Description
Infection by Mycobacterium tuberculosis (Mtb) results in a wide range of clinical presentations dependent upon the site of infection, from classic signs and symptoms of pulmonary disease (cough greater than two to three weeks' duration, lymphadenopathy, fevers, night sweats, weight loss) to silent infection with a complete absence of signs or symptoms.¹

Culture of Mtb is the gold standard for diagnosis as it is the most sensitive and provides an isolate for drug susceptibility testing and species identification.² Nucleic acid amplification tests (NAAT) use polymerase chain reactions (PCR) to enable sensitive detection and identification of low-density infections.³ Interferon-gamma release assays (IGRAs) are blood tests of cell-mediated immune response which measure T-cell release of interferon (IFN)-gamma following stimulation by specific antigens such as Mycobacterium tuberculosis antigens^1,4 used to detect a cellular immune response to M. tuberculosis which would indicate latent tuberculosis infection (LTBI).⁵

Regulatory Status
The Bactec MGIT 960 System was approved by the FDA in 1998 for the detection of mycobacteria growth from clinical specimens (except blood).

In 1994 the FDA approved the Ge-Probe Amplified Mycobacterium Tuberculosis Direct Test as a Nucleic acid-based in vitro diagnostic devices for the detection of Mycobacterium tuberculosis complex in respiratory specimens. These devices are non-multiplexed and intended to be used as an aid in the diagnosis of pulmonary tuberculosis when used in conjunction with clinical and other laboratory findings.

In 2015 the FDA approved the Xpert^® MTB/RIF Assay, performed on the GeneXpert^® Instrument Systems, as a qualitative, nested real-time polymerase chain reaction (PCR) in vitro diagnostic test for the detection of Mycobacterium tuberculosis complex DNA in raw sputum or concentrated sputum sediment prepared from induced or expectorated sputum. In specimens where Mycobacterium tuberculosis complex (MTB-complex) is detected, the Xpert MTB/RIF Assay also detects the rifampin-resistance associated mutations of the rpoB gene.

The QuantiFERON-TB^® assay (CSL Biosciences, Australia) for detection of gamma interferon production is a blood test that has been used in humans in Australia. In November 2001, this test received approval from the U.S. Food and Drug Administration (FDA) in the United States for the following indication: "The QuantiFERON-TB test is intended as an aid in the detection of latent Mycobacterium tuberculosis infection."

In December of 2004, QuantiFERON-TB^® GOLD received FDA approval for the detection of latent TB. This test differs from the first-generation test in that instead of using PPD as the stimulus for interferon production, 2 antigens, ESAT-6 and CFP-10, are used. These antigens are present in mycobacterium tuberculosis but are not present in those exposed to BCG or non-tuberculous mycobacteria.

The QFT-GIT measures IFN-γ plasma concentration using an enzyme-linked immunosorbent assay (ELISA), has been approved by the US Food and Drug Administration (FDA) and has replaced the QuantiFERON-TB Gold (QFT-G) test.

The T-SPOT assay enumerates T cells releasing IFN-γ using an enzyme-linked immunospot (ELISPOT) assay. The T-SPOT.TB assay is currently available in Europe, Canada, and has been approved for use in the United States with revised criteria for test interpretation.

A search for “tuberculosis” on the FDA website on July 17, 2021, yielded 11 results. Additionally, many labs have developed specific tests that they must validate and perform in house. These laboratory-developed tests (LDTs) are regulated by the Centers for Medicare & Medicaid Services (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88). As an LDT, the U.S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use.

Policy:
Application of coverage criteria is dependent upon an individual’s benefit coverage at the time of the request. 

This policy only addresses testing for the purpose of medical decision making in the outpatient setting. This policy does not address work, school, or government mandated tuberculosis testing.

1. Screening for latent tuberculosis (TB) infection with an interferon gamma release assay (IGRA) is considered MEDICALLY NECESSARY for any of the following situations:
   1. For individuals who have been in close contact with an individual with a known TB infection: testing no more than once every 24 weeks.
   2. For individuals requiring routine screening: testing no more than once every 12 months.
2. For all individuals with radiologic or clinical findings (see Note 1) suggestive of a TB infection, the following tests is considered MEDICALLY NECESSARY:
   1. Acid-fast bacilli (AFB) smear/stain.
   2. Culture and culture-based drug susceptibility testing of Mycobacteria spp.
   3. Qualitative nucleic acid amplification testing (NAAT) for Mycobacteria spp., M. tuberculosis, and M. avium complex.
3. For individuals whose sputum is AFB smear positive or NAAT positive for TB, molecular-based drug susceptibility testing is considered MEDICALLY NECESSARY when one of the following criteria is met:
   1. The individual has been treated for TB in the past.
   2. The individual was born in or has lived for at least 1 year in a foreign country with at least a moderate TB incidence (≥20 per 100, 000) or a high primary multi-drug resistant (MDR)-TB prevalence (≥2%).
   3. The individual is a contact of an individual with MDR-TB.
   4. The individual is HIV infected.
4. Repeat drug susceptibility testing is considered MEDICALLY NECESSARY in any of the following situations:
   1. For individuals whose sputum cultures remain positive after 3 months of treatment.
   2. When there is bacteriological reversion from negative to positive.
5. In HIV-infected individuals who have signs and symptoms of tuberculosis (see Note 1), urine-based detection of mycobacterial cell wall glycolipid lipoarabinomannan (LAM) is considered MEDICALLY NECESSARY.
6. For individuals with active tuberculosis, IGRA is considered NOT MEDICALLY NECESSARY.

The following does not meet coverage criteria due to a lack of available published scientific literature confirming that the test(s) is/are required and beneficial for the diagnosis and treatment of an individual’s illness.

7. Quantitative nucleic acid testing for Mycobacterium spp, M. tuberculosis, and M. avium complex is considered NOT MEDICALLY NECESSARY.
8. Whole genome sequencing of Mycobacterium spp. for the detection of drug resistance is considered NOT MEDICALLY NECESSARY.
9. Genotyping of Mycobacterium spp. is considered NOT MEDICALLY NECESSARY.
10. Testing of adenosine deaminase (ADA) and interferon-gamma (IFN- γ) levels in cerebrospinal, pleural, peritoneal, pericardial, and other fluids for the diagnosis of extrapulmonary TB is considered NOT MEDICALLY NECESSARY.
11. Testing of serum protein biomarkers or panels of biomarkers for the detection and diagnosis of TB is considered NOT MEDICALLY NECESSARY.

NOTES:

Note 1: Clinical findings suggestive of a TB infection: individuals who are symptomatic for a TB infection or individuals who have tested positive for TB with IGRA or a tuberculosis skin test (TST).

Signs and symptoms of active TB in the lungs:⁶

• A bad cough lasting three weeks or longer
• Pain in the chest
• Coughing up blood or sputum
• Weakness or fatigue
• Weight loss
• No appetite
• Chills
• Fever
• Sweating at night

Signs and symptoms of active TB in other parts of the body:⁶

• Firm red or purple swelling under the skin (TB disease of the lymph nodes)
• Blood in the urine (TB disease of the kidney)
• Headache or confusion (TB disease of the brain)
• Back pain (TB disease of the spine)
• Hoarseness (TB disease of the larynx)

Table of Terminology

Term	Definition
AAP	American Academy of Pediatrics
ADA	Adenosine deaminase
AFB	Acid fast bacilli
ASM	American Society of Microbiology
ATS	American Thoracic Society
BCG	Bacillus Calmette-Guérin
CCs	Critical concentrations
CD4	Cluster of differentiation 4
CDC	U.S. Centers for Disease Control and Prevention
CLIA ’88	Clinical Laboratory Improvement Amendments of 1988
CMS	Centers for Medicare and Medicaid Services
CSF	Cerebrospinal fluid
DOR	Diagnostic odds ratio
DR-TB	Drug resistant tuberculosis
DST	Drug susceptibility testing
DSTs	Drug susceptibility tests
ECDC	European Centre for Disease Prevention and Control
ELISA	Enzyme-linked immunosorbent assay
ELISPOT	Enzyme-linked immunospot
ERS	European Respiratory Society
FDA	Food and Drug Administration
HIV	Human immunodeficiency virus
IDSA	Infectious Diseases Society of America
IFN	Interferon
IFN- γ	Interferon-gamma
IGRA	Interferon gamma release assay
IMIDs	Immune-mediated inflammatory diseases
LAM	Lipoarabinomannan
LD/LDH	Lactate dehydrogenase
LDTs	Laboratory-developed tests
LF-LAM	Lipoarabinomannan assay
LPA	Line probe assay
LTBI	Latent tuberculosis infection
MDR	Multi-drug resistant
MIC	Minimum inhibitory concentration
MMR	Measles-mumps-rubella
Mtb	Mycobacterium tuberculosis
MTBC	Mycobacterium tuberculosis complex
MTD	Mycobacterium tuberculosis direct
NAA	Nucleic acid amplification
NAAT	Nucleic acid amplification tests/techniques
NICE	National Institute for Health and Care Excellence
NIH	National Institute of Health
NLR	Negative likelihood ratio
NPF	National Psoriasis Foundation
NPV	Negative predictive value
NSTC	National Society of Tuberculosis Clinicians
NTCA	National Tuberculosis Controllers Association
NTM	Non-Tuberculosis Mycobacterium Species
OR	Odds ratio
PCR	Polymerase chain reactions
pDST	Phenotypic drug susceptibility testing
PLR	Positive likelihood ratio
PPV	Positive predictive value
QFT-G/QFT-GT	Quantiferon- Tuberculosis Gold
QFT-GIT	Quantiferon- Tuberculosis Gold In-Tube
RBS	Rapid biosensor
RIF	Rifampicin
RR-TB	Rifampicin-resistant tuberculosis
SLIDs	Second line injectable drugs
SL-LPA	Second-line line probe assays
TB	Tuberculosis
TBNET	Tuberculosis Network European Trials Group
TNF	Tumor necrosis factor
TNF- α	tumor necrosis factor–α
TNFi	Tumor necrosis alpha inhibitor
TST	Tuberculin skin tests
USPSTF	United States Preventive Services Task Force
WGS	Whole genome sequencing
WHO	World Health Organization

Rationale
Tuberculosis (TB) continues to be a major public health threat globally, causing an estimated 10.0 million new cases and 1.09 million deaths from TB among HIV-negative individuals and 161,000 deaths among HIV-positive individuals in 2023,⁷ with the emergence of multi-drug-resistant strains only adding to the threat.⁸ The lungs are the primary site of infection by Mtb and subsequent TB disease. Onset of symptoms is usually gradual with a persistent cough being most frequently reported (95%) followed by the typical symptoms of fever (75%), night sweats (45%), and weight loss (55%).⁹ Clinical manifestations include primary TB, reactivation TB, laryngeal TB, endobronchial TB, lower lung field TB infection, and tuberculoma.² Extrapulmonary infection represents approximately 20% of cases of active TB with an additional 7% having concurrent pulmonary and extrapulmonary infections.¹⁰

In most individuals, initial Mycobacterium tuberculosis infection is eliminated, or contained by host defenses, while infection remains latent.^11,12 Individuals with LTBI are considered to be asymptomatic and not infectious; however, latent Mtb bacilli may remain viable and reactivate to cause active, contagious infection. Identification and treatment of LTBI are important TB control strategies, especially in settings with a low TB incidence, where reactivation of LTBI often accounts for the majority of nonimported TB disease.^5,13,14

Latent TB Testing (LTBI)

The goal of testing for LTBI is to identify individuals who are at increased risk for the development of tuberculosis and therefore who would benefit from treatment of latent TB infection. Only those who would benefit from treatment should be tested so a decision to test presupposes a decision to treat if the test is positive.⁴

Proprietary Testing
In 2015 the FDA approved the Xpert® MTB/RIF Assay, performed on the GeneXpert® Instrument Systems, as a qualitative, nested real-time PCR in vitro diagnostic test for the detection of Mycobacterium tuberculosis complex DNA in raw sputum or concentrated sputum sediment prepared from induced or expectorated sputum. In specimens where Mycobacterium tuberculosis complex (MTB-complex) is detected, the Xpert MTB/RIF Assay also detects the rifampin resistance associated mutations of the rpoB gene.¹

The QuantiFERON-TB® assay (CSL Biosciences, Australia) for detection of gamma interferon production is a blood test that has been used in humans in Australia. In November 2001, this test received approval from the U.S. Food and Drug Administration (FDA) in the United States for the following indication: "The QuantiFERON-TB test is intended as an aid in the detection of latent Mycobacterium tuberculosis infection."¹⁵

In December of 2004, QuantiFERON-TB® GOLD received FDA approval for the detection of latent TB. This test differs from the first-generation test in that instead of using PPD as the stimulus for interferon production, two antigens, ESAT-6 and CFP-10, are used. These antigens are present in mycobacterium tuberculosis but are not present in those exposed to BCG or non-tuberculous mycobacteria.¹

The QFT-GIT, which measures IFN-γ plasma concentration using an enzyme-linked immunosorbent assay (ELISA), has been approved by the FDA and has replaced the QuantiFERON-TB Gold (QFT-G) test.¹ Even more recently, QFT-Plus, which contains additional short peptides designed to elicit a response from both CD4 and CD8 T cells and thereby provides a broader immunological response, has been approved by the FDA.¹⁶ The T-SPOT assay enumerates T cells releasing IFN-γ using an enzyme-linked immunospot (ELISPOT) assay. The T-SPOT.TB assay is currently available in Europe, Canada, and has been approved for use in the United States with revised criteria for test interpretation.¹

Analytical Validity
Mycobacterial infection results in a predominantly cell-mediated immune response.¹⁷ Skin testing (TST) has long been a convenient, cost-effective method for assessing cell-mediated immune responses to a variety of antigens and has been the “gold standard” for diagnostic screening for Mycobacterium tuberculosis infections. However, multiple factors challenge the accuracy of the skin test, including skill requirements for and variability in placement and reading, cross-reactivity, and underlying illness or immunosuppression.¹⁷ The sensitivity of the TST is approximately 71%–82%.^1,18,19

The cell-mediated immune response to M. tuberculosis involves production of gamma interferon (IFN-γ).²⁰ IGRAs, which are in vitro culture assays measuring IFN-γ production in response to tuberculin antigen stimulation, have been developed as diagnostic screening tests.^19,21 IGRAs have specificity >95% for diagnosis of latent TB infection and a sensitivity of 80-90%.^5,22 The two commercially available IGRAs are the QuantiFERON-TB Gold In-Tube (QFT-GIT) assay and T-SPOT.TB assay. Both assays are FDA approved and available worldwide. These tests are not used to diagnose an active infection (as active infections are microbiologic diagnoses), but they still provide use as a confirmatory test for the TST.⁴

Clinical Utility and Validity

LTBI Testing

Diel, et al. (2012) performed a meta-analysis investigating the “positive and the negative predictive value (PPV and NPV, respectively) from a test-determined LTBI state for progression to active TB of interferon-γ release assays (IGRAs) and the tuberculin skin test (TST).” The authors found that the “pooled PPV for progression for all studies using commercial IGRAs was 2.7% compared with 1.5% for the TST.” PPV was found to increase to 6.8% and 2.4% respectively when only high-risk groups were included. The authors concluded that “Commercial IGRAs have a higher PPV and NPV for progression to active TB compared with those of the TST.”²³

Ruan, et al. (2016) further assessed the “diagnostic value of interferon-γ release assays (IGRAs) for latent tuberculosis infection (LTBI) in patients with rheumatic disease before receiving biologic agents.” 11 studies (n = 1940) were included. The authors found that “compared with the tuberculin skin test (TST), the pooled agreements in QFT-G/GIT and T-SPOT.TB were 72% and 75%, respectively. BCG vaccination was positively correlated with positive rates of TST (pooled odds ratio [OR] 1.64). Compared with TST, IGRAs were better associated with the presentence of one or more tuberculosis (TB) risk factors.” The authors concluded that “in rheumatic patients with previous BCG vaccination or currently on steroid therapy, IGRAs would be the better choice to identify LTBI by decreasing the false-positivity and false-negativity rate compared with conventional TST.”²⁴

Auguste, et al. (2017) compared IGRA and TST for identifying latent tuberculosis infection that progresses to active tuberculosis. A total of 17 studies were included. However, no significant differences were observed, and the authors concluded that “prospective studies comparing IGRA testing against TST on the progression from LTBI to TB were sparse, and these results should be interpreted with caution due to uncertainty, risk of bias, and unexplained heterogeneity. Population-based studies with adequate sample size and follow-up are required to adequately compare the performance of IGRA with TST in people at high risk of TB.”²⁵

Nasiri, et al. (2019) performed a meta-analysis focusing on the diagnostic accuracy of IGRA and TST for LTBI in transplant patients. A total of 16 articles were included, and the results are as follows: “pooled sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratio (DOR) for TST were 46%, 86%, 46.3%, 88.7%, 3.3, 0.63, and 5 respectively. For QFT-G (an IGRA), the pooled sensitivity, specificity, PPV, NPV, PLR, NLR, and DOR were 58%, 89%, 72.7%, 80.6%, 5.3, 0.47, and 11, respectively. Likewise, for T-SPOT.TB (another IGRA), the pooled sensitivity, specificity, PPV, NPV, PLR, NLR, and DOR were 55%, 92%, 60.4%, 90.2%, 6.7, 0.52, and 16, respectively.” The authors concluded that “IGRAs were more sensitive and specific than the TST with regard to the diagnosis of LTBI in the transplant candidates. They have added value and can be complementary to TST.”²⁶

Khanna, et al. (2021) performed a retrospective review of QuantiFERON-TB test (QFT) results to evaluate the utility of serial LTBI screening in patients taking biologics and to identify risk factors in patients. They found that “Repeat LTBI testing in patients taking biologics revealed a low rate of conversion (1.17%),” and concluded that their “results suggest clinical utility and cost-effectiveness of repeat LTBI screening in patients on biologics may be more valuable if not performed routinely, but driven by a focused review of TB exposure risk factors in each patient.”²⁷

In a prospective observational study conducted in a tertiary care center in India, Neema, et al. (2021) found that “Treatment of LTBI prevents up to 60–70% patients from developing active tuberculosis; however, a patient may develop active tuberculosis despite prophylaxis especially with TNF inhibitors and patient should be followed up regularly.” As such, “A thorough search for active tuberculosis should be performed. Timely detection of LTBI helps in the prevention of development of active tuberculosis in the patients on immunosuppressive treatment.” However, it should be noted that the target study population for this study is the Indian population, which the authors acknowledged has a high prevalence of tuberculosis and latent tuberculosis infection already, and so it is unclear if the value may not be extrapolated to other populations.

Ren, et al. (2024) studied the sensitivity of interferon-γ release assays (IGRAs) in identifying MTB-infected individuals. The study included 302 individuals, assigned into the following groups: healthy control, LTBI, IGRA-positive TB, and IGRA-negative TB. The Luminex xMAP assay was used to measure MTB antigen-specific blook plasma chemokine concentrations. “Levels of CXCL9, CXCL10, IL-2, and CCL8 biomarkers were predictive for active TB.” The CXCL9-based enzyme-linked immunosorbent assay sensitivity rate was 95.9% and the specificity rate as 100%. CXCL9 and CXCL9-CXCL10 assays had statistically similar area under the curve values, “thus demonstrating that combined analysis of CXCL10 and CXCL9 levels did not improve active TB diagnostic performance.” The authors concluded that “The MTB antigen stimulation-based CXCL9 assay may compensate for low IGRA diagnostic accuracy when used to diagnose IGRA-negative active TB cases and thus is an accurate and sensitive alternative to IGRAs for detecting MTB infection.”²⁹

Active TB Testing

The diagnosis of TB disease should be suspected in patients with relevant clinical manifestations and exposure history.¹ Laboratory testing is an integral part of the rapid and accurate diagnosis of TB to facilitate timely initiation of treatment.

Microbiologic testing is used to evaluate an active TB infection. These tests may include the acid-fast bacilli smear (AFB), the mycobacterial culture, and molecular testing. Smears are the fastest and cheapest diagnostic tool, cultures are the most sensitive, and molecular testing is used for assessing drug resistance.²

The detection of AFB on microscopic examination of stained sputum smears is the most rapid and inexpensive technique;² however, it is limited by its lack of sensitivity in certain situations, such as extrapulmonary infection or coinfection with HIV.³⁰ The mycobacteria retain the stain in a mineral-acid or acid-alcohol solution, and microscopy identifies these strains. LED microscopy has seen more use recently than the traditional light microscopy.²

Rapid and accurate diagnosis is critical for timely initiation of TB treatment.³⁰ Although sensitive, culture can take over two weeks to return results.¹ Three specimens should be examined to assure a sensitivity of approximately 70%. The first specimen has a sensitivity of approximately 53.8%, increasing by 11.1% with a second specimen, and another 2-5% with a third.³¹ A first morning specimen increases sensitivity by 12%, and concentrating specimens can increase sensitivity by 18%.³² Use of fluorescence microscopy also increases sensitivity 10% over conventional microscopy.^1,33 The positive predictive value has been reported to be 97.9-100%,³⁴ but it is impacted by non-tuberculosis Mycobacterium species (NTM).³⁵

Nucleic acid amplification techniques (NAAT) have been developed for rapid diagnosis of TB. Two major tests are available, the Amplified Mycobacterium tuberculosis Direct (MTD) test and the Xpert MTB/RIF test. NAAT-based assays are more sensitive than smear, but less sensitive than culture, with a reported sensitivity of 96% and specificity of 99%.^1,36 NAAT testing has >95% positive predictive value in the setting of AFB smear-positive specimens for distinguishing tuberculous from non-tuberculous mycobacteria, and it can establish the presence of tuberculosis in 50 to 80% of AFB smear-negative specimens.³⁷ NAAT does not replace the roles of AFB smear and culture³⁸ in the diagnostic algorithm for tuberculosis and results must be interpreted in conjunction with AFB smear results while mycobacterial culture is pending.^1,39

Sequence-based assays provide the genetic identity of a particular mutation and, therefore, can predict drug resistance with greater accuracy than probe-based assays. The testing identifies genetic mutations associated with rifampin and isoniazid resistance as well as resistance to second-line drugs including fluoroquinolones and the injectables amikacin, kanamycin, and capreomycin. Molecular testing results are generally available within days and can be used to guide initial treatment decisions and inform design of prevention regimens for contacts.^2,40

More proprietary tests exist for the assessment of TB. Rapid Biosensor offers a breath test “TB Breathalyzer” for TB. The test proposes that it can detect actively infectious bacilli instead of relying on sputum (which some patients do not produce). The test estimates its limit of detection at 25-75 bacilli and notes that it can be used easily in rural communities. When an individual coughs in the collection tube, any TB bacilli will react with the biochemical formulation at the bottom of the tube, which is then detected by the diode laser in the reader unit.⁴¹

The reference standard for diagnosis of any TB infection is isolation of M. tuberculosis.³⁰ The isolate recovered should be identified according to the Clinical and Laboratory Standards Institute guidelines⁴² and the American Society for Microbiology Manual of Clinical Microbiology,^1,43 and all United States jurisdictions require submission of culture isolates identified as M. tuberculosis for confirmation of identification and drug susceptibility testing.⁴⁰ Positive cultures are also reported to public health authorities for oversight and case management.²

Cruciani, et al. (2004) performed a meta-analysis of 10 studies (1381 strains from 14745 clinical specimens) which found that both liquid and solid culture media methods are highly specific (99%). Liquid culture methods are more sensitive (81.5-85.8%) and have a shorter time to detection (13.2-15.2 day) than solid media but are more prone to contamination (4-9%). Solid media has a sensitivity of 76% and averages 25.8 days for detection. The use of both culture methods increases the overall sensitivity to 87.7-89.7%.

Bourgi, et al. (2017) “aimed to evaluate the reliability and projected impact of nucleic acid amplification (NAA) testing in patients with AFB smear-positive respiratory samples.” The authors identified a retrospective cohort of AFB smear-positive patients and evaluated the projected change in “duration of airborne isolation and unnecessary Mycobacterium tuberculosis (MTB) treatment with introducing NAA testing into clinical decision making for AFB smear-positive patients.” A total of 130 patients were found to be AFB positive, of which 80 tested positive on NAA. Eighty-two patients grew MTB on culture. NAA testing was found to have a sensitivity of 97.6% and specificity of 100%. Integrating NAA testing into clinical decision-making led to shortened time in airborne isolation (6.0 ± 7.6 vs 23.1 ± 38.0) and 9.5 ± 11.32 fewer days of “unnecessary MTB treatment in patients with negative NAA test.” The authors concluded, “Nucleic acid amplification testing provided a rapid and accurate test in the diagnosis of MTB while significantly reducing the duration of isolation and unnecessary medications in patients with negative NAA test.”⁴⁵

Urine testing for mycobacterial cell wall glycolipid⁴⁶ has been investigated as a point of care assay for diagnosis of TB in HIV infected patients.⁴⁷ The test was 97.6% specific and 67.9% sensitive in patients with CD4<100. It is useful in addition to routine diagnostic tests for HIV-infected patients with signs and symptoms of TB and CD4 ≤100 cells/microL and for all HIV-infected patients who are seriously ill.^48,49 Gupta-Wright et al.⁵⁰ evaluated the sputum Xpert MTB/RIF with or without urine lipoarabinomannan (LAM) testing. There was no difference in overall mortality over 2574 patients, but they found that urine LAM testing might benefit some high-risk subgroups (CD4 <100, severe anemia, and patients with clinically suspected tuberculosis).⁵⁰

Adenosine deaminase (ADA) and interferon-gamma (IFN- γ) levels in cerebrospinal, pleural, peritoneal, and pericardial fluids have been studied in the diagnosis of extrapulmonary TB. In 2017, a joint review by the ATS, IDSA, and CDC found the sensitivity of ADA in these fluids to be 79% and the specificity to be 83% for TB. The sensitivity of IFN- γ in these fluids was 89% and the specificity was 97%. However, the authors remarked that neither the ADA level nor the IFN-γ level provide a definitive diagnosis of TB disease.¹

De Groote, et al. (2017) developed a panel based on proteomic analysis. A total of 1470 serum samples were collected from individuals “with symptoms and signs suggestive of active pulmonary TB that were systematically confirmed or ruled out for TB by culture and clinical follow-up.” Six protein biomarkers were identified: “SYWC, kallistatin, complement C9, gelsolin, testican-2, and aldolase C,” which performed well in a training set (area under curve = 0.92) to distinguish between TB and non-TB. It was also found to have 90% sensitivity and 80 % specificity. The authors concluded that their panel “warrants diagnostic development on a patient-near platform.”⁵¹

Heyckendorf, et al. (2018) compared the utility of genotypic and phenotypic assays for evaluation of tuberculosis (TB) drug resistance. The authors used the results from the assays to develop treatment regimens for the 25 multi- and extensively drug-resistant tuberculosis patients in the study. Compared to phenotypic assay-developed regimens, whole genome sequencing (WGS) yielded a regimen of drugs at 93% agreement with the phenotypic assay’s regimen. Further, the whole genome sequencing-derived regimen did not contain any drugs identified as resistant by the phenotypic assay. However, the authors commented that “MIC [minimum inhibitory concentration] testing revealed that pDST [phenotypic drug susceptibility testing] likely underestimated the true rate of resistance for key drugs (rifampin, levofloxacin, moxifloxacin, and kanamycin) because critical concentrations (CCs) were too high.” Results derived from other genotypic assays (Xpert, line probe assays) had lower agreement with the phenotypic assay (49% and 63%, respectively). The authors concluded that “WGS can be used to rule in resistance even in M/XDR strains with complex resistance patterns, but pDST for some drugs is still needed to confirm susceptibility and construct the final regimens. Some CCs for pDST need to be reexamined to avoid systematic false-susceptible results in low-level resistant isolates.”⁵²

Ustinova, et al. (2019) investigated an assay’s ability to identify and distinguish between non-tuberculous mycobacteria and Mycobacterium tuberculosis complex (MTBC) in culture and sputum. A total of 301 NTM cultures with mycobacteriosis were measured, and sputum samples were contributed by “104 patients with mycobacteriosis, 3627 patients with tuberculosis and 118 patients with other lung diseases.” The authors' results were as follows: “Specificity and sensitivity of the assay for MTBC was found to be 100% both in culture and sputum samples; for NTM, the specificity was 100% in culture and sputum, the sensitivity reached 100% in culture and 73.1% in sputum samples. PPV and negative predictive value (NPV) of the assay for culture were both 100%, for clinical material 100% and 80.8%, respectively.”⁵³

Adams, et al. (2019) compared the performances of the TST and two IGRAs. Five hundred and five health-care workers (HCWs) in Cape Town, South Africa, were screened for LTBI using the three assays. The authors identified LTBI prevalence to be 81%. TST at a cutoff of 10 mm had the highest sensitivity at 93% and the lowest specificity at 57%. The QFT-GIT IGRA sensitivity was 80% and specificity was 96%; the TSPOT.TB IGRA sensitivity was 74% and specificity was 96%. Positive predictive values for IGRAs was 90% and 96% for TST and the highest negative predictive value was 66%. However, a composite rule using both TST and QFT-GIT improved negative predictive value to 90%. The authors concluded that “in an endemic setting a positive TST or IGRA was highly predictive of LTBI, while a combination of TST and IGRA had high rule-out value.”⁵⁴

Zürcher, et al. (2019) evaluated the “mortality in patients with tuberculosis from high-burden countries, according to concordance or discordance of results from drug susceptibility testing done locally and in a reference laboratory.” A total of 634 individuals were included, 272 of which were HIV-positive. The authors identified 394 strains (62%) to be “pan-susceptible,” 45 (7%) to be monoresistant, 163 (27%) to be multi-drug resistant, and 30 (5%) to be “extensively” resistant. The laboratory results were concordant for 513 (81%) patients and discordant for 121 (19%) patients, resulting in a 90.8% sensitivity and 84.3% specificity. The authors identified a 7.33 odds ratio of death for patients with discordant results, which potentially led to under-treatment. The authors concluded “inaccurate drug susceptibility testing by comparison with a reference standard leads to under-treatment of drug-resistant tuberculosis and increased mortality.”⁵⁵

Jain, et al. (2021) conducted a cross-sectional study in India to “compare the performance of GeneXpert MTB/RIF (GXpert) assay with [the] composite reference standard in diagnosing cases of tubercular pleural effusion (TPE) and to evaluate the reliability of rifampicin resistance.” In diagnosing TPE, the sensitivity of the assay was 16.6% among 158 study participants, with a specificity of 100%, diagnostic accuracy of 52.5%, positive predictive value of 100%, and negative predictive value of 47.5%. Because of these findings, the researchers concluded that this GXpert assay would need to be combined with “routine pleural fluid analysis” to accurately diagnose TPE in suspected patients.⁵⁶

Karthek, et al. (2021) evaluated the usage of the same GeneXpert MTB/RIF assay in the context of spinal tuberculosis. In conducting a retrospective review from 136 patients that underwent spinal biopsy for spondylodiscitis, 86 final patients met the criteria for spinal tuberculosis (61.6% demonstrated Mtb positivity in tissue samples and 38.4% were positive through pus samples). From this data, the researchers found a 65.1% sensitivity, 100% specificity, 100% PPV, and 56.5% NPV for this assay. It was also accurate in detecting drug resistance among patient specimens.⁵⁷

Medina-Marino, et al. (2024) conducted a randomized study in South Africa to assess the acceptability and feasibility of in-home TB testing of household contacts. The study included 84 households with at least one eligible symptomatic contact, for a total of 98 household contacts. The household contacts were all randomized, with 51 receiving in-home testing and 47 receiving standard-of-care. In-home testing included GeneXpert MTB/RIF molecular testing, and referrals for clinic-based treatment for positive cases. Standard-of-care testing included clinic-based sputum collection and testing. The median number of days between screening and receiving testing results was zero for the in-home testing group, and 16.5 for the standard-of-care testing group. The authors concluded that “in-home testing for TB was acceptable, feasible, and increased HHCs with a molecular test result” and that “in-home testing mitigates a major limitation of household contact investigations (dependency on clinic-based referral), revealing new strategies for enhancing early case detection.”⁵⁸

Ma, et al. (2024) performed a long-term follow-up of close contacts to TB-positive individuals to monitor their infection status. This was done by interviewing and screening TB patients and their household contacts for TB infection by IGRA during a 12-month longitudinal investigation. There was a total of 92 index TB patients with 184 household contacts. Of the 184 individuals, 87 (47.3%) progressed to TB infection, of whom 86 developed into IGRA positive within 24 weeks. Ma, et al. (2024) concluded that “repeated IGRA tests are sensible to be conducted among close contacts at 24 weeks after exposure to identify the IGRA-positive individuals.”⁵⁹

U.S. Centers for Disease Control and Prevention (CDC)
For the diagnosis of tuberculosis, the CDC recommends the following:

“All persons with signs or symptoms of TB disease, a positive result from a TB blood test (interferon-gamma release assay [IGRA]), or a positive result from a tuberculin skin test (TST) should be medically evaluated for TB disease.

A diagnosis of latent TB infection is made if a person has a positive TB blood test or TB skin test result, and a medical evaluation does not indicate TB disease.

A complete medical evaluation for TB disease has five components:

1. Medical history
2. Physical examination
3. Test for TB infection (TB blood test or TB skin test)
4. Chest radiograph
5. Bacteriologic examination (sputum smear microscopy, nucleic acid amplification testing, culture, and drug susceptibility testing)

Culture is the gold standard microbiologic test for the diagnosis of TB disease.”⁶⁰

The CDC and the USPSTF recommend testing people who are at increased risk for TB infection. Testing for TB infection is a routine and integral part of health care for patients with increased risk for TB. People who are at low risk generally should not be tested since the predictive value of a positive result is lower, resulting in an increasing number of false positive test results. The CDC breaks down risk factors for TB in two categories: people who are at higher risk of exposure to TB bacteria and People who are at higher risk of TB disease developing once infected with TB bacteria. The frequency of testing depends on a person's risk factors. This could range from one-time only testing among persons at low risk for future TB exposure to annual testing among those at continued risk of exposure.⁶⁰

“People at higher risk of exposure to TB bacteria

• Contacts of people known or presumed to have infectious TB disease
• People who were born in or who frequently travel to countries where TB disease is common
• People who currently live or used to live in large group settings where TB is more common, such as homeless shelters, correctional facilities, or nursing homes
• Employees of high-risk congregate settings
• Health care workers who serve patients with TB disease
• Populations defined locally as having an increased incidence of latent TB infection or TB disease, possibly including medically underserved populations, low-income populations, or persons with alcohol use or substance use disorders
• Infants, children, and adolescents exposed to adults who are at increased risk for latent TB infection or TB disease

People who are at higher risk of developing TB disease once infected with TB bacteria

• People with HIV
• Children younger than 5 years of age
• People recently infected with TB bacteria (within the last 2 years)
• People with a history of untreated or inadequately treated TB disease
• People who are receiving immunosuppressive therapy such as tumor necrosis factor-alpha (TNF) antagonists, systemic corticosteroids equivalent to/greater than 15 mg of prednisone per day, or immunosuppressive drug therapy following organ transplantation
• People with silicosis; chronic renal failure; leukemia; or cancer of the head, neck, or lung
• People with diabetes mellitus
• People who have had a gastrectomy or jejunoileal bypass
• People with low body weight (<90% of ideal body weight)
• People who use substances (such as injection drug use)
• Populations defined locally as having an increased incidence of TB disease, including medically underserved and low-income populations”⁶⁰

World Health Organization (WHO)
The WHO published the fourth edition of consolidated guidelines on TB with Module 3 focusing on diagnosis of TB in 2025. In these guidelines, WHO included a table of classes and products of TB tests for detection of TB, drug-resistant TB, and TB infection that were included in the guidelines, shown below.⁶¹

Technology Class	Included Products
Initial tests for TB diagnosis with drug-resistance detection
Low-complexity automated nucleic acid amplification tests (NAATs) for detection of TB and resistance to rifampicin	Xpert® MTB/RIF and Xpert MTB/RIF Ultra (Cepheid) Truenat® MTB Plus and Truenat MTB-RIF Dx (Molbio)
Moderate-complexity automated NAATs for detection of TB and resistance to rifampicin and isoniazid	Abbott RealTime® MTB and Abbott RealTime MTB RIF/INH (Abbott) BD MAX™ MDR-TB (Becton Dickinson) cobas® MTB and cobas MTB-RIF/INH (Roche) FluoroType® MTB and FluoroType MTBDR (Hain Lifescience/Bruker)
Initial tests for TB diagnosis without drug-resistance detection
Low-complexity manual NAATs for detection of TB	LoopampTM MTBC Detection Kit (TB LAMP) (Eiken Chemical)
Antigen detection in a lateral flow format (biomarker-based detection) (LF-LAM) for detection of TB	Determine™ TB LAM Ag (Alere/Abbott)
Follow-on tests for detection of TB drug resistance
Low-complexity automated NAATs for detection of resistance to isoniazid and second-line anti-TB agents	Xpert® MTB/XDR (Cepheid)
Line probe assays (LPAs) for detection of TB drug resistance	GenoType® MTBDRplus v1 and v2; and GenoType MTBDRsl (Hain Lifescience/Bruker) Genoscholar™ NTM+MDRTB II and Genoscholar PZA-TB II (Nipro)
Targeted next-generation sequencing (NGS) tests for detection of TB drug resistance	Deeplex® Myc-TB (GenoScreen/Illumina) AmPORE-TB® (Oxford Nanopore Technologies) TBseq® (Shengting Medical Technology Company)
Tests for TB infection
Mycobacterium tuberculosis antigen-based skin tests (TBSTs)	Diaskintest® (Generium) Siiltibcy™ (Serum Institute of India) C-TST (Anhui Zhifei Longcom)
Interferon-gamma release assays (IGRAs)	T-SPOT.TB (T-Spot) (Revvity) TB-IGRA (Wantai BioPharm) QuantiFERON-TB Gold Plus (QFT-Plus) (QIAGEN) STANDARD E TB-Feron ELISA (SD BIOSENSOR) LIAISON QFT-Plus CLIA (Diasorin)
Tuberculin skin tests	Tuberculin purified protein derivative (PPD) products

The WHO published the following complete list of recommendations for diagnosis of TB disease.⁶¹

1. “For adults and adolescents with signs or symptoms of TB or who screened positive for pulmonary TB, low-complexity automated NAATs should be used on respiratory samples as initial diagnostic tests for TB, rather than smear microscopy or culture. (Strong recommendation, high certainty of evidence)
2. For people with bacteriologically confirmed TB2, low-complexity automated NAATs should be used on respiratory samples as initial tests for detection of resistance to rifampicin, rather than culture-based DST. (Strong recommendation, high certainty of evidence)
3. For people with signs and symptoms of TB meningitis, low-complexity automated NAATs on cerebral spinal fluid should be used for the initial diagnosis of TB meningitis, rather than smear microscopy or culture. (Strong recommendation, moderate certainty of evidence)
4. For people with signs and symptoms of extrapulmonary TB, low-complexity automated NAATs on lymph node tissue aspirate, pleural tissue, pleural fluid, synovial fluid, peritoneal fluid or pericardial fluid should be used for the initial diagnosis of TB, rather than smear microscopy or culture. (Strong recommendation, low certainty of evidence for synovial fluid and pericardial fluid; very low certainty of evidence for lymph node tissue aspirate, pleural tissue, pleural fluid and peritoneal fluid)
5. For people with signs and symptoms of pulmonary TB, moderate-complexity automated NAATs may be used on respiratory samples for the detection of pulmonary TB, and of rifampicin and isoniazid resistance, rather than culture and phenotypic DST. (Conditional recommendation, moderate certainty of evidence)
6. For adults and adolescents with signs or symptoms or who screen positive for pulmonary TB, low-complexity manual NAATs should be used on respiratory samples as initial diagnostic tests for TB, rather than smear microscopy or culture. (Strong recommendation, high certainty of evidence)
7. For adults and adolescents with HIV who have signs or symptoms of TB, screen positive for TB, are seriously ill or have advanced HIV disease, concurrent testing using low-complexity automated NAATs on respiratory samples and LF-LAM on urine should be used as the initial diagnostic strategy for diagnosing TB, rather than low complexity automated NAATs on respiratory samples alone. (Strong recommendation, low certainty of evidence)
8. For children who are HIV-negative or have an unknown HIV status, who have signs or symptoms or screen positive for pulmonary TB, concurrent testing using low complexity automated NAATs on respiratory and stool samples should be used as the initial diagnostic strategy for diagnosing TB, rather than low-complexity automated NAATs on respiratory or stool samples alone. (Strong recommendation, low certainty of evidence)
9. For children with HIV who have signs or symptoms or screen positive for pulmonary TB, concurrent testing using low-complexity automated NAATs on respiratory and stool samples and LF-LAM on urine may be used as the initial diagnostic strategy for diagnosing TB, rather than low-complexity automated NAATs on respiratory or stool samples alone. (Conditional recommendation, low certainty of evidence)
10. For people with bacteriologically confirmed pulmonary TB, low-complexity automated NAATs may be used on sputum for the initial detection of resistance to isoniazid and fluoroquinolones, rather than culture-based phenotypic DST. (Conditional recommendation, moderate certainty of evidence)
11. For people with bacteriologically confirmed pulmonary TB and resistance to rifampicin, low-complexity automated NAATs may be used on sputum for the initial detection of resistance to ethionamide, rather than DNA sequencing of the inhA promoter. (Conditional recommendation, very low certainty of evidence)
12. For people with bacteriologically confirmed pulmonary TB and resistance to rifampicin, low-complexity automated NAATs may be used on sputum for the initial detection of resistance to amikacin, rather than culture-based phenotypic DST. (Conditional recommendation, low certainty of evidence)
13. For people with a sputum smear-positive specimen or a cultured isolate of MTBC, commercial molecular LPAs may be used as the initial test instead of phenotypic culture-based DST to detect resistance to rifampicin and isoniazid. (Conditional recommendation, moderate certainty of evidence)
14. For people with confirmed MDR/RR-TB, SL-LPA may be used as the initial test, instead of phenotypic culture-based DST, to detect resistance to fluoroquinolones. (Conditional recommendation, moderate certainty of evidence for test accuracy)
15. For people with confirmed MDR/RR-TB, SL-LPA may be used as the initial test, instead of phenotypic culture-based DST, to detect resistance to the SLIDs. (Conditional recommendation, low certainty of evidence for test accuracy)
16. For people with bacteriologically confirmed TB, high-complexity reverse hybridization based NAATs may be used on Mtb culture isolates for detection of pyrazinamide resistance rather than culture-based phenotypic DST. (Conditional recommendation, very low certainty of evidence)
17. For people with bacteriologically confirmed pulmonary TB disease, targeted next generation sequencing technologies may be used on respiratory samples to diagnose resistance to rifampicin, isoniazid, fluoroquinolones, pyrazinamide and ethambutol, rather than culture-based phenotypic DST. (Conditional recommendation, certainty of evidence moderate [isoniazid and pyrazinamide] and low [rifampicin, fluoroquinolones and ethambutol])
18. For people with bacteriologically confirmed rifampicin-resistant pulmonary TB disease, targeted next-generation sequencing technologies may be used on respiratory samples to diagnose resistance to isoniazid, fluoroquinolones, bedaquiline, linezolid, clofazimine, pyrazinamide, ethambutol, amikacin and streptomycin, rather than culture-based phenotypic DST. (Conditional recommendation, certainty of evidence high [isoniazid, fluoroquinolones and pyrazinamide], moderate [ethambutol], low [bedaquiline, linezolid, clofazimine and streptomycin] and very low [amikacin])
19. Mycobacterium tuberculosis antigen-based skin tests may be used to test for TB infection. (Conditional recommendation, very low certainty of evidence for test accuracy)
20. Either a tuberculin skin test or an interferon-gamma release assay can be used to test for TB infection. (Strong recommendation, very low certainty of evidence for test accuracy)
21. Interferon-gamma release assays (IGRAs) and tuberculin skin tests (TSTs) should not be used in low- and middle-income countries for the diagnosis of pulmonary or extrapulmonary TB or for the diagnostic work-up of adults (including people living with HIV) with suspected active TB. (Strong recommendation)”⁶¹

The WHO has also published recommendations for the diagnosis of TB in 2015, stating that:⁶²

• “Mycobacteria can be cultured in specific solid or liquid media. Bacterial growth can be identified visually (that is, by identifying specific characteristics) or by automated detection of its metabolism. All positive mycobacterial cultures must be tested to confirm the identification of M. tuberculosis complex (MTBC).”
• “Differentiation of the members of the MTBC is necessary for the treatment of individual patients and for epidemiological purposes, especially in areas of the world where tuberculosis has reached epidemic proportions or wherever the transmission of M. bovis between animals or animal products and humans is a problem. In addition, it can be important to rapidly identify isolates of M. bovis bacillus Calmette-Guérin (BCG) recovered from immunocompromised patients. Differentiation of species with the MTBC can be achieved using either phenotypic26 and/ or genotypic methods.”
• “The use of rapid immunochromatographic assays (or strip tests for speciation) to identify cultured isolates is recommended because they provide definitive identification of all members of the MTBC (including M. bovis) in 15 minutes.”
• “It is strongly recommended that commercial serodiagnostic tests not be used for the diagnosis of pulmonary and extra-pulmonary TB. Currently available commercial serodiagnostic tests (also referred to as serological tests) provide inconsistent and imprecise findings. There is no evidence that existing commercial serological assays improve patient outcomes, and high proportions of false positive and false-negative results may have an adverse impact on the health of patients.”⁶²

The following recommendations involve LTBI from 2018.⁶³

• “LTBI testing by TST or IGRA is not a requirement for initiating preventive treatment in people living with HIV or child household contacts aged < 5 years. (Strong recommendation, moderate-quality evidence. Updated recommendation).”
• “Adults and adolescents living with HIV should be screened for TB according to a clinical algorithm. Those who do not report any of the symptoms of current cough, fever, weight loss or night sweats are unlikely to have active TB and should be offered preventive treatment, regardless of their ART status.”
• “People living with HIV who have a positive test for LTBI benefit more from preventive treatment than those who have a negative LTBI test; LTBI testing can be used, where feasible, to identify such individuals.”
• “Patients initiating anti-TNF treatment, patients receiving dialysis, patients preparing for an organ or haematological transplant and patients with silicosis should be systematically tested and treated for LTBI. (Strong recommendation, low–very low-quality evidence. Updated recommendation).”
• “In countries with a low TB incidence, systematic testing for and treatment of LTBI may be considered for prisoners, health workers, immigrants from countries with a high TB burden, homeless people and people who use illicit drugs. (Conditional recommendation, low–very low-quality evidence. Existing recommendation).”
• “Systematic testing for LTBI is not recommended for people with diabetes, people with harmful alcohol use, tobacco smokers and underweight people unless they are already included in the above recommendations. (Conditional recommendation, very low-quality evidence. Existing recommendation).”
• “There is no gold standard method for diagnosing LTBI. TST and IGRA require a competent immune response in order to identify people infected with TB and are imperfect tests for measuring progression to active disease.”⁶³

• “There is no strong evidence that one test should be preferred over the other in terms of predicting progression from TB infection to TB disease. Neither TSTs nor IGRAs should be used in persons having a low risk of TB infection and disease.”
• A testing algorithm was also published in the guideline, which discusses latent TB testing and subsequent treatment in individuals at risk. The guideline writes that both asymptomatic household contacts (of patients with TB), as well as members of non-HIV risk groups (such as patients with “silicosis, dialysis, anti-TNF agent treatment, preparation for transplantation or other risks in national guidelines”) should be tested with TST or IGRA

American Thoracic Society/Infectious Diseases Society of America/U.S. Centers for Disease Control and Prevention
The ATS/IDSA/CDC published clinical practice guidelines for diagnosis of TB in 2017 that stated the following:

LTBI:

• “We recommend performing an interferon-γ release assay (IGRA) rather than a tuberculin skin test (TST) in individuals 5 years or older who meet the following criteria: (1) are likely to be infected with Mtb, (2) have a low or intermediate risk of disease progression, (3) it has been decided that testing for LTBI is warranted, and (4) either have a history of BCG vaccination or are unlikely to return to have their TST read (strong recommendation, moderate-quality evidence).”
• “We suggest performing an IGRA rather than a TST in all other individuals 5 years or older who are likely to be infected with Mtb, who have a low or intermediate risk of disease progression, and in whom it has been decided that testing for LTBI is warranted (conditional recommendation, moderate-quality evidence).”
• “There are insufficient data to recommend a preference for either a TST or an IGRA as the first-line diagnostic test in individuals 5 years or older who are likely to be infected with Mtb, who have a high risk of progression to disease, and in whom it has been determined that diagnostic testing for LTBI is warranted.”
• “Guidelines recommend that persons at low risk for Mtb infection and disease progression NOT be tested for Mtb infection. We concur with this recommendation. However, we also recognize that such testing may be obliged by law or credentialing bodies. If diagnostic testing for LTBI is performed in individuals who are unlikely to be infected with Mtb despite guidelines to the contrary:”
  • “We suggest performing an IGRA instead of a TST in individuals 5 years or older (conditional recommendation, low-quality evidence). Remarks: A TST is an acceptable alternative in settings where an IGRA is unavailable, too costly, or too burdensome.”
  • “We suggest a second diagnostic test if the initial test is positive in individuals 5 years or older (conditional recommendation, very low-quality evidence). Remarks: The confirmatory test may be either an IGRA or a TST. When such testing is performed, the person is considered infected only if both tests are positive.”
• “We suggest performing a TST rather than an IGRA in healthy children <5 years of age for whom it has been decided that diagnostic testing for LTBI is warranted (conditional recommendation, very low-quality evidence).”
• “While both IGRA and TST testing provide evidence for infection with Mtb, they cannot distinguish active from latent TB. Therefore, the diagnosis of active TB must be excluded prior to embarking on treatment for LTBI. This is typically done by determining whether or not symptoms suggestive of TB disease are present, performing a chest radiograph and, if radiographic signs of active TB (eg, airspace opacities, pleural effusions, cavities, or changes on serial radiographs) are seen, then sampling is performed, and the patient managed accordingly.”

TB Disease:

• “We recommend that acid-fast bacilli (AFB) smear microscopy be performed, rather than no AFB smear microscopy, in all patients suspected of having pulmonary TB.”
• “We suggest that both liquid and solid mycobacterial cultures be performed, rather than either culture method alone, for every specimen obtained from an individual with suspected TB disease.”
• “We suggest performing a diagnostic nucleic acid amplification test (NAAT), rather than not performing a NAAT, on the initial respiratory specimen from patients suspected of having pulmonary TB.”
• “We recommend performing rapid molecular drug susceptibility testing for rifampin with or without isoniazid using the respiratory specimens of persons who are either AFB smear positive or Hologic Amplified MTD positive and who meet one of the following criteria: (1) have been treated for tuberculosis in the past, (2) were born in or have lived for at least 1 year in a foreign country with at least a moderate tuberculosis incidence (≥20 per 100000) or a high primary multi-drug-resistant tuberculosis prevalence (≥2%), (3) are contacts of patients with multidrug-resistant tuberculosis, or (4) are HIV infected.”
• “We suggest mycobacterial culture of respiratory specimens for all children suspected of having pulmonary TB.”
• “We suggest that cell counts, and chemistries be performed on amenable fluid specimens collected from sites of suspected extrapulmonary TB.
• “We suggest that adenosine deaminase levels be measured, rather than not measured, on fluid collected from patients with suspected pleural TB, TB meningitis, peritoneal TB, or pericardial TB.”
• ”We suggest that free IFN-γ levels be measured, rather than not measured, on fluid collected from patients with suspected pleural TB or peritoneal TB.”
• “We suggest that AFB smear microscopy be performed, rather than not performed, on specimens collected from sites of suspected extrapulmonary TB.
• “We recommend that mycobacterial cultures be performed, rather than not performed, on specimens collected from sites of suspected extrapulmonary TB.”
• “We suggest that NAAT be performed, rather than not performed, on specimens collected from sites of suspected extrapulmonary TB.”
• “We suggest that histological examination be performed, rather than not performed, on specimens collected from sites of suspected extrapulmonary TB.”
• “Recently, whole-genome sequencing (WGS) has been applied to investigation of tuberculosis outbreaks. This technique may add discriminatory power to strain identification, but the role of WGS in outbreak investigation is still being determined.”
• “We recommend one culture isolate from each mycobacterial culture-positive patient be submitted to a regional genotyping laboratory for genotyping.”¹

National Institute of Health (NIH)
The NIH published a set of guidelines regarding opportunistic infections in HIV-positive patients. The NIH writes that “All people with HIV should be evaluated for LTBI at the time of HIV diagnosis, regardless of their epidemiological risk of TB exposure.”

The NIH also comments on diagnostic testing, stating that “sputum acid-fast bacilli (AFB) smear, nucleic acid amplification (NAA) testing, and AFB culture should be performed in people with HIV with symptoms of TB disease who have a normal chest radiograph, as well as in those with no pulmonary symptoms but evidence of TB disease elsewhere in the body.” The NIH remarks that “pleural fluid, pericardial fluid, ascites, and cerebrospinal fluid should be sampled if there is clinical evidence of involvement.”

The NIH also discusses drug resistance testing, recommending that “Drug resistance should be considered in all people with HIV, especially those who meet any of the following criteria:

• Known exposure to a person with drug-resistant TB,
• Residence in a setting with high rates of primary drug-resistant TB,
• Persistently positive smear or culture results at or after four months of treatment, or
• Previous TB treatment, particularly if it was not directly observed or was interrupted for any reason.”

The NIH recommends “Rapid molecular DST for rifampin (and isoniazid, if available) should be performed on the initial isolates from all patients suspected of having TB, because resistance to rifampin is associated with an increased risk of treatment failure, recurrent TB, and amplification of resistance to additional TB medications.”

Overall, the NIH recommends that “For all patients with TB disease, phenotypic DST to first-line TB drugs (isoniazid, rifampin, ethambutol, and pyrazinamide) should be performed, regardless of the source of the specimen. Given the alternative of a shorter drug-susceptible TB regimen containing moxifloxacin, public health laboratories in the U.S. may add routine moxifloxacin susceptibility testing as well. Molecular resistance testing should be performed, and resistance testing should be repeated if sputum cultures remain positive for M. tuberculosis at or after four months of treatment or become positive again 1 month or longer after culture conversion to negative. Resistance testing for second-line TB medications (including bedaquiline, linezolid, clofazimine, pretomanid, cycloserine, ethionamide, and others) should be limited to specimens with resistance to first-line TB medications and should be performed in reference laboratories with substantial experience in these techniques.” The NIH makes a further stipulation that “isolates with an initial reading of rifampin by commercial NAA test should undergo confirmatory testing (rpoB gene sequencing and phenotypic DST), with results taken into consideration for treatment decisions. Clinicians who suspect drug-resistant TB in a patient with HIV should make every effort to expedite a diagnosis and consult with their state TB program and then the CDC as needed.”⁶⁴

American Thoracic Society, U.S. Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Diseases Society of America (ATS/CDC/ERS/IDSA)
This joint guideline was published to discuss the treatment of drug-resistant tuberculosis. The guideline notes that “molecular DSTs should be obtained for rapid detection of mutations associated with resistance. When rifampin resistance is detected, additional DST should be performed immediately for first-line drugs, fluoroquinolones, and aminoglycosides.” The guideline further stated that “A rapid test for a [sic] least rifampin resistance should ideally be done for every patient, but especially for those at risk of drug resistance.” Individuals who “have or recently had close contact with a patient with infectious DR-TB [drug resistant tuberculosis] especially when the contact is a young child or has HIV infection, are at risk of developing DR-TB.”

The guideline also remarks that if “sputum cultures remain positive after three months of treatment, or if there is bacteriological reversion from negative to positive at any time, DST should be repeated” and that monthly cultures help to “identify early evidence of failure.” Finally, this guideline refers to the above 2017 Lewinsohn guideline as providing “additional details on the optimal use of diagnostic tools and algorithms.”⁶⁵

United States Preventive Services Task Force (USPSTF)
A 2023 recommendation from USPSTF found adequate evidence that accurate screening tests for LTBI are available, that the treatment of LTBI provides a moderate health benefit in preventing progression to active disease, and that the harms of screening and treatment are small. The USPSTF has moderate certainty that screening for LTBI in persons at increased risk for infection provides a moderate net benefit. “This recommendation applies to asymptomatic adults 18 years or older at increased risk for tuberculosis(TB). It does not apply to adults with symptoms of TB or to children and adolescents.”⁶⁶

The USPSTF also notes that to achieve the benefit of this screening, it is important that persons who screen positive for LTBI receive follow-up and treatment. While the USPSTF found no evidence on the optimal frequency of screening for LTBI, in the absence of evidence, they recommend that “a reasonable approach is to repeat screening based on specific risk factors; screening frequency could range from 1-time-only screening among persons at low risk for future TB exposure to annual screening among those who are at continued risk of exposure.”⁶⁶

The USPSTF provides additional information on how to implement their recommendation:

• “Populations at increased risk for LTBI, based on increased prevalence of active disease and increased risk of exposure, include persons who were born in, or are former residents of, countries with high TB prevalence and persons who live in, or have lived in, high-risk congregate settings (e.g., homeless shelters or correctional facilities).
• Clinicians can consult their local or state health departments for more information about populations at increased risk in their community, since local demographic patterns may vary across the US.
• Two types of screening tests for LTBI are currently available in the US: the tuberculin skin test (TST) and the interferon-gamma release assay (IGRA).
  • The TST requires trained personnel to administer intradermal purified protein derivative and interpret the response 48 to 72 hours later.
  • The IGRA requires a single venous blood sample that measures the CD4 T-cell response to specific Mycobacterium tuberculosis antigens and laboratory processing within 8 to 30 hours after collection.
  • Testing with IGRA may have advantages over TST for persons who have received a BCG vaccination, as IGRA does not cross-react with the vaccine, and for persons who may be unlikely to return for TST interpretation.”⁶⁶

The USPSTF provides the following additional information for clinicians to know pertaining to their recommendation:

 

• “TB disproportionately affects Asian, Black, Hispanic/Latino, Native American/Alaska Native, and Native Hawaiian/Pacific Islander persons. Incidence of TB varies by geography and living accommodations, suggesting an association with social determinants of health.
• LTBI is an infection with M tuberculosis in which the bacteria are alive but contained by the immune system. Persons with LTBI have no apparent symptoms, do not feel sick, cannot spread TB to others, and usually have a positive TB skin test or positive TB blood test reaction.
• Active TB or TB disease is an illness in which TB bacteria are multiplying and attacking a part of the body, usually the lungs. TB disease may be symptomatic (including weakness, weight loss, fever, no appetite, chills, sweating at night, bad cough, pain in the chest, or coughing up blood). A person with TB disease may be infectious and spread TB bacteria to others.”⁶⁶

Infectious Diseases Society of America (IDSA)/American Society of Microbiology (ASM)
In the 2024 update to the IDSA/ASM joint guideline, A Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases, concerning Mycobacterium tuberculosis, they recommend AFB smear or AFB culture when performing laboratory diagnosis. They do allow for the use of NAAT for diagnosing M. tuberculosis; however, they state, “A negative result does not rule out Mycobacterium tuberculosis.” They also state “although most molecular tests have excellent sensitivity, a Mycobacterium tuberculosis NAAT test should be an adjunct to a culture and never ordered alone. No current commercial methods are FDA-cleared for these specimens, so laboratories must have validated the test they use.”

In cases of laboratory diagnosis of pulmonary infections in cystic fibrosis due to suspected Mycobacterium spp, they recommend performing a mycobacterial culture from the expectorated sputum, bronchoscopically obtained cultures, or other respiratory cultures.⁶⁷

In the 2024 update to the IDSA/ASM joint guideline, A Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases, concerning Mycobacterium tuberculosis, they recommend AFB smear or AFB culture when performing laboratory diagnosis. They do allow for the use of NAAT for diagnosing M. tuberculosis; however, they state, “A negative result does not rule out Mycobacterium tuberculosis.” They also state “although most molecular tests have excellent sensitivity, a Mycobacterium tuberculosis NAAT test should be an adjunct to a culture and never ordered alone. No current commercial methods are FDA-cleared for these specimens, so laboratories must have validated the test they use.”

In cases of laboratory diagnosis of pulmonary infections in cystic fibrosis due to suspected Mycobacterium spp, they recommend performing a mycobacterial culture from the expectorated sputum, bronchoscopically obtained cultures, or other respiratory cultures.⁶⁷

Committee on Infectious Diseases, American Academy of Pediatrics, 32nd Edition (2021-2024, Red Book)
Highlights from the updated Red Book include the following:

• The AAP notes that there are NAATs cleared by the FDA for detection of M. tuberculosis from smear-positive and smear-negative sputum specimens.
• For children younger than two years, the TST is the preferred method for detection of infection.
• “For children 2 years and older, either TST or IGRA [interferon gamma release assay] can be used, but in people previously vaccinated with BCG, IGRA is preferred to avoid a false-positive TST result caused by a previous vaccination with BCG.”
• Universal testing with either TST or IGRA is discouraged “because it results in either a low yield of positive results or a large proportion of false-positive results, leading to an inefficient use of health care resources.”
• All organ transplant candidates should be given a TST or IGRA before starting immunosuppressive therapy.
• The AAP recommends the following for an “immediate” TST or IGRA:
  • children who are contacts of people with confirmed or suspected contagious tuberculosis (contact investigation)
  • children with clinical or radiographic findings suggesting TB
  • children immigrating from countries with endemic infection (e.g., Asia, Middle East, Africa, Latin America, countries of the former Soviet Union), including international adoptees
  • children with history of significant travel to countries with endemic infection who have substantial contact with the resident population
• The AAP also recommends an annual TST/IGRA for children with HIV.⁶⁸

The AAP also released guidelines on Tuberculosis Infection in Children and Adolescents: Testing and Treatment. Here they recommend:⁶⁹

• “Only children who have a risk factor for TBI or are at risk for progressing to disease, are suspected of having TB disease, or who have an immunosuppressive disease or about to start immunosuppressive therapy should be tested with a TST or an IGRA.
• There is no compelling evidence to support the use of one IGRA (QFT, T-SPOT) over the other.
• If the child of any age has been exposed to an infectious case of TB disease, he or she should be evaluated and, if determined not to have TB disease, given a full course of treatment of TBI if either a TST or IGRA result is interpreted to be positive.
• Even with a negative initial test result, contacts of a person with known TB disease should be retested in 8 to 10 weeks, usually with the same test, regardless of whether the initial test used was a TST or IGRA.”
  • The known incubation period of M. tuberculosis is 8-10 weeks after initial contact.
• “When evaluating a child of any age for TB disease, both a TST and one or both IGRAs can be performed to maximize sensitivity. However, neither method can be used to rule out TB disease, and a negative result of either the TST or an IGRA should be considered especially unreliable in a child younger than 3 months.
• Indeterminate/invalid IGRA results are more common in very young children (younger than 2 years) and immunosuppressed patients. When an IGRA result is indeterminate/invalid, either a repeat IGRA test using the same or the other IGRA can be performed, ensuring proper technique of specimen collection and processing, or a TST can be performed.
• For children without TB risk factors other than foreign birth who have an unexpected low-level positive IGRA result (QFT <1.00 IU/mL, T-SPOT with 5–7 spots), a second diagnostic test, either an IGRA or a TST, should be performed; the child is considered infected only if results of both tests are positive.
• Although IGRAs are more expensive than the TST, their use may be more cost-effective than the TST because of time savings for the family and the elimination of many false-positive results.”⁶⁹

Tuberculosis Network European Trials Group (TBNET)/RESIST-TB
This consensus statement encompasses molecular drug resistance testing for Mycobacterium tuberculosis.

• “Although they do not cover all mutations involved in RMP resistance, molecular methods for RMP could be considered a standard for the diagnostic evaluation of patients with presumptive MDR-TB. In low MDR-TB prevalence countries, physicians should be aware of possible false-positive resistance results of molecular tests, and RMP resistance should be confirmed by a second molecular test on a different sample or by phenotypic tests.”
• “Although >90% of RMP-resistant strains are also resistant to INH, molecular testing for INH drug resistance is important.”
• “In all patients with evidence of M. tuberculosis with a rpoB mutation in a direct specimen or when DST indicates MDR-TB, molecular testing for second-line resistance should be undertaken to guide treatment and to reduce the time to diagnose XDR-TB.”
• “WGS provides the complete sequence information of the bacterial genome. However, due to the lack of correlation with in vitro (phenotypic DST) and in vivo (treatment outcome) data at present, it is not possible to interpret the clinical value of the vast majority of mutations or polymorphisms detected.”
• “The level of discordance between molecular and culture-based DST depends on the drug and the genomic region evaluated. Despite the fact that results of phenotypic methods do not always correspond to response to clinical treatment, culture-based methods are still regarded by most experts involved in this document as the gold standard for DST.”⁷⁰

National Institute for Health and Care Excellence (NICE)
NICE has published guidelines for assessment of TB, which include the following recommendations:

• “If the Mantoux test is positive but a diagnosis of active TB is excluded, consider an interferon gamma release assay if more evidence of infection is needed to decide on treatment.”
• “For adults who are severely immunocompromised, such as those with HIV and CD4 counts of fewer than 200 cells/mm³, or after solid organ or allogeneic stem cell transplant, offer an interferon‑gamma release assay and a concurrent Mantoux test.”
• “For other adults who are immunocompromised, consider an interferon‑gamma release assay alone or an interferon‑gamma release assay with a concurrent Mantoux test. If either test is positive (for Mantoux, this is an induration of 5 mm or larger, regardless of BCG history), assess for active TB.”
• “Only consider using interferon‑gamma release assays alone in children and young people if Mantoux testing is not available or is impractical.”
• “If TB is a possibility, microbiology staff should consider carrying out TB culture on samples, even if it is not requested.”
• “Request rapid diagnostic nucleic acid amplification tests for the M. tuberculosis complex (M. tuberculosis, M. bovis, M. africanum) on primary specimens if there is clinical suspicion of TB disease, and:
  • the person has HIV or
  • rapid information about mycobacterial species would alter the person's care or
  • the need for a large contact‑tracing initiative is being explored.”
• “For people with clinically suspected TB, a TB specialist should request rapid diagnostic nucleic acid amplification tests for rifampicin resistance on primary specimens if a risk assessment for multidrug resistance identifies any of the following risk factors:
  • “history of previous TB drug treatment, particularly if there was known to be poor adherence to that treatment”
  • “contact with a known case of multidrug-resistant TB”
  • “birth or residence in a country in which the World Health Organization reports that a high proportion (5% or more) of new TB cases are multidrug‑resistant.”
• If the rapid diagnostic nucleic acid amplification test for the M. tuberculosis complex is negative in a person at high risk of multidrug‑resistant TB:
  • “obtain further specimens for nucleic acid amplification testing and culture, if possible”
  • “use rapid rifampicin resistance detection on cultures that become positive for the M. tuberculosis complex”
• “If the rapid diagnostic nucleic acid amplification test for rifampicin resistance is positive:
  • “test for resistance to second-line drugs.”⁷¹

European Respiratory Society (ERS) and the European Centre for Disease Prevention and Control (ECDC) Statement: European Union Standards for Tuberculosis Care
This joint guideline was intended to “define the essential level of care for managing patients who have or are presumed to have TB, or are at increased risk of developing the disease.”

• “All patients (adults, adolescents and children who are capable of producing sputum) thought to have pulmonary tuberculosis should have at least two sputum specimens submitted for microscopic examination and one for rapid testing for the identification of tuberculosis and drug resistance using an internationally recommended (rapid) molecular test. The sample should be sent for liquid culture and, if positive, for culture-based drug susceptibility testing (DST) in a quality-assured laboratory.”
• “For all patients (adults, adolescents and children) presumed to have extrapulmonary tuberculosis, appropriate specimens from the suspected sites of involvement should be obtained for microbiological testing (microscopy, rapid molecular tests, culture, species identification, DST with rapid molecular tests and culture-based techniques) and histopathological examination in quality-assured laboratories.”
• “All persons with chest radiographic findings suggestive of pulmonary tuberculosis should have sputum specimens submitted for microscopic examination, rapid molecular tests, culture, species identification and DST with rapid molecular tests and culture-based techniques in a quality-assured laboratory.”⁷²

National Society of Tuberculosis Clinicians (NSTC) of the National Tuberculosis Controllers Association (NTCA)
In 2025, the NSTC of the NTCA jointly released an update to the set of clinical recommendations for “Testing and Treatment of Latent Tuberculosis Infection in the United States.” In relation to testing, the NTSC/NTCA states that “IGRAs are generally preferred, but the TST is acceptable… In choosing which test to use, consider the patient’s history of BCG, age, and ability to return for a second appointment. IGRAs offer greater specificity than a TST in persons who were BCG vaccinated or who have non-tuberculous mycobacterial infections. For this reason, IGRAs are preferred for most non-US-born patients who received, or may have received, BCG vaccination. For other persons, either a TST or IGRA can be used depending on test availability and cost.”

When discussing immunocompromised patients, the organizations stated that “dual testing with TST and an IGRA simultaneously increases the overall specificity for infection.” However, “Dual testing should not be routine, but it may be considered for patients when there is concern about their ability to mount a strong immune response to a test, for persons who are at risk of severe forms of TB disease, or for persons in whom TB infection is strongly suspected because of exposure risks or symptomatology. Children aged <2 years old can be included in a dual testing strategy if one of the above circumstances is present.”

In regard to serial testing, “When serial or periodic testing is required, as with some health care personnel at ongoing risk for TB exposure, either an IGRA or the TST may be used. For TST testing, the initial test should be a two-step TST. Because IGRAs do not cause boosting, serial testing with IGRAs does not require two-step testing to establish a baseline.”

For persons who are “at low risk for TB infection or active TB disease are required to be tested by law for other reasons, use either an IGRA or TST. If the result is positive, perform a second test with the same or a different method to confirm the test result.”

When an MMR vaccine and TB test are both indicated, the Advisory Committee on Immunization Practices recommends:

• “Administer the TST or IGRA simultaneously with the live vaccine (preferred scenario).
• If a TST or IGRA has already been administered, a live vaccine can be administered at any time >1 day after the administration of the TB test.
• If a live vaccine has already been administered, wait at least 28 days before administering a TST or IGRA.
• In two-step testing, wait at least 28 days after the live vaccine is administered before administering the first TST. Continue from there to complete the two-step testing. Wait to administer any additional doses of live vaccine until after the second TST is measured.”

In terms of officially diagnosing latent tuberculosis infection, the NSTC states, “At the completion of pretreatment clinical evaluation, if a patient with a positive test result for TB infection does not have any symptoms of TB, and the CXRs and other diagnostic tests results are normal, then active TB disease is excluded and LTBI is diagnosed.”⁷³

National Psoriasis Foundation (NPF)
In reviewing the literature surrounding immunosuppressive therapies and the risk of tuberculosis, the National Psoriasis Foundation found that “The biologic TNF–α inhibitors are very promising in the treatment of psoriasis. However, because TNF–α is also an important cytokine in preventing TB infection and in keeping latent TB infection from becoming active disease, the use of TNF–α inhibitors has been associated with an increased risk of developing active TB. A higher incidence of TB has also been reported with other immunosuppressive/immunomodulatory treatments for psoriasis. It is, therefore, of utmost importance to appropriately screen all patients for latent TB infection prior to initiating any immunologic therapy. Delaying immunologic therapy until latent TB infection prophylaxis is completed is preferable. However, if the patient is adhering to his prophylactic regimen and is appropriately tolerating the regimen, therapy may be started after one to two months if the clinical condition requires.”⁷⁴ This screening “for latent TB infection before commencement of treatment is of utmost importance when beginning treatment with the tumor necrosis factor–α inhibitors, T-cell blockers, cyclosporine, or methotrexate” and the “currently recommended method for screening is the tuberculin skin test.” However, the authors also acknowledge that “There are few evidence-based studies on screening for latent TB infection in psoriasis patients treated with systemic and biologic agents,” and so the power of the results may be limited.⁷⁴

In 2025 NPF and the International Psoriasis Council released a joint position on routine testing for latent tuberculosis infection prior to and during treatment of psoriasis patients with interleukin 17 or interleukin 23 inhibitors. Here the societies reiterate that “treatment of psoriasis and other immune-mediated inflammatory diseases (IMIDs) with TNF inhibitors can inhibit granuloma formation or function and can promote progression of latent TB infection to active disease. Thus, testing for latent TB infection prior to and during treatment with TNF inhibitors has been an integral and important part of clinical trial designs and clinical practice for decades.” However, they go on to state that clinical data suggest that progression of latent tuberculosis infection to active disease during psoriasis treatment with interleukin-17 or interleukin-23 inhibitors is rare. Therefore, the joint position highlights that “Routine testing for latent tuberculosis infection is not required prior to or during treatment of psoriasis patients with IL-17 or IL-23 inhibitors.”⁷⁵

References  

1.    Lewinsohn DM, Leonard MK, LoBue PA, et al. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. Jan 15 2017;64(2):111-115. doi:10.1093/cid/ciw778

2.    Bernardo J. Diagnosis of pulmonary tuberculosis in adults. Updated July 16, 2026. https://www.uptodate.com/contents/diagnosis-of-pulmonary-tuberculosis-disease-in-adults

3.    Pai M, Flores LL, Hubbard A, Riley LW, Colford JM, Jr. Nucleic acid amplification tests in the diagnosis of tuberculous pleuritis: a systematic review and meta-analysis. BMC infectious diseases. 2004;4:6. doi:10.1186/1471-2334-4-6

4.    Menzies D. Use of interferon-gamma release assays for diagnosis of tuberculosis infection (tuberculosis screening) in adults. Updated April 8, 2026. https://www.uptodate.com/contents/use-of-interferon-gamma-release-assays-for-diagnosis-of-tuberculosis-infection-tuberculosis-screening-in-adults

5.    Pai M, Denkinger CM, Kik SV, et al. Gamma interferon release assays for detection of Mycobacterium tuberculosis infection. Clinical microbiology reviews. 2014;27(1):3-20. doi:10.1128/cmr.00034-13

6.    CDC. Signs and Symptoms of Tuberculosis. Updated January 17, 2025. https://www.cdc.gov/tb/signs-symptoms/index.html

7.    WHO. Global tuberculosis report 2024. 2024. https://iris.who.int/server/api/core/bitstreams/7292c91e-ffb0-4cef-ac39-0200f06961ea/content

8.    Dheda K, Gumbo T, Gandhi NR, et al. Global control of tuberculosis: from extensively drug-resistant to untreatable tuberculosis. The Lancet Respiratory medicine. Apr 2014;2(4):321-38. doi:10.1016/s2213-2600(14)70031-1

9.    Heemskerk D, Caws M, Marais B, Farrar J. Clinical Manifestations. Tuberculosis in Adults and Children. Springer; 2015.

10.  Peto HM, Pratt RH, Harrington TA, LoBue PA, Armstrong LR. Epidemiology of extrapulmonary tuberculosis in the United States, 1993-2006. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2009;49(9):1350-7. doi:10.1086/605559

11.  Dheda K, Schwander SK, Zhu B, van Zyl-Smit RN, Zhang Y. The immunology of tuberculosis: from bench to bedside. Respirology (Carlton, Vic). 2010;15(3):433-50. doi:10.1111/j.1440-1843.2010.01739.x

12.  Barry CE, 3rd, Boshoff HI, Dartois V, et al. The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nature reviews Microbiology. 2009;7(12):845-55. doi:10.1038/nrmicro2236

13.  Landry J, Menzies D. Preventive chemotherapy. Where has it got us? Where to go next? The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease. Dec 2008;12(12):1352-64.

14.  ATS. Targeted tuberculin testing and treatment of latent tuberculosis infection. . American journal of respiratory and critical care medicine. Apr 2000;161(4 Pt 2):S221-47. doi:10.1164/ajrccm.161.supplement_3.ats600

15.  FDA. Summary of Safety and Effectiveness Data. https://www.accessdata.fda.gov/cdrh_docs/pdf/p010033b.pdf

16.  Shafeque A, Bigio J, Hogan CA, Pai M, Banaei N. Fourth-Generation QuantiFERON-TB Gold Plus: What Is the Evidence? Journal of clinical microbiology. Aug 24 2020;58(9)doi:10.1128/jcm.01950-19

17.  Daniel TM. The immunology of tuberculosis. Clinics in chest medicine. 1980;1(2):189-201.

18.  Francis J, Seiler RJ, Wilkie IW, O'Boyle D, Lumsden MJ, Frost AJ. The sensitivity and specificity of various tuberculin tests using bovine PPD and other tuberculins. The Veterinary record. 1978;103(19):420-5.

19.  Katial RK, Hershey J, Purohit-Seth T, et al. Cell-Mediated Immune Response to Tuberculosis Antigens: Comparison of Skin Testing and Measurement of In Vitro Gamma Interferon Production in Whole-Blood Culture. Clin Diagn Lab Immunol. 2001;8(2):339-45. doi:10.1128/cdli.8.2.339-345.2001

20.  Fenton MJ, Vermeulen MW, Kim S, Burdick M, Strieter RM, Kornfeld H. Induction of gamma interferon production in human alveolar macrophages by Mycobacterium tuberculosis. Infection and immunity. 1997;65(12):5149-56.

21.  Lein AD, Von Reyn CF. In vitro cellular and cytokine responses to mycobacterial antigens: application to diagnosis of tuberculosis infection and assessment of response to mycobacterial vaccines. The American journal of the medical sciences. Jun 1997;313(6):364-71.

22.  Menzies D, Pai M, Comstock G. Meta-analysis: new tests for the diagnosis of latent tuberculosis infection: areas of uncertainty and recommendations for research. Annals of internal medicine. 2007;146(5):340-54.

23.  Diel R, Loddenkemper R, Nienhaus A. Predictive value of interferon-gamma release assays and tuberculin skin testing for progression from latent TB infection to disease state: a meta-analysis. Chest. 2012;142(1):63-75. doi:10.1378/chest.11-3157

24.  Ruan Q, Zhang S, Ai J, Shao L, Zhang W. Screening of latent tuberculosis infection by interferon-gamma release assays in rheumatic patients: a systemic review and meta-analysis. Clinical rheumatology. 2016;35(2):417-25. doi:10.1007/s10067-014-2817-6

25.  Auguste P, Tsertsvadze A, Pink J, et al. Comparing interferon-gamma release assays with tuberculin skin test for identifying latent tuberculosis infection that progresses to active tuberculosis: systematic review and meta-analysis. BMC infectious diseases. 2017;17(1):200. doi:10.1186/s12879-017-2301-4

26.  Nasiri MJ, Pormohammad A, Goudarzi H, et al. Latent tuberculosis infection in transplant candidates: a systematic review and meta-analysis on TST and IGRA. Infection. 2019;47(3):353-361. doi:10.1007/s15010-019-01285-7

27.  Khanna U, Ellis A, Gallop J, Galadari A, Hu J, Fernandez AP. AB008. Utility of repeat latent tuberculosis testing in patients with immune-mediated diseases taking biologics. Ann Transl Med. Mar 2021;9(5)doi:10.21037/atm.2021.AB008

28.  Neema S, Radhakrishnan S, Dabbas D, Vasudevan B. Latent Tuberculosis in Psoriasis Patients Planned for Systemic Therapy - A Prospective Observational Study. Indian Dermatol Online J. 2021;12(3):429-432. doi:10.4103/idoj.IDOJ_698_20

29.  Ren W, Ma Z, Li Q, et al. Antigen-specific chemokine profiles as biomarkers for detecting Mycobacterium tuberculosis infection. Front Immunol. 2024;15:1359555. doi:10.3389/fimmu.2024.1359555

30.  Pai M, Nicol MP, Boehme CC. Tuberculosis Diagnostics: State of the Art and Future Directions. Microbiology spectrum. 2016;4(5)doi:10.1128/microbiolspec.TBTB2-0019-2016

31.  Mase SR, Ramsay A, Ng V, et al. Yield of serial sputum specimen examinations in the diagnosis of pulmonary tuberculosis: a systematic review. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease. May 2007;11(5):485-95.

32.  Steingart KR, Ng V, Henry M, et al. Sputum processing methods to improve the sensitivity of smear microscopy for tuberculosis: a systematic review. The Lancet Infectious diseases. 2006;6(10):664-74. doi:10.1016/s1473-3099(06)70602-8

33.  Steingart KR, Henry M, Ng V, et al. Fluorescence versus conventional sputum smear microscopy for tuberculosis: a systematic review. The Lancet Infectious diseases. 2006;6(9):570-81. doi:10.1016/s1473-3099(06)70578-3

34.  Gordin F, Slutkin G. The validity of acid-fast smears in the diagnosis of pulmonary tuberculosis. Archives of pathology & laboratory medicine. 1990;114(10):1025-7.

35.  Yajko DM, Nassos PS, Sanders CA, Madej JJ, Hadley WK. High predictive value of the acid-fast smear for Mycobacterium tuberculosis despite the high prevalence of Mycobacterium avium complex in respiratory specimens. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 1994;19(2):334-6.

36.  Greco S, Girardi E, Navarra A, Saltini C. Current evidence on diagnostic accuracy of commercially based nucleic acid amplification tests for the diagnosis of pulmonary tuberculosis. Thorax. 2006;61(9):783-90. doi:10.1136/thx.2005.054908

37.  Cheng VC, Yew WW, Yuen KY. Molecular diagnostics in tuberculosis. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. 2005;24(11):711-20. doi:10.1007/s10096-005-0039-1

38.  Ling DI, Flores LL, Riley LW, Pai M. Commercial nucleic-acid amplification tests for diagnosis of pulmonary tuberculosis in respiratory specimens: meta-analysis and meta-regression. PloS one. Feb 6 2008;3(2):e1536. doi:10.1371/journal.pone.0001536

39.  CDC. Updated guidelines for the use of nucleic acid amplification tests in the diagnosis of tuberculosis. MMWR Morbidity and mortality weekly report. 2009;58(1):7-10.

40.  Taylor Z, Nolan CM, Blumberg HM. Controlling tuberculosis in the United States. Recommendations from the American Thoracic Society, CDC, and the Infectious Diseases Society of America. MMWR Recommendations and reports : Morbidity and mortality weekly report Recommendations and reports. 2005;54(Rr-12):1-81.

41.  RBS. TB Breathalyser - TB Breath Test. http://www.rapidbiosensor.com/tbbreathalyser

42.  Institute CaLS. Laboratory Detection and Identification of Mycobacteria, 2nd Edition. M48. Wayne, PA: Clinical and Laboratory Standards Institute.; 2018.

43.  Woods GL, Lin S-YG, Desmond EP. Susceptibility Test Methods: Mycobacteria, Nocardia, and Other Actinomycetes. Manual of Clinical Microbiology, Eleventh Edition. ASM; 2015.

44.  Cruciani M, Scarparo C, Malena M, Bosco O, Serpelloni G, Mengoli C. Meta-analysis of BACTEC MGIT 960 and BACTEC 460 TB, with or without solid media, for detection of mycobacteria. Journal of clinical microbiology. 2004;42(5):2321-5.

45.  Bourgi K, Patel J, Samuel L, Kieca A, Johnson L, Alangaden G. Clinical Impact of Nucleic Acid Amplification Testing in the Diagnosis of Mycobacterium Tuberculosis: A 10-Year Longitudinal Study. Open forum infectious diseases. 2017;4(2):ofx045. doi:10.1093/ofid/ofx045

46.  Shah M, Martinson NA, Chaisson RE, Martin DJ, Variava E, Dorman SE. Quantitative analysis of a urine-based assay for detection of lipoarabinomannan in patients with tuberculosis. Journal of clinical microbiology. 2010;48(8):2972-4. doi:10.1128/jcm.00363-10

47.  Nakiyingi L, Moodley VM, Manabe YC, et al. Diagnostic accuracy of a rapid urine lipoarabinomannan test for tuberculosis in HIV-infected adults. Journal of acquired immune deficiency syndromes (1999). 2014;66(3):270-9. doi:10.1097/qai.0000000000000151

48.  Shah M, Hanrahan C, Wang ZY, et al. Lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in HIV-positive adults. The Cochrane database of systematic reviews. 2016;(5):Cd011420. doi:10.1002/14651858.CD011420.pub2

49.  WHO. Guidelines on the Management of Latent Tuberculosis Infection. https://www.ncbi.nlm.nih.gov/books/NBK293809/

50.  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 (London, England). 2018;392(10144):292-301. doi:10.1016/s0140-6736(18)31267-4

51.  De Groote MA, Sterling DG, Hraha T, et al. Discovery and Validation of a Six-Marker Serum Protein Signature for the Diagnosis of Active Pulmonary Tuberculosis. Journal of clinical microbiology. 2017;55(10):3057-3071. doi:10.1128/jcm.00467-17

52.  Heyckendorf J, Andres S, Köser CU, et al. What Is Resistance? Impact of Phenotypic versus Molecular Drug Resistance Testing on Therapy for Multi- and Extensively Drug-Resistant Tuberculosis. Antimicrob Agents Chemother. 2018;62(2)doi:10.1128/aac.01550-17

53.  Ustinova VV, Smirnova TG, Sochivko DG, et al. New assay to diagnose and differentiate between Mycobacterium tuberculosis complex and nontuberculous mycobacteria. Tuberculosis (Edinburgh, Scotland). 2019;114:17-23. doi:10.1016/j.tube.2018.10.004

54.  Adams S, Ehrlich R, Baatjies R, Dendukuri N, Wang Z, Dheda K. Evaluating Latent Tuberculosis Infection Test Performance Using Latent Class Analysis in a TB and HIV Endemic Setting. Int J Environ Res Public Health. Aug 14 2019;16(16)doi:10.3390/ijerph16162912

55.  Zürcher K, Ballif M, Fenner L, et al. Drug susceptibility testing and mortality in patients treated for tuberculosis in high-burden countries: a multicentre cohort study. The Lancet Infectious diseases. 2019;19(3):298-307. doi:10.1016/s1473-3099(18)30673-x

56.  Jain J, Jadhao P, Banait S, Salunkhe P. Diagnostic accuracy of GeneXpert MTB/RIF assay for detection of tubercular pleural effusion. PloS one. 2021;16(6):e0251618. doi:10.1371/journal.pone.0251618

57.  Karthek V, Bhilare P, Hadgaonkar S, et al. Gene Xpert/MTB RIF assay for spinal tuberculosis- sensitivity, specificity and clinical utility. J Clin Orthop Trauma. May 2021;16:233-238. doi:10.1016/j.jcot.2021.02.006

58.  Medina-Marino A, Bezuidenhout D, Bezuidenhout C, et al. In-home TB Testing Using GeneXpert Edge is Acceptable, Feasible, and Improves the Proportion of Symptomatic Household Contacts Tested for TB: A Proof-of-Concept Study. Open forum infectious diseases. 2024;11(6):ofae279. doi:10.1093/ofid/ofae279

59.  Ma Z, Duan S, Wang W, et al. Surveillance of close contacts of patients with infectious tuberculosis: a prospective cohort study. Antimicrobial Resistance & Infection Control. 2024/06/09 2024;13(1):59. doi:10.1186/s13756-024-01419-z

60.  CDC. Clinical Testing and Diagnosis for Tuberculosis. Updated April 17, 2025. https://www.cdc.gov/tb/hcp/testing-diagnosis/index.html

61.  WHO. WHO consolidated guidelines on tuberculosis: Module 3: diagnosis. 2025. https://iris.who.int/server/api/core/bitstreams/ae20e43e-17fd-4951-b475-3e36e166e7ae/content

62.  WHO. Implementing Tuberculosis Diagnostics. https://iris.who.int/bitstream/handle/10665/162712/9789241508612_eng.pdf

63.  WHO. Latent TB Infection : Updated and consolidated guidelines for programmatic management. https://apps.who.int/iris/bitstream/handle/10665/260233/9789241550239-eng.pdf

64.  NIH. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV: Mycobacterium tuberculosis Infection and Disease. https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/mycobacterium-0

65.  Nahid P, Mase SR, Migliori GB, et al. Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline. American journal of respiratory and critical care medicine. 2019;200(10):e93-e142. doi:10.1164/rccm.201909-1874ST

66.  USPSTF, Mangione CM, Barry MJ, et al. Screening for Latent Tuberculosis Infection in Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2023;329(17):1487-1494. doi:10.1001/jama.2023.4899

67.  Miller JM, Binnicker MJ, Campbell S, et al. Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2024 Update by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM). Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2024;doi:10.1093/cid/ciae104

68.  AAP. Red Book® 2021-2024: Report of the Committee on Infectious Diseases, 32nd Edition. 2021.

69.  Nolt D, Starke JR, DISEASES COI. Tuberculosis Infection in Children and Adolescents: Testing and Treatment. Pediatrics. 2021;148(6)doi:10.1542/peds.2021-054663

70.  Domínguez J, Boettger EC, Cirillo D, et al. Clinical implications of molecular drug resistance testing for Mycobacterium tuberculosis: a TBNET/RESIST-TB consensus statement. The International Journal of Tuberculosis and Lung Disease. 2016;20(1):24-42. doi:10.5588/ijtld.15.0221

71.  NICE. Tuberculosis. https://www.nice.org.uk/guidance/ng33/chapter/Recommendations

72.  ERS/ECDC. ERS/ECDC Statement: European Union Standards for Tuberculosis Care - 2017 update https://www.ecdc.europa.eu/sites/default/files/documents/ESTC-leaflet-September-2018.pdf

73.  NSTC. Testing and Treatment of Latent Tuberculosis Infection in the United States. https://tbcontrollers.org/docs/NSTC/LTBI_Clinical_Guide_Feb2025_FINAL.pdf

74.  Doherty SD, Van Voorhees A, Lebwohl MG, et al. National Psoriasis Foundation consensus statement on screening for latent tuberculosis infection in patients with psoriasis treated with systemic and biologic agents. J Am Acad Dermatol. 2008;59(2):209-17. doi:10.1016/j.jaad.2008.03.023

75.  Blauvelt A, Strober BE, Eakin GS, et al. Joint position statement from the National Psoriasis Foundation Medical Board and the International Psoriasis Council on routine testing for latent tuberculosis infection prior to and during treatment of psoriasis patients with interleukin 17 or interleukin 23 inhibitors. Journal of the American Academy of Dermatology. 2026;94(3):802-809. doi:10.1016/j.jaad.2025.11.033

Coding Section

Code	Code Number	Code Description
	86480	Tuberculosis test, cell mediated immunity antigen response measurement; gamma interferon
	86481	Tuberculosis test, cell mediated immunity antigen response measurement; enumeration of gamma interferon-producing T-cells in cell suspension
	87551	Infectious agent detection by nucleic acid (DNA or RNA); Mycobacteria species, amplified probe technique
	87552	Infectious agent detection by nucleic acid (DNA or RNA); Mycobacteria species, quantification
	87556	Infectious agent detection by nucleic acid (DNA or RNA); Mycobacteria tuberculosis, amplified probe technique
	87557	Infectious agent detection by nucleic acid (DNA or RNA); mycobacteria tuberculosis, quantification
	87561	Infectious agent detection by nucleic acid (DNA or RNA); mycobacteria avium-intracellulare, amplified probe technique
	87562	Infectious agent detection by nucleic acid (DNA or RNA); mycobacteria avium-intracellulare, quantification
	87564	Infectious agent detection by nucleic acid (DNA or RNA); Mycobacterium tuberculosis, rifampin resistance, amplified probe technique
	0574U	Mycobacterium tuberculosis, culture filtrate protein–10-kDa (CFP-10), serum or plasma, liquid chromatography mass spectrometry (LC-MS)
ICD-10
	C76.0	Malignant Neoplasm of Head, Face and Neck
	C81.00-C81.99	Hodgkin Lymphoma
	C82.00-C82.99	Follicular Lymphoma Grade I
	C83.00-C83.99	Small Cell B-Cell Lymphoma
	C84.00-C84.99	Cutaneous T-Cell Lymphoma
	C85.10-C85.99	Unspecified B-Cell Lymphoma
	C86.0-C86.6	T-Cell Lymphoma
	C88-C88.9	Waldenstrom Macroglobulinemia
	C90-C90.32	Solitary Plasmacytoma
	C91.00-C91.92	Acute Lymphoblastic Leukemia
	C92.00-C92.92	Acute Myeloblastic Leukemia
	C93.00-C93.92	Chronic Myelomonocytic Leukemia
	C94.00-C94.82	Acute Erythroid Leukemia
	C95.00-C95.92	Acute Leukemia of Unspecified Cell Type
	E08.00-E08.9	Diabetes Mellitus Due to Underlying Conditions
	E09.00-E09.9	Drug or chemical Induced Diabetes Mellitus
	E10.10-E10.9	Type 1 Diabetes Mellitus
	E11.00-E11.9	Type 2 Diabetes Mellitus
	E13.00-E13.9	Other Specified Diabetes Mellitus
	F11.10-F11.99	Opioid Abuse
	F13.10-F13.99	Sedative, Hypnotic or Anxiolytic Abuse
	F14.10-F14.99	Cocaine Abuse
	F15.10-F15.99	Other Stimulant Abuse
	F16.10-F16.99	Hallucinogen Abuse
	F17.210-F17.219	Nicotine Dependence
	F19.10-F19.99	Other Psychoactive Substance Abuse
	J62.8	Pneumoconiosis Due to other Dust containing Silica
	K50.00-K50.919	Crohn’s Disease
	M05.00-M06.9	Felty’s Syndrome
	M08.20-M08.99	Unspecified Juvenile Rheumatoid Arthritits
	N17.0-N17.9	Acute Kidney Failure
	N18.4	Chronic Kidney Disease, Stage 4 (Severe)
	N18.5	Chronic Kidney Disease, Stage 5
	N18.6	End State Renal Disease
	N19	Unspecified Kidney Failure
	R05.1	Acute Cough
	R05.2	Subacute Cough
	R05.3	Chronic Cough
	R05.4	Cough Syncope
	R05.8	Other Specified Cough
	R05.9	Cough, Unspecified
	Z02.89	Encounter for Other Administrative Examinations
	Z59.0	Homelessness
	Z68.1	Body Mass Index (BMI) 19.9 or Less, Adult
	Z68.20	Body Mass Index (BMI) 20.0 – 20.9, Adult
	Z72.0	Tobacco Use
	Z79.52	Long Term (Current) Use of Systemic Steroids
	Z79.899	Other Long Term (Current) Drug Therapy
	Z92.21	Personal History of Antineoplastic Chemotherapy
	Z92.241	Personal History of Systemic Steroid Therapy
	Z92.25	Personal History of Immunosuppression Therapy
	Z99.2	Dependence on Renal Dialysis

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community,  and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2013 Forward          

10/23/2026	Annual review, updating policy for clarity and consisitency. Adding disclaimer prior to coverage criteria, frequency of testing for routine screening and for those with exposure, and adding notes. Also updating description, table of terminology, rationale, and references. Removing CPT codes 81099, 81425, 81426, 81479, 82945, 83520, 83615, 84157, 84311, 87070, 87077, 87116, 87150, 87153, 87181, 87182, 87183, 87184, 87186 and deleted CPT code 87185.
01/15/2026	Added new CPT code 87182 effective 01/01/2026. No other changes made.
01/14/2026	Added new CPT code 87183 effective 01/01/2026
10/06/2025	Annual review, removing direct probe testing from coverage criteria as direct probe testing is no longer recommended. Also updating background, table of terminology, rationale and references. Remvoing CPT codes 87149, 87550, 87555, 87560.
06/12/2025	Added CPT code 0574U effective 07/01/2025.
01/22/2025	Added CPT code 87564 effective 01/01/2025
10/08/2024	Annual review, no change to policy intent. Updating table of terminology, rationale and references.
10/26/2023	Annual review, no change to policy intent. Entire policy updated for clarity and consistency.
11/07/2022	Annual review, no change to policy intent. Policy reformatted for clarity. Updating rationale and references. Adding table of terminology.)
10/19/2021	Annual review, removing 5 years or older language regarding testing. Also updating description, background, rationale and references. Also updating coding (adding multiple ICD 10 codes).
10/02/2020	Annual review. Updating policy to include verbiage regarding repeat drug susceptibility testing. Also updating description, rationale, references and coding.
10/23/2019	Annual review, no change to policy intent. Reformatting for clarity. Updating coding.
09/24/2019	Updated coding. No other changes made
11/12/2018	Annual review with extensive revision. Policy is being expanded to address active tuberculosis in addition to latent tuberculosis. Policy and coding sections revised to include criteria for active tuberculosis testing and coding. Intent for latent tuberculosis testing is unchanged.
11/16/2017	Correct typo in policy section.
11/02/2017	Annual review, no change to policy intent, however policy verbiage re-written for clarity and specificity.
04/26/2017	Updated category to Laboratory. No other changes.
11/07/2016	Annual review, adding clarifying language to the policy section.
09/19/2016	Annual review, no change to policy intent.
09/21/2015	Added ICD-10 codes.
11/06/2014	Annual review, no change to policy intent. Added policy guideline and coding.
11/01/2013	Annual Review. Added Benefit Application and Rationale.