Clinical and histopathological spectrum of delayed adverse cutaneous reactions following COVID-19 vaccination

Abstract

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.

Keywords: COVID-19; cutaneous adverse reaction; vaccine.

FIGURE 1

Histopathological findings from injection‐site reactions. A, Patient 1: Superficial perivascular and interstitial mixed‐cell infiltrate with eosinophils and focal interface changes; ×100 original magnification. B, ×400 original magnification. C, Patient 2: Epidermal hyperplasia with spongiosis; ×100 original magnification. D, Numerous eosinophils are seen within the infiltrate; ×400 original magnification

FIGURE 2

Exanthematous drug‐like reactions. A, Patient 3: Generalized morbilliform eruption with scale. B, Perivascular lymphocytic infiltrate with vacuolar interface changes and necrotic epidermal keratinocytes; ×400 original magnification. C, Patient 4: Mixed‐cell infiltrate with eosinophils (arrows), vacuolar interface changes, and mild epidermal spongiosis; ×400 original magnification. D, Patient 5: Vacuolar interface changes with papillary dermal edema and a mixed‐cell infiltrate with eosinophils (arrows); ×400 original magnification

FIGURE 3

Eczematous reactions. A, Patient 6: Epidermal hyperplasia, spongiosis, and a eosinophil‐rich infiltrate; ×200 original magnification. B, Patient 7: Pityriasis‐rosea‐like eruption characterized by mild epidermal spongiosis and mounds of parakeratosis; ×400 original magnification. C, Patient 8: Epidermal hyperplasia, spongiosis, and parakeratotic scale‐crust in addition to a lymphohistiocytic infiltrate with eosinophils (arrows); ×400 original magnification

FIGURE 4

Vasculitic reactions. A, Patient 9: Sparse perivascular and interstitial infiltrate consistent with urticarial vasculitis; ×100 original magnification. B, Neutrophils and early fibrin deposition are seen within vessel walls; ×400 original magnification. C, Patient 10: Leukocytoclastic vasculitis with a dense perivascular and interstitial neutrophilic infiltrate, fibrin within vessels walls, and extravasated erythrocytes; ×100 original magnification

FIGURE 5

Bullous pemphigoid. A, Patient 11: Clustered, tense bullae on an erythematous base. B, Subepidermal separation with superficial infiltrate containing eosinophils; ×200 original magnification. C, Direct immunofluorescence showing linear deposition of C3 along the basement membrane zone from lesional tissue; ×200 original magnification. D, Patient 12: Scattered erythematous papulovesicles. E, Dense eosinophilic infiltrate with eosinophilic spongiosis and an intraepidermal vesicle; ×200 original magnification. F, Direct immunofluorescence showing linear deposition of C3 along the basement membrane zone from perilesional skin; ×200 original magnification