Severe Cutaneous Adverse Reactions After COVID‐19 Vaccination: A Systematic Review

Since the outbreak of COVID-19, various vaccines have been developed to prevent viral transmission. Meanwhile, COVID-19 vaccines have been reported potentially to induce severe cutaneous adverse reactions (SCARs).1-3 SCARs, encompass several disease entities including Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS). However, a comprehensive review is still lacking. Thus, we performed this systematic review to investigate the demographics and outcomes of SCARs after COVID-19 vaccination. This systematic review was registered in the PROSPERO (CRD42022304144) and performed in accordance with the PRISMA guidance. A literature search was conducted in PubMed, Embase, Web of Science, and Cochrane Library until June 20, 2022. The search strategy was presented in Table S1. We included studies reporting at least one patient who developed SJS, TEN, AGEP, and DRESS after at least one dose of a COVID-19 vaccine. Quality assessment was presented in Tables S2 and S3. A total of 25 SCARs patients, including 15 SJS/TEN cases, 7 AGEP cases, 2 DRESS cases, and 1 overlapping AGEP/DRESS case, were identified. The data of 24 studies involving these 25 patients were presented in Table 1, Figure 1, and Table S4. Asia 7 (46.7%) Africa 2 (13.3%) America 1 (6.7%) Australia 1 (6.7%) Europe 4 (26.7%) M 6 (50.0%) F 6 (50.0%) NR 3 AZ 2 (15.4%) SP 5 (38.5%) MOD 3 (23.1%) BNT 3 (23.1%) NR 2 First 5 (55.6%) Second 4 (44.4%) NR 6 Improved 3 (27.3%) Resolved 8 (72.7%) NR 4 Asia 1 (14.3%) America 1 (14.3%) Europe 5 (71.4%) M 1 (20.0%) F 4 (80.0%) NR 2 AZ 2 (40.0%) MOD 2 (40.0%) BNT 1 (20.0%) NR 2 First 4 (100%) NR 3 Improved 1 (20.0%) Resolved 4 (80.0%) NR 2 Asia 1 (50.0%) Europe 1 (50.0%) M 1 (50.0%) F 1 (50.0%) AZ 1 (50.0%) BNT 1 (50.0%) First 1 (50.0%) Second 1 (50.0%) Improved 1 (50.0%) Resolved 1 (50.0%) Asia 9 (36.0%) Africa 2 (8.0%) America 3 (12.0%) Australia 1 (4.0%) Europe 10 (40.0%) M 9 (45.0%) F 11 (55.0%) NR 5 AZ 5 (23.8%) SP 5 (23.8%) MOD 5 (23.8%) J&J 1 (4.8%) BNT 5 (23.8%) NR 4 First 10 (66.7%) Second 5 (33.3%) NR 10 Improved 6 (31.6%) Resolved 13 (68.4%) NR 6 The mean age and standard deviation for the patients with SCARs was 48.5 ± 15.9 years. Most patients with SJS/TEN were from Asian countries, whereas AGEP were mostly from European countries. SCARs were recognized after the AstraZeneca (23.8%), Sinopharm (23.8%), Moderna (23.8%), and Pfizer vaccines (23.8%). SCARs were observed mostly after the first dose (66.7%). The onset time ranged from 6 hours to 7 weeks, while the resolution time ranged from 5 days to 8 weeks. Sixteen (64.0%) of the SCARs patients required systemic immunomodulant treatments, including corticosteroid (n = 13), cyclosporine (n = 1), and tumor necrosis factors-α inhibitors (n = 2). There was no mortality reported. Notably, a SJS patient following the first dose of Sinopharm vaccine recurred after she was rechallenged with the same vaccine in the second dose.2 We re-evaluated all included studies using Naranjo algorithm and RegiSCAR criteria (Table S5–S8). Based on the Naranjo score, only one SJS/TEN case ranked as probable,2 while in the other cases the causality of the COVID-19 vaccine was only possible. By the RegiSCAR criteria, definite cases were identified in 4 SJS/TEN, 1 AGEP, and 1 DRESS. Drugs are by far the most common cause of SCARs. The development of SCARs was rarely reported after the administration of vaccines. Childhood vaccines, including measles, mumps, rubella; combined diphtheria, tetanus, and acellular pertussis; pneumococcal conjugate; and influenza vaccines, were more commonly reported to be associated with SJS and TEN according to a retrospective study.4 Influenza vaccines were also reported about the association with the development of DRESS and AGEP.5, 6 Although the exact pathomechanism of COVID-19 vaccine-associated SCARs remains unclear, a delayed-type hypersensitivity response and the T-cell mediated immune response involving both CD4+ and CD8+ T cells are speculated.1 This study has several limitations. First, the relationship between SCARs and COVID-19 vaccination could not be ascertained due to the limited number of case reports available and a lack of detailed data in many studies. Second, ALDEN score, the causality algorithm for SJS and TEN, was not applicable, since the data of half-life of every COVID-19 vaccine were lacking. Third, although COVID-19 vaccination is considered to induce SCARs due to the absence of other new drug exposure, information about the survey of non-drug etiologies of SCARs was not fully reported in some studies. In conclusion, SCARs were reported as potential cutaneous adverse events following COVID-19 vaccination. More data from pharmacovigilance and pathogenesis research are warranted to demonstrate the casual relationship between SCARs and COVID-19 vaccines. None. This study was supported by research grants from the Ministry of Science and Technology, Taiwan (grant no. NSTC 111-2314-B-182A-111-MY3, NSTC 111-2622-B-182A-001 to C.-B.C.; grant nos. NSTC 108-2314-B-182A-104-MY3, NSTC 108–2320- B-182A-023-MY3, NSTC 108-2320-B-182A-024-MY2, NSTC 109-2320-B- 182A-008 -MY3, NSTC 111-2314-B-182A-113-MY3 to W.-H.C.) and Chang Gung Memorial Hospital, Taiwan (grant nos: CMRPG3L0851, CORPG3M0361, CMRPG3M2221 to C.-B.C.; and grant nos. CORPG3L0471, CORPG3L0472 to W.-H.C.). Po-Chien Wu, I-Hsin Huang, Chuang-Wei Wang, Wen-Hung Chung, and Chun-Bing Chen declared no conflicts of interest. The content of this manuscript has not been published entirely or in part, is not under consideration by another journal, and will not be simultaneously submitted elsewhere. Appendix S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.