TB MAC

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M2 level notes on tuberculosis, MAC/MAI

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Tuberculosis infectious granulomatous lung disease
Mycobacteria
Rod-shaped, slow growing obligate aerobe
Acid fast: mycolic acid in cell wall retains carbol-fuchsin dye after treatment w/ 3% HCl
Acid-fast stain = Ziehl Neelsen stain
Non-motile, non-spore forming, non-encapsulated

Pulmonary Tuberculosis
Tuberculosis (TB)
Bacterial infection due to Mycobacterium – acid-fast, weakly G+ obligate aerobic rods,
slow-growing
Slender rods with waxy, lipid-rich cell walls composed of glycolipids/lipid including mycolic
acid  acid fast staining
Cord factor: INH PMN migration, toxic to mammalian cells
Sulfatides: INH phagolysosome fusion == can survive in phagocytic cells
Wax-D
M. tuberculosis responsible for most cases of pulmonary TB
Lung usu 1˚ site, major cause of M/M; less commonly: intestinal, oropharyngeal, skin, and
lymph node

Epidemiology
TB affects >1 billion worldwide (yearly incidence 8–10mill, mort: 1.4 million)
Poverty, overcrowding, chronically debilitating illness; in US: elderly, immigrants from high
risk countries, HIV/AIDS
May increase risk of TB: DM, HL, chronic lung dz (silicosis), CRF, malnutrition, alcoholism and
immunosuppression
Person to person airborne transmission  Infx != dz (clinically significant or active)
10% lifetime risk of clinically active TB after inhalation of TB aerosol
^untreated, 5% develop dz w/in 1-2yrs; 5% develop dz sometime w/in lifetime; if coinfx
MTB+HIV, risk ~7-10% yearly
Clinical: variable course, depends on activity and extent of dz
PRIMARY TB – often asx; if sx – fever, pleural effusion, possible small fibrocalcific nodule at site of
infx
Viable organisms may remain dormant for yrs + immune suppression  reactivation +
infectious dz + development of delayed hypersensitivity to M. tuberculosis Ag 
detected by PPD tuberculin skin test 2-4wks post infx
(+) skin test = T cell-mediated immunity to mycobacterial Ag
^Visible/palpable skin
induration w/in 48–72hrs
Does NOT differentiate between infx and active disease
False (-): immunosuppression: Hodgkin’s, viral infx, sarcoidosis, malnutrition, overwhelming
active TB infx

False (+): infx with atypical mycobacteria, prior vaccination with BCG (Bacillus Calmette-Guerin)
– attenuated strain of M. bovis – used as vaccine in some countries

Pathogenesis
Anti-mycobacterial cell-mediated immunity = hypersensitivity to mycobacterial Ag + resistance
to bacteria
Effector cells that mediate immune response also mediate hypersensitivity and tissue
destruction
Pathology: TB – caseating granulomas and cavitation
Inhaled M. tuberculosis enters alveolar macrophages by phagocytosis via macrophage
receptors (mannose receptor, CR3)  replicates in phagosome by blocking fusion of phagosome
and lysosome  bacteria proliferate in alveolar macrophages and airspaces (7-21d)
3wks post infx TH1 response (eg in LN and lung) produce IFN-γ (stimulates formation of
phagolysosomes and NO antimicrobial peptides) – activates macrophages to become
bactericidal/contain infx
TH1 response causes formation of granuloma/tubercle and caseous necrosis
Activated macrophages also secrete TNF (recruits monocytes)
>21d: bronchial invasion = tuberculous pneumonia; arterial invasion = systemic miliary TB;
lymphatic drainage to venous circulation; tubercle liquification  bronchial rupture (cavity
formation, pulmonary spread)
Classic histology – caseating granuloma – center caseous material surrounded by epithelioid
histiocytes and multinucleated giant cells with fibroblastic rim containing lymphocytes (tubercle)
Clinical: possible hxof cough +/- sputum production, fever/night sweats, weight loss, hemoptysis,
pleurisy, exposure
Exam: evidence of chronic illness, lungs usu sound CLEAR (eg, CXR looks surprisingly bad),
findings of pleural effusion ONLY if pleurisy present
Rarer: adenopathy, in primary node dz = scrofula, erythemoa nodosum in 1˚ dz, skin
involvement = lupus vulgaris

Primary Pulmonary TB
Develops in previously unexposed/unsensitized patients: seen
in infants/children and immunodeficient adults
Inhaled bacilli implant in distal airspaces of lower
portion of upper lobe or upper portion of lower lobe, close
to pleura
Sensitization develops: 1 – 1.5 cm gray white nodule
inflammation and necrosis – Ghon focus
Formation of Ghon focus, then bacilli drain to nodes 
Ghon complex
Ghon complex:
Parenchymal subpleural lesion
(Ghon focus) + enlarged caseous LN that drains parenchymal
lesion
Both caseating and non-caseating granulomas – lung and nodes
Most are asx or have mild flu-like symptoms
^tubercle =
necrotizing granuloma
In 95% of cases, cell mediated immunity develops and controls infx w/ resultant
fibrosis/calcification (healing)
Control of infx via cell mediated immunity, lesion becomes fibrotic / calcifies – asymptomatic
Calcification of ghon complex  Ranke complex
Progressive spread after primary infection  5% will develop clinically significant disease
Types: cavitation, tuberculous pneumonia, or miliary TB

Possible imaging: paratracheal adenopathy, hilar adenopathy, possible faint parenchymal
infiltrate visible on CT

Secondary (Reactivation) Pulmonary TB
In previously sensitized host = reinfection (usu due to immunosuppression or waning immunity,
only 5-10% of 1˚infx)
If remains localized, may be asx, otherwise a/w insidious onset of symptoms – malaise,
hemoptysis, B sx
Secondary TB produces more damage
Findings: TB lesion located at apex of upper lobes of lungs (<2cm), less commonly involve
regional LN
Firm gray white areas w/ peripheral fibrosis and variable central necrosis
Fibrocalcific scar (coalescent granuloma with surrounding fibroblasts, +/- necrosis)
Outcome: Localized lesions may heal with fibrosis +/- progressive pulmonary TB

Progressive Pulmonary TB
More common in elderly and immunosuppressed
Cavitary fibrocaseous TB
Apical lesion - caseous focus erodes into bronchiole drains and creates a cavity, usu in apex
Lined by yellow-gray caseous material w/ surrounding fibrous tissue
Infective material can spread thru airways to other parts of lung
If tx  healing with fibrosis = distortion of lung/cavity
If untreated/immunosuppressed: spread via lymphatics or miliary spread via blood to other
organs
Miliary TB  implies poor cell-mediated immunity
Spread by lymphohematogenous dissemination: miliary pulmonary or systemic miliary
TB
If reach systemic arteries: involve other organs (BM, liver, spleen, adrenals, kidneys)
If remain confined to lungs: bacilli filtered out by alveolar capillary bed (so never reach
arterial circulation)
Lesions usually small (mm’s) firm yellow white nodules w/o gross central necrosis
TB bronchopneumonia
Rapid spread of infection through large areas of lung – diffuse bronchopneumonia
Well-developed tubercles may NOT form, looks like bronchopneumonia but numerous
acid-fast+ bacilli
Endobronchial, endotracheal or laryngeal TB
^TREE IN BUD opacities  cavity erodes into bronchus, emptying contents into bronchial
tree
Develops by spread through lymphatic channels or from expectorated infectious material
Mucosal lining studded with minute/microscopic granulomas +/- central necrosis
Isolated TB
Occurs in any organ seeded hematogenously, may be presenting manifestation
Meninges (tuberculous meningitis), adrenals (Addison’s disease), bone (osteomyelitis),
fallopian tubes (salpingitis), vertebral bodies (Pott’s disease), cervical lymphadenitis
(scrofula)  most common
If HIV (-): unifocal localized lesion; HIV (+): multifocal systemic disease

Intestinal TB, (historically
due to drinking
contaminated/nonpasteurized milk), can also be
due to coughing up and
swallowing infective material
in adv pulmonary disease 
organisms seeded to mucosal
lymphoid aggregates in small
and large bowel 
granulomatous inflammation
w/ mucosal ulceration 
stricture formation

Mycobacterium
avium &
intracellulare
Complex =
MAC/MAI
Separate species but causes similar infx; found in soil, water, dust and domestic animals
Clinically significant infx uncommon except among those with T-cell immunodeficiency
due to AIDS and immunosuppression for transplant rejection or autoimmune disease
In AIDS – disseminated infx in many organs incl lung and GI tract, a/w B sx
In non HIV – primarily lung infx w/ productive cough, occasional fever, and weight loss
May be a/w bronchiectasis (Lady Windermere syndrome)
Classic: older men w/ COPD, constitutional sx, sputum production, chronic fibrocavitary opacities
favoring upper lobes, many bacilli, smear usu (+)  mimics usual TB
Lady Windermere syndrome: women > men, non-smokers, previously normal lungs, chronic
cough usu sole sx, radiography reveals nodules and bronchiectasis favoring right middle lobe and
lingular, paucibacillary, smear often (-)
Pathology: numerous acid fast bacilli in macrophages
Enlarged LN, liver and spleen or localized areas in lung; RARE: Granulomas, inflammation and
tissue destruction
Resistant to usual anti-tubercular meds
EVANS – TB lecture
Phases post transmission to susceptible host
I. infx or not?
II. early proliferation and spread
III. evolution of CMI: mild DTH  latent TB infx (LTBI)
NO infiltrates/cavities seen on chest radiograph but (+) skin test (PPD/TST) or IGRA
PPD: intradermal injx of purified protein derivative = PPD = protein derivative from
killed TB
Produces wheal 6-10mm diameter  measure induration diameter in 48-72hrs
Serial testing: repeat negatives in 1-4wks = two-step testing, looking for booster effect
NOT symptomatic, NOT contagious
Preventive tx usu single drug
IV. evolution of CMI: aggressive DTH  TB dz
Infiltrates/cavities seen on chest radiograph
Symptomatic: fever, weight loss, cough, hemoptysis
Potentially contagious
Requires therapy w/ multiple drugs

Dx: chest radiograph, tuberculin skin test, IFN-ϒ release test
Ghon or Ranke complex: calcified peripheral lesion and IPSIlateral LN
Get an organism: confirms dx, allows sensitivity testing:
• Specimen collection: spontaneous cough, induced sputum (3% aerosolized NaCl),
bronchoscopy, gastric aspirate
• AFB smear
• NAA testing
• Culture and identification
• Drug susceptibility testing
(+) tuberculin rxn ≥ 5mm in HIV infected pts (8-10% risk per yr), recent contacts of active TB
cases (5% 1st 1-2yrs, 5% lifetime), persons w/ fibrotic changes in apex of lung on CXR consistent
w/ old healed TB (Simon foci), pts w/ immunosuppression; normal lifetime (+)TST 10%
(+) tuberculin rxn ≥ 10mm in recent arrivals (<5yrs) from high-prevalence countries, injx drug
users, residents/employees of high risk congregate settings, mycobacteriology laboratory
personnel, persons w/ clinical conditions that put them @ high risk: lymphoma, renal failure,
silicosis, etc, children <4yo or children/adolescents exposed to adults likely to be contagious
(+) tuberculin rxn ≥ 15mm in persons w/ NO known risk factors for TB
• Positive TST in “normal host” = 10% per lifetime
• Recent converter = 5% first 1-2 years, then 5% remainder of lifetime
• HIV infected = 8-10% per year

(+) TST/IGRA is NOT diagnostic of active TB; (-) TST/IGRA does NOT
rule out active dz
BCG vaccine made from attenuated strain of M. bovis, goal: prevent severe TB dz in infants

Not all patients with active disease are skin test (+): 10-15% FN
rate – even in HIV(-) patients
Sputum smears to dx TB may also be (-) if infx w/o cavities, eg if also +HIV
Real-time PCR has better sensitivity
Prophylaxis tx: INH for 9mo; INH + rifapentine 1x/wk for 3mo; rifampin for 4mo
IFN-ϒ release test = IGRA: whole blood test used to detect M. tuberculosis infx – mix pt blood
w/ synthetic Ag not common to BCG  incubated for 16-24hrs  cells that recognize TB Ag
release IFN-ϒ; amt released compared to response for control Ag
Useful for distinguishing immune response due to BCG vs M. tuberculosis
Unaffected by BCG and nearly all non-TB mycobacteria
Specificity >99%, sensitivity 89%; simple yes/no result; should NOT be used for serial
screening

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