TB 1
Content
Diagnostic Accuracy of Chest Radiography for the
Diagnosis of Tuberculosis (TB) and Its Role in the
Detection of Latent TB Infection: a Systematic Review
Riccardo Piccazzo, Francesco Paparo, and Giacomo Garlaschi
ABSTRACT. In this systematic review we evaluate the role of chest radiography (CXR) in the diagnostic flow
chart for tuberculosis (TB) infection, focusing on latent TB infection (LTBI) in patients requiring
medical treatment with biological drugs. In recent findings, patients scheduled for immunomodulatory therapy with biologic drugs are a group at risk of TB reactivation and, in such patients,
detection of LTBI is of great importance. CXR for diagnosis of pulmonary TB has good sensitivity,
but poor specificity. Radiographic diagnosis of active disease can only be reliably made on the basis
of temporal evolution of pulmonary lesions. In vivo tuberculin skin test and ex vivo interferon-g
release assays are designed to identify development of an adaptive immune response, but not necessarily LTBI. Computed tomography (CT) is able to distinguish active from inactive disease. CT is
considered a complementary imaging modality to CXR in the screening procedure to detect past and
LTBI infection in specific subgroups of patients who have increased risk for TB reactivation,
including those scheduled for medical treatment with biological drugs. (J Rheumatol Suppl. 2014
May; 91:32–40; doi:10.3899/jrheum.140100)
Key Indexing Terms:
CHEST RADIOGRAPHY
LATENT TUBERCULOSIS INFECTION
Pulmonary tuberculosis (TB) remains a common worldwide
infection that produces high mortality and morbidity,
especially in developing countries1,2. Latent TB infection
(LTBI) is defined as a state of persistent infection, in the
absence of clinical symptoms of active disease3,4. When
clinically manifest illness is present, the term TB, without
further qualifications, is used to designate the disease4.
Given these definitions, both LTBI and TB may be
considered different moments in a continual pathological
process, and both conditions are usually distinguished on
the basis of the presence (TB) or absence (LTBI) of clinical,
laboratory, and chest radiography (CXR) findings3.
Control of TB infection relies on the identification and
preventive treatment of individuals who are latently infected
by Mycobacterium tuberculosis (Mtb)5. The diagnostic tests
used to identify individuals with LTBI are the in vivo tuberculin skin test (TST) and the ex vivo interferon-g release
From the School of Radiology, University of Genoa; Unit of Radiology,
Department of Diagnostic Imaging, E.O. Galliera Hospital; and
Department of Health Sciences (DISSAL), Section of Radiology,
University Hospital IRCCS San Martino-IST National Institute for Cancer,
Genoa, Italy.
R. Piccazzo, MD, School of Radiology, University of Genoa; F. Paparo,
MD, Unit of Radiology, Department of Diagnostic Imaging, E.O. Galliera
Hospital; G. Garlaschi, MD, Professor, School of Radiology, University of
Genoa; and Department of Health Sciences (DISSAL), Section of Radiology,
University Hospital IRCCS San Martino-IST National Institute for Cancer.
Address correspondence to Prof. Garlaschi, Department of Health
Sciences (DISSAL), Section of Radiology, University Hospital IRCCS San
Martino-IST National Institute for Cancer, Via Pastore 1, 16132 Genoa,
Italy. E-mail: [email protected]
32
TUBERCULOSIS
BIOLOGICS
assays (IGRA); both are designed to identify an adaptive
immune response against (but not necessarily a latent
infection with) Mtb. The problem of LTBI screening has
become more and more relevant in recent years because of
the introduction of immunomodulatory biologic drugs in
clinical practice6,7, especially in the field of rheumatic
diseases. In fact, tumor necrosis factor-a (TNF-a) antagonists can be the cause of either de novo TB infection or
reactivation of LTBI. Therefore, different surveillance
agencies for disease control and prevention have issued
recommendations to ensure the detection and treatment of
LTBI before TNF-a antagonist initiation8,9,10.
This systematic review focuses on the role and value of
CXR in TB diagnosis and screening for LTBI detection in
patients who undergo medical treatment with biological
drugs. The main objective of this work was to give
evidence-based answers to relevant clinical issues regarding
the value of diagnostic imaging in the screening for LTBI.
Methods
A systematic review of the medical literature was performed
by searching PubMed up to January 2013, with no time
limits, using the following MeSH terms as keywords in
variable associations: “chest” or “thoracic” + “radiography”
or “radiograph” or “x-rays” + “post primary tuberculosis” or
“postprimary tuberculosis” or “post-primary tuberculosis”
or “latent tuberculosis” or “tuberculosis reactivation.”
“Chest” or “thoracic” + “radiography” or “radiograph” or
“x-rays” + “tumor necrosis factor-alpha” or “tumor necrosis
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The Journal of Rheumatology Supplement 2014; 41 Suppl 91; doi:10.3899/jrheum.140100
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factor-alpha antagonists” or “biologics” were used as
additional keywords. A manual search of the references of
the retrieved articles was performed. Articles in languages
other than English or Italian were excluded. We included
only original papers dealing with latent and post-primary
TB imaging and diagnosis, with particular attention to those
related to TB reactivation in patients under treatment with
biologics.
Results
A total of 1111 papers were retrieved (Figure 1). A large
number (936 articles) were initially excluded on the basis of
the title or abstract, i.e., considered not pertinent. The
remaining were analyzed according to the close relevance of
their title or abstract. This method led us to read 157 articles,
and at the end of the review process, 67 papers were
selected. All included papers were in English. The
remaining 90 articles were excluded because they were not
pertinent or not focused on our topic.
What is the Current Role of CXR in the Screening for
LTBI?
The World Health Organization once estimated that about
one-third of the world’s population had been infected by
Mtb, with 8.7 million new cases of infection in 20111. A
complete diagnostic evaluation for TB infection should
include medical history, physical examination, CXR, TST,
serologic test (IGRA), microbiologic smears, and cultures.
The gold standard for the diagnosis of TB is obtained by
culturing Mtb from a specimen taken from the
patient11,12,13, but owing to the slow-growth of this aerobic,
non-motile, non-spore-forming rod11,14, diagnosis usually
takes a long time. Worldwide clinical trials and
post-marketing surveillance data have demonstrated an
increased incidence of TB infection associated with
anti-TNF-a agents10,15,16,17. The majority of these cases are
presumed to result from a reactivation of an LTBI, while the
rate of new infections is unknown. So, several studies have
suggested screening patients for LTBI before anti-TNF-a
therapy18,19, but it is currently not possible to identify the
presence of living bacilli in subjects thought to have
LTBI4,20,21,22,23,24,25. Different screening programs for LTBI
detection in patients scheduled for medical treatment with
biologics include as the first step the case history, TB risk
factor assessment, and physical examination. CXR is used
in conjunction with TST or IGRA, but its position in the
screening procedure may vary among different guidelines
and recommendations. The American College of
Rheumatology panel and the National Psoriasis Foundation
recommend screening to identify LTBI in patients with
rheumatoid arthritis (RA) and psoriatic diseases who are
scheduled for therapy with biologic agents, indicating TST
Figure 1. Flowchart of the articles selected for review.
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33
and IGRA as the first screening tests. CXR is considered in
the case of positive TST/IGRA26,27. Other scientific
societies suggest that CXR should be considered as the first
step of the screening process8,9,28,29. CXR is useful when
TST results are unreliable, reading of the skin test is impractical, or the risk of transmission of undiagnosed cases is
high, as occurs in institutional settings (jails, hospitals,
longterm care facilities)30,31. It must be remembered that
patients with RA could have an attenuated response to
TST32,33,34,35. In addition, the diagnosis of TB can be
elusive, and symptomatic, culture-positive pulmonary TB
with a normal CXR is not uncommon36.
What is the Diagnostic Performance of CXR in the
Detection of TB Infection?
CXR screening for TB/LTBI in high-risk populations may
demonstrate findings consistent with prior and/or active
infection37. Apart from fibrous scarring of the lung
parenchyma, there are specific CXR patterns indicative of
prior and/or current TB infection. A Ghon lesion is a
calcified tuberculous caseating granuloma that represents
the sequelae of primary TB infection. Ranke complex is the
combination of a Ghon focus with enlarged or calcified
hilar/mediastinal lymph nodes; Simon foci are apical
nodules, often calcified, that result from hematogenous
seeding at the time of initial infection11,37,38,39. When
examining a CXR it is important to identify findings
suggestive of active TB infection, bearing in mind their
differential diagnosis with other conditions: areas of
parenchymal consolidation should be distinguished from
tumors and other infections (e.g., mycetomas); mediastinal
lymph node enlargement has to be correlated with corresponding parenchymal changes or contextualized within
systemic diseases such as infections, hematopoietic
disorders, lymphomas, sarcoidosis; cavitations should be
distinguished from tumors, abscesses, and parasitic infections11,39 (Table 1). TB can sometimes present with
Table 1. Most common tuberculosis (TB) findings on chest radiography.
TB Chest Radiography Findings
Primary disease
Lymphadenopathy (83–96%, decreases with age)
Parenchymal opacities (on the same side as nodal enlargement;
78–84%)
Obstructive atelectasis (by adjacent enlarged nodes, especially in
children)
Pleural effusion (29–38%)
Post-primary disease
Cavitations (40–45%)
Parenchymal opacities situated in the apical and posterior segments of
the upper lobes (83–85%) and the superior segment of the lower
lobes (11–14%)
Pleural effusion (18%)
Tuberculomas (round or oval, sharply marginated lesions, 0.5–4.0 cm)
Hilar and mediastinal lymphadenopathy (5%)
Endobronchial involvement (2–4%)
34
consolidation in the lower lung fields and, when compared
to the cases involving the upper lobes, it produces less
cavitation and residual fibrotic changes, but more
parenchymal atelectasis40,41.
According to a joint statement issued by the American
Thoracic Society and the US Centers for Disease Control
and Prevention, subjects infected with Mtb, as evidenced by
a positive TST, should be classified starting from clinical,
radiographic, and bacteriologic findings into one of the
following categories: (a) TB infection, no disease; (b) TB
infection, clinically active; (c) TB infection, clinically
inactive37. CXR has a high negative predictive value for the
presence of active TB. In the adult immunocompetent
population, the frequency of false negative examinations is
about 1%, increasing to 7%–15% in individuals seropositive
for human immunodeficiency virus (HIV)20,42. The
detection of any abnormality (parenchymal, lymph nodal, or
pleural), with or without associated calcification, cannot
give precise information on disease activity on a single
screening CXR. Temporal evolution is the only variable that
allows a radiographic differentiation between active and
inactive disease43. Lack of radiographic change over a time
interval of 4 to 6 months generally indicates inactive
disease37. However, given that longterm stability of
radiographic findings may occasionally be associated with
culture-positive disease, Miller and MacGregor underline
that such findings should be described as “radiographically
stable” rather than “inactive”44.
CXR has been used for over a century to diagnose
pulmonary TB; however, it is limited by modest specificity
with a high interobserver variability in radiological
reports35,46. Different studies aimed to determine the sensitivity and specificity of CXR findings for the diagnosis of
TB (Figure 2). Cohen, et al found a sensitivity of 73–79%
and a specificity of 60–63% in a high-risk population47.
Similar results were found by den Boon, et al, who
compared the diagnostic value of typical TB symptoms
(cough, sputum production, fever, weight loss, night sweats,
hemoptysis, anorexia, and dyspnea) versus chest radiography in a TB prevalence survey. The presence of any
abnormalities on CXR had the highest sensitivity for
detecting subjects with bacteriologically positive TB (0.97,
95% CI 0.90–1.00), while the specificity for any detectable
abnormalities was 0.67 (95% CI 0.64–0.70)48. For peculiar
findings, such as miliary TB, it is possible to reach sensitivity values ranging from 59 to 69%, and specificity from
97 to 100%49. The detection of enlarged lymph nodes in
children has a sensitivity of 67% and a specificity of 59%.
Performing an additional lateral view of the chest, the sensitivity increased by 1.8%, and specificity by 2.5%50. A
correct diagnosis of pulmonary TB on CXR is dependent on
the reader’s expertise, because the technique of CXR interpretation is currently not well standardized45,46. In this
regard, several authors have attempted to introduce
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Figure 2. Tubercular cavity. Posteroanterior chest radiography (A) and computerized tomography reformatted image on the coronal plane (B). Panel
A shows an irregularly round opacity at the apex of the right lung (arrow). Panel B demonstrates that the lesion in the apical lung parenchyma is a
tubercular cavity (arrow). A smaller focus of parenchymal consolidation, which was not detectable on chest radiography, is appreciable in panel B in
correspondence to the paravertebral portion of the mid-lung field (arrowhead).
standardized scoring systems that would increase CXR
sensitivity and specificity. Results of a recent metaanalysis
indicate that none of the scoring systems that have been
proposed from 1899 to 2012 was based on the exclusive use
of imaging findings. In fact, only the multimodal integration
of clinical, laboratory, and imaging data allows to improve
the diagnostic performance of CXR, reaching an overall
sensitivity and specificity of 96% and 46%, respectively45.
A simplified scoring system has been recently proposed,
including 4 easy-to-recognize features on CXR: upper lobe
opacities, cavities, unilateral pleural effusion, and
mediastinal/hilar lymphadenopathy51. The authors obtained
a high negative predictive value (91.5%, 95% CI
87.1–94.7), but a low positive predictive value (49.4%, 95%
CI 42.9–55.9). Eisenberg and Pollock assessed the
frequency and spectrum of abnormalities on routine
screening of CXR in the preemployment evaluation of
healthcare workers with positive TST, finding that CXR is
of low yield in the detection of active TB or increased LTBI
reactivation risk, and provided no assistance in deciding
which individuals to prioritize for LTBI treatment52.
Computed tomography (CT) is a corroborative imaging
modality to study TB53,54,55,56,57,58,59. It helps to distinguish
between active and inactive disease34, and is more sensitive
than CXR in the detection of both localized and disseminated disease and mediastinal lymphadenopathy11,60,61,62.
Woodring, et al said that the first CXR diagnosis of TB is
correct in only 49% of cases (i.e., 34% of primary TB and
59% of TB reactivation)11,39. Chest CT can effectively
detect 80% of patients with active TB and 89% of those with
inactive TB34. CT is very useful when there is a
disagreement between clinical and radiological findings
and/or when imaging findings are equivocal or inconclusive11,63. Subjects with normal or equivocal CXR may
have findings indicative of active TB on chest CT35,64
(Figure 3). Lew, et al3 showed that no diagnostic test has a
100% sensitivity for TB diagnosis, suggesting a combined
diagnostic approach including TST, CXR, IGRA, and CT65.
Findings suggestive of active TB were detected by CT in
17 (32.7%) of the 52 subjects with a high probability of
infection (30 subjects who were IGRA-positive and 22
subjects in whom the TST induration size was ≥ 20 mm).
Collectively, among 21 (1.1%) patients with TB, all were
TST-positive, 12 (57.1%) were IGRA-positive, and active
TB was diagnosed by CT, but not by CXR, in 11 subjects3.
When compared to the conventional approach with TST
and CXR, the combined use of IGRA and chest CT in
TST-positives may be more effective in differentiating
between active TB, LTBI, and non-infected subjects in a
contact investigation3. On the other hand, as commented by
Marais, et al66, the use of chest CT for screening of asymptomatic contacts is not safe because it leads to overdiagnosis
of “active TB,” exposing patients to high radiation doses
and undermining confidence in existing screening
tools67,68,69. Introduction of CT is considered only in certain
groups of individuals at high risk for TB reactivation, such
as immunocompromised patients3,63,70. A more effective
detection of active TB would prevent the prescription of
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35
Figure 3. Miliary tuberculosis from hematogenous seeding. Posteroanterior (A) and lateral (B) chest radiographs. Panel A demonstrates peribronchovascular interstitial thickening with a micronodular appearance. Computerized tomography (CT) image on the axial plane (C) shows multiple
micronodules disseminated in both lungs, and the reconstructed CT image with maximum intensity projection technique clearly demonstrates their
centrilobular location (D).
inappropriate LTBI treatment and the subsequent development of drug resistance3. Lee, et al evaluated the advantages of chest CT in a TB outbreak investigation in the
South Korean army. Lesions indicative of active TB were
detected in 18 participants (21%), including 9 without any
lesion on CXR and positive results in either TST or IGRA.
The authors conclude that CT can be helpful for differentiating active TB from LTBI. Otherwise this diagnostic tool
should be carefully considered, taking into account its risk
and cost71,72. Other authors commented on the article by
Lee, et al, suggesting that chest CT leads to a significantly
36
higher radiation dose than CXR73, and to higher costs. They
underlined that the use of CT as a screening test during TB
outbreak investigations is not justified74,75, but it could only
be performed in symptomatic patients76, and in certain
high-risk groups75. The importance of identifying LTBI has
become even greater since TNF-a antagonists have been
introduced in routine clinical practice for the treatment of
RA and other inflammatory rheumatologic disorders17,77,78.
Tannus Silva, et al evaluated the advantages of CT as a
screening tool for LTBI detection in patients with RA59. CT
showed changes compatible with LTBI in 52.9% of patients,
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including 8 of the 11 patients with negative TST and IGRA.
These results underline the importance of a combined use of
different diagnostic modalities for an effective detection of
LTBI.
What About “Atypical” Patterns and Peculiar
Conditions?
Since the 1950s the incidence of TB infection in industrialized countries has decreased markedly. However, in recent
years this trend has started to reverse because of changing
population characteristics, such as an influx of immigrants
from high-incidence areas and the wide diffusion of the
HIV79,80,81,82,83. In comparison to the past, it mainly affects
younger adults who belong to certain groups8, such as
immunocompromised patients. These patients may present
with “atypical” or “unusual” patterns on CXR (i.e., solitary
pleural effusion, miliary pattern, lesions in the lung bases,
solitary mediastinal or hilar lymphadenopathies)79,84,85.
HIV-associated pulmonary TB has CXR patterns that are
dependent on the level of immunosuppression37,86,87.
Correlating CXR and CD4 T lymphocyte levels, a
significantly higher prevalence of mediastinal and/or hilar
lymphadenopathy and a lower prevalence of cavitation were
identified in patients with a CD4 T lymphocyte count of less
than 200/mm3. With the worsening of immunosuppression,
a higher incidence has been reported of miliary pattern,
extrapulmonary disease, and atypical presentation88,89. CT
evaluation of pulmonary TB in HIV-seropositive patients
with normal CXR usually demonstrates subtle abnormalities37,89, and some authors have identified some specific
CT patterns such as multiple parenchymal nodules, tuberculoma, and lymphadenopathy89. Lymphadenopathy can
present on CT images with a central low attenuation area
and peripheral enhancement, as for example in immunocompetent patients90. HIV-seropositive patients had a lower
prevalence of localized parenchymal disease and a higher
prevalence of disseminated disease at CT88,89.
When a child has positive TST, normal CXR, and no
symptoms, the child is considered to have LTBI. When the
findings are positive TST, pathological CXR, and
symptoms, the child is considered to have TB. In a child in
whom previous contact with TB is certain, the presence of
positive TST and pathological CXR with or without
symptoms suggests a diagnosis of TB. On the basis of
indirect signs of low specificity, symptoms, CXR, and TST,
the diagnosis of primary TB is difficult to achieve60,91,92. In
this context, the correct interpretation of CXR is a crucial
requirement, and chest CT is recommended if CXR is
equivocal93. An abnormal thoracic CT occurs in 92.8% of
children with positive TST and negative CXR. So, Garrido,
et al suggested that, in children younger than 4 years with
positive TST and normal CXR, it would be advisable to
perform CT67,94. A recent study on post-liver transplantation
patients demonstrated that a pretransplant chest CT scan is
more useful to show LTBI than a CXR in a TB endemic
country. An increased risk for pulmonary TB is associated
with findings such as a “tree-in-bud” appearance (indicative
of endobronchial spread), lobular consolidation, and large
nodules on CT scans95,96.
In subgroups of individuals with a high probability of
infection, the combined use of TST, IGRA, CXR, and CT
is effective in differentiating between active TB, LTBI,
and uninfected subjects. The usefulness of chest CT
among immunocompromised patients should be further
investigated3.
Statement
CXR must be performed after positive TST/IGRA. Because
patients undergoing medical treatment with biologics are a
group at high risk for TB reactivation, CT may be indicated
when faced with a positive TST/IGRA and inconclusive
CXR findings.
The role of CXR in the detection of LTB1 can be summarized as follows:
• Chest radiography for the diagnosis of pulmonary TB
has good sensitivity but poor specificity
• Radiographic diagnosis of active disease can only be
reliably made on the basis of temporal evolution of
pulmonary lesions
• The radiographic diagnosis of TB can be elusive, and
symptomatic, culture-positive pulmonary TB with a
normal CXR is not uncommon
• In specific subgroups of patients, including candidates
for anti-TNF-a treatment, the combined approach
based on immunological tests, CXR, and CT could be
very useful for LTBI detection
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Diagnosis of Tuberculosis (TB) and Its Role in the
Detection of Latent TB Infection: a Systematic Review
Riccardo Piccazzo, Francesco Paparo, and Giacomo Garlaschi
ABSTRACT. In this systematic review we evaluate the role of chest radiography (CXR) in the diagnostic flow
chart for tuberculosis (TB) infection, focusing on latent TB infection (LTBI) in patients requiring
medical treatment with biological drugs. In recent findings, patients scheduled for immunomodulatory therapy with biologic drugs are a group at risk of TB reactivation and, in such patients,
detection of LTBI is of great importance. CXR for diagnosis of pulmonary TB has good sensitivity,
but poor specificity. Radiographic diagnosis of active disease can only be reliably made on the basis
of temporal evolution of pulmonary lesions. In vivo tuberculin skin test and ex vivo interferon-g
release assays are designed to identify development of an adaptive immune response, but not necessarily LTBI. Computed tomography (CT) is able to distinguish active from inactive disease. CT is
considered a complementary imaging modality to CXR in the screening procedure to detect past and
LTBI infection in specific subgroups of patients who have increased risk for TB reactivation,
including those scheduled for medical treatment with biological drugs. (J Rheumatol Suppl. 2014
May; 91:32–40; doi:10.3899/jrheum.140100)
Key Indexing Terms:
CHEST RADIOGRAPHY
LATENT TUBERCULOSIS INFECTION
Pulmonary tuberculosis (TB) remains a common worldwide
infection that produces high mortality and morbidity,
especially in developing countries1,2. Latent TB infection
(LTBI) is defined as a state of persistent infection, in the
absence of clinical symptoms of active disease3,4. When
clinically manifest illness is present, the term TB, without
further qualifications, is used to designate the disease4.
Given these definitions, both LTBI and TB may be
considered different moments in a continual pathological
process, and both conditions are usually distinguished on
the basis of the presence (TB) or absence (LTBI) of clinical,
laboratory, and chest radiography (CXR) findings3.
Control of TB infection relies on the identification and
preventive treatment of individuals who are latently infected
by Mycobacterium tuberculosis (Mtb)5. The diagnostic tests
used to identify individuals with LTBI are the in vivo tuberculin skin test (TST) and the ex vivo interferon-g release
From the School of Radiology, University of Genoa; Unit of Radiology,
Department of Diagnostic Imaging, E.O. Galliera Hospital; and
Department of Health Sciences (DISSAL), Section of Radiology,
University Hospital IRCCS San Martino-IST National Institute for Cancer,
Genoa, Italy.
R. Piccazzo, MD, School of Radiology, University of Genoa; F. Paparo,
MD, Unit of Radiology, Department of Diagnostic Imaging, E.O. Galliera
Hospital; G. Garlaschi, MD, Professor, School of Radiology, University of
Genoa; and Department of Health Sciences (DISSAL), Section of Radiology,
University Hospital IRCCS San Martino-IST National Institute for Cancer.
Address correspondence to Prof. Garlaschi, Department of Health
Sciences (DISSAL), Section of Radiology, University Hospital IRCCS San
Martino-IST National Institute for Cancer, Via Pastore 1, 16132 Genoa,
Italy. E-mail: [email protected]
32
TUBERCULOSIS
BIOLOGICS
assays (IGRA); both are designed to identify an adaptive
immune response against (but not necessarily a latent
infection with) Mtb. The problem of LTBI screening has
become more and more relevant in recent years because of
the introduction of immunomodulatory biologic drugs in
clinical practice6,7, especially in the field of rheumatic
diseases. In fact, tumor necrosis factor-a (TNF-a) antagonists can be the cause of either de novo TB infection or
reactivation of LTBI. Therefore, different surveillance
agencies for disease control and prevention have issued
recommendations to ensure the detection and treatment of
LTBI before TNF-a antagonist initiation8,9,10.
This systematic review focuses on the role and value of
CXR in TB diagnosis and screening for LTBI detection in
patients who undergo medical treatment with biological
drugs. The main objective of this work was to give
evidence-based answers to relevant clinical issues regarding
the value of diagnostic imaging in the screening for LTBI.
Methods
A systematic review of the medical literature was performed
by searching PubMed up to January 2013, with no time
limits, using the following MeSH terms as keywords in
variable associations: “chest” or “thoracic” + “radiography”
or “radiograph” or “x-rays” + “post primary tuberculosis” or
“postprimary tuberculosis” or “post-primary tuberculosis”
or “latent tuberculosis” or “tuberculosis reactivation.”
“Chest” or “thoracic” + “radiography” or “radiograph” or
“x-rays” + “tumor necrosis factor-alpha” or “tumor necrosis
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Rheumatology
factor-alpha antagonists” or “biologics” were used as
additional keywords. A manual search of the references of
the retrieved articles was performed. Articles in languages
other than English or Italian were excluded. We included
only original papers dealing with latent and post-primary
TB imaging and diagnosis, with particular attention to those
related to TB reactivation in patients under treatment with
biologics.
Results
A total of 1111 papers were retrieved (Figure 1). A large
number (936 articles) were initially excluded on the basis of
the title or abstract, i.e., considered not pertinent. The
remaining were analyzed according to the close relevance of
their title or abstract. This method led us to read 157 articles,
and at the end of the review process, 67 papers were
selected. All included papers were in English. The
remaining 90 articles were excluded because they were not
pertinent or not focused on our topic.
What is the Current Role of CXR in the Screening for
LTBI?
The World Health Organization once estimated that about
one-third of the world’s population had been infected by
Mtb, with 8.7 million new cases of infection in 20111. A
complete diagnostic evaluation for TB infection should
include medical history, physical examination, CXR, TST,
serologic test (IGRA), microbiologic smears, and cultures.
The gold standard for the diagnosis of TB is obtained by
culturing Mtb from a specimen taken from the
patient11,12,13, but owing to the slow-growth of this aerobic,
non-motile, non-spore-forming rod11,14, diagnosis usually
takes a long time. Worldwide clinical trials and
post-marketing surveillance data have demonstrated an
increased incidence of TB infection associated with
anti-TNF-a agents10,15,16,17. The majority of these cases are
presumed to result from a reactivation of an LTBI, while the
rate of new infections is unknown. So, several studies have
suggested screening patients for LTBI before anti-TNF-a
therapy18,19, but it is currently not possible to identify the
presence of living bacilli in subjects thought to have
LTBI4,20,21,22,23,24,25. Different screening programs for LTBI
detection in patients scheduled for medical treatment with
biologics include as the first step the case history, TB risk
factor assessment, and physical examination. CXR is used
in conjunction with TST or IGRA, but its position in the
screening procedure may vary among different guidelines
and recommendations. The American College of
Rheumatology panel and the National Psoriasis Foundation
recommend screening to identify LTBI in patients with
rheumatoid arthritis (RA) and psoriatic diseases who are
scheduled for therapy with biologic agents, indicating TST
Figure 1. Flowchart of the articles selected for review.
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Piccazzo, et al: Chest radiography in latent TB
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Rheumatology
33
and IGRA as the first screening tests. CXR is considered in
the case of positive TST/IGRA26,27. Other scientific
societies suggest that CXR should be considered as the first
step of the screening process8,9,28,29. CXR is useful when
TST results are unreliable, reading of the skin test is impractical, or the risk of transmission of undiagnosed cases is
high, as occurs in institutional settings (jails, hospitals,
longterm care facilities)30,31. It must be remembered that
patients with RA could have an attenuated response to
TST32,33,34,35. In addition, the diagnosis of TB can be
elusive, and symptomatic, culture-positive pulmonary TB
with a normal CXR is not uncommon36.
What is the Diagnostic Performance of CXR in the
Detection of TB Infection?
CXR screening for TB/LTBI in high-risk populations may
demonstrate findings consistent with prior and/or active
infection37. Apart from fibrous scarring of the lung
parenchyma, there are specific CXR patterns indicative of
prior and/or current TB infection. A Ghon lesion is a
calcified tuberculous caseating granuloma that represents
the sequelae of primary TB infection. Ranke complex is the
combination of a Ghon focus with enlarged or calcified
hilar/mediastinal lymph nodes; Simon foci are apical
nodules, often calcified, that result from hematogenous
seeding at the time of initial infection11,37,38,39. When
examining a CXR it is important to identify findings
suggestive of active TB infection, bearing in mind their
differential diagnosis with other conditions: areas of
parenchymal consolidation should be distinguished from
tumors and other infections (e.g., mycetomas); mediastinal
lymph node enlargement has to be correlated with corresponding parenchymal changes or contextualized within
systemic diseases such as infections, hematopoietic
disorders, lymphomas, sarcoidosis; cavitations should be
distinguished from tumors, abscesses, and parasitic infections11,39 (Table 1). TB can sometimes present with
Table 1. Most common tuberculosis (TB) findings on chest radiography.
TB Chest Radiography Findings
Primary disease
Lymphadenopathy (83–96%, decreases with age)
Parenchymal opacities (on the same side as nodal enlargement;
78–84%)
Obstructive atelectasis (by adjacent enlarged nodes, especially in
children)
Pleural effusion (29–38%)
Post-primary disease
Cavitations (40–45%)
Parenchymal opacities situated in the apical and posterior segments of
the upper lobes (83–85%) and the superior segment of the lower
lobes (11–14%)
Pleural effusion (18%)
Tuberculomas (round or oval, sharply marginated lesions, 0.5–4.0 cm)
Hilar and mediastinal lymphadenopathy (5%)
Endobronchial involvement (2–4%)
34
consolidation in the lower lung fields and, when compared
to the cases involving the upper lobes, it produces less
cavitation and residual fibrotic changes, but more
parenchymal atelectasis40,41.
According to a joint statement issued by the American
Thoracic Society and the US Centers for Disease Control
and Prevention, subjects infected with Mtb, as evidenced by
a positive TST, should be classified starting from clinical,
radiographic, and bacteriologic findings into one of the
following categories: (a) TB infection, no disease; (b) TB
infection, clinically active; (c) TB infection, clinically
inactive37. CXR has a high negative predictive value for the
presence of active TB. In the adult immunocompetent
population, the frequency of false negative examinations is
about 1%, increasing to 7%–15% in individuals seropositive
for human immunodeficiency virus (HIV)20,42. The
detection of any abnormality (parenchymal, lymph nodal, or
pleural), with or without associated calcification, cannot
give precise information on disease activity on a single
screening CXR. Temporal evolution is the only variable that
allows a radiographic differentiation between active and
inactive disease43. Lack of radiographic change over a time
interval of 4 to 6 months generally indicates inactive
disease37. However, given that longterm stability of
radiographic findings may occasionally be associated with
culture-positive disease, Miller and MacGregor underline
that such findings should be described as “radiographically
stable” rather than “inactive”44.
CXR has been used for over a century to diagnose
pulmonary TB; however, it is limited by modest specificity
with a high interobserver variability in radiological
reports35,46. Different studies aimed to determine the sensitivity and specificity of CXR findings for the diagnosis of
TB (Figure 2). Cohen, et al found a sensitivity of 73–79%
and a specificity of 60–63% in a high-risk population47.
Similar results were found by den Boon, et al, who
compared the diagnostic value of typical TB symptoms
(cough, sputum production, fever, weight loss, night sweats,
hemoptysis, anorexia, and dyspnea) versus chest radiography in a TB prevalence survey. The presence of any
abnormalities on CXR had the highest sensitivity for
detecting subjects with bacteriologically positive TB (0.97,
95% CI 0.90–1.00), while the specificity for any detectable
abnormalities was 0.67 (95% CI 0.64–0.70)48. For peculiar
findings, such as miliary TB, it is possible to reach sensitivity values ranging from 59 to 69%, and specificity from
97 to 100%49. The detection of enlarged lymph nodes in
children has a sensitivity of 67% and a specificity of 59%.
Performing an additional lateral view of the chest, the sensitivity increased by 1.8%, and specificity by 2.5%50. A
correct diagnosis of pulmonary TB on CXR is dependent on
the reader’s expertise, because the technique of CXR interpretation is currently not well standardized45,46. In this
regard, several authors have attempted to introduce
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Rheumatology
Figure 2. Tubercular cavity. Posteroanterior chest radiography (A) and computerized tomography reformatted image on the coronal plane (B). Panel
A shows an irregularly round opacity at the apex of the right lung (arrow). Panel B demonstrates that the lesion in the apical lung parenchyma is a
tubercular cavity (arrow). A smaller focus of parenchymal consolidation, which was not detectable on chest radiography, is appreciable in panel B in
correspondence to the paravertebral portion of the mid-lung field (arrowhead).
standardized scoring systems that would increase CXR
sensitivity and specificity. Results of a recent metaanalysis
indicate that none of the scoring systems that have been
proposed from 1899 to 2012 was based on the exclusive use
of imaging findings. In fact, only the multimodal integration
of clinical, laboratory, and imaging data allows to improve
the diagnostic performance of CXR, reaching an overall
sensitivity and specificity of 96% and 46%, respectively45.
A simplified scoring system has been recently proposed,
including 4 easy-to-recognize features on CXR: upper lobe
opacities, cavities, unilateral pleural effusion, and
mediastinal/hilar lymphadenopathy51. The authors obtained
a high negative predictive value (91.5%, 95% CI
87.1–94.7), but a low positive predictive value (49.4%, 95%
CI 42.9–55.9). Eisenberg and Pollock assessed the
frequency and spectrum of abnormalities on routine
screening of CXR in the preemployment evaluation of
healthcare workers with positive TST, finding that CXR is
of low yield in the detection of active TB or increased LTBI
reactivation risk, and provided no assistance in deciding
which individuals to prioritize for LTBI treatment52.
Computed tomography (CT) is a corroborative imaging
modality to study TB53,54,55,56,57,58,59. It helps to distinguish
between active and inactive disease34, and is more sensitive
than CXR in the detection of both localized and disseminated disease and mediastinal lymphadenopathy11,60,61,62.
Woodring, et al said that the first CXR diagnosis of TB is
correct in only 49% of cases (i.e., 34% of primary TB and
59% of TB reactivation)11,39. Chest CT can effectively
detect 80% of patients with active TB and 89% of those with
inactive TB34. CT is very useful when there is a
disagreement between clinical and radiological findings
and/or when imaging findings are equivocal or inconclusive11,63. Subjects with normal or equivocal CXR may
have findings indicative of active TB on chest CT35,64
(Figure 3). Lew, et al3 showed that no diagnostic test has a
100% sensitivity for TB diagnosis, suggesting a combined
diagnostic approach including TST, CXR, IGRA, and CT65.
Findings suggestive of active TB were detected by CT in
17 (32.7%) of the 52 subjects with a high probability of
infection (30 subjects who were IGRA-positive and 22
subjects in whom the TST induration size was ≥ 20 mm).
Collectively, among 21 (1.1%) patients with TB, all were
TST-positive, 12 (57.1%) were IGRA-positive, and active
TB was diagnosed by CT, but not by CXR, in 11 subjects3.
When compared to the conventional approach with TST
and CXR, the combined use of IGRA and chest CT in
TST-positives may be more effective in differentiating
between active TB, LTBI, and non-infected subjects in a
contact investigation3. On the other hand, as commented by
Marais, et al66, the use of chest CT for screening of asymptomatic contacts is not safe because it leads to overdiagnosis
of “active TB,” exposing patients to high radiation doses
and undermining confidence in existing screening
tools67,68,69. Introduction of CT is considered only in certain
groups of individuals at high risk for TB reactivation, such
as immunocompromised patients3,63,70. A more effective
detection of active TB would prevent the prescription of
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35
Figure 3. Miliary tuberculosis from hematogenous seeding. Posteroanterior (A) and lateral (B) chest radiographs. Panel A demonstrates peribronchovascular interstitial thickening with a micronodular appearance. Computerized tomography (CT) image on the axial plane (C) shows multiple
micronodules disseminated in both lungs, and the reconstructed CT image with maximum intensity projection technique clearly demonstrates their
centrilobular location (D).
inappropriate LTBI treatment and the subsequent development of drug resistance3. Lee, et al evaluated the advantages of chest CT in a TB outbreak investigation in the
South Korean army. Lesions indicative of active TB were
detected in 18 participants (21%), including 9 without any
lesion on CXR and positive results in either TST or IGRA.
The authors conclude that CT can be helpful for differentiating active TB from LTBI. Otherwise this diagnostic tool
should be carefully considered, taking into account its risk
and cost71,72. Other authors commented on the article by
Lee, et al, suggesting that chest CT leads to a significantly
36
higher radiation dose than CXR73, and to higher costs. They
underlined that the use of CT as a screening test during TB
outbreak investigations is not justified74,75, but it could only
be performed in symptomatic patients76, and in certain
high-risk groups75. The importance of identifying LTBI has
become even greater since TNF-a antagonists have been
introduced in routine clinical practice for the treatment of
RA and other inflammatory rheumatologic disorders17,77,78.
Tannus Silva, et al evaluated the advantages of CT as a
screening tool for LTBI detection in patients with RA59. CT
showed changes compatible with LTBI in 52.9% of patients,
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Rheumatology
including 8 of the 11 patients with negative TST and IGRA.
These results underline the importance of a combined use of
different diagnostic modalities for an effective detection of
LTBI.
What About “Atypical” Patterns and Peculiar
Conditions?
Since the 1950s the incidence of TB infection in industrialized countries has decreased markedly. However, in recent
years this trend has started to reverse because of changing
population characteristics, such as an influx of immigrants
from high-incidence areas and the wide diffusion of the
HIV79,80,81,82,83. In comparison to the past, it mainly affects
younger adults who belong to certain groups8, such as
immunocompromised patients. These patients may present
with “atypical” or “unusual” patterns on CXR (i.e., solitary
pleural effusion, miliary pattern, lesions in the lung bases,
solitary mediastinal or hilar lymphadenopathies)79,84,85.
HIV-associated pulmonary TB has CXR patterns that are
dependent on the level of immunosuppression37,86,87.
Correlating CXR and CD4 T lymphocyte levels, a
significantly higher prevalence of mediastinal and/or hilar
lymphadenopathy and a lower prevalence of cavitation were
identified in patients with a CD4 T lymphocyte count of less
than 200/mm3. With the worsening of immunosuppression,
a higher incidence has been reported of miliary pattern,
extrapulmonary disease, and atypical presentation88,89. CT
evaluation of pulmonary TB in HIV-seropositive patients
with normal CXR usually demonstrates subtle abnormalities37,89, and some authors have identified some specific
CT patterns such as multiple parenchymal nodules, tuberculoma, and lymphadenopathy89. Lymphadenopathy can
present on CT images with a central low attenuation area
and peripheral enhancement, as for example in immunocompetent patients90. HIV-seropositive patients had a lower
prevalence of localized parenchymal disease and a higher
prevalence of disseminated disease at CT88,89.
When a child has positive TST, normal CXR, and no
symptoms, the child is considered to have LTBI. When the
findings are positive TST, pathological CXR, and
symptoms, the child is considered to have TB. In a child in
whom previous contact with TB is certain, the presence of
positive TST and pathological CXR with or without
symptoms suggests a diagnosis of TB. On the basis of
indirect signs of low specificity, symptoms, CXR, and TST,
the diagnosis of primary TB is difficult to achieve60,91,92. In
this context, the correct interpretation of CXR is a crucial
requirement, and chest CT is recommended if CXR is
equivocal93. An abnormal thoracic CT occurs in 92.8% of
children with positive TST and negative CXR. So, Garrido,
et al suggested that, in children younger than 4 years with
positive TST and normal CXR, it would be advisable to
perform CT67,94. A recent study on post-liver transplantation
patients demonstrated that a pretransplant chest CT scan is
more useful to show LTBI than a CXR in a TB endemic
country. An increased risk for pulmonary TB is associated
with findings such as a “tree-in-bud” appearance (indicative
of endobronchial spread), lobular consolidation, and large
nodules on CT scans95,96.
In subgroups of individuals with a high probability of
infection, the combined use of TST, IGRA, CXR, and CT
is effective in differentiating between active TB, LTBI,
and uninfected subjects. The usefulness of chest CT
among immunocompromised patients should be further
investigated3.
Statement
CXR must be performed after positive TST/IGRA. Because
patients undergoing medical treatment with biologics are a
group at high risk for TB reactivation, CT may be indicated
when faced with a positive TST/IGRA and inconclusive
CXR findings.
The role of CXR in the detection of LTB1 can be summarized as follows:
• Chest radiography for the diagnosis of pulmonary TB
has good sensitivity but poor specificity
• Radiographic diagnosis of active disease can only be
reliably made on the basis of temporal evolution of
pulmonary lesions
• The radiographic diagnosis of TB can be elusive, and
symptomatic, culture-positive pulmonary TB with a
normal CXR is not uncommon
• In specific subgroups of patients, including candidates
for anti-TNF-a treatment, the combined approach
based on immunological tests, CXR, and CT could be
very useful for LTBI detection
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