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Although classically associated with meningococcal infection, fatal cases occur across multiple infectious etiologies and heterogeneous clinical contexts. In forensic practice, diagnosis frequently relies on post-mortem interpretation rather than clinical recognition, making consistent pathological assessment essential. A systematic review was conducted according to PRISMA guidelines to identify autopsy-confirmed fatal cases consistent with WFS. PubMed\/MEDLINE and Scopus were searched from database inception to 21 February 2026, with a supplementary search conducted in Google Scholar. Eligible studies included fatal human cases with bilateral adrenal hemorrhage documented at autopsy and sufficient pathological and\/or microbiological data. Data were extracted on clinical course, gross and histopathological findings, microbiological investigations, pathogens, and predisposing factors. Owing to marked heterogeneity of case-level reporting, qualitative synthesis and semi-quantitative descriptive analysis were performed. Sixty-five studies, encompassing 86 individual fatal cases, met the inclusion criteria. Bilateral adrenal hemorrhage consistently occurred within a broader systemic septic pattern characterized by multiorgan congestion, hemorrhagic manifestations, and variable disseminated intravascular coagulation-related changes. Histopathological and microbiological findings were heterogeneous, with frequent discrepancies between culture-based and molecular results and recurrent diagnostic limitations related to post-mortem microbiology. The synthesis of evidence supports interpreting WFS as a recurrent forensic-pathological pattern rather than a single morphological diagnosis. Based on key findings identified across cases, practical forensic frameworks were developed to support autopsy interpretation, microbiological sampling, and differential diagnosis. Integration of morphology, histopathology, microbiology, and circumstantial data may improve consistency and reproducibility in the medico-legal evaluation of sudden septic deaths.<\/jats:p>","DOI":"10.1007\/s00414-026-03978-9","type":"journal-article","created":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T01:30:22Z","timestamp":1787967022000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Fatal waterhouse\u2013friderichsen syndrome at autopsy: a systematic review and forensic diagnostic framework"],"prefix":"10.1007","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-8449-1803","authenticated-orcid":false,"given":"Jessika","family":"Camatti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Laura","family":"Santunione","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8451-7212","authenticated-orcid":false,"given":"Rossana","family":"Cecchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erjon","family":"Radheshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edoardo","family":"Carretto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4889-1944","authenticated-orcid":false,"given":"Maria Paola","family":"Bonasoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,29]]},"reference":[{"key":"3978_CR1","unstructured":"Karki BR, Sedhai YR, Bokhari SRA (2023) Waterhouse-Friderichsen syndrome. 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