Shedding Light on Tuberculosis Deaths in Children and Adolescents

Tuberculosis (TB) kills ∼1.5 million people worldwide each year.¹  Among children and adolescents infected with TB, those <5 years old and those with HIV coinfection have a higher risk of death.^2–4  Not only have few researchers quantified the impact of antiretroviral therapy (ART) regarding those with coinfected with HIV,^4–6  there are important gaps in our overall knowledge for adolescents treated for TB. Numerous observational studies conducted before the availability of anti-TB antibiotics revealed that TB disease and death peaked in the first 2 years of life and then decreased until adolescence, after which it rose steeply.⁷  Some reports revealed sex-based differences in incidence and mortality during adolescence.^8–11  In recent decades, however, adolescents have received little attention in TB research, and their vulnerability to the disease has been largely forgotten, mostly because TB surveillance systems group individuals <15 years with children and those ≥15 years with adults.^1,12  Disaggregated TB data have not been reported routinely for adolescents, although this practice will change in 2021 after the World Health Organization’s request for countries to disaggregate TB data by 5-year age bands for people <25 years old.

In this issue of Pediatrics, Osman et al¹³  address these research gaps by analyzing the South African Electronic Treatment Register, a national surveillance database of individuals treated for drug-susceptible TB. The study includes ∼85 000 HIV coinfected children and adolescents, of whom nearly one-half were not receiving ART at TB diagnosis. The authors found that, compared with HIV-uninfected children and adolescents, those with HIV on ART were >5 times as likely to die within 6 months of TB diagnosis, whereas those with HIV not on ART were >8 times more likely to die. These findings highlight the importance of TB preventive therapy and timely ART initiation in HIV-infected children and adolescents.^4,5 

Using finely age-disaggregated case fatality ratios (CFRs), Osman et al¹³  found that the risk of death was high in the first year of life for both sexes (4.1%), early adolescence for boys (4.3%), and late adolescence for girls (4.2%). Estimating standardized mortality ratios (SMRs), the authors found that, in 2016, observed TB deaths occurred at 4 to 5 times the rate of expected deaths in children <5 years of age. In contrast, in 2016, TB deaths occurred at 77 to 92 times the rate of expected deaths in adolescents 10 to 14 years old. Notably, SMRs were much higher for adolescent girls than for adolescent boys. As the authors hypothesize, lower SMRs in young children may reflect their susceptibility to other diseases, and the discrepancy between adolescent boys and girls may reflect the high risk of death from injury and violence among boys in South Africa. Nonetheless, SMRs reveal the impact of TB on specific groups and should be incorporated into future research to inform public health decisions.

Another strength of this study is its examination of time trends between 2004 and 2016. The authors observed similar CFRs in all age groups in 2004. Thereafter, CFRs declined in children <10 years old (most steeply in those <5 years old) but remained stable in adolescents. This discrepancy is consistent with a global trend of sharp mortality declines in young children, compared with adolescents.¹⁴  Taken together, the study observations underscore the need to devote more resources to adolescents: identifying and addressing their risk factors for TB mortality, prioritizing them in TB-contact investigations and screening activities, and increasing the prescription of and adherence to TB preventive treatment in this age group.

A key consideration is that the data available for this study do not include people who are diagnosed with TB but do not initiate treatment, are never diagnosed with TB at all, or have drug-resistant TB. Because an estimated 20% of children <15 years old with untreated TB disease die within 1 year and treatment outcomes for those with drug-resistant TB are likely worse,⁴  the findings represent the “best case scenario” for child and adolescent TB mortality in South Africa.

In the study, Osman et al¹³  clarify the impact of HIV and ART on TB mortality in children and adolescents and expose adolescents’ overall high risk of poor TB outcomes. In future research efforts, researchers should incorporate the study’s granular age categories and innovative use of both CFRs and SMRs to examine TB deaths in children and adolescents in diverse settings. For example, in former Soviet republics, where >15% of adolescents have rifampin-resistant TB, characterizing the impact of drug-resistance on TB mortality is particularly important.¹⁵  The World Health Organization’s recent request for data disaggregation by 5-year age bands will facilitate more detailed evaluations of TB deaths among children and adolescents around the world. By analyzing these disaggregated data, researchers can help improve outcomes for the most vulnerable children and adolescents.

ART

antiretroviral therapy

CFR

case fatality ratio

SMR

standardized mortality ratio

TB

tuberculosis