Expanding the Diagnostic Lens: Mast Cell Activation Syndromes and the Hidden Spectrum of Angioedema-Associated Mortality in COVID-19

To the Editor,

The new publication that I find interesting, entitled “Quorum Deaths from Angioedema Subtilities Anaphylaxis and COVID-19,” has highlighted a totally overlooked problem of quorum death due to angioedema-anaphylaxis syndromes associated with COVID-19. That a quorum of deaths has a mechanistic overlap, as proposed by the authors, is welcome and overdue. I write to expand on their argument by proposing a diagnostic and forensic extension that encompasses mast cell activation disorders, complement system maladaptation, and endothelial dysfunction caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through converging pathways mechanisms that may culminate in fatal angioedema/anaphylaxis yet be misclassified at death investigation.

Contextual Framework and Diagnostic Indeterminacy

The authors are right in pointing out that fatal angioedema is frequently mistaken for primary respiratory failure or cardiac arrest, especially when there is no apparent urticarial rash or exposure to a probable allergen. This diagnosis uncertainty arises from clinical overlap between bradykinin-mediated angioedema and histaminergic anaphylaxis. I submit, however, that the existing forensic kaleidoscope can be too superficial and needs additional mechanistic intermediate links like mast cell activation syndrome (MCAS) and C1-inhibitor deficiency, mostly due to a lack of methods to find it through molecular or immunohistochemical verification, along with postmortem.

Recent evidence suggests that COVID-19 may unmask subclinical cases of MCAS that instate fatal degranulation events devoid of an allergic pathway and allergens. It is an important yet undervalued aspect of forensic examination of sudden deaths, possibly related to or following SARS-CoV-2 infection.

Mast Cell Endothelium Complement Axis Unexplored COVID-19 Mortality Advancement

The first study is very accurate in specifying the applicability of the bradykinin storm and vascular permeability cascade. Expanding on this, there is also an underexplored triad consisting of mast cell endothelium-complement axis dysfunction that synergizes to generate terminal vascular collapse without significant systemic inflammation.

ACE2 receptors are reported to be located on mast cells widely distributed in the vasculature and respiratory mucosa, which are sensitive to viral infection and degranulate (non-IgE independent) in response (1). Such a process can be enhanced in COVID-19 by priming with IL-6 and interaction with the viral glycoprotein. Particularly, it was shown by Wu et al that the spike protein of SARS-CoV-2 directly activates the mast cells that subsequently release histamine, tryptase, and leukotrienes, in turn promoting endothelial permeability (2).

Also, complement activation, specifically via the lectin pathway, has been noted to play a role in endothelial injury in COVID-19 (3). Anaphylatoxins C3a and C5a affect mast cell degranulation, which further increases and forms a self-amplification cycle. Even asymptomatic cases of virus infection in people with hereditary angioedema (HAE) or acquired C1-inhibitor deficiency can push this balance to result in fatal consequences, especially when exogenous triggers are absent.

Therefore, I hypothesize that part of the quorum deaths that have been classified as idiopathic anaphylaxis or COVID-19-related pulmonary edema might be the end-of-life convergence of subclinical mast cell disease, dysregulated complement, and viral endothelialopathy.

Forensic Implications: Conceptualizing Postmortem Investigations

The forensic society must be provided with subtle mechanisms to detect such unusual deaths. As a common mode of test, I would propose the following:

• Serum tryptase (collect within 2–4 after death, if feasible) (4)

• Complement activity, such as C4 levels and C1-INH levels.

• Histology: perivascular mast cell degranulation of vessels within the larynx and terminal pulmonary bronchioles.

• Mutational genetic testing of the suspected cases of HAE (eg, SERPING1) or MCAS (e.g., KIT D816V).

This framework may elucidate the differences in pathophysiology between traditional anaphylaxis, COVID-mediated cytokine storm, and MCAS-driven vascular collapse, which are characterized by phenotypic similarities in presentation but pathophysiologic differences.

Medicolegal and Public Health Impact

Such medicolegal implications are not trifling. Mistakenly associating the pathophysiology of these deaths makes it harder to see the real burden of MCAS and HAE worsened by SARS-CoV-2. In addition to that, forensic ignorance prevails, which acts as a barrier in pharmacovigilance. As an example, certain COVID-19 vaccines or antiviral therapy could be mast cell destabilizers, and this could increase prior mast cell diseases (5).

Finally, this diagnostic pitfall has the potential to affect health disparities unequally by groups with misrecognized MCAS or lacking access to allergologic services. Applying such understandings to forensic procedures would enhance the detection of the cause of death, as well as help in clinical risk-stratification during pandemics.

Conclusion

The article written by your authors acts as the launchpad for reconsidering the idea of fatal angioedema and anaphylaxis in the light of COVID-19. I would encourage the forensic pathology community to embrace a wider diagnostic scope that considers the biology of mast cells, a dysregulated complement, and other novel SARS-CoV-2-specific immunopathology. In doing so, we might discover the so-called silent epidemics of misdiagnosed mast cell conditions and save further lives in terms of early detection and specific treatment.