key: cord-0695811-dvdb4rql authors: Larson, Valerie; Seidenberg, Roy; Caplan, Avrom; Brinster, Nooshin K.; Meehan, Shane A.; Kim, Randie H. title: Clinical and histopathological spectrum of delayed adverse cutaneous reactions following COVID‐19 vaccination date: 2021-08-08 journal: J Cutan Pathol DOI: 10.1111/cup.14104 sha: c5d1c055c189975f5e051acc1572b41cc4e71018 doc_id: 695811 cord_uid: dvdb4rql BACKGROUND: As more people become vaccinated against the SARS‐CoV‐2 virus, reports of delayed cutaneous hypersensitivity reactions are beginning to emerge. METHODS: In this IRB‐approved retrospective case series, biopsy specimens of potential cutaneous adverse reactions from the Pfizer‐BioNTech or Moderna mRNA vaccine were identified and reviewed. Clinical information was obtained through the requisition form, referring clinician, or medical chart review. RESULTS: Twelve cases were included. Histopathological features from two injection‐site reactions showed a mixed‐cell infiltrate with eosinophils and a spongiotic dermatitis with eosinophils. Three biopsy specimens came from generalized eruptions that showed interface changes consistent with an exanthematous drug reaction. Three biopsy specimens revealed a predominantly spongiotic pattern, consistent with eczematous dermatitis. Small‐vessel vascular injury was seen in two specimens, which were diagnosed as urticarial vasculitis and leukocytoclastic vasculitis, respectively. There were two cases of new‐onset bullous pemphigoid supported by histopathological examination and direct immunofluorescence studies. Eosinophils were seen in 10 cases. CONCLUSIONS: Dermatopathologists should be aware of potential cutaneous adverse reactions to mRNA‐based COVID‐19 vaccines. Histopathological patterns include mixed‐cell infiltrates, epidermal spongiosis, and interface changes. Eosinophils are a common finding but are not always present. Direct immunofluorescence studies may be helpful for immune‐mediated cutaneous presentations such as vasculitis or bullous pemphigoid. The rapid development of two US Food and Drug Administration (FDA)-approved mRNA vaccines against the SARS-CoV-2 virus, while hailed as a scientific breakthrough, has also raised concerns over adverse allergic events. 1 Immediate cutaneous allergic reactions occurring within minutes to hours after vaccine administration have included a diffuse erythematous rash, urticaria, and angioedema. 2 As a growing percentage of the population becomes vaccinated, a variety of delayed cutaneous reactions are also beginning to be reported. 3 Here, we describe the clinical and histopathologic features of delayed cutaneous adverse reactions from 12 patients after receiving an mRNA COVID-19 vaccine. Patients were seen in either a private practice or academic setting. Skin biopsies were submitted to a dermatopathology laboratory at a single urban academic center for microscopic examination and histopathologic diagnosis. Twenty-three potential cases were identified from our pathology data management system using the search terms "vaccine," "vaccination," "Pfizer," or "Moderna." Cases were included if sufficient clinical and vaccine-related information was available in our hospital-based electronic medical record (seven cases) or provided by the referring dermatologist on the requisition form (five cases). This study was approved by our Institutional Review Board. Table S1 . Three patients had skin biopsies that showed a spongiotic process. Eosinophils were easily identified in two of the biopsy speci- Figure 3C ). Vasculitic injury was seen in skin biopsies from two patients. with the Pfizer vaccine, albeit much more rarely. 3 We also report an We also report more severe immune-mediated events in our case series in conjunction with histopathological confirmation. In the case of patient 9, the development of urticaria within 24 hours of vaccination provided a strong temporal association. However, the persistence of these lesions 5 weeks later led to a biopsy, which showed evidence of vascular injury. Reactivation of known urticarial vasculitis has been reported in one patient following an unspecified mRNA vac- While a true association between these cutaneous adverse reactions and the COVID-19 vaccine cannot be determined from this case series or from currently published clinical trial data, data registries to report vaccine-related adverse events are available to physicians. 19 Dermatopathologists should be aware of the histopathological features of potential cutaneous adverse reactions to mRNA-based COVID-19 vaccines. In many cases, eosinophils are a prominent histopathological finding, although are not always identified. Other common histopathological features include epidermal spongiosis, vacuolar interface changes, and mixed-cell infiltrates. For immune-mediated cutaneous presentations, direct immunofluorescence studies may be helpful for diagnosis. We thank Dr Mark Halsey and Dr Jo-Ann Latkowski for providing clinical information and photographs. The data that support the findings of this study are available from the corresponding author upon reasonable request. Nooshin K. Brinster https://orcid.org/0000-0002-9731-4115 Randie H. 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