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Hyperactivated Mast Cells Pathogenesis Hypothesis for COVID-19 Cutaneous Manifestations

Open AccessPublished:August 23, 2021DOI:https://doi.org/10.1016/j.xjidi.2021.100052
Hyperactivated Mast Cells Pathogenesis Hypothesis for COVID-19 Cutaneous Manifestations
Previous ArticlePatient Satisfaction of General Dermatology Providers: A Quantitative and Qualitative Analysis of 38,008 Online Reviews

      Abbreviations:

      COX-2 (cyclooxygenase 2), SARS-CoV (severe acute respiratory syndrome coronavirus)
      To the Editor
      Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes mucocutaneous manifestations, including maculopapular eruptions, urticaria, and unusual acral vasculopathic rashes (pseudochilblains, pernio-like lesions) referred to as COVID toe. Cutaneous manifestations can occur in asymptomatic individuals, sometimes preceding COVID-19 symptoms, concurrent with COVID-19, or commonly after other COVID-19 symptoms (
      • Freeman E.E.
      • McMahon D.E.
      • Lipoff J.B.
      • Rosenbach M.
      • Kovarik C.
      • Desai S.R.
      • et al.
      The spectrum of COVID-19-associated dermatologic manifestations: an international registry of 716 patients from 31 countries.
      J Am Acad Dermatol. 2020; 83: 1118-1129
      ;
      • Seirafianpour F.
      • Sodagar S.
      • Pour Mohammad A.
      • Panahi P.
      • Mozafarpoor S.
      • Almasi S.
      • et al.
      Cutaneous manifestations and considerations in COVID-19 pandemic: a systematic review.
      Dermatol Ther. 2020; 33: e13986
      ). In a case series of 505 patients, 55% of the patients' only symptoms were pernio-like lesions lasting a median of 14 days (
      • Freeman E.E.
      • McMahon D.E.
      • Lipoff J.B.
      • Rosenbach M.
      • Kovarik C.
      • Takeshita J.
      • et al.
      Pernio-like skin lesions associated with COVID-19: a case series of 318 patients from 8 countries.
      J Am Acad Dermatol. 2020; 83: 486-492
      ). The most common cutaneous rash morphologies in a registry of 716 patients associated with COVID-19 with dermatological manifestations were morbilliform (22%), pernio-like lesions (18%), urticarial (16%), macular erythema (13%), vesicular (11%), papulosquamous (9.9%), and retiform purpura (6.4%) (
      • Freeman E.E.
      • McMahon D.E.
      • Lipoff J.B.
      • Rosenbach M.
      • Kovarik C.
      • Desai S.R.
      • et al.
      The spectrum of COVID-19-associated dermatologic manifestations: an international registry of 716 patients from 31 countries.
      J Am Acad Dermatol. 2020; 83: 1118-1129
      ). Pernio-like lesions were common in patients with mild disease, and retiform purpura presented exclusively in hospitalized patients (
      • Freeman E.E.
      • McMahon D.E.
      • Lipoff J.B.
      • Rosenbach M.
      • Kovarik C.
      • Desai S.R.
      • et al.
      The spectrum of COVID-19-associated dermatologic manifestations: an international registry of 716 patients from 31 countries.
      J Am Acad Dermatol. 2020; 83: 1118-1129
      ); these different manifestations are directly related to patient disease severity. Coronavirus particles were found in the cytoplasm of endothelial cells of the capillary and postcapillary venules of the upper dermis and secretory portion of eccrine units (
      • Colmenero I.
      • Santonja C.
      • Alonso-Riaño M.
      • Noguera-Morel L.
      • Hernández-Martín A.
      • Andina D.
      • et al.
      SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultrastructural study of seven paediatric cases.
      Br J Dermatol. 2020; 183: 729-737
      ); this establishes SARS-CoV-2 infection in the affected tissues. The pathogenesis of COVID-19‒associated cutaneous manifestations remains unknown. Other cutaneous lesions can result from SARS-CoV-2 infections reactivating latent viruses (
      • Brambilla L.
      • Maronese C.A.
      • Tourlaki A.
      • Veraldi S.
      Herpes zoster following COVID-19: a report of three cases.
      Eur J Dermatol. 2020; 30: 754-756
      ;
      • Elsaie M.L.
      • Nada H.A.
      Herpes zoster (shingles) complicating the course of COVID19 infection.
      J Dermatol Treat. 2020; : 1-3
      ;
      • Elsaie M.L.
      • Youssef E.A.
      • Nada H.A.
      Herpes zoster might be an indicator for latent COVID 19 infection.
      Dermatol Ther. 2020; 33: e13666
      ;
      • Ferreira A.C.A.F.
      • Romão T.T.
      • Macedo Y.S.
      • Pupe C.
      • Nascimento O.J.M.
      Fellow of the American Academy of Neurology (FAAN). COVID-19 and herpes zoster co-infection presenting with trigeminal neuropathy.
      Eur J Neurol. 2020; 27: 1748-1750
      ;
      • Le Balc’h P.
      • Pinceaux K.
      • Pronier C.
      • Seguin P.
      • Tadié J.M.
      • Reizine F.
      Herpes simplex virus and cytomegalovirus reactivations among severe COVID-19 patients.
      Crit Care. 2020; 24: 530
      ;
      • Tartari F.
      • Spadotto A.
      • Zengarini C.
      • Zanoni R.
      • Guglielmo A.
      • Adorno A.
      • et al.
      Herpes zoster in COVID-19-positive patients.
      Int J Dermatol. 2020; 59: 1028-1029
      ;
      • Xu R.
      • Zhou Y.
      • Cai L.
      • Wang L.
      • Han J.
      • Yang X.
      • et al.
      Co-reactivation of the human herpesvirus alpha subfamily (herpes simplex virus-1 and varicella zoster virus) in a critically ill patient with COVID-19.
      Br J Dermatol. 2020; 183: 1145-1147
      ). The majority of the observed mucocutaneous manifestations (maculopapular eruptions, urticaria, acral vasculopathic rashes, retiform purpura [late disease with likely wider dispersion], etc.) may have etiology associated with SARS-CoV-2‒hyperactivated mast cells releasing histamine and other inflammatory molecules.
      With collaborators, I have previously proposed that mast cell hyperactivation contributes to COVID-19 symptoms and disease progression (
      • Malone R.W.
      • Tisdall P.
      • Fremont-Smith P.
      • Liu Y.
      • Huang X.P.
      • White K.M.
      • et al.
      COVID-19: famotidine, histamine, mast cells, and mechanisms.
      Front Pharmacol. 2021; 12: 216
      ). As an alternative to the lesions representing a coagulation disorder or a hypersensitivity reaction, I propose that SARS-CoV-2 infection of endothelial cells and likely pericytes results in capillary vasoconstriction followed by vascular ischemia; this is followed by infiltrating lymphocytes and localized hyperactivation of mast cells releasing histamine and other inflammatory molecules. I propose that vascular ischemia and the released histamine are the most likely major initial components in the development of COVID-19‒associated cutaneous manifestations. Released local histamine is also the likely major source of the itching associated with COVID-19 cutaneous manifestations (
      • Shim W.S.
      • Oh U.
      Histamine-induced itch and its relationship with pain.
      Mol Pain. 2008; 4: 29
      ). This hypothesis concerning cutaneous manifestations of vascular ischemia and the histamine released from activated mast cells likely extends to most viral-associated cutaneous manifestations, including Kawasaki disease and multisystem inflammatory syndrome in children and multisystem inflammatory syndrome in adults (
      • Ricke D.O.
      • Gherlone N.
      • Fremont-Smith P.
      • Tisdall P.
      • Fremont-Smith M.
      Kawasaki disease, multisystem inflammatory syndrome in children: antibody-induced mast cell activation hypothesis.
      Journal of Pediatrics and Pediatric Medicine. 2020; 4: 1-7
      ). Mast cells can be activated by Fc receptor‒bound antibodies binding to virions or possibly viral proteins. The SARS-CoV-2 nucleocapsid protein has been predicted to bind to the cyclooxygenase 2 (COX-2) promoter upregulating PTGS2/COX-2, resulting in elevated prostaglandin E2 levels (
      • Yan X.
      • Hao Q.
      • Mu Y.
      • Timani K.A.
      • Ye L.
      • Zhu Y.
      • et al.
      Nucleocapsid protein of SARS-CoV activates the expression of cyclooxygenase-2 by binding directly to regulatory elements for nuclear factor-kappa B and CCAAT/enhancer binding protein.
      Int J Biochem Cell Biol. 2006; 38: 1417-1428
      ). Elevated levels of prostaglandin E2 can cause the hyperactivation of mast cells (
      • Morimoto K.
      • Shirata N.
      • Taketomi Y.
      • Tsuchiya S.
      • Segi-Nishida E.
      • Inazumi T.
      • et al.
      Prostaglandin E2–EP3 signaling induces inflammatory swelling by mast cell activation.
      J Immunol. 2014; 192: 1130-1137
      ). Another potential pathway for upregulating COX-2 includes the SARS-CoV-2 spike protein interacting with TNF-α‒converting enzyme inducing TNF-α production such as observed for the SARS-CoV-1 spike protein (
      • Haga S.
      • Yamamoto N.
      • Nakai-Murakami C.
      • Osawa Y.
      • Tokunaga K.
      • Sata T.
      • et al.
      Modulation of TNF-alpha-converting enzyme by the spike protein of SARS-CoV and ACE2 induces TNF-alpha production and facilitates viral entry.
      Proc Natl Acad Sci USA. 2008; 105: 7809-7814
      ); the NF-κB pathway is activated by inducing I-κBα degradation (
      • Wang W.
      • Ye L.
      • Ye L.
      • Li B.
      • Gao B.
      • Zeng Y.
      • et al.
      Up-regulation of IL-6 and TNF-alpha induced by SARS-coronavirus spike protein in murine macrophages via NF-kappaB pathway.
      Virus Res. 2007; 128: 1-8
      ). TNF-α stimulates COX-2 expression (
      • Kim J.
      • Lee S.
      • Jeoung D.
      • Kim Y.M.
      • Choe J.
      Activated human B cells stimulate COX-2 expression in follicular dendritic cell-like cells via TNF-α.
      Mol Immunol. 2018; 94: 1-6
      ). COVID-19‒associated cutaneous manifestations resolve after the immune system eliminates localized SARS-CoV-2‒infected cells. Persistent infections can result in localized anoxia and possibly gangrene (
      • Adekiigbe R.
      • Ugbode F.
      • Seoparson S.
      • Katriyar N.
      • Fetterman A.
      A 47-year-old Hispanic man who developed cutaneous vasculitic lesions and gangrene of the toes following admission to hospital with COVID-19 pneumonia.
      Am J Case Rep. 2020; 21: e926886
      ;
      • Novara E.
      • Molinaro E.
      • Benedetti I.
      • Bonometti R.
      • Lauritano E.C.
      • Boverio R.
      Severe acute dried gangrene in COVID-19 infection: a case report.
      Eur Rev Med Pharmacol Sci. 2020; 24: 5769-5771
      ).
      Treatments are consistent with the mast cell hypothesis associated with preliminary reports of clinical efficacy in patients with COVID-19. On the basis of initial responses of patients with COVID-19 to famotidine, we proposed the mast cell hypothesis (
      • Malone R.W.
      • Tisdall P.
      • Fremont-Smith P.
      • Liu Y.
      • Huang X.P.
      • White K.M.
      • et al.
      COVID-19: famotidine, histamine, mast cells, and mechanisms.
      Front Pharmacol. 2021; 12: 216
      ). Independently, montelukast (leukotriene receptor antagonist) (
      • Khan A.R.
      • Misdary C.
      • Yegya-Raman N.
      • Kim S.
      • Narayanan N.
      • Siddiqui S.
      • et al.
      Montelukast in hospitalized patients diagnosed with COVID-19.
      J Asthma. 2021; : 1-7
      ), dexchlorpheniramine (HRH1 antagonist) (
      • Morán Blanco J.I.
      • Alvarenga Bonilla J.A.
      • Homma S.
      • Suzuki K.
      • Fremont-Smith P.
      • Villar Gómez de Las Heras K.
      Antihistamines and azithromycin as a treatment for COVID-19 on primary health care - a retrospective observational study in elderly patients.
      Pulm Pharmacol Ther. 2021; 67: 101989
      ), and cetirizine (HRH1) (
      • Morán Blanco J.I.
      • Alvarenga Bonilla J.A.
      • Homma S.
      • Suzuki K.
      • Fremont-Smith P.
      • Villar Gómez de Las Heras K.
      Antihistamines and azithromycin as a treatment for COVID-19 on primary health care - a retrospective observational study in elderly patients.
      Pulm Pharmacol Ther. 2021; 67: 101989
      ) were discovered to exhibit efficacy in patients with COVID-19 consistent with the proposed mast cell hypothesis. Combining COX-2 inhibition with celecoxib (
      • Hong W.
      • Chen Y.
      • You K.
      • Tan S.
      • Wu F.
      • Tao J.
      • et al.
      Celebrex adjuvant therapy on COVID-19: an experimental study.
      Front Pharmacol. 2020; 11: 1795
      ) with famotidine is demonstrating efficacy in patients with COVID-19 (
      • Tomera K.
      • Malone R.
      • Kittah J.
      Hospitalized COVID-19 patients treated with celecoxib and high dose famotidine adjuvant therapy show significant clinical responses.
      SSRN. 2020;
      ,
      • Tomera K.M.
      • Malone R.W.
      • Kittah J.
      Brief report: rapid clinical recovery from severe COVID-19 with high dose famotidine and high dose celecoxib adjuvant therapy.
      Enliven: Pharmacovigilance and Drug Safety. 2020;
      ). Aspirin, with possible roles in anticoagulation, mast cell stabilization, and COX-2 inhibition, also exhibits efficacy in patients with COVID-19 (
      • Chow J.H.
      • Khanna A.K.
      • Kethireddy S.
      • Yamane D.
      • Levine A.
      • Jackson A.M.
      • et al.
      Aspirin use is associated with decreased mechanical ventilation, intensive care unit admission, and in-hospital mortality in hospitalized patients with coronavirus disease 2019.
      Anesth Analg. 2021; 132: 930-941
      ;
      • Osborne T.F.
      • Veigulis Z.P.
      • Arreola D.M.
      • Mahajan S.M.
      • Röösli E.
      • Curtin C.M.
      Association of mortality and aspirin prescription for COVID-19 patients at the Veterans Health Administration.
      PLoS One. 2021; 16e0246825
      ). Note that combining celecoxib with either dexamethasone or aspirin is contraindicated. It is possible that the observed efficacy from these treatments may be from alternative mechanism(s), including modulating neutrophil responses as an alternative to the proposed mast cell hypothesis. Case reports and/or case series evaluating responses of patients with COVID-19 with cutaneous manifestations receiving current standard of care compared with responses of matched patients receiving standard of care plus adjunctive therapy evaluating exemplar(s) from these proposed treatments (e.g., cetirizine and/or famotidine plus celecoxib) will inform follow-up studies if warranted.

      Distribution statement

      Data presented in this study are approved for public release. Distribution is unlimited.

      Data availability statement

      No datasets were generated or analyzed during this study.

      ORCID

      Darrell O. Ricke: http://orcid/org/0000-0002-2842-2809

      Author Contributions

      Conceptualization: DOR; Writing - Original Draft Preparation: DOR; Writing - Review and Editing: DOR

      Acknowledgments

      The author acknowledges the Department of Defense, Defense Threat Reduction Agency, and the Joint Science and Technology Office of the Chemical and Biological Defense Program for their support under the Discovery of Medical countermeasures Against Novel Entities initiative. This material is based on work supported under Air Force Contract number FA8702-15-D-0001.

      Disclaimer

      Any opinions, findings, conclusions, or recommendations expressed in this material are those of the author and do not necessarily reflect the views of the United States Air Force.

      Conflict of Interest

      The author states no conflict of interest.

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        • Ugbode F.
        • Seoparson S.
        • Katriyar N.
        • Fetterman A.
        A 47-year-old Hispanic man who developed cutaneous vasculitic lesions and gangrene of the toes following admission to hospital with COVID-19 pneumonia.
        Am J Case Rep. 2020; 21: e926886
        View in Article
        • Malone R.W.
        • Tisdall P.
        • Fremont-Smith P.
        • Liu Y.
        • Huang X.P.
        • White K.M.
        • et al.
        COVID-19: famotidine, histamine, mast cells, and mechanisms.
        Front Pharmacol. 2021; 12: 216
        View in Article
        • Morán Blanco J.I.
        • Alvarenga Bonilla J.A.
        • Homma S.
        • Suzuki K.
        • Fremont-Smith P.
        • Villar Gómez de Las Heras K.
        Antihistamines and azithromycin as a treatment for COVID-19 on primary health care - a retrospective observational study in elderly patients.
        Pulm Pharmacol Ther. 2021; 67: 101989
        View in Article
        • Brambilla L.
        • Maronese C.A.
        • Tourlaki A.
        • Veraldi S.
        Herpes zoster following COVID-19: a report of three cases.
        Eur J Dermatol. 2020; 30: 754-756
        View in Article
        • Chow J.H.
        • Khanna A.K.
        • Kethireddy S.
        • Yamane D.
        • Levine A.
        • Jackson A.M.
        • et al.
        Aspirin use is associated with decreased mechanical ventilation, intensive care unit admission, and in-hospital mortality in hospitalized patients with coronavirus disease 2019.
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        View in Article
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        SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultrastructural study of seven paediatric cases.
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        View in Article
        • Elsaie M.L.
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        Herpes zoster (shingles) complicating the course of COVID19 infection.
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        View in Article
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        • Youssef E.A.
        • Nada H.A.
        Herpes zoster might be an indicator for latent COVID 19 infection.
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        View in Article
        • Ferreira A.C.A.F.
        • Romão T.T.
        • Macedo Y.S.
        • Pupe C.
        • Nascimento O.J.M.
        Fellow of the American Academy of Neurology (FAAN). COVID-19 and herpes zoster co-infection presenting with trigeminal neuropathy.
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        • Kovarik C.
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        The spectrum of COVID-19-associated dermatologic manifestations: an international registry of 716 patients from 31 countries.
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        Pernio-like skin lesions associated with COVID-19: a case series of 318 patients from 8 countries.
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        • et al.
        Celebrex adjuvant therapy on COVID-19: an experimental study.
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        View in Article
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        • Misdary C.
        • Yegya-Raman N.
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        Montelukast in hospitalized patients diagnosed with COVID-19.
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        View in Article
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        Activated human B cells stimulate COX-2 expression in follicular dendritic cell-like cells via TNF-α.
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        Herpes simplex virus and cytomegalovirus reactivations among severe COVID-19 patients.
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        Prostaglandin E2–EP3 signaling induces inflammatory swelling by mast cell activation.
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        Severe acute dried gangrene in COVID-19 infection: a case report.
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        View in Article
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        View in Article
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        • Gherlone N.
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        • Tisdall P.
        • Fremont-Smith M.
        Kawasaki disease, multisystem inflammatory syndrome in children: antibody-induced mast cell activation hypothesis.
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        View in Article
        • Seirafianpour F.
        • Sodagar S.
        • Pour Mohammad A.
        • Panahi P.
        • Mozafarpoor S.
        • Almasi S.
        • et al.
        Cutaneous manifestations and considerations in COVID-19 pandemic: a systematic review.
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        View in Article
        • Shim W.S.
        • Oh U.
        Histamine-induced itch and its relationship with pain.
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        View in Article
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        • Spadotto A.
        • Zengarini C.
        • Zanoni R.
        • Guglielmo A.
        • Adorno A.
        • et al.
        Herpes zoster in COVID-19-positive patients.
        Int J Dermatol. 2020; 59: 1028-1029
        View in Article
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        • Malone R.
        • Kittah J.
        Hospitalized COVID-19 patients treated with celecoxib and high dose famotidine adjuvant therapy show significant clinical responses.
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        View in Article
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        Brief report: rapid clinical recovery from severe COVID-19 with high dose famotidine and high dose celecoxib adjuvant therapy.
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        • Yang X.
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        Co-reactivation of the human herpesvirus alpha subfamily (herpes simplex virus-1 and varicella zoster virus) in a critically ill patient with COVID-19.
        Br J Dermatol. 2020; 183: 1145-1147
        View in Article
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        • Hao Q.
        • Mu Y.
        • Timani K.A.
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        • Zhu Y.
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        Nucleocapsid protein of SARS-CoV activates the expression of cyclooxygenase-2 by binding directly to regulatory elements for nuclear factor-kappa B and CCAAT/enhancer binding protein.
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        View in Article

      Article info

      Publication history

      Published online: August 23, 2021
      Accepted manuscript published online 23 August 2021; corrected proof published online 2 December 2021

      Footnotes

      Cite this article as: JID Innovations 2021;1:100052

      Identification

      DOI: https://doi.org/10.1016/j.xjidi.2021.100052

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      © 2021 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology.

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