Abstract
Gray et al's investigation into angioedema–anaphylaxis deaths amidst the COVID-19 pandemic raises important forensic implications, particularly concerning differential diagnostics in postmortem settings ( 1). However, a critical avenue requiring deeper contextualization is the immunopathological intersection between SARS-CoV-2-induced mast cell activation and bradykinin-mediated pathways ( 2).
Keywords: anaphylaxis, COVID-19, forensic complexity, pseudoangioedema
Emerging evidence suggests that COVID-19 may potentiate non-IgE-mediated angioedema through dysregulation of the kallikrein–kinin system, leading to bradykinin storm-like presentations even in the absence of classic anaphylaxis triggers (3). This blurs the line between primary allergic reactions and COVID-induced pseudoanaphylaxis. Given that histamine and tryptase elevations may not uniformly present postmortem, forensic misclassification is a pressing risk (4).
Moreover, we note the underrepresentation of genetic factors such as SERPING1 variants or acquired C1-inhibitor deficiencies (5)—both of which may predispose individuals to bradykinin-mediated angioedema postinfection or postvaccination. A recent autopsy-based review in East Asia identified multiple cases of fatal angioedema with undiagnosed hereditary angioedema, suggesting a latent burden in underserved populations (6).
To strengthen future forensic analyses, we propose integrating complement profiling, SARS-CoV-2 tissue immunohistochemistry, and mast cell-specific immunomarkers in sudden death protocols where airway obstruction is evident but classical signs of anaphylaxis are absent. Such an approach would also refine death certification and surveillance systems, especially in low-resource settings disproportionately affected by diagnostic ambiguities during the pandemic.
We commend the authors for initiating this dialogue and urge the forensic pathology community to adopt a more nuanced, pathophysiology-guided framework in adjudicating immunologic deaths in the era of emerging infectious threats.
ACKNOWLEDGMNTS
Not applicable.
Footnotes
ETHICAL APPROVAL: Not applicable.
STATEMENT OF HUMAN AND ANIMAL RIGHTS: Not applicable.
STATEMENT OF INFORMED CONSENT: Not applicable.
FUNDING: The authors received no financial support for the research, authorship, and/or publication of this article.
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
DATA AVAILABILITY STATEMENT: Not applicable.
ORCID iD: Jomar L. Aban https://orcid.org/0000-0003-3068-5648
Contributor Information
Jomar L. Aban, Secondary Education Department, College of Education, North La Union Campus, Don Mariano Marcos Memorial State University, Bacnotan, La Union, Philippines, Roles: A, B, C, D, E, 1.
Don Eliseo Lucero-Prisno, III, Department of Global Health and Development, London School of Hygiene and Tropical Medicine, London, UK, Roles: D, E, 4, 5, 6.
Jerico Bautista Ogaya, Department of Medical Technology, Far Eastern University, Manila, Philippines;; Center for University Research, University of Makati, Makati City, Philippines, Roles: D, E, 4, 5, 6
Christian Joseph N. Ong, Department of Biology, College of Science, De La Salle University, Manila, Philippines, Roles: D, E, 4, 5, 6.
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