Background: Noma (cancrum oris) is a severe gangrenous disease of the mouth and oro-facial structures. Noma often presents in young children alongside extreme poverty, malnutrition and poor environmental sanitation. Gaps however remain in understanding its aetiology, pathogenesis, preventative and treatment efficacy. Methods and findings: We systematically searched databases to find all primary research studies reporting patients of any age diagnosed with noma (including clinical trials, cohort studies, case-control, cross-sectional, other observational studies, case studies and case series) up to 7 December 2022. The 366 publications included in our review describe 15,082 noma patients, from manuscripts published between 1839 and 2022. While several cohort (n=53) and cross-sectional (n=29) studies were identified, accounting for a total of 13,489 enrolled noma patients, only 6 interventional studies enrolling a total of 101 patients (range 7 to 26 patients) were identified, with only one interventional study from the last decade. Over 380 different treatment modalities were described for noma management. Disease aetiology reports identified 117 different microorganisms across 113 publications, but none were more widespread or uniquely related to noma development. Since 2000, most (91.2%) cases are reported in Sub-Saharan Africa, but not solely in the historical noma belt. Noma was also observed in Asia and the Americas. There were 212 different possible noma risk factors presented in 269 (73.5%) publications, with substantial heterogeneity. Definition and harmonisation of noma progression staging are poorly standardised and reported. Conclusion: The current literature provides very weak evidence to guide policy. Our thorough review also identified substantial knowledge gaps, and highlights the lack of prospective high-quality studies on the physiopathology of the disease that can guide therapeutic and preventive policies. Urgent research investment is therefore essential to improve the situation, especially as noma is now duly recognised as a Neglected Tropical Disease (NTD) by the World Health Organization (WHO).

The authors have declared no competing interest.

The World Health Organization (WHO) oral health programme commissioned this research with financial support from Hilfsaktion Noma e.V. The authors have been given permission to publish this article. The author(s) alone is/are responsible for the views expressed in this publication and they do not necessarily represent views, decisions or policies of the World Health Organization. Paul Newton is supported by the Wellcome Trust.

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Literature searches were initially conducted from databases inception to 4 March 2019, and updated on 7 December 2022, using the search strategy and information sources detailed below. The following databases were searched: MEDLINE, CAB Abstracts, Embase, Global Health (all via Ovid); Scopus; Web of Science (Core Collection); African Index Medicus; Pascal (French language search); ClinicalTrials.gov; and WHO ICTRP. African Journals Online: Health and OpenGrey.eu were searched in 2019. WHO-identified and grey literature was also searched

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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The project contains the following underlying and extended data provided in supplementary files to this publication: Supplementary File 1 (SF1): including literature search strategies, search terms by database, search results, PRISMA diagram, PRISMA Checklist Supplementary File 2 (SF2): including list of included studies, data and variable dictionary, results data associated with this article, studies excluded at full-text screening stage with reasons. Supplementary File 3 (SF3): extended results Copies of all supplementary files, custom scripts and data associated with the protocol publication and this article will also be made accessible online following publication at Open Science Framework: Extended data for Protocol for a systematic review of the evidence-based knowledge on the distribution, associated risk factors, the prevention and treatment modalities for noma, https://doi.org/10.17605/OSF.IO/3DN6G 12

https://doi.org/10.17605/OSF.IO/3DN6G