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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mashal Awais, M.D.[2];Sophia Saad, Associate Editor - WikiDoc [3] Alejandro Lemor, M.D. [4]

Other Diagnostic Studies

This microchapter covers the non-imaging diagnostic studies used to confirm tuberculosis, identify drug resistance, and support extrapulmonary diagnosis: sputum smear microscopy, mycobacterial culture (the reference standard), molecular WHO-recommended rapid diagnostics (mWRDs — Xpert MTB/RIF, Xpert Ultra, Truenat), phenotypic and molecular drug-susceptibility testing (DST) including targeted next-generation sequencing (tNGS), body-fluid adenosine deaminase (ADA), urine lipoarabinomannan (LAM) in HIV, and the immune-based tests (TST, IGRA) used for infection rather than disease. Current guidelines recommend a rapid molecular test as the initial diagnostic test in anyone with presumptive pulmonary TB; culture remains mandatory for confirmation and phenotypic DST; and universal rapid rifampin-resistance testing should accompany initial diagnosis.[1][2]

Sputum Smear Microscopy (AFB)

The ATS/IDSA/CDC 2017 guideline recommends AFB smear microscopy in all patients with suspected pulmonary TB (strong recommendation, moderate-quality evidence), using concentrated specimens and fluorescence (LED) microscopy, with three specimens the US norm to offset poor sample quality.[1] Smear neither confirms nor excludes TB: false negatives and false positives (nontuberculous mycobacteria) are both common, and smear correlates chiefly with infectiousness/transmission risk.[1] Smear sensitivity is especially poor in children (0–10%).[3] WHO no longer recommends smear as an initial diagnostic test where an mWRD is available, though it retains a role in treatment monitoring.[3]

Mycobacterial Culture (Reference Standard)

Culture is the microbiologic gold standard and is required for definitive diagnosis, species identification, and phenotypic DST.[1] Both liquid and solid culture are suggested for every specimen (conditional, low-quality evidence); at minimum liquid culture should be performed on all specimens.[1] The key limitation is turnaround — growth and subsequent phenotypic DST can take more than 2 weeks.[1]

mWRDs are the frontline confirmatory tests. WHO and ATS/IDSA/CDC recommend performing a NAAT on the initial respiratory specimen from patients with suspected pulmonary TB.[1][2]

  • Xpert MTB/RIF detects M. tuberculosis complex DNA and rpoB mutations conferring rifampin resistance in <2 hours with minimal biosafety requirements. Pooled sensitivity/specificity against culture are ~85%/98%; sensitivity falls to ~79% in people with HIV, largely reflecting paucibacillary/smear-negative disease.[4][5][6]
  • Xpert Ultra is the more sensitive successor. Cochrane high-certainty estimates for Xpert Ultra are sensitivity ~90.7% / specificity ~94.8% (2025 update; 32 studies), versus 84.7% / 98.4% for Xpert MTB/RIF in the earlier head-to-head review; the sensitivity advantage is greatest in smear-negative and HIV-associated disease. Both detect rifampin resistance with sensitivity/specificity ~95%/99%. Ultra sensitivity and specificity are both lower in patients with a prior history of TB, where DNA from dead bacilli produces false/"trace" positives — such results warrant phenotypic confirmation.[7][2][4]
  • Truenat MTB / MTB Plus (chip-based, battery-operated, decentralized) is WHO-recommended as an initial test since 2020 (conditional, moderate certainty), with reflex Truenat MTB-RIF Dx for rifampin resistance (conditional, very low certainty). Head-to-head accuracy approximates Xpert, but with higher invalid (~6%) and RIF-indeterminate rates offset by lower cost, supporting a tiered deployment strategy.[2][3][8]

mWRD (Xpert Ultra) sensitivity on extrapulmonary specimens is lower and site- and reference-standard–dependent: against a microbiological reference, summary sensitivity/specificity are ~88%/96% for CSF, ~74%/88% for pleural fluid, and ~71%/97% for lymph node aspirate; sensitivity for rifampicin resistance on extrapulmonary specimens is high (~100%/99%). Ultra is more sensitive than Xpert MTB/RIF across sites, and neither test can rule out extrapulmonary or meningeal TB. Neither Xpert nor Xpert Ultra can rule out tuberculous meningitis; both have insufficient negative predictive value in CSF. Large-volume, centrifuged CSF improves yield (pooled Ultra sensitivity ~93% concentrated vs ~81% unconcentrated), and 30–50% of patients must be treated empirically on clinical, CSF, and neuroimaging grounds pending culture.[9][10]

Drug-Susceptibility Testing (DST)

WHO endorses universal rapid rifampin-resistance testing at diagnosis for all presumptive TB.[2] Rapid molecular DST (Xpert, line-probe assays) detects rifampin resistance with sensitivity/specificity >97% and can confirm or exclude rifampin resistance in respiratory specimens; for isoniazid, sensitivity ~90% and specificity ~99% means it can confirm but not exclude resistance.[1] Because positive predictive value for rifampin resistance is low where drug resistance is uncommon (e.g., much of the US), the ATS/IDSA/CDC guideline reserves initial rapid molecular DST for higher-risk subgroups (prior TB treatment, birth/residence in a country with TB incidence ≥20/100,000 or primary MDR ≥2%, MDR contacts, HIV).[1] Culture-based phenotypic DST remains the reference and is performed whenever M. tuberculosis is isolated.[1] For resistance beyond rifampin, the WHO-endorsed Xpert MTB/XDR assay rapidly detects isoniazid, fluoroquinolone, ethionamide, and second-line injectable (amikacin/kanamycin/capreomycin) resistance and can bridge the interval between initial rifampin testing and tNGS or phenotypic DST. Specificity is high (>98%) for all targets, but sensitivity is high only for isoniazid (~94%) and fluoroquinolones (~94%) and is substantially lower for ethionamide (~54%, inhA-promoter only) and the injectables (~61–86%) — so a negative result for those drugs does not exclude resistance.[11][12]

Targeted next-generation sequencing (tNGS) was endorsed by WHO in March 2024 and is positioned in the 2025 WHO consolidated guidelines as a reflex test following an initial positive automated NAAT, performed directly on clinical specimens without culture. It provides simultaneous resistance prediction across first- and second-line drugs, interpreted against the WHO mutation catalogue. Accuracy is high for rifampin, isoniazid, fluoroquinolones, and injectables, but remains lower/less mature for bedaquiline (sensitivity ~68%) and linezolid (~69%), and phenotypic DST is still required for pretomanid/delamanid and when tNGS fails (~10% of paucibacillary samples). Whole-genome sequencing gives comprehensive profiling but generally requires cultured isolates.[13][14][15]

Adenosine Deaminase (ADA) and Free IFN-γ in Body Fluids

ADA is a supportive (not confirmatory) test for serosal/meningeal TB and is recommended by ATS/IDSA/CDC in pleural, peritoneal, pericardial, and CSF fluid (conditional, low-quality evidence).[1] Approximate meta-analytic performance: pleural sensitivity/specificity 89–99%/88–97% (thresholds clustering ~40 U/L); pericardial 88%/83%; peritoneal high; CSF 79%/91% (threshold-dependent).[1] Diagnostic value is threshold-driven — a low pleural cutoff (e.g., <30 U/L) is useful to exclude TB (high NPV), whereas a high cutoff (≥60 U/L) supports empiric treatment pending culture.[16] Free IFN-γ in pleural/peritoneal fluid has higher specificity (≥97%).[1][17] These markers must be interpreted alongside fluid chemistry, NAAT, culture, and histopathology.[17]

Urine Lipoarabinomannan (LAM) in HIV

Urine LAM is a point-of-care, non-sputum antigen test whose sensitivity increases as CD4 count falls — the reverse of sputum tests. WHO recommends it in people with HIV who are seriously ill, hospitalized with advanced disease, or have CD4 <200 (inpatient) or <100 (outpatient).[18] The original LF-LAM (Alere Determine) has limited sensitivity (~52% inpatient, ~29% outpatient) but reduces mortality when incorporated into inpatient algorithms in RCTs.[18] The newer Fujifilm SILVAMP TB-LAM (FujiLAM) is substantially more sensitive (pooled ~63%, up to ~76–87% at CD4 ≤100) with specificity ~90%.[19][20] Disseminated NTM disease can cause false positives.[18] Combining urine LAM with sputum (or urine) Xpert Ultra raises inpatient diagnostic yield to ~71–73%.[18][21]

Immune-Based Tests for Infection (TST and IGRA)

TST and IGRAs detect immune sensitization to M. tuberculosis and are used to diagnose latent infection — they cannot distinguish LTBI from active disease and cannot monitor treatment.[22] USPSTF-pooled estimates: TST sensitivity 60–81% (threshold-dependent) with specificity 95–99%; IGRA sensitivity 81–90% with specificity 95–99%.[23][24] IGRAs are unaffected by BCG and are preferred in BCG-vaccinated adults; TST remains acceptable. (Detailed screening indications are covered in the Screening microchapter.)[22]

Clinical Recommendations

  • Obtain an mWRD (Xpert Ultra or Truenat) on the initial respiratory specimen in all suspected pulmonary TB, plus at least liquid culture on every specimen for confirmation and phenotypic DST.[1][2]
  • Perform universal rapid rifampin-resistance testing at diagnosis; in low-resistance settings, interpret a positive rifampin result cautiously (low PPV) and confirm with phenotypic/molecular DST.[1][2]
  • In a smear-positive patient, a negative NAAT makes TB unlikely (consider NTM); in a smear-negative patient with intermediate–high suspicion, a positive NAAT is presumptive TB but a negative NAAT does not exclude it.[1]
  • In prior-TB patients, treat a positive Ultra/"trace" result with caution and confirm with culture/phenotypic testing.[7][2]
  • Send tNGS (reflex after positive NAAT) or refer isolates for the CDC MDDR service when drug resistance is suspected, to guide regimen selection for BPaL/BPaLM-era drugs.[13][25]
  • For suspected serosal/meningeal TB, send fluid ADA (and free IFN-γ where available) with cell count/chemistry, plus NAAT, culture, and biopsy/histology.[1][17]
  • In people with HIV with advanced immunosuppression, add urine LAM and combine with sputum/urine Xpert Ultra.[18]

High-Yield Clinical Pearls

  • A negative NAAT in a smear-positive patient should prompt consideration of NTM, not reassurance.[6]
  • Urine LAM sensitivity rises as CD4 falls — the opposite of sputum-based tests.[18]
  • Rifampin resistance on molecular testing is a surrogate for MDR-TB only where rifampin monoresistance is rare.[1]
  • Pleural ADA <30 U/L helps rule out TB; ≥60 U/L supports empiric treatment pending culture.[16]
  • Always obtain culture even when the mWRD is positive — it is required for phenotypic DST and species confirmation.[1]

Common Pitfalls

  • Using a single negative NAAT to exclude TB in a patient with moderate–high clinical suspicion.[1]
  • Acting on a positive rapid rifampin-resistance result in a low-prevalence population without confirmatory DST (low PPV).[1]
  • Interpreting a positive Ultra result in a recently treated patient as active disease without phenotypic confirmation.[2]
  • Treating ADA or IGRA/TST as confirmatory — ADA is supportive, and TST/IGRA diagnose infection, not disease.[1][22]
  • Omitting urine LAM in seriously ill inpatients with advanced HIV.[18]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 Lewinsohn DM, Leonard MK, LoBue PA; et al. (2017). "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. 64 (2): e1–e33. doi:10.1093/cid/ciw694.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 Inbaraj LR, Daniel J, Sathya Narayanan MK; et al. (2025). "Truenat MTB Assays for Pulmonary Tuberculosis and Rifampicin Resistance in Adults and Adolescents". The Cochrane Database of Systematic Reviews. 3: CD015543. doi:10.1002/14651858.CD015543.pub2.
  3. ↑ 3.0 3.1 3.2 Kay AW, Madison M, Scandrett K; et al. (2025). "Xpert MTB/RIF Ultra Assay for Tuberculosis Disease and Rifampicin Resistance in Children". The Cochrane Database of Systematic Reviews. 10: CD013359. doi:10.1002/14651858.CD013359.pub4.
  4. ↑ 4.0 4.1 Shapiro AE, Ross JM, Yao M; et al. (2021). "Xpert MTB/RIF and Xpert Ultra Assays for Screening for Pulmonary Tuberculosis and Rifampicin Resistance in Adults, Irrespective of Signs or Symptoms". The Cochrane Database of Systematic Reviews. 3: CD013694. doi:10.1002/14651858.CD013694.pub2.
  5. ↑ Field SK, Escalante P, Fisher DA, Ireland B, Irwin RS (2018). "Cough Due to TB and Other Chronic Infections: CHEST Guideline and Expert Panel Report". Chest. 153 (2): 467–497. doi:10.1016/j.chest.2017.11.018.
  6. ↑ 6.0 6.1 Benson C, Brooks J, Dhanireddy S; et al. (2026). "Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents With HIV". Office of AIDS Research Advisory Council.
  7. ↑ 7.0 7.1 Horne DJ, Zifodya JS, Shapiro AE; et al. (2025). "Xpert MTB/RIF Ultra Assay for Pulmonary Tuberculosis and Rifampicin Resistance in Adults and Adolescents". The Cochrane Database of Systematic Reviews. 7: CD009593. doi:10.1002/14651858.CD009593.pub6.
  8. ↑ Sidiq Z, Anand A, Dwivedi KK; et al. (2026). "Diagnostic Accuracy, Operational Feasibility, and Cost Considerations of Truenat MTB Plus and Xpert MTB/RIF Ultra for Pulmonary Tuberculosis". PloS One. 21 (7): e0341988. doi:10.1371/journal.pone.0341988.
  9. ↑ Kohli M, Inbaraj LR, Salomon A; et al. (2025). "Low‐complexity automated nucleic acid amplification tests for extrapulmonary tuberculosis and rifampicin resistance in adults and adolescents". The Cochrane Database of Systematic Reviews. 8: CD012768. doi:10.1002/14651858.CD012768.pub4.
  10. ↑ Donovan J, Cresswell FV, Tucker EW; et al. (2026). "A Clinical Practice Guideline for Tuberculous Meningitis". The Lancet Infectious Diseases. 26 (2): e96–e111. doi:10.1016/S1473-3099(25)00364-0.
  11. ↑ Penn-Nicholson A, Georghiou SB, Ciobanu N; et al. (2022). "Detection of Isoniazid, Fluoroquinolone, Ethionamide, Amikacin, Kanamycin, and Capreomycin Resistance by the Xpert MTB/XDR Assay: A Cross-Sectional Multicentre Diagnostic Accuracy Study". The Lancet Infectious Diseases. 22 (2): 242–249. doi:10.1016/S1473-3099(21)00452-7.
  12. ↑ Pillay S, Steingart KR, Davies GR; et al. (2022). "Xpert MTB/XDR for Detection of Pulmonary Tuberculosis and Resistance to Isoniazid, Fluoroquinolones, Ethionamide, and Amikacin". The Cochrane Database of Systematic Reviews. 5: CD014841. doi:10.1002/14651858.CD014841.pub2.
  13. ↑ 13.0 13.1 Durairaj E, Rajbongshi J, Vincent M (2026). "Performance of Next-Generation Sequencing Technologies for Detecting Drug-Resistant Tuberculosis in People With Pulmonary Tuberculosis". The Cochrane Database of Systematic Reviews. 7: CD016368. doi:10.1002/14651858.CD016368.
  14. ↑ Schwab TC, Perrig L, Göller PC; et al. (2024). "Targeted Next-Generation Sequencing to Diagnose Drug-Resistant Tuberculosis: A Systematic Review and Meta-Analysis". The Lancet Infectious Diseases. 24 (10): 1162–1176. doi:10.1016/S1473-3099(24)00263-9.
  15. ↑ Naidoo K, Perumal R, Cox H; et al. (2024). "The Epidemiology, Transmission, Diagnosis, and Management of Drug-Resistant Tuberculosis—Lessons From the South African Experience". The Lancet Infectious Diseases. 24 (9): e559–e575. doi:10.1016/S1473-3099(24)00144-0.
  16. ↑ 16.0 16.1 Boscals de Réals Q, Françoise U, Vignier N, Delacour H, Méchaï F (2025). "Diagnostic Performance of Adenosine Deaminase for Extrapulmonary Tuberculosis in a Higher-Prevalence Area of Mainland France: A 10-Year Retrospective Study". Infection. doi:10.1007/s15010-025-02579-9.
  17. ↑ 17.0 17.1 17.2 Miller JM, Binnicker MJ, Campbell S; et al. (2024). "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. doi:10.1093/cid/ciae104.
  18. ↑ 18.0 18.1 18.2 18.3 18.4 18.5 18.6 Meintjes G, Maartens G (2024). "HIV-Associated Tuberculosis". The New England Journal of Medicine. 391 (4): 343–355. doi:10.1056/NEJMra2308181.
  19. ↑ Taye B, Tesfaye H, Churiso G (2025). "FujiLAM Assays for Tuberculosis Detection in People With HIV: A Systematic Review and Meta-Analysis". BMC Infectious Diseases. 25 (1): 1710. doi:10.1186/s12879-025-12055-2.
  20. ↑ Broger T, Nicol MP, Székely R; et al. (2020). "Diagnostic Accuracy of a Novel Tuberculosis Point-of-Care Urine Lipoarabinomannan Assay for People Living With HIV: A Meta-Analysis of Individual in- And Outpatient Data". PLoS Medicine. 17 (5): e1003113. doi:10.1371/journal.pmed.1003113.
  21. ↑ Stead D, Wasserman S, Steenkamp E; et al. (2025). "Comparative Performance of Urine Lipoarabinomannan and Urine Xpert MTB/RIF Ultra for Diagnosing Tuberculosis in Adult Inpatients With HIV in East London, South Africa". Clinical Infectious Diseases. 81 (4): e146–e152. doi:10.1093/cid/ciaf080.
  22. ↑ 22.0 22.1 22.2 Shah M, Dorman SE (2021). "Latent Tuberculosis Infection". The New England Journal of Medicine. 385 (24): 2271–2280. doi:10.1056/NEJMcp2108501.
  23. ↑ US Preventive Services Task Force, Mangione CM, Barry MJ; et al. (2023). "Screening for Latent Tuberculosis Infection in Adults: US Preventive Services Task Force Recommendation Statement". JAMA. 329 (17): 1487–1494. doi:10.1001/jama.2023.4899.
  24. ↑ Jonas DE, Riley SR, Lee LC; et al. (2023). "Screening for Latent Tuberculosis Infection in Adults". JAMA. 329 (17): 1495–1509. doi:10.1001/jama.2023.3954.
  25. ↑ Nahid P, Mase SR, Migliori GB; et al. (2019). "Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline". American Journal of Respiratory and Critical Care Medicine. 200 (10): e93–e142. doi:10.1164/rccm.201909-1874ST.

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