Bullous Pemphigoid After Vaccination With the Inactivated Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine: Two Cases in China

Coronavirus disease-2019 (COVID-19) led to a global pandemic in March 2020 due to a novel species of coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) that involved tens of millions of people.^1,2 Older adults, as well as individuals with coexisting conditions, including neurologic disease, are more susceptible to the virus and have a higher risk for complications.^3,4 To date, prophylactic vaccines have been found to be the most effective method to contain the COVID-19 pandemic.

Bullous pemphigoid (BP) is an autoimmune skin disease that mainly affects the elderly population. BP is typically characterized by the appearance of tense blisters on an erythematous base; these blisters are firm and difficult to break.⁵ When pressure is applied to the surrounding skin, a negative Nikolsky’s sign suggests a diagnosis of BP. On further evaluation, most individuals with BP have circulating immunoglobulin G (IgG) autoantibodies directed against the hemidesmosomal proteins, BP180 and BP230.⁵

In recent years, the incidence of BP has increased due to the aging of the population worldwide; improved technology in clinical diagnosis has also contributed to this increase.^6,7 Various precipitants have been identified in approximately 15% of patients with BP, including drugs (eg, dipeptidyl peptidase-4 inhibitors, diuretics, and vaccines), viruses, and exposure to ultraviolet or X-ray irradiation.^7,8 In a systematic review and meta-analysis, Lai et al⁹ reported that patients with BP were 5 times more likely to have neurologic disorders, including multiple sclerosis, dementia, Parkinson’s disease, epilepsy, and stroke, and most of these neurologic events occurred before the diagnosis of BP. In addition to conducting a clinical evaluation with a thorough dermatologic examination of the skin and mucosa, the clinician should make note of any precipitants, such as radiation therapy or the addition of a new drug to patient’s existing regimen, that would facilitate the diagnosis of suspected BP.¹⁰ The diagnosis of BP also relies on laboratory findings, including immunopathologic findings; enzyme-linked immunosorbent assay (ELISA) results have shown circulating autoantibodies against BP180 in brain tissue from patients with neurologic disease.^7,9

The purpose of the following case reports is to describe the clinical course of BP that developed in 2 patients with history of cerebral infarction who received the inactivated SARS-CoV-2 vaccine. The study was approved by The First Affiliated Hospital of Anhui Medical University in Hefei, China. Informed consent was obtained from both patients.

Case 1. A 67-year-old woman of Asian descent was hospitalized for a generalized rash that appeared 7 days after receiving the first dose of inactivated COVID-19 vaccine (Sinovac; Sinovac Biotech Life Sciences) and worsened after she received the second vaccine dose. This patient had a history of a cerebral infarction. She had no history of other medical conditions, including hypertension, hyperlipidemia, atrial fibrillation, or skin problems. The patient’s family medical history was unremarkable.

The clinical examination revealed tense blisters over erythematous patches on the trunk and extremities with rare mucosal involvement (Figure 1 A-C). Intense pruritus was noted. Results of initial laboratory studies, including complete blood count, were within the normal range, except for eosinophil count (Table).

A skin biopsy was performed, and histologic examination showed subepidermal detachment with eosinophils, neutrophils, and fibrin in the blister content, and a dermal inflammatory infiltrate (Figure 1D). Indirect immunofluorescence (IIF) on monkey esophagus exhibited linear IgG deposition at the dermal-epidermal junction (Figure 1E). In addition, direct immunofluorescence (DIF) showed linear deposits of C3 along the basement membrane zone (BMZ), as shown in Figure 1F.

Serum anti-BP180 autoantibodies were positive, while anti-DSG1 and anti-DSG3 autoantibodies were negative based on an ELISA (Table). Genetic testing and analysis showed the expression of HLA-DQB1*0302.

Case 2. A 66-year-old woman was hospitalized for a generalized, intensely pruritic rash that appeared 10 days after she received the first dose of inactivated COVID-19 vaccine (Sinovac). The patient had a history of a cerebral infarction with no significant history of other diseases or prescribed medications.

The clinical examination revealed “tense blisters” (a typical manifestation of BP that indicates that the blisters are firm and hard to be broken, with negative Nikolsky’s sign) over erythematous patches on the trunk and extremities accompanied by intense pruritus and rare mucosal involvement (Figure 2 A-C). As in the first patient, there were no abnormal findings on the initial blood test results except for eosinophil count (Table).

Similar to the first patient, histologic examination of the skin biopsy showed subepidermal detachment with eosinophils, neutrophils, and fibrin in the blister content and a dermal inflammatory infiltrate (Figure 2D). Linear IgG deposition at the dermal-epidermal junction was seen on IIF (Figure 2E). Again, DIF showed linear deposits of C3 along the BMZ (Figure 2F). Serum anti-BP180 autoantibodies were positive by ELISA, and anti-DSG1 and anti-DSG3 autoantibodies were negative.  As with the first patient, genetic testing showed the expression of HLA-DQB1*0302.

After consideration of the laboratory results, the diagnosis of BP was confirmed in both patients. The patients were treated with systemic glucocorticoids, antibiotics, topical corticosteroids, and emollients, which resulted in a marked reduction of pruritus and a regression of the lesions after 2 weeks.

BP has been reported after administration of viral vaccines, including tetanus, diphtheria, pertussis, polio, rabies, hepatitis B, rotavirus, pneumococcus, and influenza.^3,11 The latency period ranges from 1 day to the entire month after the vaccination, which may be shorter in the pediatric population.¹² The mechanism underlying vaccine-induced BP has not been established and therefore warrants further study. It is unlikely that the vaccine fully explains the association with BP due to the heterogeneity of vaccine structures and different basement membrane antigens.⁸ It has been hypothesized that mRNA vaccination against COVID-19 triggers a severe autoimmune response in patients with a relevant immunologic predisposition.^8,12 Furthermore, the COVID-19 vaccine activates B-cell immunity, which leads to the production of antibodies.^13,14 In addition, there are several case reports and studies showing that both inactivated SARS-CoV-2 and mRNA vaccines induce the development of BP.^13-15 The present case report adds to the body of literature studying patients who developed BP after receiving the inactivated SARS-CoV-2 vaccine; however, the results should be considered with caution because of limited evidence. Additional data and research are needed to establish a correlation between BP and COVID-19 mRNA and inactivated vaccines.

Because BP is an autoimmune skin disease, a genetic predisposition together with a history of triggering factors participate in the pathogenesis of BP. Several studies have shown the presence of the major histocompatibility complex class II genes, HLA-DRB1*04, HLA-DRB1*1101, and HLA-DQB1*0302, in patients with BP and mucous membrane pemphigoid in patients of Asian descent.¹⁶ In this study, genetic analyses in both patients showed the expression of HLA-DQB1*0302, which may be the genetic background for the autoimmune response in patients after COVID-19 mRNA vaccination.

Cases of BP have been previously associated with various causes,^15-17 and the current authors present 2 cases of BP occurring after receiving the inactivated SARS-CoV-2 COVID-19 vaccine. However, this finding should not discourage the use of vaccines that are currently the most promising method of combatting the COVID-19 pandemic. There was not enough evidence to call for genetic screening before receiving inactivated SARS-CoV-2 vaccines, or in those patients of a certain age or with history of neurologic events.

Ze Guo, PhD¹; Yifan Wang, MM¹; Huayang Tang, PhD¹; Min Fan, MM¹; Wenjun Wang, PhD¹; Yantao Ding, MM¹; Songke Shen, MM¹; Wenming Zhou, MD¹; Yuekang Zhang, BD²; and Zaixing Wang, PhD¹

¹Department of Dermatology, First Affiliated Hospital of Anhui Medical University, Hefei 230000, Anhui Province, China
²School of Clinical Medicine, Anhui Medical University, Hefei 230000, Anhui Province, China

Address all correspondence to: Ze Guo, PhD, Department of Dermatology, The First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Shushan District, Hefei 230000, Anhui Province, China; tel: 86-0551-62923042; email: guoze895@sina.com

none disclosed

This study was funded by the National Natural Science Foundation of China (no. 81502740); Natural Science Research Project of Anhui Universities (no. KJ2021A0283); Scientific Research Fund of Anhui Medical University (no. 2021XKJ133).