Publication date: Jun 01, 2025

Children in febrile coma in Africa are frequently hospitalised, with poorer outcomes than those in high-income settings. Cerebral malaria is historically the most common cause of febrile coma. Due to limited diagnostic and radiological resources and a decrease in malaria prevalence, there might be under-recognition of non-malarial coma. However, prospective data are scarce. We aimed to determine causes, neuroradiological features, risk factors for mortality, and neurosequelae of children in febrile coma in Malawi. In this prospective cohort study, we enrolled children in a coma (Blantyre Coma Scale score ≤2) who were aged between 3 months and 15 years at Queen Elizabeth Central Hospital, Blantyre, Malawi. We used pathogen-specific PCR analysis of blood and cerebrospinal fluid for 15 pathogens including Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, Salmonella spp, non-typhoidal Salmonella, Salmonella enterica serotype Typhi (S Typhi), Klebsiella spp, Escherichia coli, Mycobacterium tuberculosis (also using GeneXpert), Streptococcus agalactiae, herpes simplex virus (types 1 and 2), varicella zoster virus, cytomegalovirus, enteroviruses, and SARS-CoV-2; microscopy for malaria; admission brain MRI to enhance the diagnosis of cause and identify brain injury, swelling, and any other complications; and electroencephalography tracings were used identify subclinical seizures or non-convulsive status epilepticus. Assessment of malarial retinopathy was performed by a trained ophthalmologist. We used regression models to estimate risk factors for (and the difference in) 30-day mortality and 180-day neurosequelae (outcome assessed in-person) between children with non-malarial coma and cerebral malaria. Between Jan 31, 2018, and June 30, 2021, we recruited 352 children with febrile coma. Cerebral malaria was the most common cause (in 231 [66%] of 352 children). Pathogenic diagnosis was possible in 289 (82%) of 352 children. Co-infection was identified in 63 (27%) of 231 children with cerebral malaria, of which 49 (78%) were bacterial. The most common non-malarial causes of coma were meningitis (48 [14%] of 352 children) and encephalitis (24 [7%] of 352); 32 (9%) cases had an unknown cause. Compared with standard cultures, PCR significantly increased pathogen diagnosis (p

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