Waterhouse–Friderichsen syndrome (WFS) is a fulminant septic condition characterized by bilateral adrenal hemorrhage and rapid clinical deterioration. Although traditionally associated with meningococcal disease, fatal instances are reported across diverse infectious agents and clinical settings. In forensic practice, WFS is often identified or suspected after death, so consistent autopsy assessment and post‑mortem interpretation are crucial. This systematic review aimed to synthesise autopsy-confirmed fatal cases consistent with WFS and to develop practical forensic frameworks to support autopsy interpretation, microbiological sampling, and differential diagnosis.
The review was conducted according to PRISMA guidelines. Databases searched included PubMed/MEDLINE and Scopus from inception to 21 February 2026, with a supplementary search in Google Scholar. Eligible reports were screened to identify fatal human cases with documented bilateral adrenal hemorrhage at autopsy and with sufficient pathological and/or microbiological data to inform forensic interpretation. Data extraction targeted clinical course, gross and histopathological findings, microbiological investigations and results, identified pathogens, and reported predisposing factors. Because reporting at the case level was markedly heterogeneous, the authors performed qualitative synthesis supplemented by semi-quantitative descriptive analysis rather than meta-analysis.
Included studies were those reporting fatal human cases in which bilateral adrenal hemorrhage was documented on autopsy and where pathological and/or microbiological details were available to support interpretation. Reports lacking essential autopsy documentation or microbiological data were excluded. The methods emphasized the need for integrated pathological and microbiological information to characterise WFS in the forensic setting.
Sixty-five studies reporting a total of 86 individual fatal cases met the inclusion criteria. Cases spanned variable clinical contexts and infectious aetiologies. The review documents consistent associations between adrenal hemorrhage and a systemic septic pattern, but it also highlights substantial heterogeneity in the detail and quality of case-level reporting, which limited quantitative aggregation.
Bilateral adrenal hemorrhage in the included cases consistently occurred within a broader pattern of severe systemic sepsis. Common gross and microscopic features accompanying adrenal bleeding included multiorgan congestion and variable haemorrhagic manifestations. Histopathological changes were heterogeneous across cases. Findings compatible with disseminated intravascular coagulation (DIC) were variably reported, reflecting the complex haemostatic disturbances seen in fulminant sepsis. The review supports treating the constellation of adrenal haemorrhage plus systemic haemorrhagic signs as a recurrent forensic-pathological pattern rather than a single, uniform morphological diagnosis.
Microbiological investigations reported in the cases were heterogeneous, encompassing both culture-based and molecular methods. The authors note frequent discrepancies between culture results and molecular findings and recurring limitations intrinsic to post-mortem microbiology, such as interpretive difficulties distinguishing true ante-mortem pathogens from post-mortem contaminants or translocation. These challenges complicate attribution of a specific infectious agent as the definitive cause of adrenal haemorrhage in some cases.
The synthesis of case evidence led the authors to recommend interpreting WFS as a forensic-pathological pattern characterized by bilateral adrenal haemorrhage within fulminant sepsis, rather than a single morphological endpoint tied to one pathogen. This perspective acknowledges diverse infectious causes, variable histopathology, and the limits of post-mortem microbiology while focusing on reproducible features useful for medico-legal assessment.
Based on recurring findings across cases, the authors developed practical forensic frameworks intended to guide autopsy interpretation, sampling strategy for microbiological testing, and differential diagnosis. The proposed approach stresses integration of macroscopic morphology, targeted histopathology, microbiological results (both culture and molecular where available), and circumstantial and clinical data to enhance consistency and reproducibility in evaluating sudden septic deaths with adrenal haemorrhage. Specific procedural or sampling details from the framework are not reproduced here beyond the general principle of multidisciplinary integration, as those operational elements were derived from case synthesis within the reviewed studies.
The authors emphasize the marked heterogeneity of case-level reporting in the literature, which limited quantitative analysis and the level of inference that can be drawn. Recurrent diagnostic limitations in post‑mortem microbiology, including discrepancies between culture and molecular diagnostics and the potential for contamination or post-mortem overgrowth, reduce certainty in pathogen attribution. As a systematic review of published cases, the study also inherits reporting biases and variable methodological detail from primary reports.
The review of 65 studies encompassing 86 autopsy-confirmed fatal cases supports viewing Waterhouse–Friderichsen syndrome as a recurrent forensic-pathological pattern defined by bilateral adrenal hemorrhage within fulminant sepsis and often accompanied by features of disseminated intravascular coagulation and multiorgan haemorrhagic change. Heterogeneous histopathology and limitations of post-mortem microbiology mean that pathogen identification may be inconsistent. The authors propose practical forensic frameworks to support autopsy interpretation and microbiological sampling and recommend integrating morphological, histopathological, microbiological, and circumstantial data to improve consistency and reproducibility in medico-legal evaluations of sudden septic deaths.