Persistent immune, coagulation and cardiac dysregulation are correlated with later post-discharge mortality in children with severe malnutrition

Abstract Background Children with complicated severe malnutrition (CSM) face high mortality after hospital discharge, yet the underlying mechanisms remain poorly understood. While early post-discharge mortality (< 2 months) has been linked to a sepsis-like inflammatory profile measured at discharge, it is unclear whether this relationship persists (later mortality; 2–6 months post-discharge). This study investigated whether immune, inflammatory, and endothelial dysfunction at 2 months post-discharge are associated with later mortality in children recovering from CSM. Methods We conducted a case–control study nested within a randomised placebo-controlled trial of daily co-trimoxazole in HIV-negative children aged 2–59 months with CSM in four Kenyan hospitals. Cases were children who died between 2 and 6 months post-discharge; controls were survivors frequency-matched by sex, site, and trial arm. Plasma cytokines, chemokines, endothelial markers, and untargeted proteomics were measured at discharge and 2 months post-discharge. Conditional Cox regression, adjusted for age, sex, site, mid-upper arm circumference (MUAC), and randomisation arm, was used to identify biomarkers associated with later mortality. Results Cases were younger (had a median of 7 vs. 11 months), had longer hospital stays (14 vs. 10 days), and showed lower anthropometry (MUAC = 10.7 vs. 12.0 cm) and lower haemoglobin (9.7 vs. 10.6 g/dL) at 2 months post-discharge (all p < 0.05). Mortality 2–6 months post-discharge was associated with elevated inflammatory mediators (e.g. IL-10 [hazard ratio, HR: 1.47, 95% confidence interval, CI: 1.00–2.14], IL-15 [1.65, 95% CI: 1.08–2.51], IFN-α2 [1.51, 95% CI: 1.02–2.23]), acute phase proteins, apolipoproteins and coagulation markers, including fibrinogen, histidine-rich glycoprotein (1.40, 95% CI: 1.01–1.94), protein C inhibitor (SERPINA5, 1.50, 95% CI: 1.07–2.08), SERPINA10 (1.42, 95% CI: 1.02–1.99), and ADAMTS13 (0.41, 95% CI: 0.24–0.70). Additionally, cardiovascular and muscle-related proteins such as angiotensinogen (1.46, 95% CI: 1.03–2.08), α- and β-tropomyosin (0.68, 95% CI: 0.48–0.98), PI16 (0.72, 95% CI:0.54–0.97), and zyxin (0.61, 95% CI: 0.40–0.92) were elevated in cases. Conclusions Later mortality in children recovering from CSM is associated with persistent immune activation, a sepsis-like phenotype involving multiple systems. These findings suggest that children at risk of later mortality may benefit from biomarker-guided interventions initiated at discharge.