Adverse events of first-line therapy for pediatric tuberculosis: A systematic review and meta-analysis

Abstract

Background

In 2010, the World Health Organization (WHO) increased recommended doses of first-line tuberculosis (TB) drugs for children. This systematic review aimed to determine the proportion of children who develop adverse events (AEs) on first-line TB treatment and to determine whether there has been a change in toxicity observed with WHO 2010 dosing.

Methods

We searched MEDLINE, Embase, Scopus, Cochrane Database of Systematic Reviews, WHO Global Index Medicus, and ClinicalTrials.gov for studies that reported AEs for children and adolescents ≤19 years old with TB disease receiving first-line medications. A meta-analysis of proportions was performed to generate pooled proportions of AEs. The protocol was registered with the International Prospective Register of Systematic Reviews (CRD42023418496).

Results

Forty studies comprising 5,021 participants were included. 682 (13.6%) participants experienced 712 AEs; 60 (1.2%) participants experienced a change in therapy due to an AE. The proportion of children with any AE was significantly higher with WHO 2010 dosing (26%, 95% CI 18-34%) compared to pre-WHO 2010 dosing (8%, 95% CI 4-15%), as was the proportion of children who developed severe AEs. There was no statistically significant difference in hepatotoxicity before and after 2010 dosing recommendations, however, significant increases in hepatotoxicity were seen in several subgroups with 2010 dosing. There was substantial heterogeneity between studies; none were at high risk of bias.

Conclusions

Higher dose regimens in children were associated with increased AEs, raising caution for further dose increases and necessitating additional study of treatment tolerability. These findings are limited by publication bias in observational trials.

Graphical abstract

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tuberculosis, children, adolescents, adverse events, treatment

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