Mortality in childhood tuberculosis: has there been progress?

Childhood tuberculosis is usually a curable disease. Many cases can be prevented with chemotherapy and BCG vaccination. WHO estimates that, in 2015, 1 million children younger than 15 years got tuberculosis, and 210 000 died as a result of the disease.1

How can this be?

WHO estimates that only about a third of cases of childhood tuberculosis are notified to national tuberculosis programmes.1 This low proportion is explained only partly by the difficulty in confirming clinically diagnosed childhood tuberculosis with microscopy, PCR, or culture. Accurate estimates of the incidence and mortality of childhood tuberculosis have been notoriously difficult to obtain. The first attempt was in 2012, when WHO estimated 490 000 cases of tuberculosis and 64 000 deaths in children without HIV. 2 WHO’s report also delineated the necessary steps to create more accurate estimates, including improved case detection and reporting to national tuberculosis programmes, and validated statistical methods. Since then, several modelling studies have helped to inform WHO estimates of morbidity and mortality 3,4 and the burden of tuberculosis infection in children, which might be as high as 100 million. 4,5

In this issue of The Lancet Infectious Diseases, Helen E Jenkins and colleagues 6 used strict inclusion criteria (and recognised potential study limitations) to analyse the results of published series and other datasets containing 82 436 children with tuberculosis and compare mortality from childhood tuberculosis between the pre-treatment, pre-BCG vaccine era (ie, before 1946) and modern times (ie, after 1980). They showed that, in the pre-treatment era, the pooled case fatality ratio was 21·9% (95% CI 18·1–26·4), and was significantly higher in children aged 0–4 years than in those aged 5–14 years (43·6% [95% CI 36·8–50·6] vs 14·9% [11·5–19·1]). By contrast, in studies since 1980, in which most included children had access to treatment, the pooled case fatality ratio was 0·9% (95% CI 0·5–1·6) and only 2·0% (95% CI 0·5–7·4%) in children aged 0–4 years. On the basis of less robust data, they showed that the case fatality ratio for children with tuberculosis and HIV before widespread access to antiretroviral therapy was 14·3% (95% CI 7·4–24·1), compared with 3·4% (95% CI 0·7–9·6) for those with access to antiretroviral therapy.

In view of Jenkins and colleagues’ study, further analysis of the childhood morbidity and mortality data in the WHO 2016 Global Tuberculosis Report is highly disturbing (table).1 The pooled case fatality ratio is 22%, almost identical to that determined by Jenkins and colleagues in the pre-chemotherapy era. There are vast differences between the regions, with the case fatality ratio ranging from 2% in Europe to 34% in Africa (table). Africa has the second highest morbidity (numerically), the highest case fatality ratio, and the highest proportion of deaths in children with HIV. By contrast, the southeast Asia region has the highest morbidity and second highest case fatality ratio, but a low proportion of deaths in children with HIV. Clearly, the epidemiology of childhood tuberculosis, including case rates by age, varies between regions, and different control strategies will be necessary. However, such variations do not explain all the differences. Why are some regions and countries lagging so far behind?

The major problem is that a large proportion of cases of childhood tuberculosis are not being detected and thus children are dying untreated. Tuberculosis diagnosis and management is lacking in many childhood HIV and malnutrition programmes, two conditions known to be major risk factors for childhood tuberculosis.7,8 Maternal and child health programmes in countries with high burdens of tuberculosis are just beginning to include tools for tuberculosis detection and prevention. Clinical and autopsy studies 9 demonstrate that, in regions with high tuberculosis burdens, many cases of childhood tuberculosis are misdiagnosed as acute severe pneumonia. Many national tuberculosis programmes do not have a comprehensive plan for childhood tuberculosis, and treatment of vulnerable household contacts does not occur. Regions with the highest mortality generally have the lowest proportion of children younger than 5 years who are contacts to cases receiving preventive therapy (table), an activity that is recommended by WHO and highly effective in preventing tuberculosis disease and mortality.

Better diagnostic tests and a more effective vaccine are needed, but the number of childhood tuberculosis cases and deaths could be substantially and rapidly decreased with available and inexpensive tools and strategies that can be applied anywhere, such as screening for tuberculosis symptoms, reporting of clinically defined cases, provision of the new, child-friendly tuberculosis drugs, and provision of preventive therapy to household contacts. The Roadmap for Childhood Tuberculosis 10 outlined the principles for addressing the disease, many of which are also included in the WHO End TB Strategy. Although the End TB Strategy emphasises patient centred care, to address the disease in children, family centred care is essential. The solutions ultimately will be local, so national tuberculosis programmes need to develop plans and provide resources for this effort. What is needed most is the political will within the tuberculosis community to finally address the needs of children.

1 WHO. Global Tuberculosis Report 2016. Geneva: World Health Organization, 2016.

2 WHO. Global Tuberculosis Report 2012. Geneva: World Health Organization, 2012.

3 Jenkins HE, Tolman AW, Yuen CM, et al. Incidence of multidrug-resistant tuberculosis disease in children: systematic review and global estimates. Lancet 2014; 383: 1572–79.

4 Dodd 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: e453–59.

5 Houben RM, Dodd PJ. The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling. PLoS Med 2016; 13: e1002152.

6 Jenkins HE, Yuen CM, Rodriguez CA, et al. Mortality among children diagnosed with tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis 2016; published online Dec 5. http://dx.doi.org/10.1016/ S1473-3099(16)30474-1.

7 Baliff M, Renner L, Dusingize JC, et al. Tuberculosis in pediatric antiretroviral therapy programs in low- and middle-income countries: diagnosis and screening practices. J Pediatr Infect Dis Soc 2015; 4: 30–38.

8 Bhat PG, Kumar AM, Naik B, et al. Intensifi ed tuberculosis case fi nding among malnourished children in nutritional rehabilitation centres of Karnataka, India: missed opportunities. PLoS One 2013; 8: e84255.

9 Oliwa JN, Karumbi JM, Marais BJ, Madhi SA, Graham SM. Tuberculosis as a cause or comorbidity of childhood pneumonia in tuberculosis-endemic areas: a systematic review. Lancet Respir Med 2015; 3: 235–43.

10 WHO. Roadmap for childhood tuberculosis. Geneva: World Health Organization, 2013.