HIV co-infection increases mortality risk in younger children with TB

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Without adequate treatment, children with tuberculosis, especially those younger than five years, are at high risk of death, while children with HIV have an increased mortality risk, even when receiving TB treatment.

“Given that so many children with [TB] are never diagnosed, estimation of childhood [TB] mortality presents unique challenges,” Dr Helen E Jenkins, from the department of biostatistics at the Boston University School of Public Health, and colleagues wrote. “Cohort studies from the past three decades have included very few children who did not receive [TB] treatment. Mortality … estimates often rely on vital registration data, but attribution of deaths to undiagnosed [TB] posthumously is hampered by autopsy costs and the unreliability of vital record and verbal autopsy.”

To provide better comprehension of the mortality risks associated with TB among children, Jenkins and colleagues performed the first systematic review and meta-analysis of the available literature to estimate case fatality ratios stratified by treatment, age group and HIV infection. The researchers searched PubMed and Embase for reports including terms related to TB, children, mortality and population representativeness published before 12 August, 2016.

In addition, the researchers divided the reports into three eras: the pre-treatment era included studies published prior to 1946 before streptomycin was available; 1946 to 1980 were classified as the middle era, during which the researchers assumed some children would receive appropriate treatment; and studies after 1980 were considered recent era. The researchers concluded that most children had received TB treatment in the recent era because many countries adopted the short-course model providing the directly observed treatment at the beginning of the 1980s.

However, many children in TB endemic areas infected with HIV were not appropriately treated for TB or went undiagnosed altogether. The researchers identified 31 papers in the systemic meta-analysis, which comprised 35 datasets and included 82,436 children, of whom 9,274 died of disease. Among children with TB in the pre-treatment era, the pooled case fatality ratio was 21.9% (95% CI, 18.1-26.4). In addition, children aged between infancy and 4 years had a greater mortality rate than children aged 5 to 14 years (43.6% [95% CI, 36.8-50.6] vs. 14.9% [95% CI, 11.5-19.1]).

Moreover, in HIV-infected children who received TB treatment prior to ART access, the case fatality ratio was 14.3% (95% CI, 7.4-24.1); however, among children who received TB treatment and had access to ART, mortality rates were still higher compared with children without HIV who received appropriate TB treatment (3.4% [95% CI, .7-9.6] vs. 0.4% [95% CI, 0.3-0.7]).

“The findings of our systematic review and meta-analysis suggest that the risk of death in children with [TB] is particularly high in children also infected with HIV and children who do not receive [TB] treatment, showing the urgent need to extend [TB] treatment to children in [TB] endemic areas,” the researchers wrote. “Our findings point to a large and invisible burden of preventable child deaths related to [TB], particularly in areas with uncontrolled [TB] transmission where children have poor access to appropriate care.”

In an accompanying editorial, Dr Jeffrey R Starke, professor of pediatrics at Baylor College of Medicine and Infectious Diseases in Children editorial board member, wrote that Jenkins and colleagues’ systematic meta-analysis described that many children are not being diagnosed on time or at all for TB, and that solutions to the lack in screening and therapy methods need to come from within government powers.

“The solutions ultimately will be local, so national [TB] programs need to develop plans and provide resources for this effort,” Stark wrote. “What is needed most is the political will within the [TB] community to finally address the needs of children.”

Summary
Background: Case fatality ratios in children with tuberculosis are poorly understood—particularly those among children with HIV and children not receiving tuberculosis treatment. We did a systematic review of published work to identify studies of population-representative samples of paediatric (ie, Methods: We searched PubMed and Embase for reports published in English, French, Portuguese, or Spanish before Aug 12, 2016, that included terms related to tuberculosis, children, mortality, and population representativeness. We also reviewed our own files and reference lists of articles identified by this search. We screened titles and abstracts for inclusion, excluding studies in which outcomes were unknown for 10% or more of the children and publications detailing non-representative samples. We used random-effects meta-analysis to produce pooled estimates of case fatality ratios from the included studies, which we divided into three eras: the pre-treatment era (ie, studies before 1946), the middle era (1946–80), and the recent era (after 1980). We stratified our analyses by whether or not children received tuberculosis treatment, age (0–4 years, 5–14 years), and HIV status.
Findings: We identified 31 papers comprising 35 datasets representing 82 436 children with tuberculosis disease, of whom 9274 died. Among children with tuberculosis included in studies in the pre-treatment era, the pooled case fatality ratio was 21·9% (95% CI 18·1–26·4) overall. The pooled case fatality ratio was significantly higher in children aged 0–4 years (43·6%, 95% CI 36·8–50·6) than in those aged 5–14 years (14·9%, 11·5–19·1). In studies in the recent era, when most children had tuberculosis treatment, the pooled case fatality ratio was 0·9% (95% CI 0·5–1·6). US surveillance data suggest that the case fatality ratio is substantially higher in children with HIV receiving treatment for tuberculosis (especially without antiretroviral therapy) than in those without HIV.
Interpretation: Without adequate treatment, children with tuberculosis, especially those younger than 5 years, are at high risk of death. Children with HIV have an increased mortality risk, even when receiving tuberculosis treatment.

Authors
Dr Helen E Jenkins, Courtney M Yuen, Carly A Rodriguez, Ruvandhi R Nathavitharana, Megan M McLaughlin, Peter Donald, Ben J Marais, Mercedes C Becerra

Healio report
The Lancet Infectious Diseases article summary
The Lancet Infectious Diseases comment summary


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