Meta-Analysis

. 2025 Jun;13(6):e1043-e1056.

doi: 10.1016/S2214-109X(25)00055-5. Epub 2025 Apr 22.

The aetiologies, mortality, and disability of non-traumatic coma in African children: a systematic review and meta-analysis

Stephen T J Ray¹, Charlotte E Fuller², Alex Boubour³, Taty Tshimangani⁴, Edith Kafoteka³, Alice Muiruri-Liomba³, Albert Malenga³, Andrew Tebulo³, Paul Pensulo³, Monfort B Gushu³, Maryke Nielsen⁵, Madiha Raees⁶, Elisabeth Stockdale³, Josephine Langton⁷, Gretchen L Birbeck⁸, Naomi Waithira⁹, Laura J Bonnett¹⁰, Marc Yr Henrion¹¹, Ericka L Fink¹², Douglas G Postels¹³, Nicole O'Brien¹⁴, Anne-Laure Page¹⁵, Emmanuel Baron¹⁵, Stephen B Gordon¹¹, Elizabeth Molyneux⁷, Arjen Dondorp⁹, Elizabeth C George¹⁶, Kathryn Maitland¹⁷, Benedict D Michael¹⁸, Tom Solomon¹⁹, Yamikani Chimalizeni²⁰, David G Lalloo¹¹, Christopher A Moxon²¹, Terrie Taylor²², Macpherson Mallewa⁷, Richard Idro²³, Karl Seydel²⁴, Michael J Griffiths²⁵

Affiliations

¹ Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; The Brain Infection and Inflammation Group, University of Liverpool, Liverpool, UK; Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi; Department of Paediatric Infectious Disease and Immunology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Wilson Lab, Weil Institute for Neurosciences, University of San Francisco, San Francisco, CA, USA. Electronic address: stephen.ray@paediatrics.ox.ac.uk.
² The Brain Infection and Inflammation Group, University of Liverpool, Liverpool, UK; Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi; Department of Paediatric Immunology, Allergy and Infectious Diseases, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK.
³ Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi.
⁴ Hôpital Pédiatrique de Kalembe Lembe, Cliniques Universitaires de Kinshasa, Kinshasa, Democratic Republic of the Congo.
⁵ Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK; Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi.
⁶ Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
⁷ Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi.
⁸ Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Neurology, University of Rochester, Rochester, NY, USA.
⁹ Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Nakhon Pathom, Thailand.
¹⁰ Department of Health Data Science, University of Liverpool, Liverpool, UK.
¹¹ Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Liverpool School of Tropical Medicine, Liverpool, UK.
¹² Division of Critical Care Medicine, Department of Anaesthesiology and Critical Care, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, PA, USA.
¹³ Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Division of Neurology, George Washington University and Children's National Health System, Washington, DC, USA.
¹⁴ Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Hôpital Pédiatrique de Kalembe Lembe, Cliniques Universitaires de Kinshasa, Kinshasa, Democratic Republic of the Congo; Department of Pediatrics, Division of Critical Care Medicine, Nationwide Children's Hospital and Ohio State University, Columbus, OH, USA.
¹⁵ Epicentre, Paris, France.
¹⁶ Medical Research Council Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, London, UK.
¹⁷ Department of Infectious Disease and Institute of Global Health and Innovation, Faculty of Medicine, Imperial College, London, UK; Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, Kenya.
¹⁸ The Brain Infection and Inflammation Group, University of Liverpool, Liverpool, UK; National Institute for Health and Care Research Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool, UK; Walton Centre NHS Foundation Trust, Liverpool, UK.
¹⁹ The Brain Infection and Inflammation Group, University of Liverpool, Liverpool, UK; National Institute for Health and Care Research Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool, UK; Walton Centre NHS Foundation Trust, Liverpool, UK; The Pandemic Institute, University of Liverpool, Liverpool, UK.
²⁰ Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi; School of Infection and Immunity, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
²¹ Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi; School of Infection and Immunity, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK; College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA.
²² Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi; College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA.
²³ Department of Paediatrics and Child Health, College of Health Sciences, Makerere University, Kampala, Uganda.
²⁴ Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi; College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA.
²⁵ The Brain Infection and Inflammation Group, University of Liverpool, Liverpool, UK; Centre for Child and Adolescent Health Research, Western Sydney (Baludarri) Precinct, Faculty of Medicine & Health, University of Sydney, Sydney, NSW, Australia.

PMID: 40280144
DOI: 10.1016/S2214-109X(25)00055-5

Free article

Meta-Analysis

The aetiologies, mortality, and disability of non-traumatic coma in African children: a systematic review and meta-analysis

Stephen T J Ray et al. Lancet Glob Health. 2025 Jun.

Free article

. 2025 Jun;13(6):e1043-e1056.

doi: 10.1016/S2214-109X(25)00055-5. Epub 2025 Apr 22.

Authors

Affiliations

¹ Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; The Brain Infection and Inflammation Group, University of Liverpool, Liverpool, UK; Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi; Department of Paediatric Infectious Disease and Immunology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Wilson Lab, Weil Institute for Neurosciences, University of San Francisco, San Francisco, CA, USA. Electronic address: stephen.ray@paediatrics.ox.ac.uk.
² The Brain Infection and Inflammation Group, University of Liverpool, Liverpool, UK; Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi; Department of Paediatric Immunology, Allergy and Infectious Diseases, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK.
³ Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi.
⁴ Hôpital Pédiatrique de Kalembe Lembe, Cliniques Universitaires de Kinshasa, Kinshasa, Democratic Republic of the Congo.
⁵ Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK; Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi.
⁶ Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
⁷ Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi.
⁸ Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Neurology, University of Rochester, Rochester, NY, USA.
⁹ Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Nakhon Pathom, Thailand.
¹⁰ Department of Health Data Science, University of Liverpool, Liverpool, UK.
¹¹ Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Liverpool School of Tropical Medicine, Liverpool, UK.
¹² Division of Critical Care Medicine, Department of Anaesthesiology and Critical Care, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, PA, USA.
¹³ Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Division of Neurology, George Washington University and Children's National Health System, Washington, DC, USA.
¹⁴ Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Hôpital Pédiatrique de Kalembe Lembe, Cliniques Universitaires de Kinshasa, Kinshasa, Democratic Republic of the Congo; Department of Pediatrics, Division of Critical Care Medicine, Nationwide Children's Hospital and Ohio State University, Columbus, OH, USA.
¹⁵ Epicentre, Paris, France.
¹⁶ Medical Research Council Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, London, UK.
¹⁷ Department of Infectious Disease and Institute of Global Health and Innovation, Faculty of Medicine, Imperial College, London, UK; Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, Kenya.
¹⁸ The Brain Infection and Inflammation Group, University of Liverpool, Liverpool, UK; National Institute for Health and Care Research Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool, UK; Walton Centre NHS Foundation Trust, Liverpool, UK.
¹⁹ The Brain Infection and Inflammation Group, University of Liverpool, Liverpool, UK; National Institute for Health and Care Research Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool, UK; Walton Centre NHS Foundation Trust, Liverpool, UK; The Pandemic Institute, University of Liverpool, Liverpool, UK.
²⁰ Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi; School of Infection and Immunity, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
²¹ Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi; School of Infection and Immunity, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK; College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA.
²² Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi; College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA.
²³ Department of Paediatrics and Child Health, College of Health Sciences, Makerere University, Kampala, Uganda.
²⁴ Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi; College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA.
²⁵ The Brain Infection and Inflammation Group, University of Liverpool, Liverpool, UK; Centre for Child and Adolescent Health Research, Western Sydney (Baludarri) Precinct, Faculty of Medicine & Health, University of Sydney, Sydney, NSW, Australia.

PMID: 40280144
DOI: 10.1016/S2214-109X(25)00055-5

Erratum in

Correction to Lancet Glob Health 2025; published online April 22. https://doi.org/10.1016/S2214-109X(25)00055-5.
[No authors listed] [No authors listed] Lancet Glob Health. 2025 Apr 23:S2214-109X(25)00176-7. doi: 10.1016/S2214-109X(25)00176-7. Online ahead of print. Lancet Glob Health. 2025. PMID: 40286805 No abstract available.

Abstract

Background: Non-traumatic coma in African children is a common life-threatening presentation often leading to hospital attendance. We aimed to estimate the distribution of non-traumatic coma causes and outcomes, including disease-specific outcomes, for which evidence is scarce.

Methods: We systematically reviewed MEDLINE, Embase, and Scopus databases from inception to Feb 6, 2024. We included studies recruiting children (aged 1 month to 16 years) with non-traumatic coma (Blantyre Coma Scale score ≤2, ie deep coma or comparable alternative) from any African country. Disease-specific studies were included if outcomes were reported. Primary data were requested where required. We used a DerSimonian-Laird random effects model to calculate pooled estimates for prevalence of causes, mortality, and morbidity (in-hospital and post-discharge), including analysis of mortality by temporality. This study was registered with PROSPERO (CRD4202014193).

Findings: We screened 16 666 articles. 138 studies were eligible for analysis, reporting causes, outcome data, or both from 35 027 children with non-traumatic coma in 30 African countries. 114 (89%) of 128 studies were determined to be high quality. Among the causes, cerebral malaria had highest pooled prevalence at 58% (95% CI 48-69), encephalopathy of unknown cause was associated with 23% (9-36) of cases, and acute bacterial meningitis was the cause of 10% (8-12) of cases, with all other causes representing lower proportions of cases. Pooled overall case-fatality rates were 17% (16-19) for cerebral malaria, 37% (20-55) for unknown encephalopathy, and 45% (34-55) for acute bacterial meningitis. By meta-regression, there was no significant difference in cerebral malaria (p=0·98), acute bacterial meningitis (p=0·99), or all-cause coma (p=0·081) mortality by year of study. There was no substantial difference in deaths associated with cerebral malaria in-hospital compared with post-discharge (17% [16-19] vs (18% [16-20]). Mortality was higher post-discharge than in-hospital in most non-malarial comas, including acute bacterial meningitis (39% [26-52]) vs 53% [38-69]). Disability associated with cerebral malaria was 11% (9-12). Pooled disability outcomes associated with other non-malarial diseases were largely absent.

Interpretation: The prevalence and outcomes of cerebral malaria and meningitis associated with non-traumatic coma were strikingly static across five decades. Enhanced molecular and radiological diagnostics, investment, policy making, community awareness, and health service provision are all required to facilitate earlier referral to specialist centres, to drive a step-change in diagnostic yield and treatment options to improve these outcomes.

Funding: Wellcome Trust.

Translations: For the Chichewa, French and Portuguese translations of the abstract see Supplementary Materials section.

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Conflict of interest statement

Declaration of interests DGL, MYRH, and SBG are supported by The Wellcome core award (award number 206545/Z/17/Z) to Malawi–Liverpool–Wellcome Trust. STJR and MN are also supported by Wellcome to conduct paediatric infectious diseases research (203919/Z/16/Z). STJR is also supported by a Thrasher child health early career award, Academy of Medical Sciences starter grant, and European Society of Paediatric Infectious Diseases Society diagnostic grant; and is a Centre for Human Genetics Well Institute Olink-48 grant prize winner and early research career committee member, both at The University of Oxford. MN is also supported by Roche Diagnostics for a Baby and Mother Biomarkers of Infection study; Liverpool School of Tropical Medicine as a clinical fellow for The DIAMONDS Research Consortia; FIND Diagnostics for a literature review on the utility of CRP testing in primary care in low-resource settings for supporting patient management and antibiotic stewardship; is an invited speaker at The Paediatric Infectious Diseases Games; and is deputy convenor, research co-lead, and winter meeting lead at the Royal College Of Paediatrics and Child Health's International Child Health group. MJG is supported to conduct neuroscience and infection research internationally by the Medical Research Council (MRC) Newton Fund (MR/S019960/1), MRC Developmental Pathway Funding Scheme (MR/R015406/1), and National Institute of Health and Care Research (NIHR; 153195 17/60/67, 126156 17/63/11, and 200907). CAM is a UKRI MRC Future Leaders Fellow (MR/V025856/1). TS is supported by the NIHR Health Protection Research Unit in Emerging and Zoonotic Infections (IS-HPU-1112–10117 and NIHR200907), NIHR Global Health Research Group on Brain Infections (17/63/110), the UK MRC Global Effort on COVID-19 Programme (MR/V033441/1), the EU's Horizon 2020 research and innovation programme (ZikaPLAN; 734584), and The Pandemic Institute; receives royalties from Oxford University Press, Liverpool University Press, Cambridge University, and Elsevier for published books he has written on brain infections; co-chaired the Medicines and Healthcare Products Regulatory Agency (MHRA) Expert Working Group on COVID-19 vaccines between 2020 and 2023; was a member of the COVID-19 Vaccines Benefit Risk Expert working group for the Commission on Human Medicines (CHM) committee of MHRA between 2020 and 2023; is a Committee Member of the Wellcome Trust Pathogen Biology and Disease Transmission Discovery advisory group; was a member of the MRC's Infections and Immunity Board between 2018 and 2022; sat on the Research Excellence Framework Panel between 2021 and 2022; and was on the data safety monitoring committee of the GSK Study to Evaluate the Safety and Immunogenicity of a Candidate Ebola Vaccine in Children (ChAd3 EBO-Z) vaccine (GSK3390107A). BDM is supported for COVID-19 neuroscience research by UK Research and Innovation (UKRI) and MRC (MR/V03605X/1); and for additional neurological inflammation due to viral infection research by grants from the MRC and UKRI (MR/V007181/1), MRC (MR/T028750/1), and the Wellcome Trust (ISSF201902/3). TTa is supported by a research grant from the US National Institutes of Health (NIH); is the President-Elect for the American Society of Tropical Medicine and Hygiene; and is a member of the Malaria Advisory Council for Novartis Pharma. GB is supported by two active and two recent research grants from US NIH; consults on educational materials for Neurotorium, Temp Traq, and similar devices at Blue Spark Technologies; lectures for The University of Calgary; participates on an advisory board for the BRIDGE clinical trial; and is on the editorial board of the Lancet Neurology, Neurotorium, and Zambian League against Epilepsy. ECG is funded by the MRC as core support to the Medical Research Council Clinical Trials Unit at University College London (MC_UU_00004/05). STJR, BDM, and TS are members of the Encephalitis International Scientific Advisory Panel—BDM is Scientific Chair and TS is President. All other authors declare no competing interests.

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The aetiologies, mortality, and disability of non-traumatic coma in African children: a systematic review and meta-analysis

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The aetiologies, mortality, and disability of non-traumatic coma in African children: a systematic review and meta-analysis

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