As of October 2023, nearly 45,000,000 Koreans received at least one vaccine dose against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and nearly 34,000,000 Koreans were diagnosed at least once with coronavirus dis- ease 2019 (COVID-19)¹. Although the global community rallied together to develop vaccines against SARS-CoV-2 following the emergence of the unprecedented COVID-19 pandemic, more than five million individuals across the globe died from the disease². Furthermore, the urgent need for vaccines did not allow for a sufficient period of vaccine development, raising concerns regarding the efficacy and safety of the many newly developed vaccines and leading to vaccine refusal by some individuals. Nevertheless, concerted efforts by experts and government officials have led to the complete vaccination of a majority of the population, resulting in a subsiding trend in the COVID-19 pandemic.

Since the beginning of the global battle against the COVID-19 pandemic, numerous studies and case reports have documented the development of cutaneous reactions following SARS-CoV-2 vaccination or infection. Initial observations of cutaneous manifestations in vaccinated or infected patients have piqued the interest of researchers and clinicians alike. Previous studies have reported diverse dermatologic findings related to SARS-CoV-2 vaccination, including injection-site reactions, urticarial eruptions, papulosquamous eruptions, alopecia areata, and herpes zoster, among others^3-7. The estimated incidence of cutaneous reactions following SARS-CoV-2 vaccination is 30%, albeit with a large variation among the studies⁶. Similarly, cutaneous manifestations of COVID-19 have been extensively documented, such as one study by Recalcati et al.⁸, which identified various cutaneous lesions, including erythematous rash, vesicular eruptions, urticaria, and chilblain-like lesions, in afflicted individuals⁹.

The majority of the large number of clinical studies elucidating the epidemiology of cutaneous manifestations of COVID-19 and those stemming from SARS-CoV-2 vaccination have been conducted in Western populations, and scholarly contributions originating from the Eastern Asian region are lacking from the current literature. The geographical imbalance in research output indicates a gap in our current understanding of the cutaneous reactions to SARS-CoV-2 infection and vaccination and highlights the need for the incorporation of the Eastern Asian perspective. Therefore, we conducted a questionnaire-based survey on the epidemiology and clinical characteristics of the cutaneous manifestations of SARS-CoV-2 infection and vaccination.

1. Study design

This multicenter, questionnaire-based survey was performed in 12 university hospitals across the Republic of Korea as follows: Asan Medical Center, Uijeongbu St. Mary's Hospital, Kyung Hee University Hospital, Daegu Catholic University Hospital, Jeonbuk National University Hospital, Konkuk University Hospital, Kyungpook National University Hospital, Inje University Busan Paik Hospital, National Medical Center, Chosun University Hospital, Pusan National University Yangsan Hospital, and Hanyang University Guri Hospital. Approval was obtained from the Institutional Review Boards of all participating hospitals before the survey.

2. Questionnaire-based survey

The study questionnaire included 35 and 42 questions related to cutaneous manifestations observed after SARS-CoV-2 infection and vaccination, respectively. The question- naire was administered to patients who visited the dermatology outpatient clinic of the participating hospitals. Informed consent was obtained from all survey participants. The survey was conducted between October 2022 and May 2023, and all responses were collected by July 31, 2023. Both the original Korean version and the English version of the questionnaire can be found in Supplementary Materials. After the collection of all responses, causality assessment was performed by a dermatologist, and the World Health Organization-Uppsala Monitoring Centre criteria were used for causality assessment based on the cutaneous lesions present at the time of the survey and the clinical information provided by respondents¹⁰.

3. Statistical Analysis

Data were presented as numbers and percentages of responders. Unanswered questionnaire items were excluded from the analysis. The χ² or Fisher's exact test was used to compare categorical variables, and Student's t test was used to compare continuous variables. All statistical analyses were performed using IBM SPSS statistics version 22 (IBM, Armonk, NY, USA). A p value of <0.05 was considered statistically significant.

1. Cutaneous reactions to SARS-CoV-2 vaccin- ation

A total of 707 participants who received SARS-CoV-2 vaccinations completed the questionnaire. Five different SARS-CoV-2 vaccines (AstraZeneca, Janssen, Moderna, Novavax, and Pfizer-BioNTech) were used in Korea during the CVID-19 pandemic. Fig. 1 summarizes the proportions of respondents who developed cutaneous reactions to specific SARS-CoV-2 vaccines.

Figure 1. Proportions of re-spondents who developed cutaneous reactions to specific SARS-CoV-2 vaccines

Modify Delete

1) Demographic characteristics of participant and risk for cutaneous manifestations after SARS-CoV-2 vaccination

The demographic characteristics of participants categorized by the vaccine type are presented in Table 1. The mean respondent age was 44.26 years, with a male/female ratio of 1:1.1. Following SARS-CoV-2 vaccination, 20.23% and 5.94% of the respondents reported the onset of new cutaneous lesions or aggravation of preexisting cutaneous conditions, respectively. Most of the respondents were patients visiting dermatology outpatient clinics, as reflected in their diverse dermatologic conditions. The most common dermato- logic condition was atopic dermatitis, followed by psoriasis and hair loss, which included all types of hair loss diseases. The risk for the onset of new cutaneous lesions following SARS-CoV-2 vaccination varied from 10.71% (Janssen) to 0% (Novavax), albeit without statistically significant difference among the vaccines. Conversely, the risk for the aggravation of preexisting cutaneous conditions after SARS-CoV-2 vaccination was the lowest for the AstraZeneca vaccine (0%), which was significantly lower than that for the other vaccines (p = 0.018).

2) Clinical characteristics of the respondents with new-onset cutaneous lesions after SARS-CoV-2 vaccination

The new-onset cutaneous lesions reported after SARS- CoV-2 vaccination were classified according to the vaccine product administered prior their development (Table 2). The types of the new-onset cutaneous lesions were not significantly different among the vaccine products. The most com- mon cutaneous lesion was urticaria/morbilliform eruption, which accounted for 61.86% of all new-onset cutaneous lesions, followed by eczema (46.61%), hair loss (22.88%), local injection-site reaction (16.10%), and psoriasiform erup- tion (11.02%). Pruritus was the most common subjective symptom of the cutaneous lesions, reported by 92.37% of the respondents, followed by heating sensation (44.92%). Pain and sensory changes were reported by 19.49% and 9.32% of the respondents, respectively. Approximately 30% of all cutaneous lesions developed after the first vaccination. The same percentage of cutaneous lesions developed after the second vaccination, whereas 36.44% of the cutaneous lesions developed following the third vaccination. While 60% of the respondents who received the AstraZeneca vaccine developed new cutaneous lesions after the first vaccination, new cutaneous reactions were noted more frequently after the second or third vaccination in respondents who received the Pfizer or Moderna vaccine. Only 10.17% of all new-onset cutaneous lesions developed either the fourth or the fifth vaccination. The distribution of new-onset cutaneous lesion types is shown in the Supplementary Table 1. Overall, more than half of the new-onset cutaneous lesions were located on arms, legs, and back.

3) Demographic characteristics and the clinical course of respondents with common new-onset cutaneous lesions after SARS-CoV-2 vaccination

The questionnaire included queries on the clinical course of cutaneous lesions. However, sufficient data for analysis were available only for the three most common conditions after the exclusion of the questions that were left blank by the respondents. Data on the clinical course and risk factors for the three most common cutaneous lesions (urticaria/ morbilliform rash, eczema, and hair loss) are summarized in Table 3. Briefly, the male/female ratio, age, and the time of onset did not significantly differ among the three most common cutaneous reactions. Respondents reported various systemic symptoms associated with vaccination, among which myalgia was the most common. Albeit exhibiting variation, the frequency of systemic symptoms did not significantly differ among the respondents with different cutaneous reactions. Fewer than 30% of the respondents who had urticaria/ morbilliform rash after vaccination received treatment. Con- versely, 52.73% and 65.22% of the respondents who developed eczema and hair loss after vaccination, respectively, received treatment. The majority of the respondents either visited outpatient clinics for treatment or waited for spontaneous improvement. Only two respondents were admitted. The final outcome varied among the cutaneous lesion types. The proportion of respondents who reported worsening of the cutaneous lesions over time was significantly higher for eczema than for urticaria/morbilliform rash or hair loss (23.64% vs. X% and y%, respectively; p = 0.040). In contrast, 14.16% of the respondents with urticaria/morbilliform rash reported the complete clearance of cutaneous lesions at some point, which was significantly higher than that reported for eczema and hair loss (X% and Y%, respectively; p = 0.033).

4) Causality assessment of new-onset cuta- neous lesions after SARS-CoV-2 vaccination

Based on the cutaneous lesion type and the clinical in- formation including the time of onset, causality assessment was performed for each case by dermatologists. Only 9.3% (18 out of 194) of all cases were determined as unlikely to be caused by SARS-CoV-2 vaccination. Causality assessment could not be performed in 28.9% (56 out of 194) of the cases. The majority of the remaining cases were assessed as possibly caused by SARS-CoV-2 vaccination.

5) Demographic characteristics of respond- ents who reported aggravation of preexisting cutaneous conditions after SARS-CoV-2 vaccination

Aggravation of the preexisting cutaneous conditions was reported by 42 (5.94%) respondents, whose demographic characteristics are summarized in Table 4. Briefly, the male /female ratio was 1:1.63. None of the respondents who received the AstraZeneca vaccine reported aggravation of preexisting cutaneous conditions. There was no significant difference in the proportion of specific preexisting cutaneous diseases that exhibited aggravation among the different vaccines. Atopic dermatitis (21.43%) was the most commonly reported preexisting cutaneous condition that aggravated following vaccination. Although systemic symptoms was reported by respondents who experienced aggravation of preexisting cutaneous conditions after vaccination, the rates were low, below 8% for all. Across all vaccine products, 42.86% of the respondents experienced aggravation of cutaneous lesions after the first vaccination, with a consistently decline in the frequency of aggravation with each booster shot. Fig. 2A illustrates the proportions of respondents who reported aggravation of specific preexisting cutaneous conditions. The three most common preexisting cutaneous conditions were atopic dermatitis, psoriasis, and alopecia, which were reported to be aggravated after SARS-CoV-2 vaccination by comparable proportions of respondents. Interestingly, no respondent with rosacea reported aggravation.

Figure 2. Proportions of respondents who reported aggravation of specific preexisting cutaneous lesions after (A) SARS-CoV-2 vaccination and (B) SARS-CoV-2 infection

Modify Delete

6) Risk factors for the new onset and aggra- vation of preexisting cutaneous lesions after SARS-CoV-2 vaccination

We assessed the potential risk factors for the development of new cutaneous lesions and the aggravation of preexisting cutaneous lesions after SARS-CoV-2 vaccination (Table 5). The respondents who developed new cutaneous lesions after SARS-CoV-2 vaccination were significantly older than those who did not experience any cutaneous reactions (43.29 ± 17.63 vs. 48.51 ± 16.97 years, p = 0.001). The presence of underlying disease, including malignancy, hypertension, diabetes mellitus, respiratory disease, and autoimmune disease, was not associated with a higher risk for the onset or aggravation of cutaneous lesions after SARS-CoV-2 vaccination. Myalgia was the only systemic symptom following SARS-CoV-2 vaccination that was significantly associated with a higher risk for the aggravation of preexisting cutaneous conditions (odds ratio [OR] 45.33, 95% confidence interval [CI] 3.16~650.97, p = 0.011). However, the presence of systemic symptoms associated with SARS-CoV-2 vaccination was strongly associated with a higher risk for the new onset of cutaneous lesions; the observed increased risk was present for all five reported symptoms (fever: OR 13.03, 95% CI 4.74~48.92, p < 0.001; chill: OR 5.31, 95% CI 1.93~20.45, p = 0.005; cough: OR 7.34, 95% CI 1.50~11.53, p = 0.038; sore throat: OR 13.39, 95% CI 1.77~101.55, p = 0.002; and myalgia: OR 22.34, 95% CI 8.77~83.75, p < 0.001) (Fig. 3A).

Figure 3. Presence of systemic symptoms and risk for cutaneous reactions after (A) SARS-CoV-2 vaccination and (B) SARS-CoV-2 infection *p < 0.05 **p < 0.001

Modify Delete

2. Cutaneous complications of SARS-CoV-2 infection

1) Demographic and clinical characteristics of respondents who experienced cutaneous complications after SARS-CoV-2 infection

A total of 682 participants who were infected with SARS-CoV-2 completed the questionnaire. Table 6 shows the demographic and clinical characteristics of all respondents. Among these 682 respondents, 91 (13.3%) and 66 (9.7%) reported the development of new cutaneous lesions and the aggravation of preexisting cutaneous conditions, respectively, after COVID-19 diagnosis. Urticaria/morbilliform rash was the most common new-onset cutaneous lesion (72.53%), followed by hair loss (23.08%), vesicular eruption (15.38%), acne and folliculitis (13.19%), and eczema (9.89%). Only one respondent reported chilblain-like eruptions in acral regions. Among all respondents who reported aggravation of preexisting cutaneous lesions after SARS-CoV-2 infection, atopic dermatitis was the most common condition (34.85%), followed by psoriasis (13.64%), hair loss (7.58%), and urticaria (7.58%). Fig. 2B shows the number of respondents with specific cutaneous lesions and the proportion of those who reported aggravation after SARS-CoV-2 infection. Pruritus was the most common symptom of cutaneous complications. Respondents who developed new cutaneous lesions following COVID-19 were significantly older than those without new cutaneous lesions (p = 0.046). Systemic COVID-19 symptoms were more common in respondents who developed new cutaneous lesions than in those without new cutaneous lesions (fever: OR 7.49, 95% CI 3.93~14.29, p < 0.001; chill: OR 4.23, 95% CI 2.16~8.27, p < 0.001; cough: OR 6.42, 95% CI 3.40~12.12, p < 0.001; sore throat: OR 6.62, 95% CI 3.48~12.62, p < 0.001; and myalgia: OR 6.06, 95% CI 3.19~11.51, p < 0.001) (Fig. 3B). Moreover, the proportion of respondents with underlying autoimmune diseases was significantly higher in those who developed COVID-19-associated new-onset new cutaneous lesions than in those without new cutaneous lesions (OR 3.88; 95% CI, 1.22~12.31; p = 0.038). Other underlying diseases, including hypertension, diabetes mellitus, respiratory diseases, and malignancy, were not associated with an increased risk for the development of new cutaneous lesions. Neither underlying diseases nor systemic COVID-19 symptoms were associated with a higher risk for the aggravation of preexisting cutaneous lesions. Information on the final outcome of the new-onset cutaneous lesions following COVID-19 infection was avail- able in 13 respondents. The cutaneous lesions persisted in 5 (38.5%) respondents, aggravated over time in 3 (23.1%) respondents, and exhibited partial and complete resolution in 3 (23.1%) and 2 (15.4%) respondents, respectively.