
for trichomoniasis, 296
toenail onychomycosis, 51, 52
togaviruses. See rubella (German measles)
toll-like receptor-(TLR)-2 association with
lepromatous leprosy, 77
tolnaftate solution, for tinea unguium
(onychomycosis), 219
topical clindamycin, 20, 214
topical mupirocin
for localized impetigo, 20
for nasal carriage issues, 21, 196
topical therapy, agent formulary/guidelines,
11
total dystrophic onychomycosis, 272
toxic shock syndrome (TSS), 196, 305.
See also staphylococcal toxic shock
syndrome; streptococcal toxic shock
syndrome
Transcription Mediated Amplification
(TMA), 5
transplant recipients, bacterial/viral diseases
bacillary angiomatosis, 197
B-hemolytic streptococcus, 196–197
gram-negative bacilli (GNB), 197
historical background, 195
necrotizing fascitis, 197
nocardiosis, 198
Staphylococcus aureus, 195–196
vibrio vulnificus, 197
transplantation-related viral disease
cytomegalovirus, 201–202
Epstein-Barr virus, 201
herpes simplex virus, 1 and 2, 199–200
Herpetoviridae (human herpes viruses),
199
human herpes virus-8, 202
human papilloma virus, 203
molluscum contagiosum, 202–203
varicella-zoster virus, 200–201
trematodes, 130–131
fasciolasis, 130
paragonimiasis, 131
schistosomiasis, 130
treponemal serology test, 4
tretinoin (topical), for molluscum
contagiosum, 187
Triamota infestans arthropod, 160
Trichinella britovi, 127
Trichinella murrelli, 127
Trichinella native, 127
Trichinella nelsoni, 127
Trichinella papuae, 127

Trichinella pseudospiralis, 127
Trichinella solium, 128
Trichinella spiralis, 127
trichinellosis, 127–128
diagnosis, 128
treatment, 128
trichloroacetic acid (80%)
for anogenital warts, 319
for Butcher’s warts, 26
for common warts, 25
for condyloma acuminata, 26, 188
for molluscum contagiosum, 23
Trichoderma spp., 113
trichomycosis axillaris, in children, 214
Trichophytin test, 4
Trichophyton mentagrophytes, 243, 257–258
Trichophyton rubrum, 243, 270–271
Trichophyton schoenleinii, 256, 258
Trichophyton soudanense, 272
Trichophyton tonsurans, 256–258
Trichophyton verrucosum, 257–258
Trichophyton violaceum, 256, 272
Trichosporon asahii, 112, 258
Trichosporon asteroides, 258
Trichosporon beigelii yeast, 153
Trichosporon cutaneum, 258
Trichosporon inkin, 258
Trichosporon interdigitale, 271
Trichosporon mucoides, 258
Trichosporon ovoides, 258
triclabendazole, for fasciolasis, 130
triclosan, for skin colonization issues, 21
tricyclic antidepressants
for herpes zoster, 235
for post-herpetic neuralgia, 31
trifluridine, for herpes simplex virus, 200
trimethoprim/sulfamethoxazole
(TMP-SMX)
for atypical mycobacterioses, 90
for CA-MRSA, 20
for cat-scratch disease, 215
for granuloma inguinale, 191, 315
for nocardiosis, 198
tropical infections
in athletes (ulcers), 240
general information, 150
historical background, 150–151
pitfalls and myths, 164–165
protozoa
Chagas’ disease, 159–160
mucocutaneous/tegmental
leishmaniasis, 160–164
subcutaneous/deep mycoses
chromoblastomycoses, 156 (see also
chromoblastomycosis)
lobomycosis, 151, 157–158 (see also
lobomycosis)
mycetoma, 97–98, 156–157
paracoccidioidomycosis, 158–159 (see
also paracoccidioidomycosis)
sporotrichosis, 155 (see also
sporotrichosis)
superficial mycoses
black piedra, 154
piedra nigra, 151

tinea nigra, 154–155
white piedra, 153–154
viruses
Barmah Forest virus (BFV), 152–153
Dengue fever, 92, 95, 151–152
hemorrhagic fevers, 151
Lassa fever, 153
Marburg/Ebola virus, 153
South American hemorrhagic fevers,
153
West Nile virus (WNV), 152
Yellow fever, 152
Trypanosoma cruzi parasite, 159
Trypanosomatidae family, 161, 117. See also
Leishmania entries
trypanosomiasis, 92, 122–123, 150
American trypanosomiasis, 123
human African trypanosomiasis,
122–123
Trypanosomiasis brucei gambiense, 122
Trypanosomiasis brucei rhodesiense, 122
Trypanosomiasis cruzi, 122
tuberculids, 68
Tuberculin test (PPD/purified protein
derivative), 4
tuberculoid granulomas, 6, 7, 62, 70. See also
leishmaniasis; sporotrichosis
tuberculosis. See cutaneous tuberculosis;
extrapulmonary tuberculosis;
Mycobacterium tuberculosis
tuberculosis (TT) leprosy, 79
tuberculosis chancre (primary inoculation
tuberculosis), 67
tuberculosis cutis miliaris acuta generalisata
(acute disseminated miliary
tuberculosis ), 67
tuberculosis gumma, 68, 74
tuberculosis of the breast, 72
tuberculosis verrucosa cutis (warty
tuberculosis), 60, 65, 74, 78
vs. Hansen’s disease lesions, 78
tuberculous lymphadenitis with lupus
vulgaris, 63
tularemia, 67, 74, 92
tumor necrosis factor A (TNFA) association
with lepromatous leprosy, 77
ulceration (as sign of acute infection), 8
Uncinaria stenocephala, 125, 176
uncomplicated skin and skin structure
infections (uSSSIs). See also
Staphylococcus aureus; Streptococcus
pyogenes
abscesses/carbuncles/furuncles, 17
cellulitis, 17–18
diagnosis of, 20
ecthyma, 18
epidemiology of, 19–20
erysipelas, 18
folliculitis, 17
historical background, 18–19
impetigo, 18
therapies for, 20–21
unilateral regional lymphadenopathy, 74
urethral secretions, 2

Index — 347

uSSSIs. See uncomplicated skin and skin
structure infections
vaccinations
for Argentinian hemorrhagic fevers,
153
Bacillus Calmette-Guerin (BCG), 4, 62,
65, 72–73
for diphtheria, 294
measles, 37
for measles, mumps, rubella (MMR),
278, 283
meningococcal conjugate
vaccine A, C, Y, W-135, 323
smallpox virus, 23, 229
varicella zoster virus, 31–32, 201
for Yellow fever, 152
vaccinia
in children, 229–230
clinical manifestations, 24
treatment, 24
vaginal candidiasis, 47, 248, 252
valacyclovir
for congenital herpes simplex, 30
for genital herpes, 319
for herpes simplex virus, 200, 277
for herpes zoster, 31, 235, 264
for HSV, 186
for HSV-1/HSV-2, 29
for oral hairy leukoplakia, 187
for varicella zoster virus, 31, 201
valganciclovir, for CMV, 33, 187,
202, 279
vancomycin
for cellulitis/erysipelas, 234
for impetigo/folliculitis/furunculosis,
234–235
for MRSA strains, 20
for S. aureus, 196
for staphylococcal TSS, 325
varicella zoster virus (HHV-3), 5, 30
in acute exanthem of HIV infection,
186–187
children’s treatment, 31
in mucous membrane infections, 278
neonatal varicella, 31
in transplantation recipients, 200–201

vasculitic appearance (as sign of acute
infection), 8
Vedic scriptures, 59
verrucous carcinoma
treatment, 27
types of
epithelioma cuniculatum, 26–27
giant condyloma of Buschke and
Lowenstein, 27
oral florid papillomatosis, 27
verrucous zoster, 186
vesiculation (as sign of acute infection), 8
Viana, Gaspar, 150, 160–161
Villemin, Jean Antoine, 59
vinblastine, for KS, 34, 202, 280
viral disease in transplantation
cytomegalovirus, 201–202
Epstein-Barr virus, 201
herpes simplex virus, 1 and 2, 199–200
herpetoviridae (human herpes viruses),
199
human herpes virus-8, 202
human papilloma virus, 203
molluscum contagiosum, 202–203
varicella-zoster virus, 200–201
viral encephalitis, 92
viral hemorrhagic fevers, 92
viral infections in athletes
herpes simplex
activation, 240
skin-to-skin transmission, 240–241
molluscum contagiosum, 241–242
verruca, 242
Virchow, Rudolph, 59, 59
visceral leishmaniasis, 4
Vitamin A
for measles, 37
topical, for oral hairy leukoplakia,
279
volume expanders, for Dengue fever, 152
voriconazole
with amphotericin B, for
hyalohyphomycosis, 113–114
for aspergillosis, 288
Wangiella dermatitidis, 98–99, 113
warmth (as sign of acute infection), 8

warts. See Butcher’s warts; common warts
(verruca vulgaris); condyloma
acuminatum (genital warts); flat warts
(verrucae plana); palmoplantar warts
(myrmecia)
warty tuberculosis (tuberculosis verrucosa
cutis), 60, 65, 74
Waterhouse-Friderichsen syndrome
(fulminant meningococcal disease),
323
West Nile virus (WNV), 92, 152
clinical manifestations, 152
diagnosis/treatment, 152
mosquito vectors, 152
white piedra, 153–154, 220, 258
white superficial onychomycosis (WSO),
236, 271–272
Whitfield’s ointment
for erythrasma, 214
for tinea imbricata (tokelau), 219
Willan, Robert (British Dermatology
founder), 59
World Health Organization (WHO)
classification of Hansen’s disease, 76, 80
hepatitis C estimates, 37
leishmaniasis data
mucocutaneous/tegmental
leishmaniasis, 160
Old World cutaneous leishmaniasis,
135–136
paucibacillary disease treatment
guidelines, 84
TB infection estimates, 59
Wuchereria bancrofti, 123
Yellow fever, 151, 152
clinical findings, 152
diagnosis, 152
mosquito vectors, 152
treatment, 152
zinc pyrithione, for tinea capitis, 51
zinc sulfate, for Old World CL, 144
zoonosis infection, 126, 161. See also
American trypanosomiasis;
leishmaniasis
zygomycosis, 96, 103, 109, 209