Response to McMahon et al's “Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: A registry-based study of four hundred fourteen cases”
Authors: Konstantinos Poulas, Konstantinos Farsalinos
Journal: Journal of the American Academy of Dermatology (2021)

To the Editor: McMahon et al1McMahon D.E. Amerson E. Rosenbach M. et al.Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: a registry-based study of 414 cases.J Am Acad Dermatol. 2021; 85: 46-55https://doi.org/10.1016/j.jaad.2021.03.092Abstract Full Text Full Text PDF PubMed Scopus (609) Google Scholar reported cutaneous reactions that occurred after the administration of messenger RNA (mRNA) COVID-19 vaccines. The authors recorded 414 unique patients and observed a broad spectrum of reactions after vaccination, from local injection site reactions and delayed large local reactions to urticaria and morbilliform eruptions. Several unusual reactions (erythromelalgia, pernio/chilblains, filler reactions, and pityriasis rosea-like eruptions) were also observed. All these lesions were characterized as local (near the injection site), according to the authors. Similar lesions, which were characterized as injection site reactions, were also reported by Blumenthal et al2Blumenthal K.G. Freeman E.E. Saff R.R. et al.Delayed large local reactions to mRNA-1273 vaccine against SARS-CoV-2.N Engl J Med. 2021; 384: 1273-1277https://doi.org/10.1056/NEJMc2102131Crossref PubMed Scopus (211) Google Scholar and Baden et al3Baden L.R. El Sahly H.M. Essink B. et al.Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.N Engl J Med. 2021; 384: 403-416https://doi.org/10.1056/NEJMoa2035389Crossref PubMed Scopus (6728) Google Scholar after the administration of the mRNA1273 vaccine. A close examination of the data presented by McMahon et al1McMahon D.E. Amerson E. Rosenbach M. et al.Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: a registry-based study of 414 cases.J Am Acad Dermatol. 2021; 85: 46-55https://doi.org/10.1016/j.jaad.2021.03.092Abstract Full Text Full Text PDF PubMed Scopus (609) Google Scholar in Figs 1 and 2 shows that the reactions were not limited to the injection site but were also distant. These findings should be considered as distant skin reactions, seemingly having the same origin/pathophysiology as the local reactions observed at the injection site. Additionally, many patients exhibited other systemic symptoms concurrently with the skin reactions. Fatigue was reported by 62% of vaccine recipients after the second dose of the mRNA1273 vaccine, while 25% experienced myalgia after the second dose of the BNT162b2. Other symptoms and clinical signs were also reported, such as gastrointestinal symptoms (3.9% after mRNA1273 second dose), syncope episodes, metallic taste, and hematuria. All these findings were not discussed in depth and, in our opinion, deserve further consideration. The case series by McMahon et al1McMahon D.E. Amerson E. Rosenbach M. et al.Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: a registry-based study of 414 cases.J Am Acad Dermatol. 2021; 85: 46-55https://doi.org/10.1016/j.jaad.2021.03.092Abstract Full Text Full Text PDF PubMed Scopus (609) Google Scholar presented 3 types of adverse effects: local skin reactions at the injection site, distant skin reactions, and/or more generalized adverse reactions. The authors did not consider the possibility that these phenomena may be closely linked. They did, however, mention that these exanthemas mimicked dermatologic manifestations of COVID-19 and suggested that an unexplained immune response may have been responsible for the findings. Since similar skin reactions and generalized adverse events have been reported after the administration of all SARS-CoV-2 vaccines available so far (mRNA and viral vectored), we formulate the hypothesis that the spike glycoprotein, which is produced as a result of the vaccination with all currently available vaccines, is responsible for these phenomena. In silico modeling studies suggest that an epitope of the SARS-CoV-2 spike protein, adjacent to the receptor–binding domain, may interact with the α7 nicotinic acetylcholine receptors.4Farsalinos K. Eliopoulos E. Leonidas D.D. Papadopoulos G.E. Tzartos S. Poulas K. Nicotinic cholinergic system and COVID-19: in silico identification of an interaction between SARS-CoV-2 and nicotinic receptors with potential therapeutic targeting implications.Int J Mol Sci. 2020; 21: 5807https://doi.org/10.3390/ijms21165807Crossref Scopus (60) Google Scholar These receptors are widely present in different cells, including T-lymphocytes and macrophages, and have a pivotal role as part of the cholinergic anti-inflammatory pathway. The potential interaction of the spike with α7 nicotinic acetylcholine receptors in macrophages was recently described.5Tanmay S. Labrou D. Farsalinos K. Poulas K. Is SARS-CoV-2 spike glycoprotein impairing macrophage function via α7-nicotinic acetylcholine receptors?.Food Chem Toxicol. 2021; 152: 112184https://doi.org/10.1016/j.fct.2021.112184Crossref PubMed Scopus (10) Google Scholar Dysregulation of this system could explain many of the clinical manifestations of COVID-19, could be linked to both systemic effects and skin lesions, and may play a role in the pathophysiology of severe COVID-19, in which immune dysfunction and hyperinflammatory responses appear to be implicated. Since this hypothesis is based on the interaction between the spike and α7 nicotinic acetylcholine receptors, it could be applicable to adverse effects related to the vaccination (which results in spike production), and this needs to be further explored. Considering that in many cases, skin lesions are not an isolated clinical manifestation, it is important that dermatologists record systemic symptoms and signs and be alert for the possibility that similar skin and systemic reactions may appear after the second vaccine dose. The authors are participating in patent applications regarding anti-COVID-19 therapies. Skin reactions to COVID-19 vaccines: An American Academy of Dermatology/International League of Dermatological Societies registry update on reaction location and COVID vaccine typeJournal of the American Academy of DermatologyVol. 86Issue 4PreviewTo the Editor: We thank the authors for their reply to our article and would like to clarify the concerns described.1 The letter noted that the distribution of COVID-19 vaccine skin reactions was unclear and suggested we delineate each reaction pattern as local, distant, or generalized.1 While we did not specify the body part affected by each reaction, we would also like to highlight the challenges with adopting the proposed local/distant/generalized approach. Patients often experienced multiple reactions simultaneously, including reactions both local and distant to the injection site. Full-Text PDF