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Diagnosis of pulmonary tuberculosis in adults

Diagnosis of pulmonary tuberculosis in adults
Literature review current through: Jan 2024.
This topic last updated: Jan 16, 2024.

INTRODUCTION — Nearly two billion people (about one-quarter of the world population) are estimated to be infected with Mycobacterium tuberculosis. In 2022, approximately 7.5 million individuals became ill with tuberculosis (TB) and 1.5 million died [1]. Prompt diagnosis of active TB facilitates timely therapeutic intervention and minimizes community transmission [2,3].

The diagnosis of pulmonary TB in adults will be reviewed here. Issues related to diagnosis of TB in children are discussed separately, as are issues related to the clinical manifestations and treatment of TB. (See "Tuberculosis disease in children: Epidemiology, clinical manifestations, and diagnosis" and "Pulmonary tuberculosis: Clinical manifestations and complications" and "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection" and "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy".)

TERMINOLOGY — TB terminology is inconsistent in the literature [4]. Relevant terms are defined in the table (table 1).

OVERVIEW

General diagnostic approach

All patients

Clinical suspicion – The diagnosis of pulmonary TB should be suspected in patients with relevant clinical manifestations (which may include cough >2 to 3 weeks' duration, lymphadenopathy, fevers, night sweats, weight loss) and relevant epidemiologic factors (such as 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 2) [2]. 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 in health care settings", section on 'Clinical triaging'.)

Definitive diagnosis – The diagnosis of pulmonary TB is definitively established by isolation of M. tuberculosis from a bodily secretion or fluid (eg, culture of sputum, bronchoalveolar lavage, or pleural fluid) or tissue (eg, 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 (who has no prior history of treatment for pulmonary TB) is considered sufficient for diagnosis of TB (algorithm 1). Radiographic studies are important supportive diagnostic tools [2].

Clinical approach – The approach to diagnosis of TB begins with clinical suspicion for the disease with a history and physical examination to assess the patient's risk for TB (table 2). 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) [2,6,7].

In addition, a tuberculin skin test (TST), interferon-gamma release assay (IGRA), or specific antigen skin tests endorsed by the World Health Organization (WHO; not available in the United States) may be performed; these are tools that signal for immune sensitization to TB protein antigens and are designed for diagnosis of TB infection [2,8-11]. 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.

Immunocompromised patients – In immunocompromised individuals or in human immunodeficiency virus (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) [12]. (See 'Patients with HIV infection' below.)

Clinical diagnosis (in absence of microbiologic confirmation) – 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 [13,14]. In such cases, a presumptive "clinical diagnosis" may be based on epidemiologic risks 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 nonpregnant adults without HIV infection" and "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy".)

Patients with HIV infection — In settings with high incidence of HIV and TB, the urine LAM assay (which detects lipoarabinomannan, a glycolipid component of the mycobacterial cell wall) is a useful diagnostic tool, in combination with other tests including NAA testing and culture. (See 'General diagnostic approach' above.)

Urine LAM test − The assay consists of a test strip (lateral-flow antigen-capture assay) used at the point of care, with results available in as little as one hour; the tool may be especially useful for patients who cannot produce sputum and are more severely immunosuppressed. There are several commercial versions of the test, none of which is US Food and Drug Administration approved for use in the United States. (See 'Urine antigen test in HIV infection' below.)

Clinical use of urine LAM test − We are in agreement with the WHO and the Stop TB Partnership, which have issued a number of statements to guide use of urine LAM testing (in addition to other diagnostic tests) for patients with advanced HIV infection, as follows [15-18]:

Inpatient settings − For inpatient settings, the WHO recommends that urine LAM testing be used as a diagnostic tool for active TB for individuals with HIV in the following circumstances:

-Signs and symptoms of TB (pulmonary or extrapulmonary)

-CD4 count <200 cells/mm3 (irrespective of signs and symptoms of TB) or WHO HIV/acquired immunodeficiency syndrome (AIDS) clinical stage 3 or 4 [19]

-Seriously ill (defined as respiratory rate >30/minute, temperature >39°C, heart rate >120/minute, and unable to walk unaided)

Patients with positive urine LAM warrant empiric initiation of TB treatment, to be adjusted as needed based on NAA testing and/or culture results when available. A negative urine LAM does not rule out TB; such patients warrant further investigation with NAA testing and culture as discussed above.

Outpatient settings − For outpatient settings, the WHO recommends that urine LAM testing be used for individuals with HIV in the following circumstances:

-Signs and symptoms of TB (pulmonary or extrapulmonary)

-CD4 count <100 cells/mm3 (irrespective of signs and symptoms of TB)

-Seriously ill (defined as respiratory rate >30/minute, temperature >39°C, heart rate >120/minute, and unable to walk unaided)

The WHO recommends against using urine LAM testing for individuals with HIV in the following circumstances:

-Without assessing TB symptoms

-No TB symptoms and CD4 count ≥100 cells/mm3

-No TB symptoms and unknown CD4 count

Subsequent management − Patients who meet the appropriate testing criteria with positive urine LAM warrant empiric initiation of TB treatment; the regimen should be adjusted based on NAA testing and/or culture results when available. A negative urine LAM does not rule out TB; such patients warrant further investigation with nucleic testing and culture as discussed above.

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'.)

Drug-resistant TB should be suspected in the setting of relevant risk factors (table 3); 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. (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 demonstrating resistance to one or more antituberculous agents.

Sputum should be sent for the following laboratory tests:

Acid-fast bacilli smear and mycobacterial culture (three sputum specimens collected at least eight hours apart, to include at least one first morning specimen)

Culture-based drug susceptibility testing

NAA testing, with molecular detection for drug resistance (at least one sputum specimen, preferably a first-morning specimen) (see 'NAA (probe-based) 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).

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 4 and table 5) [20,21]. Sputum should represent secretions from the lower respiratory tract, and at least 5 to 10 mL is optimal for adequate diagnostic yield [2,22]; protocols for collecting high-quality sputum have been described [23]. 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 [24-28]. Obtaining three specimens is useful for culture even if the first or second specimen is smear positive. If within a health care facility, sputum should be collected in an isolation booth or in an area with appropriate environmental controls. (See "Tuberculosis transmission and control in health care settings".)

For patients who have difficulty producing sputum, sputum may be induced by inhalation of aerosolized hypertonic saline generated by a nebulizer [23,29-33]. 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 health care settings".)

In general, the yields of induced sputum and bronchoalveolar lavage specimens are comparable, and induced sputum is safer and less costly [31-33].

Bronchoscopy specimens — Bronchoscopy with bronchoalveolar lavage and brushings should be reserved for the following circumstances [2,31,32,34]:

Unsuccessful attempts to obtain adequate expectorated or induced sputum samples

Negative sputum studies in the setting of a high clinical suspicion for TB or TB with drug resistance

Potential alternative diagnosis for which diagnostic bronchoscopy is required

Urgent diagnostic information is needed (in such circumstances, transbronchial biopsy also 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, NAA testing, and mycobacterial culture to optimize diagnostic yield [2,35,36]. 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 in health care settings".)

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 show 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.

Issues related to tissue biopsy in the setting of extrapulmonary TB are discussed separately. (See "Abdominal tuberculosis" and "Tuberculous lymphadenitis" and "Bone and joint tuberculosis" and "Central nervous system tuberculosis: An overview".)

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".)

Investigational use of whole blood for study of ribonucleic acid (RNA) expression via microarray analysis has shown some promise for diagnosis of active TB disease and for predicting progression from TB infection (TBI; formerly termed latent TB infection) to active TB [37,38]. 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 TBI 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 [39].

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: Epidemiology, clinical manifestations, and diagnosis".)

There is no role for use of serologic testing in diagnosis of TB; such tests are neither accurate nor cost-effective [40-44]. 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 issued a strong negative recommendation against the use of serologic testing [43], which was based on a meta-analysis of 92 studies concluding that use of commercial serologic tests is supported only by data of very low quality [42].

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 [45-49]. 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 [47-49]. This is particularly likely among patients with advanced HIV disease for whom "atypical" radiographic presentations are common [12,50,51].

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 definition 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 [52-54]. 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 [54]. 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 [55].

Magnetic resonance imaging (MRI) may demonstrate intrathoracic lymphadenopathy, pericardial thickening, and pericardial and pleural effusions [56].

Radiographic findings in the setting of pulmonary TB are discussed further separately. (See "Pulmonary tuberculosis: Clinical manifestations and complications".)

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) [57,58]:

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 patients with HIV infection. (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, where indicated for, 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 [2]. Sputum should be of good quality and at least 3 mL in volume [2,22].

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 conventional light microscopy [59]. The sensitivity and positive predictive value of AFB smear microscopy are approximately 45 to 80 percent and 50 to 80 percent, respectively [21,60]. 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 [61-64].

In patients with HIV infection, 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 [60,65-68]. In areas with high HIV seroprevalence, sputum sensitivity is 20 to 30 percent [60]. However, sputum specificity can be high (>90 percent) for patients with and without HIV infection [69].

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) [61,70-72]. The fluorochrome technique is preferred since it is up to 10-fold more sensitive than the carbolfuchsin methods that use light microscopy [2,73]. 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 [65]. Accordingly, the World Health Organization (WHO) has recommended that conventional fluorescence microscopy be replaced by LED microscopy [74].

Acid-fast bacteria visualized on a slide may represent M. tuberculosis or nontuberculous mycobacteria (NTM), so species identification requires culture and/or NAA (algorithm 1). Acid-fast pulmonary disease in United States-born patients may be more likely to represent NTM infection than TB [75,76].

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 [77-79]. 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) [77]. 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 [2]. 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. This is important to distinguish between M. tuberculosis and nontuberculous mycobacteria. Species identification can be performed using nucleic acid hybridization with a deoxyribonucleic acid (DNA)/RNA probe, high-pressure liquid chromatography (HPLC), biochemical methods, or mass spectrophotometry (matrix-assisted laser desorption/ionization-time of flight [MALDI-TOF]) [80-83]. DNA/RNA probe-based identification had been used widely in the United States; many laboratories now use MALDI-TOF systems, which can identify any of multiple Mycobacteria species in a clinical sample.

Culture-based 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 [2].

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 [79]. 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 [21,79].

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 [84].

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 isoniazid should prompt susceptibility testing for fluoroquinolones [85]. 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: amikacin, streptomycin, fluoroquinolones, cycloserine, para-aminosalicylic acid (where available), ethionamide, rifabutin, bedaquiline, linezolid, and clofazimine, where available. In this setting, molecular testing for drug resistance also should be considered [79,85]. (See "Antituberculous drugs: An overview", section on 'Second-line agents' and 'Molecular testing' below.)

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 [86-90]. 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).

NAA (probe-based) testing — 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.

NAA testing should be used for rapid diagnosis (usually within 24 to 48 hours) of organisms belonging to the M. tuberculosis complex in patients with suspected TB [2,91]. One test platform, the Xpert MTB/RIF test, is approved by the FDA and available for use in the United States. In general, NAA is more sensitive than smear but less sensitive than culture; as few as 1 to 10 organisms/mL may give a positive NAA result [92-96]. The analytic limit of detection of the Xpert MTB/RIF assay using spiked sputum specimens has been reported to be 131 colony-forming units/mL of specimen [97]. 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) [7]. 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 [92].

NAA tests permit amplification of a specific target RNA or DNA sequence that can be detected via a nucleic acid probe [98,99]. 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 [100-102]. 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 [51,93,103]. A negative NAA result is not sufficient to exclude the presence of active TB or drug resistance [22].

NAA results must be interpreted in conjunction with AFB smear results while mycobacterial culture (the gold standard for laboratory confirmation) is pending (algorithm 1) [7]. 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 [7,23,91,104,105]; it can also reduce unnecessary treatment and contact investigations [91,103].

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 NAA test using an assay platform that does not test for drug resistance 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 [106]. In 2017, the WHO recommended use of Xpert Ultra (where available) as a replacement for Xpert in all settings [107]. 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 [102,108]. 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 [109].

Xpert MTB/RIF assay — The Xpert MTB/RIF assay is a molecular beacon assay for detection of M. tuberculosis and mutations in the rifampicin resistance–determining region of the rpoB gene [110-112]. It is the only NAA test approved by the FDA in the United States; it is approved 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 was endorsed by the WHO in 2011 and approved by the FDA in 2013 [106,113,114]. In 2017, the WHO recommended use of Xpert Ultra as a replacement for Xpert in all settings; the Ultra platform is not available in the United States [107]. (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 [115,116] as well as in high-incidence, resource-limited settings [111,117,118]. 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. 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 [110-112,116,117]:

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 [110]. 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 [116].

In a study including 972 patients with HIV infection in Mozambique starting antiretroviral therapy, use of a second Xpert test increased case finding by 22 percent [119].

However, given high implementation costs and infrastructure requirements for on-site Xpert testing, many clinics in high-burden areas refer specimens to centralized laboratories; this approach may reduce the potential advantages of rapid molecular testing [120,121]. In one study including 20 community health centers in Uganda and more than 10,000 adults with suspected TB, clusters were randomly assigned to centralized testing or implementation of on-site Xpert testing using GeneXpert Edge (a compact, battery powered platform compatible with the Xpert assay) together with infrastructure enhancements (including work flow restructuring and monthly evaluations to address site-specific barriers) [122]. Rates of completed TB testing, same-day diagnosis, and same-day treatment initiation were higher at centers with on-site testing (adjusted rate ratio 1.85, 1.89, and 2.38, respectively). These findings demonstrate that outcome improvements also require infrastructure modifications to support the advantages provided by rapid molecular testing.

It has been suggested that Xpert MTB/Rif be substituted for the sputum AFB smear in some settings [123]. However, results of NAA testing and AFB smear usually are interpreted together; this can limit overall costs and improve diagnostics precision [7]. Many laboratories will reflex to Xpert testing if a smear is AFB positive, reserving the more costly NAA testing of smear-negative specimens to those requested specifically by the provider or selected by laboratory-specific algorithm. This reduces costs [124]. Smear-positive, Xpert-negative sputum is likely to represent nontuberculous mycobacterial infection [7].

Detection of rifampin resistance via the Xpert MTB/RIF assay should prompt further drug susceptibility testing, to optimize the treatment regimen and prevent emergence of further resistance [125]. (See 'Drug susceptibility testing' above and 'Sequence-based testing' below.)

Once a diagnosis of TB is established, sputum smear status is used to monitor response to treatment, guide infection control practices, and guide contact investigations [126]. The Xpert MTB/RIF assay is of no value in monitoring the response to therapy [127]. 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 in health care settings", 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 [128,129].

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 [130]. False-positive results have been associated with recent previous infection, high cycle threshold, and chest radiograph not suggestive of TB [131]. 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 [132].

The Xpert MTB/RIF assay may be useful for diagnosis of extrapulmonary TB in some cases, although use for this purpose is off-label in the United States. 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 was approved by the FDA in 2013 [106,113,114]. In 2017, the WHO recommended use of Xpert Ultra where available as a replacement for Xpert in all settings [22]; however, the Xpert Ultra is not approved by the FDA for use in the United States.

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 newer specimen cartridge and newer software.

In general, Xpert Ultra appears to 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 individuals with HIV infection [133].

In one review including 86 studies (randomized trials, cross-sectional, and cohort studies) evaluating the diagnostic accuracy of Xpert MTB/RIF and Xpert Ultra among more than 42,000 adults with suspected pulmonary TB, the overall sensitivity and specificity for Xpert MTB/RIF were 85 and 98 percent, respectively [134].

Another study that included 462 patients with pulmonary TB with culture-positive sputum, the sensitivities of Xpert Ultra and Xpert were 88 and 83 percent, respectively [135]. Among 137 patients with smear-negative, culture-positive sputum, the sensitivities were 63 and 46 percent, respectively. Overall, the specificities of Xpert Ultra and Xpert were 96 and 98 percent, respectively. For rifampicin resistance, the sensitivity and specificity of Xpert MTB/RIF and Ultra both were 95 and 98 percent, respectively [135].

In one review comparing diagnostic accuracy of Xpert Ultra and Xpert MTB/RIF for the detection of pulmonary TB and rifampicin resistance in adults, nine studies were included (including seven in high-burden countries) [136]. For detection of TB, Xpert Ultra demonstrated higher sensitivity but lower specificity compared with Xpert MTB/RIF. Among more than 2800 culture-positive patients, pooled sensitivity and specificity for Xpert Ultra was 91 and 96 percent, respectively, while Xpert MTB/RIF sensitivity and specificity were 85 and 98 percent, respectively. Among smear-negative, culture-positive patients, pooled sensitivity and specificity for Xpert Ultra were 78 and 96 percent, respectively, while Xpert MTB/RIF sensitivity and specificity were 61 and 99 percent, respectively. Among people with HIV, pooled sensitivity and specificity for Xpert Ultra were 88 and 93 percent, respectively, while Xpert MTB/RIF sensitivity and specificity were 75 and 99 percent, respectively. For detection of rifampicin resistance, the sensitivity and specificity of the two assays were similar.  

Xpert MTB/XDR — Xpert MTB/XDR is a reflex molecular test to detect resistance to isoniazid and fluoroquinolones (low-level and high-level resistance), ethionamide, and second-line injectable drugs (amikacin, kanamycin, and capreomycin; cross resistance versus individual resistance) on unprocessed sputum or concentrated sputum sediments which are positive for M. tuberculosis by Xpert MTB/RIF, Xpert MTB/RIF Ultra, or MGIT. It is recommended by the WHO as a follow-on to automated NAA testing for detection of resistance to isoniazid and second-line anti-TB drugs [137]. The test is not available in the United States.

In a prospective study including 710 individuals with pulmonary TB symptoms and at least one risk factor for drug resistance in India, Moldova, and South Africa, Xpert XDR was compared with a phenotypic drug-susceptibility testing and whole-genome sequencing [138]. There were 707 smear-positive cases and 611 culture-positive cases; 611 individuals had results from both Xpert MTB/XDR and the comparator. The sensitivity of Xpert MTB/XDR for detection of resistance to isoniazid, fluoroquinolones, ethionamide, amikacin, kanamycin and capreomycin was 94, 94, 54, 73, 86, and 61 percent, respectively; specificity was 98 to 100 percent for all drugs.

A review examining Xpert XDR performance for detection of drug resistance in six study cohorts conducted in high MDR-/rifampicin-resistant TB burden countries noted similar findings; the most accurate results were reported for isoniazid and fluoroquinolone resistance [139]. Variable performance in identifying other drug resistance is limited by the number of resistance polymorphisms in the specific genes interrogated by this test and depends on specific regional resistance mutation patterns.

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

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 [140]. 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 [141,142].

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) [143,144]. 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 [145]. 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 'Other bedaquiline-based regimens'.)

BD MAX MDR-TB – The Becton Dickinson BD MAX MDR-TB assay is an automated qualitative test for the detection of MTB complex DNA and mutations associated with isoniazid and rifampin resistance in induced or expectorated sputum or in concentrated sputum sediments from patients with fewer than three days of antituberculous therapy in the previous six months [146]. The assay uses real-time polymerase chain reaction for amplification of specific DNA targets and fluorogenic target-specific hybridization probes to detect specific DNA, including resistance mutations in rpoB and katG genes and the inhA promoter region associated with MDR-TB. BD MAX is available in Europe but not FDA approved for use in the United States.

In a study comparing BD MAX with Xpert MTB/RIF in more than 1000 patients with suspected TB, the sensitivity from raw sputum was 93 percent; among individuals categorized as "not TB," specificity was 97 percent [147]. For smear-positive samples (fluorescence microscopy), the sensitivity was 100 percent; for smear-negative samples, the sensitivity was 81 percent. Among specimens processed with both BD MAX and Xpert, sensitivity was similar (91 versus 90 percent, respectively). The sensitivity and specificity for rifampin resistance (compared with phenotypic DST) were 90 and 95 percent (95% CI 91-97 percent), respectively; the sensitivity and specificity for isoniazid resistance were 82 and 100 percent, respectively.

Other high-throughput molecular assays for detection of M. tuberculosis and resistance to rifampicin and isoniazid in clinical specimens also are available. According to a review and meta-analysis including 21 studies of five assays (FluoroType MTBDR, BD Max MDR-TB, Abbott RealTime MTB, Abbott RealTime RIF/INH, FluoroType MTB), these assays generally demonstrate similar sensitivity and specificity for diagnosis (>91 and >97 percent, respectively) and detection of drug resistance (rifampin and rifampin/isoniazid) compared with the XpertMTB/RIF, using phenotypic drug susceptibility testing as reference standards. Further study of these test platforms for use in specific programmatic situations is warranted [148].

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 [149]. 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 (CDC) for targeted next generation sequence-based molecular detection of drug resistance testing [150,151]. The testing identifies genetic mutations associated with rifampin and isoniazid resistance as well as resistance to second-line drugs including fluoroquinolones, bedaquiline, linezolid, clofazimine, and the injectables amikacin, kanamycin, and capreomycin. Acceptable specimens include MTBC NAAT-positive sediment, pure MTBC isolate on solid medium or in broth medium, or mixed cultures known to contain MTBC. With this service, specimens must be submitted to the CDC by a public health laboratory. Testing is performed at no cost to the submitter and molecular testing results generally are available within two weeks. Results can be used to guide initial treatment decisions and inform design of prevention regimens for contacts. Culture-based drug susceptibility testing also is performed, and these results are reported as they become available.

Newer technologies and applications

Metagenomics − Metagenomic (“shotgun”) analysis uses next-generation sequencing of microbial cell-free DNA (cfDNA) to identify all nucleic acid (including mycobacteria, bacteria, DNA viruses, fungi, and parasites) in a human plasma sample. The clinical utility of this test for diagnosis of TB remains to be determined, especially in patients with low-burden disease and in the context of distinguishing between active disease from latent infection. This technology is offered by some commercial laboratories as a validated laboratory developed test platform for screening or diagnosis. However, in the United States the test is not accepted by United States Centers for Disease Control and Prevention as a criterion of TB infection or disease and is not FDA approved.

In one study including 30 children and 10 adults in Peru, a metagenomic sequencing assay detected M. tuberculosis cfDNA in plasma of patients with smear-positive, culture-confirmed pulmonary TB; the overall sensitivity varied with reporting threshold [152].

Targeted molecular screening − The identification of targeted host transcriptomic signatures in blood to screen for specific infections is being investigated. The Cepheid Xpert M. tuberculosis Host Response (MTB-HR) Prototype cartridge system quantifies the expression of mRNA of three differentially expressed genes associated with TB in a single blood sample and then computes a TB score based on cycle threshold values using a proprietary algorithm [153].

In a prospective comparison of Xpert-MTB-HR-Prototype (fingerstick) with GeneXpert Ultra and sputum culture among 195 patients with symptoms consistent with pulmonary TB, tested [154]. Using study-defined criteria, the composite TB score using Xpert-MTB-HR discriminated between TB and other respiratory diseases with sensitivity of 87 percent (95% CI 77-93) and specificity of 94 percent (95% CI 88-97).

Urine antigen test in HIV infection — − In settings with high incidence of HIV and TB, the urine LAM assay (which detects lipoarabinomannan, a glycolipid component of the mycobacterial cell wall) is a useful diagnostic tool, in combination with other tests including nucleic acid testing and culture [155-162]. The approach to clinical use is discussed above. (See 'Patients with HIV infection' above.)

The urine LAM assay is most sensitive in patients with HIV infection who are ill and those with CD4 cell counts <100 cells/microL [163,164]; the sensitivity decreases as CD4 count increases, and is low in patients without HIV infection [164,165]. In the populations tested, the LAM assay has moderate to high specificity (88 to 99 percent) [163,164,166].

Studies supporting use of the urine LAM assay include [164,167-173]:

A randomized trial including 2600 patients with HIV infection hospitalized in Malawi and South Africa evaluated via sputum Xpert MTB/RIF with or without urine LAM testing; there was no difference in overall mortality between the groups; however, the diagnostic yield for urine LAM was greater than for sputum Xpert MTB/RIF (75 versus 40 percent of microbiologically confirmed cases) [167,168]. In three prespecified (but underpowered) subgroups (patients with CD4 count <100 cells per microL, patients with severe anemia, and patients with clinically suspected TB), mortality was lower among those who underwent urine LAM testing.

A subsequent review of eight studies including more than 3400 adults with HIV infection with signs and symptoms of TB (37 percent of whom had microbiologically confirmed active TB); the sensitivity and specificity of urine LAM were 42 and 91 percent, respectively [169]. Improvements in the assay may improve its impact on patient outcomes.

A study comparing a new urinary LAM assay with an existing test using banked urine samples collected from more than 900 inpatients with HIV at two South African hospitals; the new assay had an overall diagnostic sensitivity and specificity of 70 and 91 percent, respectively; the sensitivity was higher in patients with lower CD4 counts [164].

Earlier LAM assays have demonstrated cross reactivity with disseminated non-tuberculous (NTM) mycobacterial disease [174]. The results with the new assay await confirmation in clinical trials to determine specificity in patients with disseminated NTM infection and their effect on outcomes in patients with TB.

A review of three randomized trials in sub-Saharan Africa compared diagnostic strategies that using lateral flow (LF)-LAM, either alone or in combination with other tests (smear microscopy, mycobacterial culture, nucleic acid amplification, or a combination) in adults with HIV infection [170]. Among more than 5000 inpatients, use of LF-LAM testing likely reduced eight-week mortality compared with routine testing (pooled risk ratio 0.85, 95% CI 0.76-0.94). Among more than 9200 outpatients use of LF-LAM testing suggested a trend to a reduced mortality at six months (relative risk 0.89, 95% CI 0.71-1.11). A higher proportion of patients were able to produce urine for testing (compared with sputum) and the incremental diagnostic yield was higher for LF-LAM than for urine or sputum Xpert MTB/RIF.

In a study derived from ACTG clinical trial A5274 [171] including 850 patients in sub-Saharan Africa with advanced HIV (CD4 <50) and no clinical suspicion for TB who were antiretroviral therapy-naïve, retrospective urine LAM testing (performed on stored urine) was positive in 5 percent of cases [172]. Those with positive urine LAM tests ordinarily would have not been treated for TB until symptoms appeared or the disease was detected by clinical screening at a later date, suggesting that treatment could have been initiated earlier, preventing disease progression and potential transmission.

SCREENING FOR TB DISEASE IN HIGH-BURDEN SETTINGS

Symptom review and chest radiography − In high-burden settings, screening for active TB with symptom review and chest radiography may be beneficial; the World Health Organization (WHO) endorses this approach, tailoring the screening process to the resources available and to the population being screened [175].

However, the performance of such screening can be highly variable, difficult to predict, and complicated by heterogeneous conditions, such as regional TB prevalence, specific TB risks, quality of the screening process, and secondary tools used for diagnostic confirmation.

In one review including 59 studies from these settings, the overall sensitivity of screening based on symptoms alone was 71 percent, based on chest radiography was 95 percent, and based on both methods was 99 percent; sensitivity estimates were based on confirmation by a secondary diagnostic test (usually culture or nucleic acid amplification test) [176].

The use of digital chest radiography with computer-aided diagnostic (CAD) software may improve diagnostic capacity as a screening tool, alone or associated with symptom screening. In one study in which more than 3000 patients in South Africa presenting to a primary health clinic for various reasons were screened with a symptom questionnaire and digital radiography with CAD, the TB diagnostic yield was 2.3 percent (confirmed by Xpert-Ultra); 83 percent of cases were identified by radiography [177].

Rapid molecular testing  

Diagnostic tools − The WHO recommends the use of rapid molecular tests, including Xpert MTB/RIF or Xpert Ultra, as initial diagnostic tests for detection of TB and rifampicin resistance in patients with signs and symptoms raising suspicion for TB [178]. (See 'Xpert MTB/RIF assay' above and 'Xpert MTB/RIF Ultra assay' above.)

In high-TB burden settings, Xpert MTB/RIF also may be a useful screening test for diagnosis of TB in select high-risk groups. In one review including 18 studies (13,114 participants) evaluating the role of Xpert MTB/RIF for screening patients at high risk for TB in high-burden countries (eg, people with HIV infection, household contacts of people with TB, people residing in prisons, and miners, irrespective of signs or symptoms), the pooled sensitivity and specificity for diagnosis of pulmonary TB among people with HIV and nonhospitalized people in high-risk groups were similar (sensitivity 61.8 and 69.4 percent, respectively; specificity 98.8 percent both groups) [179].

Pooling specimens – Pooled sputum testing may be more efficient than individual testing in resource-constrained settings. In a prison-based study in Brazil, sputum sample pools were tested using simulated specimen pools of 4, 8, 12, and 16 specimens [180]. Each pool was spiked with one Xpert MTB/RIF positive specimen with various MTb loads; the other specimens in the pool were Xpert negative. Compared with individual testing, the sensitivity and specificity of sputum pool testing with Xpert Ultra was high (94 and 100 percent, respectively). Sensitivity was greater in pools in which the positive sample had a high mycobacterial load (100 versus 88 percent).

Importance of supporting infrastructure − To maximize benefit of the rapid diagnostic tools that have become available in the past few decades, adequate laboratory and clinical infrastructure are needed to support their use and translation to clinical care. In one review of 18 studies published between 2007 and 2021 examining patient and clinician experiences with NAA testing for detection of TB and drug resistance in high-burden regions, the potential advantages of rapid diagnostic tools were frequently undermined by lack of supporting infrastructure, resulting in underutilization and inequitable use [181].

REPORTING AND PUBLIC HEALTH — TB is a reportable disease in the United States [182]. 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) [183,184]. 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 [185].

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 [186].

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

General approach (See 'General diagnostic approach' above.)

Raising clinical suspicion for TB

-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).

-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.)

Establishing a diagnosis − 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; in most cases when used appropriately a positive NAA test (with or without AFB smear positivity) is considered sufficient for diagnosis of TB.

Clinical approach

-The approach to diagnosis of TB begins with a history and physical examination to assess the patient's risk for TB (table 2). Patients meeting clinical criteria should undergo chest radiography; if imaging suggests TB of the lungs or airways, three sputum specimens should be submitted for AFB smear, mycobacterial culture, and NAA testing (algorithm 1).

-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.

Obtaining clinical specimens − 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.)

Presumptive diagnosis − 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 susceptibility testing – Laboratory tools for drug susceptibility testing include culture-based testing (which provides phenotypic information) and molecular testing (which provides genotypic information). (See 'Microbiologic testing' above.)

Culture-based testing − 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.)

Molecular testing

-There are two major types of molecular assays: probe-based (non-sequencing) tests and sequence-based assays. Probe-based tests, also known as 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. Sequence-based assays are not approved by the US Food and Drug Administration (FDA) but may be offered as validated "laboratory developed" tests by some laboratories.

-One NAA test platform is approved by the FDA for use in the United States: Xpert MTB/RIF test. 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 'NAA (probe-based) testing' above.)

-In select cases, molecular determination of drug resistance may be performed by the Centers for Disease Control. Specimens must meet submission criteria and be submitted via the state TB laboratory. (See 'Sequence-based testing' above.)

Reporting and public health − 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.)

  1. Global Tuberculosis Report. World Health Organization, 2023. Available at: https://iris.who.int/bitstream/handle/10665/373828/9789240083851-eng.pdf (Accessed on December 15, 2023).
  2. 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.
  3. Pai M, Behr MA, Dowdy D, et al. Tuberculosis. Nat Rev Dis Primers 2016; 2:16076.
  4. Behr MA, Kaufmann E, Duffin J, et al. Latent Tuberculosis: Two Centuries of Confusion. Am J Respir Crit Care Med 2021; 204:142.
  5. Pai M, Nicol MP, Boehme CC. Tuberculosis Diagnostics: State of the Art and Future Directions. Microbiol Spectr 2016; 4.
  6. Dheda K, Barry CE 3rd, Maartens G. Tuberculosis. Lancet 2016; 387:1211.
  7. 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.
  8. Pai M, Menzies D. Interferon-gamma release assays: what is their role in the diagnosis of active tuberculosis? Clin Infect Dis 2007; 44:74.
  9. Dewan PK, Grinsdale J, Kawamura LM. Low sensitivity of a whole-blood interferon-gamma release assay for detection of active tuberculosis. Clin Infect Dis 2007; 44:69.
  10. Petnak T, Eksombatchai D, Chesdachai S, et al. Diagnostic accuracy of interferon-gamma release assays for diagnosis of smear-negative pulmonary tuberculosis: a systematic review and meta-analysis. BMC Pulm Med 2022; 22:219.
  11. World Health Organization. WHO operational handbook on tuberculosis: module 3: diagnosis: tests for tuberculosis infection. https://www.who.int/publications/i/item/9789240058347 (Accessed on October 13, 2022).
  12. Jones BE, Young SM, Antoniskis D, et al. Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection. Am Rev Respir Dis 1993; 148:1292.
  13. Taylor Z, Marks SM, Ríos Burrows NM, et al. Causes and costs of hospitalization of tuberculosis patients in the United States. Int J Tuberc Lung Dis 2000; 4:931.
  14. Centers for Disease Control and Prevention. Reported Tuberculosis in the United States: Tuberculosis Cases and Percentages by Case Verification Criterion and Site of Disease: United States, 1993–2015. https://www.cdc.gov/tb/statistics/reports/2015/pdfs/2015_surveillance_report_fullreport.pdf (Accessed on February 15, 2017).
  15. World Health Organization. Lateral flow urine lipoarabinomannan assay (LF-LAM) for the diagnosis of active tuberculosis in people living with HIV. Policy update 2019. Geneva: World Health Organization; 2019. Licence: CC BY-NC-SA 3.0 IGO. https://apps.who.int/iris/bitstream/handle/10665/329479/9789241550604-eng.pdf?sequence=1&isAllowed=y&ua=1 (Accessed on May 07, 2021).
  16. World Health Organization. WHO operational handbook on tuberculosis. Module 3: Diagnosis - Rapid diagnostics for tuberculosis detection 2021 update. https://www.who.int/publications/i/item/9789240030589 (Accessed on October 19, 2021).
  17. Global Laboratory Initiative. Stop TB Partnership: Practical implementation of lateral flow urine lipoarabinomannan assay (LF-LAM) for detection of active tuberculosis in people living with HIV. http://www.stoptb.org/wg/gli/assets/documents/practical-implementation-lf-lam.pdf (Accessed on May 07, 2021).
  18. World Health Organization. Lateral flow urine lipoarabinomannan assay (LF-LAM) for the diagnosis of active tuberculosis in people living with HIV, 2019 Update. https://www.who.int/publications/i/item/9789241550604 (Accessed on November 10, 2021).
  19. Weinberg JL, Kovarik CL. The WHO Clinical Staging System for HIV/AIDS. Virtual Mentor 2010; 12:202.
  20. Khan MS, Dar O, Sismanidis C, et al. Improvement of tuberculosis case detection and reduction of discrepancies between men and women by simple sputum-submission instructions: a pragmatic randomised controlled trial. Lancet 2007; 369:1955.
  21. Diagnostic Standards and Classification of Tuberculosis in Adults and Children. This official statement of the American Thoracic Society and the Centers for Disease Control and Prevention was adopted by the ATS Board of Directors, July 1999. This statement was endorsed by the Council of the Infectious Disease Society of America, September 1999. Am J Respir Crit Care Med 2000; 161:1376.
  22. Centers for Disease Control and Prevention. Report of an Expert Consultation on the Uses of Nucleic Acid Amplification Tests for the Diagnosis of Tuberculosis. https://nam04.safelinks.protection.outlook.com/?url=https%3A%2F%2Fwww.cdc.gov%2Ftb%2Fpublications%2Fguidelines%2Famplification_tests%2Fdefault.htm&data=04%7C01%7CEmily.Palmer%40wolterskluwer.com%7Cfd9f907fcc584072fc1008d9a44d9125%7C8ac76c91e7f141ffa89c3553b2da2c17%7C0%7C0%7C637721475944856445%7CUnkn (Accessed on November 10, 2021).
  23. Consensus statement on the use of Cepheid Xpert MTB/RIF® assay in making decisions to discontinue airborne infection isolation in healthcare settings. NTCA APHL, April 2016. http://www.tbcontrollers.org/docs/resources/NTCA_APHL_GeneXpert_Consensus_Statement_Final.pdf (Accessed on April 27, 2016).
  24. Nelson SM, Deike MA, Cartwright CP. Value of examining multiple sputum specimens in the diagnosis of pulmonary tuberculosis. J Clin Microbiol 1998; 36:467.
  25. Craft DW, Jones MC, Blanchet CN, Hopfer RL. Value of examining three acid-fast bacillus sputum smears for removal of patients suspected of having tuberculosis from the "airborne precautions" category. J Clin Microbiol 2000; 38:4285.
  26. Rieder HL, Chiang CY, Rusen ID. A method to determine the utility of the third diagnostic and the second follow-up sputum smear examinations to diagnose tuberculosis cases and failures. Int J Tuberc Lung Dis 2005; 9:384.
  27. Al Zahrani K, Al Jahdali H, Poirier L, et al. Yield of smear, culture and amplification tests from repeated sputum induction for the diagnosis of pulmonary tuberculosis. Int J Tuberc Lung Dis 2001; 5:855.
  28. Davis JL, Cattamanchi A, Cuevas LE, et al. Diagnostic accuracy of same-day microscopy versus standard microscopy for pulmonary tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis 2013; 13:147.
  29. Schoch OD, Rieder P, Tueller C, et al. Diagnostic yield of sputum, induced sputum, and bronchoscopy after radiologic tuberculosis screening. Am J Respir Crit Care Med 2007; 175:80.
  30. Brown M, Varia H, Bassett P, et al. Prospective study of sputum induction, gastric washing, and bronchoalveolar lavage for the diagnosis of pulmonary tuberculosis in patients who are unable to expectorate. Clin Infect Dis 2007; 44:1415.
  31. Anderson C, Inhaber N, Menzies D. Comparison of sputum induction with fiber-optic bronchoscopy in the diagnosis of tuberculosis. Am J Respir Crit Care Med 1995; 152:1570.
  32. Conde MB, Soares SL, Mello FC, et al. Comparison of sputum induction with fiberoptic bronchoscopy in the diagnosis of tuberculosis: experience at an acquired immune deficiency syndrome reference center in Rio de Janeiro, Brazil. Am J Respir Crit Care Med 2000; 162:2238.
  33. McWilliams T, Wells AU, Harrison AC, et al. Induced sputum and bronchoscopy in the diagnosis of pulmonary tuberculosis. Thorax 2002; 57:1010.
  34. Somu N, Swaminathan S, Paramasivan CN, et al. Value of bronchoalveolar lavage and gastric lavage in the diagnosis of pulmonary tuberculosis in children. Tuber Lung Dis 1995; 76:295.
  35. Malekmohammad M, Marjani M, Tabarsi P, et al. Diagnostic yield of post-bronchoscopy sputum smear in pulmonary tuberculosis. Scand J Infect Dis 2012; 44:369.
  36. George PM, Mehta M, Dhariwal J, et al. Post-bronchoscopy sputum: improving the diagnostic yield in smear negative pulmonary TB. Respir Med 2011; 105:1726.
  37. Sambarey A, Devaprasad A, Mohan A, et al. Unbiased Identification of Blood-based Biomarkers for Pulmonary Tuberculosis by Modeling and Mining Molecular Interaction Networks. EBioMedicine 2017; 15:112.
  38. Zak DE, Penn-Nicholson A, Scriba TJ, et al. A blood RNA signature for tuberculosis disease risk: a prospective cohort study. Lancet 2016; 387:2312.
  39. Assessment of Validity of a Blood-Based 3-Gene Signature Score for Progression and Diagnosis of Tuberculosis, Disease Severity, and Treatment Response. JAMA 2018; 1:e183779.
  40. Steingart KR, Henry M, Laal S, et al. A systematic review of commercial serological antibody detection tests for the diagnosis of extrapulmonary tuberculosis. Thorax 2007; 62:911.
  41. Dowdy DW, Steingart KR, Pai M. Serological testing versus other strategies for diagnosis of active tuberculosis in India: a cost-effectiveness analysis. PLoS Med 2011; 8:e1001074.
  42. Steingart KR, Flores LL, Dendukuri N, et al. Commercial serological tests for the diagnosis of active pulmonary and extrapulmonary tuberculosis: an updated systematic review and meta-analysis. PLoS Med 2011; 8:e1001062.
  43. World Health Organization. Commercial serodiagnostic tests for diagnosis of tuberculosis: Policy statement. World Health Organization, Geneva, Switzerland 2011. http://whqlibdoc.who.int/publications/2011/9789241502054_eng.pdf (Accessed on December 16, 2016).
  44. Broger T, Basu Roy R, Filomena A, et al. Diagnostic Performance of Tuberculosis-Specific IgG Antibody Profiles in Patients with Presumptive Tuberculosis from Two Continents. Clin Infect Dis 2017; 64:947.
  45. Meyer M, Clarke P, O'Regan AW. Utility of the lateral chest radiograph in the evaluation of patients with a positive tuberculin skin test result. Chest 2003; 124:1824.
  46. Geng E, Kreiswirth B, Burzynski J, Schluger NW. Clinical and radiographic correlates of primary and reactivation tuberculosis: a molecular epidemiology study. JAMA 2005; 293:2740.
  47. Khan MA, Kovnat DM, Bachus B, et al. Clinical and roentgenographic spectrum of pulmonary tuberculosis in the adult. Am J Med 1977; 62:31.
  48. Restrepo CS, Katre R, Mumbower A. Imaging Manifestations of Thoracic Tuberculosis. Radiol Clin North Am 2016; 54:453.
  49. Curry International Tuberculosis Center. Radiographic Manifestations of Tuberculosis: A Primer for Clinicians, Second Edition. https://www.currytbcenter.ucsf.edu/products/view/radiographic-manifestations-tuberculosis-primer-clinicians-second-edition-cd-rom (Accessed on November 10, 2021).
  50. Perlman DC, el-Sadr WM, Nelson ET, et al. Variation of chest radiographic patterns in pulmonary tuberculosis by degree of human immunodeficiency virus-related immunosuppression. The Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA). The AIDS Clinical Trials Group (ACTG). Clin Infect Dis 1997; 25:242.
  51. Havlir DV, Barnes PF. Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 1999; 340:367.
  52. Stumpe KD, Dazzi H, Schaffner A, von Schulthess GK. Infection imaging using whole-body FDG-PET. Eur J Nucl Med 2000; 27:822.
  53. Goo JM, Im JG, Do KH, et al. Pulmonary tuberculoma evaluated by means of FDG PET: findings in 10 cases. Radiology 2000; 216:117.
  54. Hara T, Kosaka N, Suzuki T, et al. Uptake rates of 18F-fluorodeoxyglucose and 11C-choline in lung cancer and pulmonary tuberculosis: a positron emission tomography study. Chest 2003; 124:893.
  55. Vorster M, Maes A, Van de Wiele C, Sathekge MM. 68Ga-citrate PET/CT in Tuberculosis: A pilot study. Q J Nucl Med Mol Imaging 2014.
  56. De Backer AI, Mortelé KJ, De Keulenaer BL, Parizel PM. Tuberculosis: epidemiology, manifestations, and the value of medical imaging in diagnosis. JBR-BTR 2006; 89:243.
  57. Palomino JC. Newer diagnostics for tuberculosis and multi-drug resistant tuberculosis. Curr Opin Pulm Med 2006; 12:172.
  58. Curry International Tuberculosis Center. Drug-Resistant Tuberculosis: A Survival Guide for Clinicians, Third Edition. CITC, Washington, DC 2016. http://www.currytbcenter.ucsf.edu/sites/default/files/tb_sg3_book.pdf (Accessed on July 12, 2016).
  59. Hobby GL, Holman AP, Iseman MD, Jones JM. Enumeration of tubercle bacilli in sputum of patients with pulmonary tuberculosis. Antimicrob Agents Chemother 1973; 4:94.
  60. Steingart KR, Ng V, Henry M, et al. Sputum processing methods to improve the sensitivity of smear microscopy for tuberculosis: a systematic review. Lancet Infect Dis 2006; 6:664.
  61. Steingart KR, Henry M, Ng V, et al. Fluorescence versus conventional sputum smear microscopy for tuberculosis: a systematic review. Lancet Infect Dis 2006; 6:570.
  62. Harries AD, Maher D, Nunn P. An approach to the problems of diagnosing and treating adult smear-negative pulmonary tuberculosis in high-HIV-prevalence settings in sub-Saharan Africa. Bull World Health Organ 1998; 76:651.
  63. Perlman DC, El-Helou P, Salomon N. Tuberculosis in patients with human immunodeficiency virus infection. Semin Respir Infect 1999; 14:344.
  64. Shingadia D, Novelli V. Diagnosis and treatment of tuberculosis in children. Lancet Infect Dis 2003; 3:624.
  65. Reid MJ, Shah NS. Approaches to tuberculosis screening and diagnosis in people with HIV in resource-limited settings. Lancet Infect Dis 2009; 9:173.
  66. Harries AD. Tuberculosis and human immunodeficiency virus infection in developing countries. Lancet 1990; 335:387.
  67. Hassim S, Shaw PA, Sangweni P, et al. Detection of a substantial rate of multidrug-resistant tuberculosis in an HIV-infected population in South Africa by active monitoring of sputum samples. Clin Infect Dis 2010; 50:1053.
  68. Bakari M, Arbeit RD, Mtei L, et al. Basis for treatment of tuberculosis among HIV-infected patients in Tanzania: the role of chest x-ray and sputum culture. BMC Infect Dis 2008; 8:32.
  69. Yajko DM, Nassos PS, Sanders CA, et al. High predictive value of the acid-fast smear for Mycobacterium tuberculosis despite the high prevalence of Mycobacterium avium complex in respiratory specimens. Clin Infect Dis 1994; 19:334.
  70. Peterson EM, Nakasone A, Platon-DeLeon JM, et al. Comparison of direct and concentrated acid-fast smears to identify specimens culture positive for Mycobacterium spp. J Clin Microbiol 1999; 37:3564.
  71. Warren JR, Bhattacharya M, De Almeida KN, et al. A minimum 5.0 ml of sputum improves the sensitivity of acid-fast smear for Mycobacterium tuberculosis. Am J Respir Crit Care Med 2000; 161:1559.
  72. Marais BJ, Brittle W, Painczyk K, et al. Use of light-emitting diode fluorescence microscopy to detect acid-fast bacilli in sputum. Clin Infect Dis 2008; 47:203.
  73. Shea YR, Davis JL, Huang L, et al. High sensitivity and specificity of acid-fast microscopy for diagnosis of pulmonary tuberculosis in an African population with a high prevalence of human immunodeficiency virus. J Clin Microbiol 2009; 47:1553.
  74. World Health Organization. Fluorescent light-emitting diode (LED) microscopy for diagnosis of tuberculosis policy: Policy statement. http://www.who.int/tb/publications/2011/led_microscopy_diagnosis_9789241501613/en/ (Accessed on December 05, 2017).
  75. Prince DS, Peterson DD, Steiner RM, et al. Infection with Mycobacterium avium complex in patients without predisposing conditions. N Engl J Med 1989; 321:863.
  76. du Moulin GC, Sherman IH, Hoaglin DC, Stottmeier KD. Mycobacterium avium complex, an emerging pathogen in Massachusetts. J Clin Microbiol 1985; 22:9.
  77. Morgan MA, Horstmeier CD, DeYoung DR, Roberts GD. Comparison of a radiometric method (BACTEC) and conventional culture media for recovery of mycobacteria from smear-negative specimens. J Clin Microbiol 1983; 18:384.
  78. Ichiyama S, Shimokata K, Takeuchi J. Comparative study of a biphasic culture system (Roche MB Check system) with a conventional egg medium for recovery of mycobacteria. Aichi Mycobacteriosis Research Group. Tuber Lung Dis 1993; 74:338.
  79. Centers for Disease Control and Prevention. Tuberculosis: Drug Susceptibility Testing. http://www.cdc.gov/tb/topic/laboratory/drug_testing.htm (Accessed on May 26, 2016).
  80. Shinnick TM, Good RC. Diagnostic mycobacteriology laboratory practices. Clin Infect Dis 1995; 21:291.
  81. Kent PT, Kubica GP. Public Health Mycobacteriology: A guide for the Level III Laboratory., Centers for Disease Control and Prevention, Atlanta 1985.
  82. Saleeb PG, Drake SK, Murray PR, Zelazny AM. Identification of mycobacteria in solid-culture media by matrix-assisted laser desorption ionization-time of flight mass spectrometry. J Clin Microbiol 2011; 49:1790.
  83. Hettick JM, Kashon ML, Slaven JE, et al. Discrimination of intact mycobacteria at the strain level: a combined MALDI-TOF MS and biostatistical analysis. Proteomics 2006; 6:6416.
  84. Association of Public Health Laboratories. Infectious Diseases. http://www.aphl.org/programs/infectious_disease/Pages/default.aspx (Accessed on June 17, 2016).
  85. Nahid P, Mase SR, Migliori GB, et al. Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline. Am J Respir Crit Care Med 2019; 200:e93.
  86. Iseman MD, Heifets LB. Rapid detection of tuberculosis and drug-resistant tuberculosis. N Engl J Med 2006; 355:1606.
  87. Shiferaw G, Woldeamanuel Y, Gebeyehu M, et al. Evaluation of microscopic observation drug susceptibility assay for detection of multidrug-resistant Mycobacterium tuberculosis. J Clin Microbiol 2007; 45:1093.
  88. Moore DA, Evans CA, Gilman RH, et al. Microscopic-observation drug-susceptibility assay for the diagnosis of TB. N Engl J Med 2006; 355:1539.
  89. Arias M, Mello FC, Pavón A, et al. Clinical evaluation of the microscopic-observation drug-susceptibility assay for detection of tuberculosis. Clin Infect Dis 2007; 44:674.
  90. Minion J, Leung E, Menzies D, Pai M. Microscopic-observation drug susceptibility and thin layer agar assays for the detection of drug resistant tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis 2010; 10:688.
  91. Marks SM, Cronin W, Venkatappa T, et al. The health-system benefits and cost-effectiveness of using Mycobacterium tuberculosis direct nucleic acid amplification testing to diagnose tuberculosis disease in the United States. Clin Infect Dis 2013; 57:532.
  92. Cheng VC, Yew WW, Yuen KY. Molecular diagnostics in tuberculosis. Eur J Clin Microbiol Infect Dis 2005; 24:711.
  93. Catanzaro A, Perry S, Clarridge JE, et al. The role of clinical suspicion in evaluating a new diagnostic test for active tuberculosis: results of a multicenter prospective trial. JAMA 2000; 283:639.
  94. Conaty SJ, Claxton AP, Enoch DA, et al. The interpretation of nucleic acid amplification tests for tuberculosis: do rapid tests change treatment decisions? J Infect 2005; 50:187.
  95. Lim TK, Mukhopadhyay A, Gough A, et al. Role of clinical judgment in the application of a nucleic acid amplification test for the rapid diagnosis of pulmonary tuberculosis. Chest 2003; 124:902.
  96. Wiener RS, Della-Latta P, Schluger NW. Effect of nucleic acid amplification for Mycobacterium tuberculosis on clinical decision making in suspected extrapulmonary tuberculosis. Chest 2005; 128:102.
  97. Blakemore R, Story E, Helb D, et al. Evaluation of the analytical performance of the Xpert MTB/RIF assay. J Clin Microbiol 2010; 48:2495.
  98. Cohen RA, Muzaffar S, Schwartz D, et al. Diagnosis of pulmonary tuberculosis using PCR assays on sputum collected within 24 hours of hospital admission. Am J Respir Crit Care Med 1998; 157:156.
  99. Centers for Disease Control and Prevention (CDC). Nucleic acid amplification tests for tuberculosis. MMWR Morb Mortal Wkly Rep 1996; 45:950.
  100. Rapid diagnostic tests for tuberculosis: what is the appropriate use? American Thoracic Society Workshop. Am J Respir Crit Care Med 1997; 155:1804.
  101. Perry S, Catanzaro A. Use of clinical risk assessments in evaluation of nucleic acid amplification tests for HIV/tuberculosis. Int J Tuberc Lung Dis 2000; 4:S34.
  102. Laraque F, Griggs A, Slopen M, Munsiff SS. Performance of nucleic acid amplification tests for diagnosis of tuberculosis in a large urban setting. Clin Infect Dis 2009; 49:46.
  103. Campos M, Quartin A, Mendes E, et al. Feasibility of shortening respiratory isolation with a single sputum nucleic acid amplification test. Am J Respir Crit Care Med 2008; 178:300.
  104. Chaisson LH, Roemer M, Cantu D, et al. Impact of GeneXpert MTB/RIF assay on triage of respiratory isolation rooms for inpatients with presumed tuberculosis: a hypothetical trial. Clin Infect Dis 2014; 59:1353.
  105. Lippincott CK, Miller MB, Popowitch EB, et al. Xpert MTB/RIF assay shortens airborne isolation for hospitalized patients with presumptive tuberculosis in the United States. Clin Infect Dis 2014; 59:186.
  106. World Health Organization. Automated real-time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB/RIF system: policy statement. https://apps.who.int/iris/handle/10665/44586 (Accessed on November 10, 2021).
  107. World Health Organization. Next-generation Xpert® MTB/RIF Ultra assay recommended by WHO. https://www.who.int/news/item/25-03-2017-next-generation-xpert-mtb-rif-ultra-assay-recommended-by-who (Accessed on November 10, 2021).
  108. Dinnes J, Deeks J, Kunst H, et al. A systematic review of rapid diagnostic tests for the detection of tuberculosis infection. Health Technol Assess 2007; 11:1.
  109. Migliori GB, Sotgiu G, Rosales-Klintz S, et al. ERS/ECDC Statement: European Union standards for tuberculosis care, 2017 update. Eur Respir J 2018; 51.
  110. Boehme CC, Nabeta P, Hillemann D, et al. Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med 2010; 363:1005.
  111. Steingart KR, Sohn H, Schiller I, et al. Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database Syst Rev 2013; :CD009593.
  112. Steingart KR, Schiller I, Horne DJ, et al. Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database Syst Rev 2014; :CD009593.
  113. Centers for Disease Control and Prevention (CDC). Availability of an assay for detecting Mycobacterium tuberculosis, including rifampin-resistant strains, and considerations for its use - United States, 2013. MMWR Morb Mortal Wkly Rep 2013; 62:821.
  114. World Health Organization. Automated real-time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB/RIF assay for the diagnosis of pulmonary and extrapulmonary TB in adults and children, Policy update. WHO, Geneva 2013. http://apps.who.int/iris/bitstream/10665/112472/1/9789241506335_eng.pdf?ua=1 (Accessed on May 17, 2016).
  115. Sohn H, Aero AD, Menzies D, et al. Xpert MTB/RIF testing in a low tuberculosis incidence, high-resource setting: limitations in accuracy and clinical impact. Clin Infect Dis 2014; 58:970.
  116. Luetkemeyer AF, Firnhaber C, Kendall MA, et al. Evaluation of Xpert MTB/RIF Versus AFB Smear and Culture to Identify Pulmonary Tuberculosis in Patients With Suspected Tuberculosis From Low and Higher Prevalence Settings. Clin Infect Dis 2016; 62:1081.
  117. Boehme CC, Nicol MP, Nabeta P, et al. Feasibility, diagnostic accuracy, and effectiveness of decentralised use of the Xpert MTB/RIF test for diagnosis of tuberculosis and multidrug resistance: a multicentre implementation study. Lancet 2011; 377:1495.
  118. O'Grady J, Bates M, Chilukutu L, et al. Evaluation of the Xpert MTB/RIF assay at a tertiary care referral hospital in a setting where tuberculosis and HIV infection are highly endemic. Clin Infect Dis 2012; 55:1171.
  119. Floridia M, Ciccacci F, Andreotti M, et al. Tuberculosis Case Finding With Combined Rapid Point-of-Care Assays (Xpert MTB/RIF and Determine TB LAM) in HIV-Positive Individuals Starting Antiretroviral Therapy in Mozambique. Clin Infect Dis 2017; 65:1878.
  120. Churchyard GJ, Stevens WS, Mametja LD, et al. Xpert MTB/RIF versus sputum microscopy as the initial diagnostic test for tuberculosis: a cluster-randomised trial embedded in South African roll-out of Xpert MTB/RIF. Lancet Glob Health 2015; 3:e450.
  121. Durovni B, Saraceni V, van den Hof S, et al. Impact of replacing smear microscopy with Xpert MTB/RIF for diagnosing tuberculosis in Brazil: a stepped-wedge cluster-randomized trial. PLoS Med 2014; 11:e1001766.
  122. Cattamanchi A, Reza TF, Nalugwa T, et al. Multicomponent Strategy with Decentralized Molecular Testing for Tuberculosis. N Engl J Med 2021; 385:2441.
  123. Lee HS, Kee SJ, Shin JH, et al. Xpert MTB/RIF Assay as a Substitute for Smear Microscopy in an Intermediate-Burden Setting. Am J Respir Crit Care Med 2019; 199:784.
  124. Han LL, Elvin P, Bernardo J. Nonclinical selection criteria for maximizing yield of nucleic acid amplification tests in tuberculosis diagnosis. J Clin Microbiol 2012; 50:2592.
  125. Jacobson KR, Barnard M, Kleinman MB, et al. Implications of Failure to Routinely Diagnose Resistance to Second-Line Drugs in Patients With Rifampicin-Resistant Tuberculosis on Xpert MTB/RIF: A Multisite Observational Study. Clin Infect Dis 2017; 64:1502.
  126. Small PM, Pai M. Tuberculosis diagnosis--time for a game change. N Engl J Med 2010; 363:1070.
  127. Friedrich SO, Rachow A, Saathoff E, et al. Assessment of the sensitivity and specificity of Xpert MTB/RIF assay as an early sputum biomarker of response to tuberculosis treatment. Lancet Respir Med 2013; 1:462.
  128. Hanrahan CF, Theron G, Bassett J, et al. Xpert MTB/RIF as a measure of sputum bacillary burden. Variation by HIV status and immunosuppression. Am J Respir Crit Care Med 2014; 189:1426.
  129. Theron G, Pinto L, Peter J, et al. The use of an automated quantitative polymerase chain reaction (Xpert MTB/RIF) to predict the sputum smear status of tuberculosis patients. Clin Infect Dis 2012; 54:384.
  130. Boyles TH, Hughes J, Cox V, et al. False-positive Xpert® MTB/RIF assays in previously treated patients: need for caution in interpreting results. Int J Tuberc Lung Dis 2014; 18:876.
  131. Theron G, Venter R, Calligaro G, et al. Xpert MTB/RIF Results in Patients With Previous Tuberculosis: Can We Distinguish True From False Positive Results? Clin Infect Dis 2016; 62:995.
  132. Sanchez-Padilla E, Merker M, Beckert P, et al. Detection of drug-resistant tuberculosis by Xpert MTB/RIF in Swaziland. N Engl J Med 2015; 372:1181.
  133. World Health Organization. WHO Meeting Report of a Technical Expert Consultation: Non-inferiority analysis of Xpert MTB/RIF Ultra compared to Xpert MTB/RIF. http://www.who.int/tb/publications/2017/XpertUltra/en/ (Accessed on December 07, 2017).
  134. Horne DJ, Kohli M, Zifodya JS, et al. Xpert MTB/RIF and Xpert MTB/RIF Ultra for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database Syst Rev 2019; 6:CD009593.
  135. Dorman SE, Schumacher SG, Alland D, et al. Xpert MTB/RIF Ultra for detection of Mycobacterium tuberculosis and rifampicin resistance: a prospective multicentre diagnostic accuracy study. Lancet Infect Dis 2018; 18:76.
  136. Zifodya JS, Kreniske JS, Schiller I, et al. Xpert Ultra versus Xpert MTB/RIF for pulmonary tuberculosis and rifampicin resistance in adults with presumptive pulmonary tuberculosis. Cochrane Database Syst Rev 2021; 2:CD009593.
  137. World Health Organization. WHO operational handbook on tuberculosis. Module 3: Diagnosis: Rapid diagnostics for tuberculosis detection. https://apps.who.int/iris/bitstream/handle/10665/342369/9789240030589-eng.pdf?sequence=1 (Accessed on January 13, 2022).
  138. Penn-Nicholson A, Georghiou SB, Ciobanu N, et al. Detection of isoniazid, fluoroquinolone, ethionamide, amikacin, kanamycin, and capreomycin resistance by the Xpert MTB/XDR assay: a cross-sectional multicentre diagnostic accuracy study. Lancet Infect Dis 2022; 22:242.
  139. Pillay S, Steingart KR, Davies GR, et al. Xpert MTB/XDR for detection of pulmonary tuberculosis and resistance to isoniazid, fluoroquinolones, ethionamide, and amikacin. Cochrane Database Syst Rev 2022; 5:CD014841.
  140. Barnard M, Albert H, Coetzee G, et al. Rapid molecular screening for multidrug-resistant tuberculosis in a high-volume public health laboratory in South Africa. Am J Respir Crit Care Med 2008; 177:787.
  141. Jacobson KR, Theron D, Kendall EA, et al. Implementation of genotype MTBDRplus reduces time to multidrug-resistant tuberculosis therapy initiation in South Africa. Clin Infect Dis 2013; 56:503.
  142. 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.
  143. 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.
  144. 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.
  145. World Health Organization. The use of molecular line probe assays for the detection of resistance to second-line antituberculosis drugs: Policy guidance. WHO, Geneva 2016. http://www.who.int/tb/WHOPolicyStatementSLLPA.pdf?ua=1 (Accessed on May 23, 2016).
  146. BD MAX™ MDR-TB Assay [package insert]. Sparks, MD; BD Life Sciences; 2019.
  147. Shah M, Paradis S, Betz J, et al. Multicenter Study of the Accuracy of the BD MAX Multidrug-resistant Tuberculosis Assay for Detection of Mycobacterium tuberculosis Complex and Mutations Associated With Resistance to Rifampin and Isoniazid. Clin Infect Dis 2020; 71:1161.
  148. Kohli M, MacLean E, Pai M, et al. Diagnostic accuracy of centralised assays for TB detection and detection of resistance to rifampicin and isoniazid: a systematic review and meta-analysis. Eur Respir J 2021; 57.
  149. CRyPTIC Consortium and the 100,000 Genomes Project, Allix-Béguec C, Arandjelovic I, et al. Prediction of Susceptibility to First-Line Tuberculosis Drugs by DNA Sequencing. N Engl J Med 2018; 379:1403.
  150. MDDR User Guide. Centers for Disease Control and Prevention, 2023. https://www.cdc.gov/tb/topic/laboratory/mddr-user-guide.htm (Accessed on July 27, 2023).
  151. TB: Next Generation Sequencing and Molecular Drug Susceptibility Testing. Association of Public Health Laboratories, 2023. Available at: https://www.aphl.org/aboutAPHL/publications/Documents/ID-TB-NGS-Mutations.pdf (Accessed on January 09, 2024).
  152. Pollock NR, MacIntyre AT, Blauwkamp TA, et al. Detection of Mycobacterium tuberculosis cell-free DNA to diagnose TB in pediatric and adult patients. Int J Tuberc Lung Dis 2021; 25:403.
  153. Sweeney TE, Braviak L, Tato CM, Khatri P. Genome-wide expression for diagnosis of pulmonary tuberculosis: a multicohort analysis. Lancet Respir Med 2016; 4:213.
  154. Sutherland JS, van der Spuy G, Gindeh A, et al. Diagnostic Accuracy of the Cepheid 3-gene Host Response Fingerstick Blood Test in a Prospective, Multi-site Study: Interim Results. Clin Infect Dis 2022; 74:2136.
  155. Shah M, Martinson NA, Chaisson RE, et al. Quantitative analysis of a urine-based assay for detection of lipoarabinomannan in patients with tuberculosis. J Clin Microbiol 2010; 48:2972.
  156. Talbot E, Munseri P, Teixeira P, et al. Test characteristics of urinary lipoarabinomannan and predictors of mortality among hospitalized HIV-infected tuberculosis suspects in Tanzania. PLoS One 2012; 7:e32876.
  157. Nakiyingi L, Moodley VM, Manabe YC, et al. Diagnostic accuracy of a rapid urine lipoarabinomannan test for tuberculosis in HIV-infected adults. J Acquir Immune Defic Syndr 2014; 66:270.
  158. Peter JG, Theron G, van Zyl-Smit R, et al. Diagnostic accuracy of a urine lipoarabinomannan strip-test for TB detection in HIV-infected hospitalised patients. Eur Respir J 2012; 40:1211.
  159. Peter JG, Zijenah LS, Chanda D, et al. Effect on mortality of point-of-care, urine-based lipoarabinomannan testing to guide tuberculosis treatment initiation in HIV-positive hospital inpatients: a pragmatic, parallel-group, multicountry, open-label, randomised controlled trial. Lancet 2016; 387:1187.
  160. Lawn SD, Gupta-Wright A. Detection of lipoarabinomannan (LAM) in urine is indicative of disseminated TB with renal involvement in patients living with HIV and advanced immunodeficiency: evidence and implications. Trans R Soc Trop Med Hyg 2016; 110:180.
  161. Bjerrum S, Broger T, Székely R, et al. Diagnostic Accuracy of a Novel and Rapid Lipoarabinomannan Test for Diagnosing Tuberculosis Among People With Human Immunodeficiency Virus. Open Forum Infect Dis 2020; 7:ofz530.
  162. Sossen B, Broger T, Kerkhoff AD, et al. "SILVAMP TB LAM" Rapid Urine Tuberculosis Test Predicts Mortality in Patients Hospitalized With Human Immunodeficiency Virus in South Africa. Clin Infect Dis 2020; 71:1973.
  163. Minion J, Leung E, Talbot E, et al. Diagnosing tuberculosis with urine lipoarabinomannan: systematic review and meta-analysis. Eur Respir J 2011; 38:1398.
  164. Broger T, Sossen B, du Toit E, et al. Novel lipoarabinomannan point-of-care tuberculosis test for people with HIV: a diagnostic accuracy study. Lancet Infect Dis 2019; 19:852.
  165. Shah M, Hanrahan C, Wang ZY, et al. Lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in HIV-positive adults. Cochrane Database Syst Rev 2016; :CD011420.
  166. Lawn SD, Kerkhoff AD, Nicol MP, Meintjes G. Underestimation of the True Specificity of the Urine Lipoarabinomannan Point-of-Care Diagnostic Assay for HIV-Associated Tuberculosis. J Acquir Immune Defic Syndr 2015; 69:e144.
  167. Gupta-Wright A, Corbett EL, van Oosterhout JJ, et al. Rapid urine-based screening for tuberculosis in HIV-positive patients admitted to hospital in Africa (STAMP): a pragmatic, multicentre, parallel-group, double-blind, randomised controlled trial. Lancet 2018; 392:292.
  168. Nathavitharana RR, Pai M. New strategies for inpatients with HIV and tuberculosis. Lancet 2018; 392:256.
  169. Bjerrum S, Schiller I, Dendukuri N, et al. Lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in people living with HIV. Cochrane Database Syst Rev 2019; 10:CD011420.
  170. Nathavitharana RR, Lederer P, Chaplin M, et al. Impact of diagnostic strategies for tuberculosis using lateral flow urine lipoarabinomannan assay in people living with HIV. Cochrane Database Syst Rev 2021; 8:CD014641.
  171. Hosseinipour MC, Bisson GP, Miyahara S, et al. Empirical tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): a multicountry open-label randomised controlled trial. Lancet 2016; 387:1198.
  172. Matoga MM, Bisson GP, Gupta A, et al. Urine Lipoarabinomannan Testing in Adults With Advanced Human Immunodeficiency Virus in a Trial of Empiric Tuberculosis Therapy. Clin Infect Dis 2021; 73:e870.
  173. Burke RM, Gupta Wright A. Diagnosing Tuberculosis in People With Advanced Human Immunodeficiency Virus: More Is Needed. Clin Infect Dis 2021; 73:e878.
  174. Nel JS, Lippincott CK, Berhanu R, et al. Does Disseminated Nontuberculous Mycobacterial Disease Cause False-Positive Determine TB-LAM Lateral Flow Assay Results? A Retrospective Review. Clin Infect Dis 2017; 65:1226.
  175. World Health Organization. WHO consolidated guidelines on tuberculosis Module 2: Screening – Systematic screening for tuberculosis disease. https://www.who.int/publications/i/item/9789240022676 (Accessed on May 25, 2022).
  176. Van't Hoog A, Viney K, Biermann O, et al. Symptom- and chest-radiography screening for active pulmonary tuberculosis in HIV-negative adults and adults with unknown HIV status. Cochrane Database Syst Rev 2022; 3:CD010890.
  177. Moodley N, Velen K, Saimen A, et al. Digital Chest Radiography Enhances Screening Efficiency for Pulmonary Tuberculosis in Primary Health Clinics in South Africa. Clin Infect Dis 2022; 74:1650.
  178. World Health Organization. Manual for selection of molecular WHO recommended rapid diagnostic tests for detection of tuberculosis and drug-resistant tuberculosis. https://www.who.int/publications/i/item/9789240042575 (Accessed on July 13, 2022).
  179. Shapiro AE, Ross JM, Yao M, et al. Xpert MTB/RIF and Xpert Ultra assays for screening for pulmonary tuberculosis and rifampicin resistance in adults, irrespective of signs or symptoms. Cochrane Database Syst Rev 2021; 3:CD013694.
  180. Dos Santos PCP, da Silva Santos A, de Oliveira RD, et al. Pooling Sputum Samples for Efficient Mass Tuberculosis Screening in Prisons. Clin Infect Dis 2022; 74:2115.
  181. Engel N, Ochodo EA, Karanja PW, et al. Rapid molecular tests for tuberculosis and tuberculosis drug resistance: a qualitative evidence synthesis of recipient and provider views. Cochrane Database Syst Rev 2022; 4:CD014877.
  182. Tuberculosis control laws--United States, 1993. Recommendations of the Advisory Council for the Elimination of Tuberculosis (ACET). MMWR Recomm Rep 1993; 42:1.
  183. 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.
  184. Centers for Disease Control and Prevention: State TB Control Offices http://www.cdc.gov/tb/links/tboffices.htm (Accessed on May 18, 2010).
  185. 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.
  186. 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 45.0

References

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