Multiomics characterization of acute child illness and mortality in Africa and South Asia

Childhood illnesses from infectious diseases in low- and middle-income
countries contribute substantially to the global under-five mortality.
Many hospitalised children experience incomplete recovery, readmission,
and post-discharge mortality despite guideline-directed care. However,
targeted interventions remain elusive due to a limited understanding of
underlying mechanisms. In this work, we employ multiomic profiling and
multivariate modeling to investigate biological drivers of inpatient and
post-discharge mortality in 3,101 acutely ill children across nine sites
in sub-Saharan Africa and South Asia. In a nested case-cohort (N=1,008),
we generate plasma proteomics, serum metabolomics and lipidomics, stool
metagenomics, and fecal pathogen data at admission and discharge.
Additionally, we profile 270 geographically matched community children for
biological baselines. We identify a generalizable mortality signature
marked by immune, inflammatory, and metabolic dysregulation with gut
dysbiosis. We show that mortality-associated signals persist from
admission through discharge, indicating unresolved disease, and that
malnourished children show greater baseline perturbations, explaining
elevated risk. We also find some children with low clinical severity
display high predicted mortality risk from targeted biomarkers. Finally,
we distill predictive models to a clinically feasible biomarker panel and
validate our findings in an independent cohort (N=100). By linking
inpatient and post-discharge mortality to specific biological mechanisms,
our findings highlight why current care can fail and demonstrate how
biomarker-guided risk stratification can identify vulnerable children
currently missed by clinical assessments, enabling targeted interventions
to reduce mortality in low- and middle-income countries.