Diagnosis of Pulmonary Tuberculosis in Adults

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Diagnosis of pulmonary tuberculosis in adults
Author: John Bernardo, MD

Section Editor: C Fordham von Reyn, MD
Deputy Editor: Elinor L Baron, MD, DTMH
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2018. | This topic last updated: Dec 07, 2018.
INTRODUCTION — More than two billion people (about one-third of the world population) are estimated to be infected with
Mycobacterium tuberculosis [1]. In 2015, approximately 10.4 million individuals became ill with tuberculosis (TB), and 1.8 million
died [2]. Prompt diagnosis of active TB facilitates timely therapeutic intervention and minimizes community transmission [3,4].
The diagnosis of pulmonary TB in HIV-uninfected adults will be reviewed here. Issues related to diagnosis of TB in HIV-infected
patients and children are discussed separately, as are issues related to the clinical manifestations and treatment of TB. (See
"Tuberculosis disease in children" and "Clinical manifestations and complications of pulmonary tuberculosis" and "Treatment of
drug-susceptible pulmonary tuberculosis in HIV-uninfected adults" and "Treatment of pulmonary tuberculosis in HIV-infected
adults: Initiation of therapy".)
OVERVIEW
General diagnostic approach — The diagnosis of pulmonary TB should be suspected in patients with relevant clinical
manifestations (cough >2 to 3 weeks' duration, lymphadenopathy, fevers, night sweats, weight loss) and relevant epidemiologic
factors (history of prior TB infection or disease, known or possible TB exposure, and/or past or present residence in or travel to
an area where TB is endemic) (table 1) [3]. Patients being evaluated for pulmonary TB who pose a public health risk for
transmission should be admitted and isolated with airborne precautions. (See "Tuberculosis transmission and control", section
on 'Clinical triaging'.)
The diagnosis of pulmonary TB is definitively established by isolation of M. tuberculosis from a bodily secretion (eg, culture of
sputum, bronchoalveolar lavage, or pleural fluid) or tissue (pleural biopsy or lung biopsy) [5]. Additional diagnostic tools include
sputum acid-fast bacilli (AFB) smear and nucleic acid amplification (NAA) testing; a positive NAA test (with or without AFB
smear positivity) in a person at risk for TB is considered sufficient for diagnosis of TB (algorithm 1). Radiographic studies are
important supportive diagnostic tools [3].
The approach to diagnosis of TB begins with a history and physical examination to assess the patient's risk for TB (table 1).
Patients meeting clinical criteria should undergo chest radiography; if imaging suggests TB of the lungs or airways, three
sputum specimens (obtained via cough or induction at least eight hours apart and including at least one early-morning
specimen) should be submitted for AFB smear, mycobacterial culture, and NAA testing (algorithm 1) [1,3,6].
In addition, a tuberculin skin test (TST) or interferon-gamma release assay (IGRA) should be performed. These are tools
designed for diagnosis of TB infection; a positive result supports (but cannot be used to establish) a diagnosis of active TB
disease, and a negative result does not rule out active TB disease [3,7,8].
In immunocompromised individuals or in HIV-infected patients with CD4 counts <100 cells/mm3, mycobacterial cultures of blood
and urine should also be performed (in addition to the above studies) [9].
Establishing a definitive laboratory diagnosis of TB may not be possible in some circumstances. No specific bacteriologic
confirmation is ever established in at least 15 to 20 percent of patients with a clinical diagnosis of TB [10,11]. In such cases, a
presumptive clinical diagnosis may be based on epidemiologic exposure together with physical findings, radiographic findings,
positive TST or IGRA, analysis of sputum or bronchoscopy specimens, and/or histopathology. In the setting of high clinical
suspicion for TB, initiation of empiric therapy based on these findings is appropriate. (See "Treatment of drug-susceptible
pulmonary tuberculosis in HIV-uninfected adults".)
Suspected drug-resistant TB — The term "drug-resistant TB" refers to TB caused by an isolate of M. tuberculosis that is
resistant to one or more antituberculous drugs. (See "Treatment of drug-resistant pulmonary tuberculosis in adults", section on
'Definitions'.)
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Drug-resistant TB should be suspected in the setting of relevant risk factors (table 2); these include prior episode of TB
treatment, progressive clinical and/or radiographic findings while on TB therapy, residence in or travel to a region with high
prevalence of drug-resistant TB (figure 1 and figure 2), and/or exposure to an individual with known or suspected infectious
drug-resistant TB. (See "Epidemiology and molecular mechanisms of drug-resistant tuberculosis".)
Definitive diagnosis of drug-resistant TB is established via laboratory identification of M. tuberculosis in sputum (or other clinical
specimen), with drug susceptibility testing (DST) demonstrating resistance to one or more antituberculous agents.
Patients for whom there is clinical suspicion for drug-resistant pulmonary TB should have sputum sent for the following
laboratory tests:
● Acid-fast bacilli smear and mycobacterial culture (three sputum specimens collected at least eight hours apart)
● Culture-based drug susceptibility testing
● Nucleic acid amplification test, with molecular detection for drug resistance (at least one sputum specimen, preferably a
first-morning specimen) (see 'Probe-based (NAA) testing' below)
Records of prior cultures, drug susceptibility testing, and treatment regimens should be obtained for the patient as well as any
known or suspected source case(s) that he or she has had contact with.
Obtaining clinical specimens
Sputum — Sputum may be obtained spontaneously (by coughing) or it may be induced; patients providing sputum samples
should understand that nasopharyngeal discharge and saliva are not sputum (table 3 and table 4) [12,13]. Sputum should
represent secretions from the lower respiratory tract, and at least 5 to 10 mL is optimal for adequate diagnostic yield [3,14];
protocols for collecting high-quality sputum have been described [15]. A series of at least three single specimens should be
collected in 8- to 24-hour intervals (with at least one specimen obtained in the early morning), although the diagnosis often can
be made with two specimens [16-20]. Obtaining three specimens is useful for culture even if the first or second specimen is
smear positive. Sputum should be collected in an isolation booth or in an area with appropriate environmental controls. (See
"Tuberculosis transmission and control".)
For patients who have difficulty producing sputum, sputum may be induced by inhalation of aerosolized hypertonic saline
generated by a nebulizer [21-23]. Such specimens may appear thin and watery and should be labeled "induced sputum" so they
will not be discarded by the laboratory as inadequate specimens. This procedure should be administered by trained personnel
using appropriate respiratory protection in an isolation booth or in an area with appropriate environmental controls. (See
"Tuberculosis transmission and control".)
In general, the yields of induced sputum and bronchoalveolar lavage specimens are comparable, and induced sputum is safer
and less costly [24-26].
Bronchoscopy specimens — Bronchoscopy with bronchoalveolar lavage and brushings should be reserved for the
following circumstances [3,24,25,27]:
● Unsuccessful attempts to obtain adequate expectorated or induced sputum samples
● Negative sputum studies in the setting of a high clinical suspicion for TB
● Potential alternative diagnosis for which diagnostic bronchoscopy is required
● Urgent diagnostic information is needed (in such circumstances, transbronchial biopsy may be warranted)
Sputum produced after bronchoscopy (during the immediate period following bronchoscopy and the day following the
procedure) should also be collected for AFB smear and mycobacterial culture to optimize diagnostic yield [3,28,29].
Bronchoscopy should be performed by personnel using appropriate respiratory protection in an area with appropriate
environmental controls, usually only after other tests (eg, sputum smears and/or NAA testing) are returned negative. Careful
disinfection and sterilization of the bronchoscope and ancillary equipment is required. (See "Tuberculosis transmission and
control".)
Tissue biopsy — Tissue biopsy may establish a definitive diagnosis of TB when other testing is not diagnostic. Biopsy
specimens allow for both microbiologic studies and histopathologic examination. Biopsy specimens should be collected with
and without fixative; specimens without fixative are required for culture. Issues related to pleural biopsy are discussed
separately. (See "Tuberculous pleural effusion".)
Microscopy of tissue biopsy specimens in the setting of TB typically demonstrates granulomatous inflammation. Granulomas of
TB characteristically contain epithelioid macrophages, Langhans giant cells, and lymphocytes (picture 1). The centers of
tuberculous granulomas often have characteristic caseation ("cheese-like") necrosis; organisms may or may not be seen with
acid-fast staining. The demonstration of characteristic caseating granulomas on a tissue section in the appropriate clinical and
epidemiologic circumstances strongly supports a diagnosis of active TB, but it is not pathognomonic; culture is required to
establish a laboratory diagnosis and to perform drug susceptibility testing [30].
Issues related to tissue biopsy in the setting of extrapulmonary TB are discussed separately. (See "Abdominal tuberculosis" and
"Tuberculous lymphadenitis" and "Skeletal tuberculosis" and "Central nervous system tuberculosis".)
Other specimens — Other specimens include pleural fluid, whole blood, gastric aspiration and serum:
● Issues related to pleural fluid are discussed separately. (See "Tuberculous pleural effusion".)
● Use of whole blood for study of RNA expression via microarray analysis has shown some promise for diagnosis of active
TB disease and for predicting progression from latent TB infection (LTBI) to active TB [31,32]. In a case-control study
describing the performance of a three-gene transcriptional analysis in three clinical cohorts, the scores from these analyses
were predictive of progression from LTBI to active TB six months prior to sputum conversion (sensitivity and specificity 86
and 84 percent, respectively); in addition, the scores were diagnostic for active TB (sensitivity and specificity 90 and 70
percent, respectively). The scores correlated with treatment response and the severity of lung pathology as determined by
positron emission tomography-computed tomography [33].
● In general, gastric aspiration is not used for adults; it can be useful in children who cannot produce sputum. This is
discussed separately. (See "Tuberculosis disease in children", section on 'Gastric aspirate'.)
● There is no role for use of serologic testing in diagnosis of TB; such tests are neither accurate nor cost-effective [34-38].
While large numbers of individuals worldwide have TB antibodies, only about 10 percent of them go on to develop active
disease. In 2011, the World Health Organization (WHO) issued a strong negative recommendation against the use of
serologic testing [37], which was based on a meta-analysis of 92 studies concluding that use of commercial serological
tests is supported only by data of very low quality [36].
DIAGNOSTIC TOOLS — Tools for diagnosis of TB include radiographic imaging and laboratory studies.
Radiographic imaging — Chest radiography is part of the initial approach to a diagnostic evaluation of a patient with
suspected TB; it is a useful tool for evaluating symptomatic patients with appropriate epidemiologic risk factors for TB [39-43].
Active pulmonary TB often cannot be distinguished from inactive disease on the basis of radiography alone, and readings of
"fibrosis" or "scarring" must be interpreted in the context of the clinical and epidemiologic presentation.
Reactivation pulmonary TB classically presents with focal infiltration of the upper lobe(s) (usually of the apical and/or posterior
segments) or the lower lobe(s) (usually of the apical, also called superior, segments) (image 1A-D). Disease may be unilateral
or bilateral. Cavitation may be present, and inflammation and tissue destruction may result in fibrosis with traction and/or
enlargement of hilar and mediastinal lymph nodes.
In some cases, pulmonary TB in adults may not present with the "classic" radiographic appearance described above. Lobar or
segmental infiltration may be visualized in other lung regions, with or without hilar adenopathy, lung mass (tuberculoma), small
fibronodular lesions (termed "miliary" because they resemble scattered millet seeds), or pleural effusions [41-43]. This is
particularly likely among patients with advanced HIV disease for whom "atypical" radiographic presentations are common
[9,44,45].
Occasionally, specialized views of the chest may be required, such as an apical lordotic projection for careful evaluation of the
lung apices or a lateral decubitus series to evaluate for presence of pleural effusion. Pleural effusion also may be detectable via
ultrasonography.
Chest computed tomography (CT) is more sensitive than plain chest radiography for identifying early or subtle parenchymal and
nodal processes. The resolution provided by CT usually is not required for diagnosis or management of pulmonary TB; it may
be reserved for circumstances in which more precise resolution of features observed in a chest radiograph is required or where
an alternative diagnosis is suspected.
There is no role for routine use of positron emission tomography (PET) for evaluation of TB [46-48]. PET uptake of F-fluoro-2-
deoxyglucose (FDG) does not differentiate infection from tumor. Macrophages in active TB do not proliferate and do not need
11C-choline, resulting in low C-choline uptake, in contrast with the macrophages in malignancy. Therefore, the combination of a
high FDG and low 11C-choline uptake on PET may be useful for distinguishing active inflammatory (eg, infectious) and/or
neoplastic processes from inactive lesions (eg, fibrosis), although its sensitivity in the setting of clinical suspicion for TB has not
been established [48]. 68Ga-citrate PET accumulates in both pulmonary and extrapulmonary tuberculous lesions and may
provide a way of distinguishing active from inactive lesions for treatment response evaluation [49].
Magnetic resonance imaging (MRI) may demonstrate intrathoracic lymphadenopathy, pericardial thickening, and pericardial and
pleural effusions [50].
Radiographic findings in the setting of pulmonary TB are discussed further separately. (See "Clinical manifestations and
complications of pulmonary tuberculosis".)
Microbiologic testing — Tools for microbiologic testing include sputum acid-fast bacilli (AFB) smear, mycobacterial culture,
and molecular tests.
Laboratory tools for drug susceptibility testing (DST) include culture-based testing (which provides phenotypic information) and
molecular testing (which provides genotypic information) [51,52]:
● Conventional (phenotypic) culture-based drug susceptibility testing is the gold standard for diagnosis of drug-resistant TB; it
allows comparison of growth on drug-containing medium with growth on control medium to establish presence or absence
of drug resistance. Culture may take at least a month to perform. The time to positive culture depends on the burden of
organisms, which may be lower in HIV-infected patients. (See 'Mycobacterial culture' below.)
● Molecular tests for drug-resistant TB have faster turnaround time than culture-based DST (results available within hours to
days) and are useful for guiding initial decisions regarding therapy until definitive culture-based DST is available. (See
'Molecular testing' below.)
Not all laboratories perform all tests; some local and hospital laboratories may perform initial tests, such as sputum smears, and
then refer samples to reference laboratories for culture, identification, and drug susceptibility testing. Some laboratories require
specific orders for testing beyond culture and identification, such as drug susceptibility testing, so close communication with the
laboratory is critical. All United States jurisdictions require submission of culture isolates identified as M. tuberculosis complex
by any laboratory to their jurisdictional public health laboratory for confirmation of identification and drug susceptibility testing.
Positive cultures are also reported to public health authorities for oversight and case management.
Sputum AFB smear — The detection of acid-fast bacilli (AFB) on microscopic examination of stained sputum smears is the
most rapid and inexpensive TB diagnostic tool. Smears may be prepared directly from clinical specimens or from concentrated
preparations; concentrated material is preferred [3]. Sputum should be of good quality and at least 3 mL in volume [3].
Sputum AFB smears are less sensitive than nucleic acid amplification (NAA) or culture; approximately 10,000 bacilli per mL are
needed for detection of bacteria in AFB smear using light microscopy [53]. The sensitivity and positive predictive value of AFB
smear microscopy are approximately 45 to 80 percent and 50 to 80 percent, respectively [13,54]. Sensitivity increases with
concentration of the specimen and increased specimen number and can be as high as 90 percent. The sensitivity of stained
smears is diminished in patients with a small organism burden [55-58].
In HIV-infected patients, the sensitivity of sputum smear is diminished because pulmonary cavities occur less frequently and the
organism burden is lower in the setting of HIV infection [54,59-62]. In areas with high HIV seroprevalence, sputum sensitivity is
20 to 30 percent [54]. However, sputum specificity can be high (>90 percent) for both HIV-uninfected and HIV-infected patients
[63].
The acid-fast staining procedure is based on the ability of the mycobacteria to retain stain when treated with mineral acid or an
acid-alcohol solution. Two common techniques for acid-fast staining are the older carbolfuchsin methods (including the Ziehl-
Neelsen and the Kinyoun methods with light microscopy) (picture 2) and the more rapid fluorochrome procedure (using
auramine-O or auramine-rhodamine dyes with fluorescence microscopy) (picture 3) [55,64-66]. The fluorochrome technique is
preferred since it is up to 10-fold more sensitive than the carbolfuchsin methods that use light microscopy [3,67]. The utility of
fluorescence microscopy may be improved by use of low-cost light-emitting diode (LED), which has a lifespan of more than
50,000 hours [59]. Accordingly, the World Health Organization (WHO) has recommended that conventional fluorescence
microscopy be replaced by LED microscopy [68].
Acid-fast bacteria visualized on a slide may represent M. tuberculosis or nontuberculous mycobacteria (NTM), so species
identification requires culture and/or nucleic acid amplification (algorithm 1). Acid-fast pulmonary disease in United States–born
patients is more likely to represent NTM infection than TB [69,70].
Among individuals at risk for drug-resistant TB with positive sputum AFB smear, rapid molecular testing for rifampin resistance
should be performed. (See 'Molecular testing' below and "Epidemiology and molecular mechanisms of drug-resistant
tuberculosis", section on 'Risk factors for development of drug resistance'.)
Mycobacterial culture
Conventional culture techniques — All clinical specimens suspected of containing mycobacteria should be cultured.
Conventional culture is the most sensitive tool for detection of TB and can detect as few as 10 bacteria/mL; the sensitivity and
specificity of sputum culture are about 80 and 98 percent, respectively [71-73]. Culture is required for drug susceptibility testing
and for species identification.
There are three types of traditional culture media: egg based (Lowenstein-Jensen), agar based (Middlebrook 7H10 or 7H11),
and liquid (Middlebrook 7H12 and other commercially available broths). Growth in liquid media is faster (generally one to three
weeks) than growth on solid media (three to eight weeks) [71]. Growth tends to be slightly better on egg-based medium, but
growth is more rapid on agar medium. Agar medium permits examination of colony morphology and detection of mixed cultures.
Commercially available automated liquid broth culture systems that use colorimetric systems for detection of mycobacteria are
important technical advances in the detection of M. tuberculosis and are widely used in the United States.
Specimens should be inoculated onto at least one container of solid medium and used in conjunction with a liquid/broth culture
system [3]. Lowenstein-Jensen slants are a useful backup for detection of strains that may not grow on other media. Automated
liquid systems should be examined for growth at least every two to three days; some platforms (such as MGIT 960) provide
real-time monitoring with immediate notification of growth detection. Solid media should be examined for growth once or twice
weekly.
Once growth is detected, a sample should be processed or forwarded to a reference laboratory for species identification and
drug susceptibility testing. Species identification can be performed using nucleic acid hybridization with a DNA/RNA probe,
high-pressure liquid chromatography (HPLC), biochemical methods, or mass spectrophotometry (matrix-assisted laser
desorption/ionization–time of flight [MALDI-TOF]) [74-77]. DNA/RNA probe-based identification is the most common method
used in the United States.
Drug susceptibility testing for at least isoniazid, rifampin, pyrazinamide, and ethambutol should be performed. In addition,
isolates from patients at risk for drug-resistant disease should undergo routine testing for susceptibility to second-line agents.
(See 'Drug susceptibility testing' below and "Epidemiology and molecular mechanisms of drug-resistant tuberculosis", section
on 'Risk factors for development of drug resistance'.)
In regions where available, routine genotyping for patients with culture-positive TB is beneficial for clinical and epidemiologic
purposes [3].
Drug susceptibility testing — Conventional (phenotypic) culture-based drug susceptibility testing is the gold standard
for diagnosis of drug-susceptible and drug-resistant TB. This technique allows comparison of growth on drug-containing
medium with growth on control medium to establish presence or absence of drug resistance [73]. Solid media (agar proportion
method is the reference standard) or liquid (also termed broth) media may be used. Culture-based DST usually requires at least
seven days for liquid media and at least a month for solid media [13,73].
The breakpoint between a resistant and susceptible strain is established via the "critical concentration"; this is the level of drug
in the culture medium that inhibits 95 percent of wild-type TB strains that have not been exposed to the drug but does not
appreciably suppress the growth of strains that are resistant to the drug (established via clinical treatment failure). Methods and
interpretation of TB drug susceptibility testing are provided by the Association of Public Health Laboratories [78].
Some drugs, such as isoniazid, are routinely tested at more than one concentration. A drug that demonstrates resistance at a
lower concentration but susceptibility at a higher concentration may be used in a treatment regimen if it is possible to achieve
sufficiently high serum drug concentrations to overcome resistance at the lower concentration while avoiding toxicity.
A critical concentration differs from a minimum inhibitory concentration (MIC) that is used for reporting drug susceptibility of
most other bacteria. MIC testing consists of growing the organism at a series of drug concentrations to identify the lowest drug
concentration that inhibits growth of the bacteria. It may be appropriate to pursue MIC testing in the setting of resistance to
fluoroquinolones or injectable agents (determined by critical concentration), to determine whether a higher drug dose may be
beneficial.
Identification of resistance to rifampin or more than one first-line drug (isoniazid, rifampin, pyrazinamide, or ethambutol) should
prompt susceptibility testing for second-line drugs including at least amikacin, capreomycin, a fluoroquinolone, and
ethionamide. Other drugs that may be important include cycloserine, para-aminosalicylic acid, rifabutin, linezolid, clofazimine,
and other agents. (See "Antituberculous drugs: An overview", section on 'Second-line agents'.)
Rapid culture techniques — Rapid culture techniques employ use of liquid rather than solid media; tools include the
Mycobacteria Growth Indicator Tube (MGIT) and Microscopic Observation Drug Susceptibility (MODS) assay.
MGIT uses liquid culture to assess whether mycobacteria grow in the absence or presence of various antituberculous drugs. If
growth is detected in the presence of a drug, the organism is resistant to the drug. MGIT results take several days and are
available more rapidly than conventional solid culture.
The MODS assay is a rapid growth-based assay using liquid media for detection of M. tuberculosis complex and drug
resistance to isoniazid and rifampin. The method is relatively labor intense; it is not US Food and Drug Administration (FDA)
approved and is not commonly used in laboratories in the United States. Drug-containing media and drug-free media are
inoculated with sputum specimens, and cultures are examined microscopically for growth [79-83]. Growth of M. tuberculosis on
drug-free media reflects a positive culture; growth on both drug-free and drug-containing media indicates drug resistance. The
median turnaround time is seven days. MODS can be used in smear-positive or smear-negative cases.
Molecular testing — Molecular methods are available for detection of M. tuberculosis complex DNA and common mutations
that are associated with drug resistance. There are two major types of molecular assays: probe-based (non-sequencing) tests
and sequence-based assays.
The chief distinction between these types of assays is that, in general, probe-based tests can detect whether a gene mutation is
present but cannot provide the sequence information for the specific mutation(s). This information may be important because
not all gene mutations within a given region confer drug resistance; silent or missense mutations may be detected by probe-
based assays and signal drug resistance even though they do not confer drug resistance in culture. In contrast, sequence-
based assays can provide information regarding the nature of a specific mutation and therefore can predict drug resistance with
greater accuracy. Therefore, results obtained from a probe-based assay suggestive of resistance should be confirmed with a
sequence-based assay or by culture.
All molecular tests for drug resistance must be confirmed by culture (agar proportion method using solid media is the reference
standard).
Probe-based (NAA) testing — Probe-based tests, also known as nucleic acid amplification (NAA) tests, amplify a
specific nucleic acid sequence that can be detected via a nucleic acid probe. Some NAA tests can detect genes encoding drug
resistance; the information available regarding drug susceptibility depends on the assay used as discussed below.
Nucleic acid amplification testing should be used for rapid diagnosis (24 to 48 hours) of organisms belonging to the M.
tuberculosis complex in patients with suspected TB [3,84]. Two test platforms are approved by the FDA for use in the United
States: the Amplified Mycobacterium tuberculosis Direct (MTD) test and the Xpert MTB/RIF test. NAA is more sensitive than
smear but less sensitive than culture; as few as 1 to 10 organisms/mL may give a positive result [85-89]. NAA testing has
excellent positive predictive value in the setting of AFB smear-positive specimens for distinguishing tuberculous from
nontuberculous mycobacteria (>95 percent), and it can rapidly establish the presence of TB in 50 to 80 percent of AFB smear-
negative specimens (which would eventually be culture positive) [6]. However, NAA does not replace the roles of AFB smear
and culture in the diagnostic algorithm for TB; culture is required for confirmation of identification and for drug susceptibility
testing [85].
NAA tests permit amplification of a specific target RNA or DNA sequence that can be detected via a nucleic acid probe [90,91].
In AFB smear-positive respiratory specimens, the sensitivity and specificity of NAA are 95 and 98 percent, respectively; in
smear-negative specimens, the sensitivity and specificity are about 75 to 88 percent and 95 percent, respectively [92-94]. A
positive NAA result supports the diagnosis of TB in the appropriate clinical and epidemiologic circumstances; smear positivity
together with positive NAA is considered sufficient for diagnosis of TB [45,86,95]. A negative NAA result is not sufficient to
exclude the presence of active TB or drug resistance [14].
NAA results must be interpreted in conjunction with AFB smear results while mycobacterial culture (the gold standard for
laboratory confirmation) is pending (algorithm 1) [6]. False-positive NAA results can occur in the setting of contamination and
laboratory error. In addition, NAA can detect nucleic acid from dead and live organisms, so the test can remain positive even
after appropriate therapy. Therefore, NAA is appropriate only for initial diagnostic purposes and cannot be used to monitor
response to treatment. The negative predictive value of an NAA test can be useful in deciding to discontinue respiratory
isolation [6,15,84,96,97]; it can also reduce unnecessary treatment and contact investigations [84,95].
Selection of an NAA test should be guided by local availability, the nature of suspected drug resistance, local resistance
patterns, and clinical history (including prior drug susceptibility testing and prior treatment regimens for the patient and the
source case, if available). Resistance to rifampin can be detected by Xpert MTB/RIF or MTBDRplus, resistance to isoniazid can
be detected by MTBDRplus, and resistance to fluoroquinolones and injectable agents can be detected by MTBDRsl. Individuals
at risk for multidrug-resistant TB with positive nucleic acid amplification test using an assay platform that does not test for drug
resistance (eg, Amplified MTD) should have additional molecular testing for rifampin resistance. (See 'Other assays' below.)
The WHO endorsed the Xpert MTB/RIF assay and the MTBDRplus line-probe assay for diagnosis of pulmonary TB for
diagnosis of both pulmonary and extrapulmonary TB in 2011 [98]. In 2017, the WHO recommended use of Xpert Ultra (where
available) as a replacement for Xpert in all settings [99]. (See 'Xpert MTB/RIF assay' below and 'Xpert MTB/RIF Ultra assay'
below.)
The Amplified MTD test is FDA approved for smear-positive or smear-negative respiratory specimens from patients with
suspected pulmonary TB and fewer than seven days of treatment; it detects TB but does not detect drug resistance. The Xpert
MTB/RIF assay is approved for only induced or expectorated sputum from untreated patients or patients on fewer than 3 days'
therapy; it detects TB and rifampin resistance. (See 'Xpert MTB/RIF assay' below.)
NAA tests may be performed for specimens other than respiratory secretions; this is an "off-label" application and is not
approved by the FDA [94,100]. Some laboratories develop, validate, and perform "in-house" NAA testing on these types of
samples. In the European Union, diagnostic guidelines for TB endorse more broad use of molecular testing for diagnosis and
drug susceptibility testing on specimens other than sputum [101].
Xpert MTB/RIF assay — The Xpert MTB/RIF assay is a molecular beacon assay for detection of M. tuberculosis and
rifampin-resistance mutations in an 81-bp region (codons 426 to 452) of the rpoB gene known as the rifampicin resistance–
determining region (RRDR) [102-104]. The assay may be used for sputum AFB smear-positive or AFB smear-negative samples
(direct or concentrated specimens, spontaneously produced or induced) from adults with suspected pulmonary TB who have
received fewer than three days of antimycobacterial therapy.
The Xpert MTB/RIF assay received endorsement by the WHO in 2011 and approval by the FDA in 2013 [98,105,106]. In 2017,
the WHO recommended use of Xpert Ultra (not available in the United States) as a replacement for Xpert in all settings [99].
(See 'Xpert MTB/RIF Ultra assay' below.)
The feasibility, diagnostic accuracy, and effectiveness of the Xpert MTB/RIF assay has been demonstrated in low-incidence,
high-resource settings [107,108] as well as in high-incidence, resource-limited settings [103,109,110]. The test has the potential
to dramatically reduce the time to diagnosis (results can be available within two hours) and the time to initiation of effective
therapy. The Xpert MTB/RIF assay is simple to perform with minimal training, is not easily prone to cross-contamination, and
requires minimal biosafety facilities. Results are available in as few as two hours. The assay requires a reliable power supply
and operating temperatures below 30°C. Sputum should be of good quality and concentrated by usual laboratory methods for
the best sensitivity, but unconcentrated sputum may be used.
The Xpert MTB/RIF assay has greater sensitivity than smear microscopy and very high specificity [102-104,108,109]:
● In one study including 1730 patients in Peru, Azerbaijan, South Africa, and India with suspected TB, Xpert MTB/RIF assay
correctly identified 98 percent of patients with AFB smear-positive TB and 72 percent of patients with
smear-negative/culture-positive TB [102]. The accuracy for identification of rifampin resistance was 98 percent.
● In one study including 992 patients in the United States, Brazil, and South Africa, performance of a single test correctly
identified 98 percent of patients with AFB smear-positive TB and 55 percent of AFB smear-negative/culture-positive TB
[108].
● In a study including 972 HIV-infected patients in Mozambique starting antiretroviral therapy, use of a second Xpert test
increased case finding by 22 percent [111].
Detection of rifampin resistance via the Xpert MTB/RIF assay should prompt drug susceptibility testing for second-line drugs to
optimize the treatment regimen and prevent emergence of further resistance [112]. (See 'Drug susceptibility testing' above and
'Sequence-based testing' below.)
The Xpert MTB/RIF assay is not able to identify patients with pulmonary TB with sputum smear positive for AFB on microscopy;
sputum smear status is used to monitor response to treatment, guide infection control practices, and guide contact
investigations [113]. The Xpert MTB/RIF assay is not of value in monitoring the response to therapy [114]. However, the Xpert
MTB/RIF assay may be used in place of serial AFB sputum smears to aid in decisions regarding whether continued airborne
infection isolation is warranted for patients with suspected TB. (See "Tuberculosis transmission and control", section on
'Discontinuing airborne precautions'.)
The Xpert MTB/RIF assay may be used (off-label) to estimate the burden of infection via the cycle threshold value (number of
reaction cycles required to obtain a positive result); the cycle threshold value is inversely correlated with the burden of infection
[115,116].
The Xpert MTB/RIF assay can detect DNA from nonviable bacilli, which may be present in patients with prior TB or patients
receiving antituberculous therapy [117]. False-positive results have been associated with recent previous infection, high cycle
threshold, and chest radiograph not suggestive of TB [118]. In addition, false-positive results can occur in regions with low rates
of drug resistance; thus, standard drug susceptibility testing should also be performed.
The Xpert MTB/RIF assay for rifampin resistance may be unreliable in regions where circulating strains contain a mutation
outside the region of rifampin-resistance mutations detected by the assay; in one report from Swaziland, the Xpert MTB/RIF
assay was not able to detect an outbreak strain found to have the rpoB I491F mutation [119].
The Xpert MTB/RIF assay may be useful for diagnosis of extrapulmonary TB in some cases, although use for this purpose is
off-label. This is discussed further separately. (See "Clinical manifestations, diagnosis, and treatment of miliary tuberculosis",
section on 'Xpert MTB/RIF assay'.)
Xpert MTB/RIF Ultra assay — The Xpert MTB/RIF assay received endorsement by the WHO in 2011 and approval by
the FDA in 2013 [98,105,106]. In 2017, the WHO recommended use of Xpert Ultra (where available) as a replacement for Xpert
in all settings [99].
The Xpert MTB/RIF Ultra was developed to improve the sensitivity of the Xpert MTB/RIF test platform; it uses the same
analyzer as Xpert but employs a new specimen cartridge and new software.
In a study including 462 patients with culture-positive sputum, the sensitivity of Xpert Ultra and Xpert were 88 and 83 percent,
respectively [120]. Among 137 participants with culture-positive sputum who were AFB smear negative, the sensitivities of Xpert
Ultra and Xpert were 63 and 46 percent, respectively. Specificity of Xpert Ultra and Xpert were 96 and 98 percent overall.
In general, Xpert Ultra may be more sensitive than Xpert for detection of MTB in smear-negative culture-positive specimens,
pediatric specimens, extrapulmonary specimens (notably cerebrospinal fluid), and specimens from HIV-infected individuals
[121].
The Xpert Ultra is not approved by the FDA and is available in the United States for off-label (research) use only.
Other assays — Other probe-based (NAA) tests include:
● Investigational Xpert assay – An automated cartridge-based molecular assay has been developed using the Xpert
platform for detection of M. tuberculosis with resistance to fluoroquinolones, aminoglycosides, and isoniazid [122]. In a
prospective study of this investigational diagnostic test including more than 300 patients with positive sputum culture for M.
tuberculosis, the sensitivity of the assay (using phenotypic drug susceptibility as the reference standard) for detection of
mutations associated with resistance to isoniazid, ofloxacin, moxifloxacin, kanamycin, and amikacin was 83, 88, 88, 71,
and 71 percent, respectively. The specificity of was ≥94 percent for all drugs except for moxifloxacin, for which specificity
was 84 percent. Using DNA sequencing as the reference standard, the sensitivity and specificity of this assay for detection
of mutations associated with resistance to isoniazid, fluoroquinolones, kanamycin, and amikacin was >95 percent for all
drugs except kanamycin, for which the sensitivity was 92 percent.
● MTBDR – MTBDR platforms (not FDA approved) include:
• MTBDRplus – The MTBDRplus is a molecular line-probe assay capable of detecting rifampin and isoniazid resistance
mutations (rpoB gene for rifampin resistance; katG and inhA genes for isoniazid resistance). This assay does not have
FDA approval for use in the United States.
In an evaluation of 536 smear-positive specimens from patients at risk for multidrug-resistant TB in South Africa,
MTBDRplus was ≥99 percent sensitive and specific for multidrug TB resistance compared with standard DST; results
were available in one to two days [123]. Since the assay does not depend on culture, it yielded results even in
specimens that were contaminated or had no growth. Molecular testing was successful even when the AFB smear was
negative [124,125].
• MTBDRsl – The MTBDRsl is a molecular line-probe assay capable of detecting resistance to fluoroquinolones and
injectable agents (second-line antituberculous agents; gyrA gene for fluoroquinolone resistance and rrs gene for
injectable agents) [126,127]. This assay does not have FDA approval for use in the United States.
The WHO issued guidance in 2016 recommending use of MTBDRsl for identifying patients with multidrug-resistant TB
or rifampicin-resistant TB who are candidates for treatment with a shortened treatment regimen [128]. The assay may
be used as the initial test for detection of resistance to fluoroquinolones and second-line injectable drugs in place of
phenotypic culture-based DST; however, DST is required to detect resistance to other drugs and to monitor for
emergence of additional drug resistance during treatment. (See "Treatment of drug-resistant pulmonary tuberculosis in
adults", section on 'Shortened regimen'.)
Sequence-based testing — Sequence-based assays can provide the genetic identity of a particular mutation and
therefore can predict drug resistance with greater accuracy than probe-based assays. Methods include pyrosequencing,
Sanger sequencing, and next-generation sequencing.
In one study including more than 10,000 clinical isolates, whole-genome sequences and associated phenotypes of resistance
or susceptibility to first-line antituberculosis drugs were obtained [129]. Resistance to isoniazid, rifampin, ethambutol, and
pyrazinamide was correctly predicted with sensitivity of 97, 97, 95, and 91 percent, respectively; susceptibility to these drugs
was correctly predicted with specificity of 99, 99, 94, and 97 percent, respectively. Genotypic predictions of the susceptibility of
M. tuberculosis to first-line drugs were found to correlate with phenotypic susceptibility to these drugs. These findings are
promising since they suggest that genetic data may be used to predict susceptibility to first-line TB drugs without having to wait
until the organisms grow in a culture (which can take several weeks).
In the United States, specimens may be forwarded from state public health TB laboratories to the Centers for Disease Control
and Prevention for sequence-based molecular detection of drug resistance (MDDR) testing [130,131]. The testing identifies
genetic mutations associated with rifampin and isoniazid resistance as well as resistance to second-line drugs including
fluoroquinolones and the injectables amikacin, kanamycin, and capreomycin. Molecular testing results are generally available
within days and can be used to guide initial treatment decisions and inform design of prevention regimens for contacts. Culture-
based drug susceptibility testing is also performed, and these results are reported as they become available.
Urine antigen test in HIV infection — Urine-based detection of mycobacterial cell wall glycolipid lipoarabinomannan (urine
LAM) assay is a point-of-care assay for diagnosis of TB. Data regarding this assay are discussed separately. (See "Clinical
manifestations, diagnosis, and treatment of miliary tuberculosis", section on 'Urine antigen test in HIV infection'.)
For regions of the world with high incidence of HIV and TB, we are in agreement with the WHO, which favors use of urine LAM
testing in addition to routine diagnostic tests for HIV-infected patients with signs and symptoms of pulmonary and/or
extrapulmonary TB and CD4 ≤100 cells/microL, and for HIV-infected patients who are seriously ill (defined as respiratory rate
>30/minute, temperature 39°C, heart rate >120/minute, and unable to walk unaided), regardless of CD4 count [132].
REPORTING AND PUBLIC HEALTH — TB is a reportable disease in the United States [133]. Individuals with confirmed or
suspected TB must be reported to a state or local public health authority promptly (in many states, this period is 24 hours)
[134,135]. Laboratories that process diagnostic specimens for TB also are required to report the isolation of M. tuberculosis
complex organisms to the provider and to the public health authority.
Case and suspect reporting initiates a series of events by the health department to assist the clinician and patient with
additional diagnostic measures and management of the disease. Public health personnel also initiate activities such as contact
notification and investigation to assess and limit the impact of the infection on the community. This includes new case finding
and prevention of disease in high-risk contacts [136].
The public health authority can provide a link to expert medical consultation for diagnosis or management; this may be
especially useful in regions with limited local expertise or where TB is not common. In the United States, the Centers for
Disease Control and Prevention also sponsors regional training and medical consultation centers [137].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of tuberculosis".)
SUMMARY AND RECOMMENDATIONS
● The diagnosis of pulmonary tuberculosis (TB) should be suspected in patients with relevant clinical manifestations (cough
>2 to 3 weeks' duration, lymphadenopathy, fevers, night sweats, weight loss) and relevant epidemiologic factors (history of
prior TB infection or disease, known or possible TB exposure, and/or past or present residence in or travel to an area
where TB is endemic). (See 'General diagnostic approach' above.)
● The diagnosis of pulmonary TB is definitively established by isolation of Mycobacterium tuberculosis from a bodily secretion
(eg, culture of sputum, bronchoalveolar lavage, or pleural fluid) or tissue (pleural biopsy or lung biopsy). Additional
diagnostic tools include sputum acid-fast bacilli (AFB) smear and nucleic acid amplification (NAA) testing; positive NAA test
(with or without AFB smear positivity) is considered sufficient for diagnosis of TB. (See 'General diagnostic approach'
above.)
● The approach to diagnosis of TB begins with a history and physical examination to assess the patient's risk for TB (table 1).
Patients meeting clinical criteria should undergo chest radiography; if imaging suggests TB of the lungs or airways, three
sputum specimens (obtained via cough or induction at least eight hours apart and including at least one early-morning
specimen) should be submitted for AFB smear, mycobacterial culture, and NAA testing (algorithm 1). (See 'General
diagnostic approach' above.)
● In addition, a tuberculin skin test (TST) or interferon-gamma release assay (IGRA) should be performed. These are tools
designed for diagnosis of latent TB infection; a positive result supports (but cannot be used to establish) a diagnosis of
active TB disease, and a negative result does not rule out active TB disease. (See 'General diagnostic approach' above.)
● Establishing a definitive laboratory diagnosis of TB may not be possible in some circumstances. In such cases, a
presumptive clinical diagnosis may be based on epidemiologic exposure together with physical findings, radiographic
findings, positive TST or IGRA, analysis of sputum or bronchoscopy specimens, and/or histopathology. In the setting of
high clinical suspicion for TB, initiation of empiric therapy based on these findings is appropriate. (See 'General diagnostic
approach' above.)
● Drug-resistant TB should be suspected in the setting of relevant risk factors; these include prior episode of TB treatment,
progressive clinical and/or radiographic findings while on TB therapy, residence in or travel to a region with high prevalence
of drug-resistant TB, and/or exposure to an individual with known or suspected infectious drug-resistant TB. Definitive
diagnosis of drug-resistant TB is established via laboratory identification of M. tuberculosis in sputum (or other clinical
specimen), with drug susceptibility testing (DST) demonstrating resistance to one or more antituberculous agents. (See
'Suspected drug-resistant TB' above.)
● Sputum may be obtained spontaneously (by coughing) or it may be induced by inhalation of aerosolized hypertonic saline
generated by a nebulizer. Bronchoscopy with bronchoalveolar lavage and brushings should be reserved for the
circumstances described above. Tissue biopsy may establish a definitive diagnosis of TB when other diagnostic techniques
are not diagnostic. (See 'Obtaining clinical specimens' above.)
● Laboratory tools for drug susceptibility testing include culture-based testing (which provides phenotypic information) and
molecular testing (which provides genotypic information). Culture-based testing is the gold standard for diagnosis of drug-
resistant TB; it allows comparison of growth on drug-containing medium with growth on control medium to establish
presence or absence of drug resistance, but it may take at least a month to perform. Molecular tests have faster turnaround
time (results available within hours to days) and are useful for guiding initial decisions regarding therapy until definitive
culture-based DST is available. (See 'Microbiologic testing' above.)
● There are two major types of molecular assays: probe-based (non-sequencing) tests and sequence-based assays. Probe-
based tests, also known as nucleic acid amplification tests, amplify a specific nucleic acid sequence that can be detected
via a nucleic acid probe; some NAA tests can detect genes encoding drug resistance. Sequence-based assays remain
investigational and are not approved by the US Food and Drug Administration (FDA). (See 'Molecular testing' above.)
● Two NAA test platforms are approved by the FDA for use in the United States: the Amplified Mycobacterium tuberculosis
Direct (MTD) test and the Xpert MTB/RIF test. The Amplified MTD test is approved for smear-positive or smear-negative
respiratory specimens from patients with suspected pulmonary TB and fewer than seven days of treatment; it detects TB
but does not detect drug resistance. The Xpert MTB/RIF assay is approved for only induced or expectorated sputum from
untreated patients or patients on fewer than three days' therapy; it detects TB and rifampin resistance. (See 'Probe-based
(NAA) testing' above.)
● Individuals with confirmed or suspected TB must be reported to a public health authority promptly. Such reporting facilitates
diagnostic and treatment support as well as contact investigation to assess and limit the impact of the infection on the
community. (See 'Reporting and public health' above.)
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predict the sputum smear status of tuberculosis patients. Clin Infect Dis 2012; 54:384.
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tuberculosis therapy initiation in South Africa. Clin Infect Dis 2013; 56:503.
125. Kipiani M, Mirtskhulava V, Tukvadze N, et al. Significant clinical impact of a rapid molecular diagnostic test (Genotype
MTBDRplus assay) to detect multidrug-resistant tuberculosis. Clin Infect Dis 2014; 59:1559.
126. Theron G, Peter J, Richardson M, et al. The diagnostic accuracy of the GenoType(®) MTBDRsl assay for the detection of
resistance to second-line anti-tuberculosis drugs. Cochrane Database Syst Rev 2014; :CD010705.
127. Theron G, Peter J, Richardson M, et al. GenoType(®) MTBDRsl assay for resistance to second-line anti-tuberculosis
drugs. Cochrane Database Syst Rev 2016; 9:CD010705.
128. World Health Organization. The use of molecular line probe assays for the detection of resistance to second-line antituber
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to First-Line Tuberculosis Drugs by DNA Sequencing. N Engl J Med 2018; 379:1403.
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U.S. Public Health Laboratories: Molecular Detection of Drug Resistance (MDDR) in Mycobacterium tuberculosis Complex
by DNA Sequencing (Version 2.0), June 2012. CDC, Atlanta, GA 2012. http://www.cdc.gov/tb/topic/laboratory/mddrusersg
uide.pdf (Accessed on June 16, 2016).
132. World Health Organization. The use of lateral flow urine lipoarabinomannan assay (LF-LAM) for the diagnosis and screeni
ng of active tuberculosis in people living with HIV: Policy update. http://www.who.int/tb/publications/use-of-lf-lam-tb-hiv/en/
(Accessed on March 16, 2016).
133. Tuberculosis control laws--United States, 1993. Recommendations of the Advisory Council for the Elimination of
Tuberculosis (ACET). MMWR Recomm Rep 1993; 42:1.
134. Sotir MJ, Parrott P, Metchock B, et al. Tuberculosis in the inner city: impact of a continuing epidemic in the 1990s. Clin
Infect Dis 1999; 29:1138.
135. Centers for Disease Control and Prevention: State TB Control Offices http://www.cdc.gov/tb/links/tboffices.htm (Accessed
on May 18, 2010).
136. Taylor Z, Nolan CM, Blumberg HM, et al. Controlling tuberculosis in the United States. Recommendations from the
American Thoracic Society, CDC, and the Infectious Diseases Society of America. MMWR Recomm Rep 2005; 54:1.
137. Centers for Disease Control and Prevention. Regional Training and Medical Consultation Centers (RTMCCs). Available at:
http://www.cdc.gov/tb/education/rtmc/default.htm (Accessed on May 21, 2010).
Topic 111683 Version 18.0
GRAPHICS
Guidelines for the evaluation of pulmonary tuberculosis in adults in five clinical scenarios
Patient and setting Recommended evaluation
Any patient with a cough of ≥2 to 3 weeks' duration, with at least Chest radiograph: If suggestive of TB*, collect three sputum
one additional symptom, including fever, night sweats, weight loss, specimens for AFB smear microscopy and culture. At least one
or hemoptysis specimen should also be tested using an NAA test.
Any patient at high risk for TB ¶ with an unexplained illness, Chest radiograph: If suggestive of TB*, collect three sputum
including respiratory symptoms, of ≥2 to 3 weeks' duration specimens for AFB smear microscopy and culture. At least one
specimen should also be tested using an NAA test.
Any patient with HIV infection and unexplained cough and fever Chest radiograph, and collect three sputum specimens for AFB
smear microscopy and culture. At least one specimen should also
be tested using an NAA test.
Any patient at high risk for TB ¶ with a diagnosis of community- Chest radiograph, and collect three sputum specimens for AFB
acquired pneumonia who has not improved after seven days of smear microscopy and culture. At least one specimen should also
treatment be tested using an NAA test.
Any patient at high risk for TB ¶ with incidental findings on chest Review of previous chest radiographs if available, three sputum
radiograph suggestive of TB even if symptoms are minimal or specimens for AFB smear microscopy and culture. At least one
absent Δ specimen should also be tested using an NAA test.
TB: tuberculosis; AFB: acid-fast bacilli; NAA: nucleic acid amplification.

* Infiltrates with or without cavitation in the upper lobes or the superior segments of the lower lobes.
¶ Patients with one of the following characteristics: recent exposure to a person with a case of infectious TB; history of a positive test result for
Mycobacterium tuberculosis; HIV infection; injection or noninjection drug use; foreign birth and immigration ≤5 years from a region in which
incidence is high; residents and employees of high-risk congregate settings; membership in a medically underserved, low-income population;
or a medical risk factor for TB (including diabetes mellitus, conditions requiring prolonged corticosteroid and other immunosuppressive therapy,
chronic renal failure, certain hematological malignancies and carcinomas, weight >10 percent below ideal body weight, silicosis, gastrectomy,
or jejunoileal bypass).
Δ Chest radiograph performed for any reason, including targeted testing for latent TB infection and screening for TB disease.
Adapted from: Controlling tuberculosis in the United States. Recommendations from the American Thoracic Society, CDC, the Infectious
Diseases Society of America. MMWR Recomm Rep 2005; 54(RR-12):1. Daley CL, Gotway MB, Jasmer RM. Radiographic manifestations of
tuberculosis: a primer for clinicians. San Francisco, CA: Francis J Curry National Tuberculosis Center; 2003: 1-30, and Updated guidelines for
the use of nucleic acid amplification tests in the diagnosis of tuberculosis. MMWR Morb Mortal Wkly Rep 2009; 58:7.
Graphic 80879 Version 5.0
Approach to interpretation of sputum AFB smear and NAA test for diagnosis of pulmonary
tuberculosis disease in adults
AFB: acid-fast bacilli; NAA: nucleic acid amplification; TB: tuberculosis; NTM: nontuberculous mycobacteria.
* A negative NAA result should be accompanied by a negative test for inhibitors that may limit amplification (if the Enhanced Amplified
Mycobacterium Tuberculosis Direct Test [E-MTD] assay was used). The Xpert MTB/RIF assay contains a positive control that signals an invalid result
if an inhibitor is detected.
¶ An invalid NAA result indicates failure of the assay. An invalid result is usually reported after the test has been repeated using the same specimen.
Receipt of an invalid NAA result should prompt a repeat test using a new specimen.
Δ TB remains possible; the organism burden may be too low to meet the sensitivity threshold for detection via NAA or smear.
Data from:
1. Lewinsohn DM, Leonard MK, LoBue PA, et al. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease
Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children. Clin Infect Dis 2017; 64:e1.
2. World Health Organization. Global Tuberculosis Report, 2016. WHO, Geneva 2016. Available at:
http://apps.who.int/iris/bitstream/10665/250441/1/9789241565394-eng.pdf?ua=1 (Accessed on March 9, 2017).
3. Centers for Disease Control and Prevention (CDC). Updated guidelines for the use of nucleic acid amplification tests in the diagnosis of
tuberculosis. MMWR Morb Mortal Wkly Rep 2009; 58:7.
Risk factors for drug-resistant tuberculosis
Patients with history of TB (current or past)
Persistent or progressive clinical and/or radiographic findings while on antituberculous therapy
Lack of conversion of cultures to negative during first three months of antituberculous therapy
Incomplete adherence to prescribed antituberculous therapy
Lack of directly observed therapy or poorly supervised antituberculous therapy
Documented treatment failure or relapse
History of an inappropriate treatment regimen, including too few effective drugs or inadequate drug dosing
Patients without prior history of TB
Exposure to an individual with known or suspected drug-resistant TB
Residence in or travel to a region with high prevalence of drug-resistant TB
Residence in or work in an institution or setting with documented drug-resistant TB
Among foreign-born individuals: Emigration within the previous two years from a region with known drug-resistant TB
TB: tuberculosis.
Data from: Curry International Tuberculosis Center and California Department of Public Health, 2016: Drug-Resistant Tuberculosis: A Survival
Guide for Clinicians, Third Edition.
Distribution of percentage of new tuberculosis cases with multidrug-

resistant tuberculosis (MDR-TB)
Figures are based on the most recent year for which data have been reported, which varies among
countries.
Reproduced, with the permission of the publisher, from the Global Tuberculosis Report 2013. Geneva, World
Health Organization, 2013. (Figure 4.2,
http://apps.who.int/iris/bitstream/10665/91355/1/9789241564656_eng.pdf, Accessed on November 18,
2013.)
Percentage of previously treated tuberculosis patients with multidrug-

resistant tuberculosis (MDR-TB)
Figures are based on the most recent year for which data have been reported, which varies among
countries. The high percentages of previously treated tuberculosis cases with multidrug-resistant
tuberculosis in Bahrain, Bonaire - Saint Eustatius and Saba, Cook Islands, Iceland, Sao Tome and
Principe, and Lebanon refer to only a small number of notified cases (<10).
Reproduced, with the permission of the publisher, from the Global Tuberculosis Report 2013. Geneva, World
Health Organization, 2013. (Figure 4.3,
http://apps.who.int/iris/bitstream/10665/91355/1/9789241564656_eng.pdf, Accessed on November 18,
2013.)
Nebulized sputum induction for tuberculosis
Purpose
To obtain sputum specimens for AFB smear microscopy and culture from a patient who has a dry, non-productive cough.
Ensure that the patient is placed in an appropriate negative air pressure room with the door shut. The air in the negative
air pressure room should be drawn out of the room and vented outside of the building.
Materials and equipment required
Sterile, filtered water or normal saline (150 to 250 mL)

Hand-held nebulizer with mouthpiece and 15 mL vial of 3% saline
NOTE: A mask may be used if a patient cannot use a mouthpiece.
N95 mask (particulate respirator) for AFB

Gloves
Box of tissues
Sterile specimen container approved by the laboratory for sputum collection and transport
Procedure
Preparation
1. If at risk for aspiration, assure that the patient is NPO for three hours prior to sputum induction.
2. Instruct the patient to gently brush his/her teeth, gingival margins, tongue, and buccal surfaces using sterile, filtered water or
normal saline to rinse.
Do not use toothpaste, commercial mouth wash preparations, nose drops, or any medications containing alcohol, or oil.
Instruct the patient to avoid taking oral antibiotics immediately before the sputum collection procedure.
3. Instruct the patient to rinse and gargle several times with sterile, filtered water or normal saline after brushing.
Do not use tap water or bottled water, as it may contain nontuberculous mycobacteria that may alter findings.
Sputum collection
1. Observe standard airborne isolation protection precautions at all times.

NOTE: N95 masks must worn by healthcare personnel for AFB cough-producing procedures.
2. The patient must be in an appropriate negative air pressure room or outdoors.

3. Place approximately 5 mL of 3% saline into the hand-held nebulizer. Set the flow at 6 to 8 L/min and nebulize saline for 7 to 10
minutes or until sputum is expectorated. The maximum nebulization time is 20 minutes.
NOTE: More saline may be added to the nebulizer if more than 10 minutes is needed to produce an adequate cough.
4. At the end of this time, ask the patient to inhale the nebulized 3% saline deeply 2 to 3 times followed by a vigorous cough. This
will assist in expectorating quality sputum. Collect the sputum into a sterile specimen container.
NOTE: Coaching the patient is very important in order to get quality results in a timely manner.
NOTE: High-quality sputum is required for smear, culture, and NAA testing. For AFB NAA testing alone, a minimum of 1 mL of
raw sputum (or 0.5 mL of sputum sediment) is needed. It is preferred to collect 5 to 10 mL of raw sputum.
5. Label the specimen with time and date of its collection and place it in a specimen bag. Attach a laboratory request form, if
applicable.
6. Document the procedure in the appropriate flow sheet or medical record.
NOTE: Documentation also is required for unsuccessful procedures.
AFB: acid-fast bacilli; NPO: nothing by mouth; NAA: nucleic acid amplification.
Modified with permission from: National Tuberculosis Controllers Association. Consensus statement on the use of Cepheid Xpert MTB/RIF assay
in making decisions to discontinue airborne infection isolation in healthcare settings, April 2016. Copyright © 2016 National TB Controllers
Association. Available at: http://www.tbcontrollers.org/docs/resources/NTCA_APHL_GeneXpert_Consensus_Statement_Final.pdf (Accessed on
June 21, 2016).
Spontaneously produced sputum collection for tuberculosis
Purpose
To obtain sputum specimens for AFB smear microscopy and culture from a patient who has a productive cough.
Ensure that the patient is outdoors or placed in an airborne isolation room or negative-pressure sputum collection booth
with the door shut. The air in the negative-pressure room or booth should be drawn out of the space and vented outside
of the building.
Materials and equipment required
Sterile, filtered water or normal saline (150 to 250 mL)

N95 mask (particulate respirator) for AFB
Gloves
Box of tissues
Sterile specimen container approved by the laboratory for sputum collection and transport
Procedure
Preparation
1. Instruct the patient to gently brush his/her teeth, gingival margins, tongue, and buccal surfaces using sterile, filtered water or
normal saline to rinse.
Do not use toothpaste, commercial mouth wash preparations, nose drops, any medications containing alcohol, or oil. Instruct
the patient to avoid taking oral antibiotics immediately before the sputum collection procedure.
2. Instruct the patient to rinse and gargle several times with sterile, filtered water or normal saline after brushing.
Do not use tap water or bottled water, as it may contain nontuberculous mycobacteria that may alter findings.
Sputum collection
1. Observe standard airborne isolation protection precautions at all times.

NOTE: N95 masks must worn by healthcare personnel for AFB cough-producing procedures.
2. The patient must be outdoors or in an appropriate negative air pressure room or booth.
3. Coach the patient and supervise the first sputum collection, at a minimum, in order to obtain a good quality sputum sample that
represents secretions from the lower respiratory tract.
NOTE: The patient should understand that sputum is material that is brought up from the lungs and that nasal secretions
and saliva or spit are not acceptable.
4. Instruct the patient to inhale deeply, as far as possible, and then exhale slowly three times.
5. After the third breath, direct the patient to inhale completely and try to cough hard to produce sputum from deep in the lungs.
The patient may feel a rattle or tickle as the sputum moves up from the lungs into the throat.
6. Instruct the patient to expectorate the sputum into a sterile specimen container.
7. When there is at least 5 mL (1 teaspoon) of sputum, replace the lid on the container and tighten it so it does not leak.
NOTE: High-quality sputum is required for smear, culture, and NAA testing. For AFB NAA testing alone, a minimum of 1 mL of
raw sputum (or 0.5 mL of sputum sediment) is needed. It is preferred to collect 5 to 10 mL of raw sputum.
8. If the patient is in a negative air pressure room or booth, ask the patient remain in the booth or room until cleared to leave.
9. Label the specimen with time and date of its collection and place it in a specimen bag. Attach a laboratory request form, if
applicable.
10. Document the procedure in the appropriate flow sheet or medical record.
NOTE: Documentation also is required for unsuccessful procedures.
AFB: acid-fast bacilli; NAA: nucleic acid amplification.
Modified with permission from: National Tuberculosis Controllers Association. Consensus statement on the use of Cepheid Xpert MTB/RIF assay
in making decisions to discontinue airborne infection isolation in healthcare settings, April 2016. Copyright © 2016 National TB Controllers
Association. Available at: http://www.tbcontrollers.org/docs/resources/NTCA_APHL_GeneXpert_Consensus_Statement_Final.pdf (Accessed on
June 21, 2016).
Tuberculous granuloma
Low-power light micrograph of a lung biopsy from a patient with tuberculosis

shows multiple granulomas (hematoxylin and eosin stain).
Courtesy of Harriet Provine.
Classic adult tuberculosis posterior-anterior view case I
Chest radiograph, posterior-anterior view, of an 18-year-old high school student exposed

four years earlier to an infectious pulmonary tuberculosis patient. She was noncompliant
with isoniazid prophylaxis. She now presents with cough for one month, fever, and night
sweats. Posterior-anterior radiograph shows right upper lobe apical and posterior
segment infiltrate with cavitation. This radiograph is "classic" for adult-type reactivation
tuberculosis.
Courtesy of John Bernardo, MD.
Classic adult TB lateral view
18-year-old high school student, chest radiograph, lateral view.
Classic adult tuberculosis posterior-anterior view case II
A 40-year-old automobile mechanic from the Dominican Republic, in the United

States eight years, presented to the urgent care clinic with four months of
productive cough, fevers, progressive hoarseness, and a 40 pound weight loss. A
chest radiograph (posterior-anterior view) demonstrates diffuse parenchymal
disease with multiple cavities and bulla formation on the left. Sputum smear was
positive for acid-fast bacilli.
Classic adult TB case 2 lateral
A 40-year-old automobile mechanic with pulmonary tuberculosis, chest radiograph lateral

view.
Sputum stained by Ziehl-Neelsen
Sputum, decontaminated and concentrated, and stained using the Ziehl-Neelsen

method.
Fluorochrome stain of sputum
Fluorochrome staining of sputum for acid-fast bacilli: Increases sensitivity, decreases

examination time versus Ziehl-Neelsen method.
Contributor Disclosures
John Bernardo, MD Nothing to disclose C Fordham von Reyn, MD Grant/Research/Clinical Trial Support: Oxford
Immunotec [Tuberculosis (vaccine)]. Elinor L Baron, MD, DTMH Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting
through a multi-level review process, and through requirements for references to be provided to support the content.
Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

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Author: John Bernardo, MD

● Culture-based drug susceptibility testing

Obtaining clinical specimens

● Unsuccessful attempts to obtain adequate expectorated or induced sputum samples

● Negative sputum studies in the setting of a high clinical suspicion for TB

● Potential alternative diagnosis for which diagnostic bronchoscopy is required

Other assays — Other probe-based (NAA) tests include:

● MTBDR – MTBDR platforms (not FDA approved) include:

SUMMARY AND RECOMMENDATIONS

Use of UpToDate is subject to the Subscription and License Agreement.

1. Dheda K, Barry CE 3rd, Maartens G. Tuberculosis. Lancet 2016; 387:1211.

Topic 111683 Version 18.0

Patient and setting Recommended evaluation

TB: tuberculosis; AFB: acid-fast bacilli; NAA: nucleic acid amplification.

Graphic 80879 Version 5.0

Graphic 112251 Version 1.0

Risk factors for drug-resistant tuberculosis

Patients with history of TB (current or past)

Persistent or progressive clinical and/or radiographic findings while on antituberculous therapy

Incomplete adherence to prescribed antituberculous therapy

Lack of directly observed therapy or poorly supervised antituberculous therapy

Documented treatment failure or relapse

Patients without prior history of TB

Exposure to an individual with known or suspected drug-resistant TB

Residence in or travel to a region with high prevalence of drug-resistant TB

Residence in or work in an institution or setting with documented drug-resistant TB

Graphic 108729 Version 3.0

Distribution of percentage of new tuberculosis cases with multidrug-

Graphic 83859 Version 2.0

Percentage of previously treated tuberculosis patients with multidrug-

Graphic 83860 Version 2.0

Nebulized sputum induction for tuberculosis

Materials and equipment required

Sterile, filtered water or normal saline (150 to 250 mL)

N95 mask (particulate respirator) for AFB

1. Observe standard airborne isolation protection precautions at all times.

2. The patient must be in an appropriate negative air pressure room or outdoors.

Graphic 108732 Version 2.0

Spontaneously produced sputum collection for tuberculosis

Materials and equipment required

Sterile, filtered water or normal saline (150 to 250 mL)

1. Observe standard airborne isolation protection precautions at all times.

AFB: acid-fast bacilli; NAA: nucleic acid amplification.

Graphic 108733 Version 2.0

Low-power light micrograph of a lung biopsy from a patient with tuberculosis

Courtesy of Harriet Provine.

Graphic 67234 Version 4.0

Classic adult tuberculosis posterior-anterior view case I

Chest radiograph, posterior-anterior view, of an 18-year-old high school student exposed

Courtesy of John Bernardo, MD.

Graphic 74846 Version 4.0

Classic adult TB lateral view

18-year-old high school student, chest radiograph, lateral view.

Courtesy of John Bernardo, MD.

Graphic 70220 Version 4.0

Classic adult tuberculosis posterior-anterior view case II

A 40-year-old automobile mechanic from the Dominican Republic, in the United

Courtesy of John Bernardo, MD.

Graphic 54807 Version 4.0

Classic adult TB case 2 lateral