Tuberculosis in children: under-counted and under-treated
Authors: Emily A Kendall
Journal: The Lancet Global Health (2017)

Tuberculosis is the number one infectious cause of death worldwide1Global Tuberculosis Report 2016. World Health Organization, Geneva2016http://www.who.int/tb/publications/global_report/en/Google Scholar but remains underappreciated as a cause of morbidity and mortality in children. Because many children have difficulty expectorating sputum and because paediatric tuberculosis is usually pauci-bacillary and often extra-pulmonary, paediatric tuberculosis is especially difficult to diagnose with standard sputum-based assays. Predicted associations between paediatric and adult tuberculosis burden2Dodd PJ Gardiner E Coghlan R Seddon JA Burden of childhood tuberculosis in 22 high-burden countries: a mathematical modelling study.Lancet Glob Health. 2014; 2: e453-e459Summary Full Text Full Text PDF PubMed Scopus (267) Google Scholar, 3Jenkins HE Tolman AW Yuen CM et al.Incidence of multidrug-resistant tuberculosis disease in children: systematic review and global estimates.Lancet. 2014; 383: 1572-1579Summary Full Text Full Text PDF PubMed Scopus (214) Google Scholar place paediatric incidence at 10% of total global tuberculosis incidence, but tuberculosis notification rates (already inadequate in adults) are lowest in children, with roughly 40% of incident cases in children younger than 15 years having been diagnosed and notified in 2015.1Global Tuberculosis Report 2016. World Health Organization, Geneva2016http://www.who.int/tb/publications/global_report/en/Google Scholar Vital registries often attribute deaths from undiagnosed paediatric tuberculosis to other causes such as pneumonia, meningitis, or AIDS, and because standard approaches to quantifying causes of child mortality rely on such registries, tuberculosis' full child mortality burden—including the burden of undiagnosed paediatric tuberculosis—is likely to be under-represented in resulting estimates of global burden of disease. In The Lancet Global Health, Peter Dodd and colleagues4Dodd PJ Yuen CM Sismanidis C Seddon JA Jenkins HE The global burden of tuberculosis mortality in children: a mathematical modelling study.Lancet Glob Health. 2017; 5: e898-e906Summary Full Text Full Text PDF PubMed Scopus (192) Google Scholar took a new approach to the estimation of paediatric tuberculosis mortality that combined estimated tuberculosis incidence rates in children—stratified by age, HIV, and tuberculosis treatment status—with systematic review-based estimates of case fatality ratios for each case type. The resulting estimates of child tuberculosis deaths do not rely on diagnostic assays known to perform poorly in children, nor on routinely-collected cause-of-death data in which undiagnosed childhood tuberculosis is almost certain to be under-represented. Using their incidence-based approach, the researchers concluded that tuberculosis causes about 239 000 deaths (95% CI 194 000–298 000) in children younger than 15 years every year. This result is somewhat higher than WHO's most recent estimate of 210 000 annual deaths (170 000–241 000),1Global Tuberculosis Report 2016. World Health Organization, Geneva2016http://www.who.int/tb/publications/global_report/en/Google Scholar yet remarkably consistent in view of the very different methodological approaches: WHO's estimate was based on vital registry and mortality survey data, with adjustments for under-diagnosis and under-reporting, whereas more than 90% of the child tuberculosis deaths estimated by Dodd and colleagues occurred in untreated children (in whom tuberculosis was unlikely to have been recognised as the cause of death). Thus, as long as under-detection is accounted for, multiple approaches lead to the same conclusion that the mortality burden of tuberculosis in children is high. Of particular significance is the investigators' estimate of global tuberculosis mortality in children younger than 5 years, which as they note places tuberculosis among the top ten causes of death in that age group. Moreover, on a regional level, their estimated under-5 tuberculosis mortality rates are on par with adult tuberculosis mortality rates1Global Tuberculosis Report 2016. World Health Organization, Geneva2016http://www.who.int/tb/publications/global_report/en/Google Scholar in all regions except Africa, and far exceed adult rates in the Western Pacific region. These results suggest that the broader global health community—in whose rankings of causes of under-5 mortality tuberculosis appears near the bottom5GBD 2015 Child Mortality CollaboratorsGlobal, regional, national, and selected subnational levels of stillbirths, neonatal, infant, and under-5 mortality, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015.Lancet Lond Engl. 2016; 388: 1725-1774Summary Full Text Full Text PDF PubMed Scopus (460) Google Scholar or not at all6Liu L Oza S Hogan D et al.Global, regional, and national causes of under-5 mortality in 2000-15: an updated systematic analysis with implications for the Sustainable Development Goals.Lancet Lond Engl. 2016; 388: 3027-3035Summary Full Text Full Text PDF PubMed Scopus (1723) Google Scholar, 7WHO and Maternal and Child Epidemiology Estimation GroupChild Mortality Estimates: Global and regional child deaths by cause.http://data.unicef.orgDate: 2015Google Scholar—has severely underestimated the true burden of paediatric tuberculosis. And because most children who die of tuberculosis do so without treatment, while children whose tuberculosis is promptly diagnosed and treated tend to do well, under-diagnosis of paediatric tuberculosis is the main driver of this mortality burden. Therefore, these estimates should motivate the ongoing development of better methods for detecting or preventing cases of paediatric tuberculosis, while also compelling health systems to make better use of existing diagnostic and case-finding options. On the diagnostic front, case detection can improve if clinicians are sufficiently aware of paediatric tuberculosis to consider it as a possible cause of syndromes from pneumonia to fever to adenitis, and if they then pursue a systematic diagnostic evaluation.8Roya-Pabon CL Perez-Velez CM Tuberculosis exposure, infection and disease in children: a systematic diagnostic approach.Pneumonia Nathan Qld. 2016; 8: 23Crossref PubMed Google Scholar Bacteriological confirmation of tuberculosis is also poised to improve in view of this year's introduction of the more-sensitive Xpert MTB/RIF Ultra cartridge, which can detect tuberculosis in most extra-pulmonary and paediatric pulmonary specimens and therefore promises particular benefit for paediatric patients.9WHOWHO Meeting Report of a Technical Expert Consultation: Non-inferiority analysis of Xpert Mtuberculosis/RIF Ultra compared to Xpert Mtuberculosis/RIF.http://www.who.int/tb/publications/2017/XpertUltra/en/Date: 2017Google Scholar However, the detection of tuberculosis in more children sick enough to seek medical care should not be the only strategy pursued. Because paediatric tuberculosis disproportionately results from recent and within-household transmission,10Marais BJ Gie RP Schaaf HS et al.The natural history of childhood intra-thoracic tuberculosis: a critical review of literature from the pre-chemotherapy era.Int J Tuberc Lung Dis Off J Int Union Tuberc Lung Dis. 2004; 8: 392-402PubMed Google Scholar, 11Middelkoop K Bekker L-G Morrow C Lee N Wood R Decreasing household contribution to tuberculosis transmission with age: a retrospective geographic analysis of young people in a South African township.BMC Infect Dis. 2014; 14: 221Crossref PubMed Scopus (37) Google Scholar contact investigations have especially high yield for child contacts, with the added benefit of facilitating early treatment or preventive treatment before significant morbidity develops. Yet household contact investigation remains severely under-utilised in most high-burden settings.1Global Tuberculosis Report 2016. World Health Organization, Geneva2016http://www.who.int/tb/publications/global_report/en/Google Scholar The large mortality burden of undiagnosed paediatric tuberculosis should therefore spur not hopelessness, but action; these new estimates identify a prime opportunity to address an under-recognised and preventable cause of child deaths. The full elimination of paediatric tuberculosis mortality will require better diagnostic technology, along with crucial advances in treatment and vaccination. However, in the meantime, more consistent preventive treatment for children exposed to tuberculosis and more persistent assessment of potential paediatric tuberculosis cases can go a long way in reducing the mortality burden. EAK is supported by National Institutes of Health award 1K08AI127908-01. The funding source had no role in the writing or publication of the manuscript. The global burden of tuberculosis mortality in children: a mathematical modelling studyTuberculosis is a top ten cause of death in children worldwide and a key omission from previous analyses of under-5 mortality. Almost all these deaths occur in children not on tuberculosis treatment, implying substantial scope to reduce this burden. Full-Text PDF Open Access