Abstract

Extrapulmonary tuberculosis (EPTB) remains diagnostically difficult because disease manifestations are heterogeneous, affected sites may be inaccessible and most clinical specimens are paucibacillary. No single investigation performs consistently across all anatomical forms. Rapid molecular assays can provide early detection of Mycobacterium tuberculosis complex and rifampicin resistance, but their sensitivity varies markedly by specimen type and a negative result cannot exclude disease. Culture remains essential for recovery of viable bacilli and phenotypic drug-susceptibility testing, whereas cytology and histopathology demonstrate tissue response and help identify alternative diagnoses. Biochemical, antigen and immune-based tests are useful only in defined settings, and imaging is most valuable for localisation, complication assessment and image-guided sampling. This Short Communication proposes a pragmatic specimen-centred approach: establish clinical probability and urgency, identify the highest-yield sampling target, divide representative material before formalin fixation and perform molecular testing, microscopy, culture and pathology in parallel. Results should then be integrated with pre-test probability, specimen quality and disease severity. This multimodal strategy reduces diagnostic delay, preserves opportunities for resistance testing and avoids over-reliance on any single negative assay

• 1.   World Health Organization. Global tuberculosis report 2025. Geneva: World Health Organization; 2025. Available from: https:// www.who.int/teams/global-programmeon-tuberculosis-and-lung-health/tb-reports/ global-tuberculosis-report-2025
• 2.   World Health Organization. WHO consolidated guidelines on tuberculosis: module 3: diagnosis. Geneva: World Health Organization; 2025. ISBN 978-92-4-010798- 4. Available from: https://www.who.int/ publications/i/item/9789240107984
• 3.   World Health Organization. WHO operational handbook on tuberculosis: module 3: diagnosis. Geneva: World Health Organization; 2025. ISBN 978-92-4-011099-1. Available from: https://www.who.int/publications/i/ item/9789240110991
• 4.   Pai M, Behr MA, Dowdy D, Dheda K, Divangahi M, Boehme CC, et al. Tuberculosis. Nat Rev Dis Primers. 2016;2:16076. https:// doi.org/10.1038/nrdp.2016.76
• 5.   Jain R, Gupta G, Mitra D, Guleria R. Diagnosis of extra pulmonary tuberculosis: an update on novel diagnostic approaches. Respir Med. 2024;225:107601. https://doi.org/10.1016/j. rmed.2024.107601
• 6.   Sharma SK, Ryan H, Khaparde S, Sachdeva KS, Singh AD, Mohan A, et al. Index-TB guidelines: guidelines on extrapulmonary tuberculosis for India. Indian J Med Res. 2017;145(4):448-463. https://doi.org/10.4103/ijmr.IJMR_1950_16
• 7.   Purohit M, Mustafa T. Laboratory diagnosis of extra-pulmonary tuberculosis in resourceconstrained settings: state of the art, challenges and the need. J Clin Diagn Res. 2015;9(4):EE01- EE06. https://doi.org/10.7860/JCDR/2015/ 12422.5792
• 8.   Parsons LM, Somoskövi A, Gutierrez C, Lee E, Paramasivan CN, Abimiku A, et al. Laboratory diagnosis of tuberculosis in resource-poor countries: challenges and opportunities. Clin Microbiol Rev. 2011;24(2):314-350. https://doi. org/10.1128/CMR.00059-10
• 9.   Kohli M, Inbaraj LR, Salomon A, Scandrett K, Korobitsyn A, Ismail N, et al. Low-complexity automated nucleic acid amplification tests for extrapulmonary tuberculosis and rifampicin resistance in adults and adolescents. Cochrane Database Syst Rev. 2025;8:CD012768. https:// doi.org/10.1002/14651858.CD012768.pub4
• 10.   Denkinger CM, Schumacher SG, Boehme CC, Dendukuri N, Pai M, Steingart KR. Xpert MTB/ RIF assay for the diagnosis of extrapulmonary tuberculosis: a systematic review and metaanalysis. Eur Respir J. 2014;44(2):435-446. https://doi.org/10.1183/09031936.0000781439 JMRR / Volume 12 Number 1 / January - June 2026
• 11.   Sehgal IS, Dhooria S, Aggarwal AN, Behera D, Agarwal R. Diagnostic performance of Xpert MTB/RIF in tuberculous pleural effusion: systematic review and meta-analysis. J Clin Microbiol. 2016;54(4):1133-1136. https://doi. org/10.1128/JCM.03205-15
• 12.   Aggarwal AN, Agarwal R, Dhooria S, Prasad KT, Sehgal IS, Muthu V. Xpert MTB/RIF Ultra versus Xpert MTB/RIF for diagnosis of tuberculous pleural effusion: a systematic review and comparative meta-analysis. PLoS One. 2022;17(7):e0268483. https://doi. org/10.1371/journal.pone.0268483
• 13.   Bahr NC, Nuwagira E, Evans EE, Cresswell FV, Bystrom PV, Byamukama A, et al. Diagnostic accuracy of Xpert MTB/RIF Ultra for tuberculous meningitis in HIV-infected adults: a prospective cohort study. Lancet Infect Dis. 2018;18(1):68-75. https://doi.org/10.1016/ S1473-3099(17)30474-7
• 14.   Cresswell FV, Tugume L, Bahr NC, Kwizera R, Bangdiwala AS, Musubire AK, et al. Xpert MTB/RIF Ultra for the diagnosis of HIV-associated tuberculous meningitis: a prospective validation study. Lancet Infect Dis. 2020;20(3):308-317. https://doi.org/10.1016/ S1473-3099(19)30550-X
• 15.   Donovan J, Thu DDA, Phu NH, Dung VTM, Quang TP, Nghia HDT, et al. Xpert MTB/RIF Ultra versus Xpert MTB/RIF for the diagnosis of tuberculous meningitis: a prospective, randomised, diagnostic accuracy study. Lancet Infect Dis. 2020;20(3):299-307. https://doi. org/10.1016/S1473-3099(19)30649-8
• 16.   Schwab TC, Perrig L, Göller PC, Guebely de la Hoz FF, Lahousse AP, Minder B, et al. Targeted next-generation sequencing to diagnose drug-resistant tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis. 2024;24(10):1162-1176. https://doi. org/10.1016/S1473-3099(24)00263-9
• 17.   Aggarwal AN, Agarwal R, Sehgal IS, Dhooria S. Adenosine deaminase for diagnosis of tuberculous pleural effusion: a systematic review and meta-analysis. PLoS One. 2019;14(3):e0213728. https://doi.org/10.1371/ journal.pone.0213728
• 18.   Aggarwal AN, Agarwal R, Dhooria S, Prasad KT, Sehgal IS, Muthu V. Unstimulated pleural fluid interferon gamma for diagnosis of tuberculous pleural effusion: a systematic review and meta-analysis. J Clin Microbiol. 2021;59(5):e02112-20. https://doi. org/10.1128/JCM.02112-20 19. Fan L, Chen Z, Hao XH, Hu ZY, Xiao HP. Interferon-gamma release assays for the diagnosis of extrapulmonary tuberculosis: a systematic review and meta-analysis. FEMS Immunol Med Microbiol. 2012;65(3):456-466. https://doi.org/10.1111/j.1574-695X.2012. 00972.x
• 20.   Bjerrum S, Schiller I, Dendukuri N, Kohli M, Nathavitharana RR, Zwerling AA, et al. Lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in people living with HIV. Cochrane Database Syst Rev. 2019;10:CD011420. https://doi. org/10.1002/14651858.CD011420.pub3
• 21.   Peter JG, Zijenah LS, Chanda D, Clowes P, Lesosky M, Gina P, et al. Effect on mortality of point-of-care, urine-based lipoarabinomannan testing to guide tuberculosis treatment initiation in HIV-positive hospital inpatients: a pragmatic, parallel-group, multicountry, open-label, randomised controlled trial. Lancet. 2016;387(10024):1187-1197. https:// doi.org/10.1016/S0140-6736(15)01092-2
• 22.   MacLean E, Broger T, Yerlikaya S, FernandezCarballo BL, Pai M, Denkinger CM. A systematic review of biomarkers to detect active tuberculosis. Nat Microbiol. 2019;4(5):748-758. https://doi.org/10.1038/s41564-019-0380-2
• 23.   Rodriguez-Takeuchi SY, Renjifo ME, Medina FJ. Extrapulmonary tuberculosis: pathophysiology and imaging findings. Radiographics. 2019;39(7):2023-2037. https:// doi.org/10.1148/rg.2019190109
• 24.   Baykan AH, Sayiner HS, Aydin E, Koc M, Inan I, Erturk SM. Extrapulmonary tuberculosis: an old but resurgent problem. Insights Imaging. 2022;13:39. https://doi.org/10.1186/s13244- 022-01172-0
• 25.   Allan-Blitz LT, Yarbrough C, Ndayizigiye M, Wade C, Goldsmith AJ, Duggan NM, et al. Point-of-care ultrasound for diagnosing extrapulmonary tuberculosis: a systematic review. Int J Tuberc Lung Dis. 2024;28(5):217- 224. https://doi.org/10.5588/ijtld.23.0471

Data Sharing Statement

Funding