Cause-specific mortality in a cohort of paediatric cerebral malaria patients

Paediatric cerebral malaria (CM) kills thousands of children globally each year. Despite multiple interventional trials, no adjunctive therapy has demonstrated a survival benefit. As CM is known to cause multiple organ dysfunction syndrome (MODS), failure to consider the immediate cause of death or cause-specific mortality may partially explain these negative findings, particularly for targeted, organ specific therapies.

A retrospective review of data from children with CM enrolled in interventional clinical trials at the Blantyre Malaria Project/Queen Elizabeth Central Hospital between 2018 and 2025 was performed. For participants who died during their hospitalization, the immediate cause of death was categorized into one of seven groups using a priori definitions.

A total of 393 children were enrolled in the study period, and 52 (13%) died. Cerebral herniation was the most common immediate cause of death (46%) followed by status epilepticus with apnea (17%). Non-neurologic immediate causes of death occurred in 37% and included: cardiac failure/shock (13%), respiratory failure (12%), renal failure (6%), hepatic failure (4%), and other/indeterminant (2%). Admission coma score was significantly lower in children who died of cerebral herniation or hepatic failure (p = 0.001). Admission oxygen saturation was lowest in patients who died of respiratory failure (p = 0.04) and admission lactate was highest in those that died of cardiac failure/shock, hepatic failure, or other/indeterminant causes (p = 0.01). MODS was prevalent across the cohort regardless of the immediate cause of death.

Multiple different immediate causes of death were identified in children with CM. This may dilute the measured impact of brain-focused therapies aimed at reducing central nervous system injury. Modifications in sample size estimates may need to be made in future clinical trials.