Abstract
The fact that almost half of the 1 million cases of childhood tuberculosis (TB) globally remain undiagnosed jeopardizes the TB elimination goal. Fortunately, there are new advances in this field which have the potential to bridge this diagnostic gap. Advances in imaging include computer assisted interpretation of chest X-rays (CXRs), point of care ultrasound (POCUS) and faster and superior computed tomography/ magnetic resonance imaging (CT/ MRI) protocols. The urine lipoarabinomannan test has proved to be a good point of care test for diagnosing TB in Human immunodeficiency virus (HIV) infected children. Stool and nasopharyngeal aspirates are emerging as acceptable alternatives for gastric lavage and induced sputum for diagnosing intrathoracic tuberculosis. Xpert MTB/RIF Ultra has improved sensitivity compared to Xpert MTB/RIF for diagnosing both pulmonary/ extrapulmonary TB. Xpert XDR is another commercially available accurate point of care test for detecting resistance to drugs other than rifampicin in smear positive samples. Other molecular methods including new line probe assays, pyrosequencing, whole genome sequencing, and targeted next generation sequencing are extremely promising but not available commercially at present. The C-Tb skin test is an acceptable alternative to the tuberculin skin test and interferon gamma release assays for diagnosis of latent infection. There is an urgent need to incorporate some of these advances in the existing diagnostic algorithms of childhood TB.
Similar content being viewed by others
References
Global Tuberculosis Report 2022. Geneva: World Health Organization. 2022. Available at: https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2022. Accessed on 28 Nov 2023.
The END TB Strategy. Global Strategy and Targets for Tuberculosis Prevention, Care and Control after 2015. Geneva: World Health Organization. 2014. Available at: https://www.who.int/tb/strategy/End_TB_Strategy.pdf. Accessed on 28 Nov 2023.
Roadmap Towards Ending TB in Children and Adolescents, Second edition. Geneva: World Health Organization. 2018. Available at: https://apps.who.int/iris/handle/10665/275422. Accessed on 28 Nov 2023.
Wobudeya E, Bonnet M, Walters EG, et al. Diagnostic advances in childhood tuberculosis—improving specimen collection and yield of microbiological diagnosis for intrathoracic tuberculosis. Pathogens. 2022;11:389.
Kontsevaya I, Cabibbe AM, Cirillo DM, et al. Update on the diagnosis of tuberculosis. Clin Microbiol Infect. 2023. https://doi.org/10.1016/j.cmi.2023.07.014.
Vaezipour N, Fritschi N, Brasier N, et al. Towards accurate point-of-care tests for tuberculosis in children. Pathogens. 2022;11:327.
Vonasek B, Ness T, Takwoingi Y, et al. Screening tests for active pulmonary tuberculosis in children. Cochrane Database Syst Rev. 2021;6:CD013693.
Brooks MB, Hussain H, Siddiqui S, et al. Two clinical prediction tools to inform rapid tuberculosis treatment decision-making in children. Open Forum Infect Dis. 2023;10:ofad245.
Zimmer AJ, Ugarte-Gil C, Pathri R, et al. Making cough count in tuberculosis care. Commun Med (Lond). 2022;2:83.
WHO. Chest Radiography in Tuberculosis Detection, 2016. Available at: https://apps.who.int/iris/bitstream/handle/10665/252424/9789241511506-eng.pdf?sequence=1. Accessed on 21 Nov 2023.
Qin ZZ, Ahmed S, Sarker MS, et al. Tuberculosis detection from chest x-rays for triaging in a high tuberculosis-burden setting: an evaluation of five artificial intelligence algorithms. Lancet Digit Health. 2021;3:e543–54.
World Health Organization. WHO Consolidated Guidelines on Tuberculosis. Module 5: Management of Tuberculosis in Children and Adolescents, 2022. Available at: https://iris.who.int/bitstream/handle/10665/352522/9789240046764-eng.pdf?sequence=1. Accessed on 20 Nov 2023.
Concepcion NDP, Laya BF, Andronikou S, Abdul Manaf Z, Atienza MIM, Sodhi KS. Imaging recommendations and algorithms for pediatric tuberculosis: Part 1-thoracic tuberculosis. Pediatr Radiol. 2023;53:1773–81.
Jain SK, Andronikou S, Goussard P, et al. Advanced imaging tools for childhood tuberculosis: Potential applications and research needs. Lancet Infect Dis. 2020;20:e289–97.
Wang B, Li M, Ma H, et al. Computed tomography-based predictive nomogram for differentiating primary progressive pulmonary tuberculosis from community-acquired pneumonia in children. BMC Med Imaging. 2019;19:63.
Ruby LC, Heuvelings CC, Grobuch MP, et al. Transthoracic mediastinal ultrasound in childhood tuberculosis: a review. Paediatr Respir Rev. 2022;41:40–8.
Sodhi KS, Khandelwal N, Saxena AK, et al. Rapid lung MRI in children with pulmonary infections: Time to change our diagnostic algorithms. J Magn Reson Imaging. 2016;43:1196–206.
Landge AA, Singhal T. Etiology of fever of unknown origin in children from Mumbai. India Indian Pediatr. 2018;55:71–2.
Seid G, Alemu A, Tsedalu T, Dagne B. Value of urine-based lipoarabinomannan (LAM) antigen tests for diagnosing tuberculosis in children: Systematic review and meta-analysis. IJID Reg. 2022;4:97–104.
Peter JG, Zijenah LS, Chanda D, et al. Effect on mortality of point-of-care, urine-based lipoarabinomannan testing to guide tuberculosis treatment initiation in HIV-positive hospital inpatients: a pragmatic, parallel-group, multicountry, open-label, randomised controlled trial. Lancet. 2016;387:1187–97.
World Health Organization. Lateral Flow Urine Lipoarabinomannan Assay (LF-LAM) for the Diagnosis of Active Tuberculosis in People Living with HIV. Policy Update. 2019. Available at: https://iris.who.int/bitstream/handle/10665/329479/9789241550604-eng.pdf?sequence=1. Accessed on 20 Nov 2023.
World Health Organization. WHO Consolidated Guidelines on Tuberculosis. Module 3: Diagnosis. Tests for Tuberculosis Infection, 2022. Available at: https://iris.who.int/bitstream/handle/10665/362936/9789240056084-eng.pdf?sequence=1. Accessed on 20 Nov 2023.
Ruhwald M, Aggerbeck H, Gallardo RV, et al. Safety and efficacy of the C-Tb skin test to diagnose Mycobacterium tuberculosis infection, compared with an interferon γ release assay and the tuberculin skin test: a phase 3, double-blind, randomised, controlled trial. Lancet Respir Med. 2017;5:259–68.
Aggerbeck H, Ruhwald M, Hoff ST, et al. C-Tb skin test to diagnose Mycobacterium tuberculosis infection in children and HIV-infected adults: a phase 3 trial. PLoS One. 2018;13:e0204554.
Mesman AW, Rodriguez C, Ager E, Coit J, Trevisi L, Franke MF. Diagnostic accuracy of molecular detection of Mycobacterium tuberculosis in pediatric stool samples: a systematic review and meta-analysis. Tuberculosis (Edinb). 2019;119:101878.
Cox H, Workman L, Bateman L, et al. Oral swabs tested with Xpert MTB/RIF Ultra for diagnosis of pulmonary tuberculosis in children: a diagnostic accuracy study. Clin Infect Dis. 2022;75:2145–52.
Chow F, Espiritu N, Gilman RH, et al. La cuerda dulce–a tolerability and acceptability study of a novel approach to specimen collection for diagnosis of paediatric pulmonary tuberculosis. BMC Infect Dis. 2006;6:67.
Williams CM, Abdulwhhab M, Birring SS, et al. Exhaled Mycobacterium tuberculosis output and detection of subclinical disease by face-mask sampling: Prospective observational studies. Lancet Infect Dis. 2020;20:607–17.
Shaikh A, Sriraman S, Vaswani S, et al. SMaRT-PCR sampling with mask and reverse transcriptase PCR, a promising non-invasive diagnostic tool for paediatric pulmonary tuberculosis. medRxiv (preprint). 2023. https://doi.org/10.1101/2023.06.17.23291480.
MacLean E, Kohli M, Weber SF, et al. Advances in molecular diagnosis of tuberculosis. J Clin Microbiol. 2020;58:e01582–19.
Yadav R, Daroch P, Gupta P, et al. Evaluation of TB-LAMP assay for detection of Mycobacterium tuberculosis in children. Infect Dis (Lond). 2021;53:942–6.
Signorino C, Votto M, De Filippo M, Marseglia GL, Galli L, Chiappini E. Diagnostic accuracy of Xpert ultra for childhood tuberculosis: a preliminary systematic review and meta-analysis. Pediatr Allergy Immunol. 2022;33:80–2.
Shen Y, Yu G, Zhao W, Lang Y. Efficacy of Xpert MTB/RIF Ultra in diagnosing tuberculosis meningitis: a systematic review and meta-analysis. Medicine (Baltimore). 2021;100:e26778.
Pillay S, Steingart KR, Davies GR, et al. Xpert MTB/XDR for detection of pulmonary tuberculosis and resistance to isoniazid, fluoroquinolones, ethionamide, and amikacin. Cochrane Database Syst Rev. 2022;5:CD014841.
Kohli M, MacLean E, Pai M, Schumacher SG, Denkinger CM. Diagnostic accuracy of centralized assays for TB detection and detection of resistance to rifampicin and isoniazid: a systematic review and meta-analysis. Eur Respir J. 2021;57:2000747.
Meehan CJ, Goig GA, Kohl TA, et al. Whole genome sequencing of Mycobacterium tuberculosis: Current standards and open issues. Nat Rev Microbiol. 2019;17:533–45.
Walker TM, Cruz ALG, Peto TE, et al. Tuberculosis is changing. Lancet Infect Dis. 2017;17:359–61.
Mahomed S, Naidoo K, Dookie N, et al. Whole genome sequencing for the management of drug-resistant TB in low-income high TB burden settings: Challenges and implications. Tuberculosis. 2017;107:137–43.
World Health Organization. Catalogue of Mutations in Mycobacterium tuberculosis Complex and their Association with Drug Resistance. 2021. Available at: https://iris.who.int/bitstream/handle/10665/341981/9789240028173-eng.pdf?sequence=1. Accessed on 23 Nov 2023.
Genoscreen. Deeplex® Myc-TB: From Clinical Samples to Drug Resistance Profile. Lille, France: Genoscreen. 2019. Available at: https://www.genoscreen.fr/en/genomic-services/products/deeplex-myc-tb. Accessed on 23 Nov 2023.
Ajbani K, Kazi M, Agrawal U, et al. Evaluation of CSF pyrosequencing to diagnose tuberculous meningitis: a retrospective diagnostic accuracy study. Tuberculosis (Edinb). 2021;126:102048.
Jin W, Pan J, Miao Q, et al. Diagnostic accuracy of metagenomic next-generation sequencing for active tuberculosis in clinical practice at a tertiary general hospital. Ann Transl Med. 2020;8:1065.
Xing XW, Zhang JT, Ma YB, et al. Metagenomic next-generation sequencing for diagnosis of infectious encephalitis and meningitis: a large, prospective case series of 213 patients. Front Cell Infect Microbiol. 2020;10:88.
Anderson ST, Kaforou M, Brent AJ, et al. Diagnosis of childhood TB in high TB/HIV burden African countries by host RNA expression. N Engl J Med. 2014;370:1712–23.
Yu G, Shen Y, Ye B, et al. Diagnostic accuracy of Mycobacterium tuberculosis cell-free DNA for tuberculosis: a systematic review and meta-analysis. PLoS One. 2021;16:e0253658.
Pollock NR, MacIntyre AT, Blauwkamp TA, et al. Detection of Mycobacterium tuberculosis cell-free DNA to diagnose TB in pediatric and adult patients. Int J Tuberc Lung Dis. 2021;25:403–5.
Author information
Authors and Affiliations
Contributions
Both authors contributed to drafting and finalization of the manuscript. TS will act as guarantor for this manuscript.
Corresponding author
Ethics declarations
Conflict of Interest
None.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Rodrigues, C., Singhal, T. What is New in the Diagnosis of Childhood Tuberculosis?. Indian J Pediatr (2024). https://doi.org/10.1007/s12098-023-04992-0
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s12098-023-04992-0