Cutaneous adverse reactions after COVID‐19 vaccines in a cohort of 2740 Italian subjects: An observational study

Abstract An in‐depth characterization of the incidence, morphology, and onset of COVID‐19‐vaccines cutaneous adverse reactions is currently lacking. The existing literature on COVID‐19 vaccination‐related cutaneous adverse reactions largely focused on messenger RNA vaccines and mainly included type 1 hypersensitivity reactions, such as urticaria and angioedema. Other cutaneous manifestations are still poorly characterized and have been classified as delayed hypersensitivity rash. Our prospective observational study on a sample of 2740 subjects who underwent the COVID‐19 vaccination aimed at defining the prevalence of cutaneous adverse reactions and at identifying their timing of onset and their correlation with the administered dose. Vaccine‐related cutaneous adverse reactions occurred in 50 subjects. Patients were asked to complete a questionnaire on the type of COVID‐19 vaccine received, the time of onset of cutaneous reactions, and the dates of administration. Out of 2740 individuals who received the COVID‐19 vaccination, 50 were diagnosed with cutaneous adverse reactions to vaccine, after the first dose in 28 patients, after the second in 20, and after both in two. We reported localized injection site erythema in 12 patients and generalized cutaneous reactions in 38 patients. Our study shows that cutaneous adverse reactions to COVID‐19 vaccination are not common and most often occur after the first dose, recurring infrequently after the second dose. These reactions are usually easily manageable and, even in severe generalized cases, oral antihistamines and corticosteroids were sufficient for resolution. Therefore, except for immediate hypersensitivity reactions, cutaneous adverse reactions do not represent a contraindication to the completion of the vaccination cycle.

January 6, 2021, January 29, 2021 and March 11, 2021, respectively. 2,3 Vaccination schedules involve a single dose for COVID-19 Vaccine Janssen and two doses administered via intramuscular route for the other vaccines; the interval between doses is 21 days for Comi-rnaty™, 28 days for Spikevax™, and 12 weeks for Vaxzevria™. During the first phase of vaccination, priority was given to healthcare providers and elderly people.
Currently, pivotal phase 3 randomized placebo-controlled trials provided data on the safety of the abovementioned vaccines, including reports of local injection-site reactions, known as "COVID-19 vaccine arm" and consisting in erythema, edema, and pain to the site of injection. 4 The existing literature on COVID-19 vaccination-related cutaneous adverse reactions (CARs) has largely focused on mRNA vaccines (Comirnaty™ and Spikevax™) 5 and mainly included type 1 hypersensitivity reactions, such as urticaria and angioedema. Other cutaneous manifestations are still poorly characterized and have been classified as delayed hypersensitivity rash. 6,7 Except for the recent American Registry systematic report of 414 CARs, 7 a deeper characterization of the incidence, morphology, and onset of COVID-19-vaccines CARs is lacking. 5,8 The objective of our study was, first, to define the prevalence of CARs in our sample, second, to identify the timing of reactions and their correlation with the administered doses (first, second, or both). A third objective was to characterize the cutaneous symptoms and, finally, to report our management of COVID-19 vaccine adverse reactions.

| MATERIALS AND METHODS
From January to July 2021, we conducted a prospective observational study on a total of 2740 subjects who underwent the COVID-19 vaccination and provided informed consent to use of their details. 2040 (74%) were health care workers and 700 (26%) were patients referring to the Department of Dermatology and Allergology of Policlinico Umberto I Hospital-Sapienza University of Rome. 2481 (91%) of subjects received Comirnaty™, 222 (8%), Vaxzevria™, and 37 (1%) Spikevax™. No subject was administered COVID-19 vaccine Janssen that was locally unavailable at the time of the study. Vaccine-related CARs occurred in 50 subjects; a thorough skin examination was performed in all patients; in seven cases histology and immunohistochemistry were also carried out to better define the diagnosis. In addition, patients were asked to complete a questionnaire on the type of COVID-19 vaccine received, the time of onset of cutaneous reactions, and the dates of administration. Comorbidities and concomitant therapies were also investigated. Serology and blood tests were carried out to investigate autoimmunity and inflammatory status.

| RESULTS
Out of 2740 individuals who received the COVID-19 vaccination during our observation period, 50 were diagnosed with CARs to vaccine, corresponding to an incidence of 31.28 cases/1000 people-year. Of these, 20 (40%) were males and 30 (60%) were females. Mean patients age was 47 (range: 22-76), and all patients were Caucasian.
In 28 patients (56%) CARs followed the first dose administration; in 20 patients (40%) and two patients (4%) CARs followed the second dose administration or both doses, respectively.
CARs occurred within 7 days from vaccine administration in 34 patients (68%), within 7-14 days in 13 patients (26%) and after more than 14 days in three patients (6%). They consisted of localized injection-site erythema in 12 patients (24%) and generalized   and Spikevax™, respectively. The most common generalized CARs were angioedema and urticarial rashes (28%) that in one patient presented with peculiar involvement of flexural areas and significant photosensitivity. Persistent generalized pruritus without any cutaneous manifestation (10%) and toxic erythema (8%), which is a typical drug-related rash, 9 were also frequent. Less common manifestations consisted in pityriasis rosea-like eruption, 10