Xpert MTB/RIF: a game changer for the diagnosis of pulmonary tuberculosis in children?
Authors: Annelies Van Rie
Journal: The Lancet Global Health (2013)

The diagnosis of pulmonary tuberculosis in young children is challenging because clinical and radiological features are often non-specific.1Nicol MP Zar HJ New specimens and laboratory diagnostics for childhood pulmonary TB: progress and prospects.Peadiatr Respir Rev. 2011; 12: 16-21Summary Full Text Full Text PDF PubMed Scopus (120) Google Scholar Achieving a definite diagnosis through microbiological confirmation is especially problematic in this population owing to the typically low bacillary burden and the difficulty in obtaining a quality respiratory specimen. For adults, WHO has endorsed a single Xpert MTB/RIF assay for initial diagnosis, especially in people with HIV and in those with suspected drug-resistant tuberculosis.2WHO Policy statement: automated real-time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB/RIF system. World Health Organization, Geneva, Switzerland2011Google Scholar A consensus has not yet been reached on the value of the Xpert MTB/RIF assay for the diagnosis of pulmonary tuberculosis in young children. Xpert MTB/RIF has been shown to give a rapid diagnosis on induced sputum,3Nicol MP Workman L Isaacs W et al.Accuracy of the Xpert MTB/RIF test for the diagnosis of pulmonary tuberculosis in hospitalized children in a high HIV-prevalence are.Lancet Infect Dis. 2011; 11: 819-824Summary Full Text Full Text PDF PubMed Scopus (263) Google Scholar, 4Sekadde MP Wobudeya E Joloba ML et al.Evaluation of the Xpert MTB/RIF test for the diagnosis of childhood pulmonary tuberculosis in Uganda: a cross-sectional diagnostic study.BMC Infect Dis. 2013; 12: 133Crossref Scopus (61) Google Scholar nasopharyngeal aspirate,5Zar HJ Workman L Isaacs W et al.Rapid molecular diagnosis of pulmonary tuberculosis in children using nasopharyngeal specimens.Clin Infect Dis. 2012; 55: 1088-1095Crossref PubMed Scopus (124) Google Scholar and gastric aspirate6Bates M O'Grady J Maeurer M et al.Assessment of the Xpert MTB/RIF assay for diagnosis of tuberculosis with gastric lavage aspirates in children in sub-Saharan Africa: a prospective descriptive study.Lancet Infect Dis. 2013; 13: 36-42Summary Full Text Full Text PDF PubMed Scopus (114) Google Scholar samples in about 70% of children in hospital with culture-confirmed tuberculosis. Most children with suspected tuberculosis, however, present to primary care clinics with less severe disease. In this context, in The Lancet Global Health, Heather Zar and colleagues report findings from the first study to assess the accuracy of Xpert MTB/RIF in young children presenting to a primary-care facility with symptoms of pulmonary tuberculosis.7Zar HJ Workman L Isaacs W Dheda K Zemanay W Nicol MP Raid diagnosis of pulmonary tuberculosis in African children in a primary care setting using Xpert MTB/RIF on respiratory specimens: a prospective study.Lancet Glob Health. 2013; 1: e98-105Summary Full Text Full Text PDF Scopus (74) Google Scholar Primary analysis was done in 309 children in whom four samples (two induced sputum samples and two nasopharyngeal aspirates) could be collected. On the first induced sputum sample, Xpert MTB/RIF assay detected 12 of 28 culture-confirmed cases, and on the first nasopharyngeal aspirate sample, it detected eight of 28 culture-confirmed cases. Tests on repeat samples improved the sensitivity of Xpert MTB/RIF to 16 of 28 culture-confirmed cases on two induced sputum samples and 11 of 28 culture-confirmed cases on two nasopharyngeal aspirate samples. On the basis of these results, the investigators suggest that Xpert MTB/RIF on two specimens should be recommended in children with suspected tuberculosis. At an estimated cost of US$26·5 per assay in South Africa (excluding the costs of biospecimen collection),8Schnippel K Meyer-Rath G Long L et al.Scaling up Xpert MTB/RIF technology: the costs of laboratory vs clinic-based roll-out in South Africa.Trop Med Int Health. 2012; 17: 1142-1145Crossref PubMed Scopus (52) Google Scholar two Xpert MTB/RIF assay on induced sputum samples would have diagnosed 16 cases of pulmonary tuberculosis at a cost of $1025 per patient diagnosed. Doing Xpert MTB/RIF on two nasopharyngeal aspirate samples, which might be more feasible in most resource-poor settings because it does not require access to electricity or oxygen, would have diagnosed 11 cases at a cost of $1491 per person diagnosed. Whether repeat sampling (induced sputum, nasopharyngeal aspirate, or both) should become the initial diagnostic for paediatric tuberculosis in low-income countries thus becomes an important question. Zar and colleagues state that studies of cost efficacy of repeated specimens in children are needed. A decision to endorse this strategy should also be guided by the ability of the Xpert MTB/RIF assay to affect the management of patients. The diagnostic thought process usually starts with the generation of a differential diagnosis, followed by estimation of the pre-test probability, performance of a diagnostic test, and estimation of a post-test probability. Health-care workers generally start treatment when the post-test probability exceeds a threshold. When a negative test result decreases the post-test probability low enough to refute the hypothesis, health-care workers rule out the diagnosis and assess the next diagnostic hypothesis.9Sox HCJ Blatt MA Higgins MC Marton KI Medical Decision Making. Butterworth-Heinemann, Boston, MA1988Google Scholar In Zar and colleagues' study, tuberculosis treatment was started in 180 (47%) of 384 participating children. Of all children started on treatment, almost 90% were Xpert-MTB/RIF-negative, suggesting that the Xpert MTB/RIF results did not substantially change health-care workers' pre-test assessment of the probability of children having tuberculosis. The possibility that the strategy of empirical treatment for paediatric tuberculosis will change in the near future is unlikely in view of the absence of a reference standard against which new diagnostics for paediatric tuberculosis can be reliably assessed. What reasoning could determine whether one or two induced sputum or nasopharyngeal aspirate samples are obtained for Xpert MTB/RIF in young children in high-burden, low-income countries? Zar and colleagues' included only 31 children with HIV, restricting the ability to assess the value of Xpert MTB/RIF stratified by HIV status. An alternative to Xpert MTB/RIF for the diagnosis of tuberculosis in young children in primary care could be the use of the urine lipoarabinomannan assay. Although this assay has been shown to be useful in adults with severe immunosuppression,10Lawn SD Kerkhoff AD Vogt M Wood R Clinical significance of lipoarabinomannan detection in urine using a low-cost point-of-care diagnostic assay for HIV-associated tuberculosis.AIDS. 2012; 26: 1635-1643Crossref PubMed Scopus (58) Google Scholar no data have been published on its performance in children with HIV. The most compelling reason might be the suspicion of drug-resistant tuberculosis. In such cases, rapid knowledge of the presence of rifampicin resistance can inform which children should receive extended treatment with potentially toxic second-line drugs. Despite the crucial need for rapid, accurate, and affordable diagnostics for pulmonary tuberculosis in young children, it seems unlikely that Xpert MTB/RIF will be the game changer that high-burden countries are desperately waiting for. I declare that I have no conflicts of interest.