Heterogeneous cutaneous reactions following COVID-19 vaccination and infection

Dear Editor, In the era of coronavirus disease 2019 (COVID-19), diverse mucocutaneous responses have emerged, linked to both active COVID-19 infection and its vaccines.[1,2] These responses ranged from common presentations, such as erythematous maculopapular lesions, urticaria, and purpuric eruptions, to rare conditions such as Stevens–Johnson syndrome, bullous diseases, and sweet syndrome. While COVID-19 infection and vaccination can have common mucocutaneous manifestations, they can also trigger distinct reactions. Herein, we present a case of lymphomatoid reaction following the Moderna (mRNA-1273; Moderna, Cambridge, MA, USA) vaccine and the subsequent development of lichen planus pemphigoides (LPP) after COVID-19 infection. Our patient, a 70-year-old male, presented with persistent erythematous, scaly, and crusted patches and plaques on the face, trunk, and limbs for 6 months [Figure 1a and b]. The symptoms were initially mild and were attributed to the first dose of the Moderna COVID-19 vaccine. His condition worsened 1 week after receiving the booster dose, leading to heightened itchiness [Figure 1]. No suspicious drug exposures were noted. Laboratory results revealed eosinophilia (1.3 × 103/μl) and elevated IgE (4460.00 IU/mL). Incisional biopsy showed subacute eczematous dermatitis [Figure 1c] with diffuse parakeratosis, exudation, spongiosis, acanthosis, and epidermotropism of atypical lymphocytes [Figure 1d and e]. These lymphoid cells expressed CD3, CD4, and CD25 but were negative for CD7, CD8, and CD20. This suggested the possibility of mycosis fungoides or adult T-cell leukemia/lymphoma. However, the antihuman T-lymphocyte virus-1/2 assay yielded negative results. Systemic steroid treatment with oral prednisolone (30 mg/day) resolved the rash. Therefore, a drug- or vaccine-induced lymphomatoid reaction with secondary eczematous changes was considered.Figure 1: Generalized erythematous, scaly, and crusted patches and plaques on (a) Anterior trunk (inset biopsy site on the abdomen) and (b) Posterior trunk, (c) Pathology showed a psoriasiform spongiotic dermatitis consistent with subacute eczematous dermatitis but also presence of epidermotropism and aggregation of (d and e) Atypical cerebriform lymphocytes. (H and E, [c] ×100, [d] ×400, [e] ×400).Three months later, the patient contracted COVID-19, and a week later, new skin lesions emerged, including vesicles, bullae, erosions, and crusted patches on the trunk [Figure 2a and b]. The patient denied using new medications, specifically antidiabetic drugs, such as dipeptidyl peptidase-4 inhibitors, during this period. Laboratory results showed no eosinophilia (0.0%). Histopathological examination revealed a lymphocyte-predominant subepidermal separation [Figure 2c]. Direct immunofluorescence analysis revealed linear IgG and C3 deposition at the dermoepidermal junction, with many IgM-deposited cytoid bodies in the papillary dermis [Figure 2d-f]. These findings suggested LPP. Due to persistent blister formation despite systemic steroid use (20–30 mg/QD) for 6 months, a repeat biopsy was conducted. Histopathological findings were still consistent with LPP. Anti-bullous pemphigoid (BP)180 testing yielded a positive result of >200 RU/mL. The patient's skin condition stabilized with continued systemic steroids (20 mg/QD), likely due to the subsidence of immune system activation against the coronavirus.Figure 2: Recurrent skin rash after COVID-19 infection. There were generalized erythema, scattered crusted or eroded papules, patches on (a) Chest, abdomen, back, and limbs, (b) Blisters were found, and blue dots marked the second skin biopsy site. The skin biopsy from the blister showed, (c) A subepidermal separation and band-like lymphocytic infiltration in the upper dermis, indicating a lichenoid infiltration. Direct immunofluorescence study showed linear, (d) IgG and (e) C3 deposition at the basement membrane zone and (f) Many IgM-deposited cytoid bodies. The findings indicated lichen planus pemphigoides, a rare variant of bullous pemphigoid. H and E, [c] ×100, [d-f] ×400).A lymphocyte activation test was performed, evaluating three biomarkers (granulysin, granzyme B [GZMB], and interferon [IFN]-γ). Results demonstrated positive reactivity to the Moderna vaccine (IFN-γ, granulysin, and GZMB) and the component with COVID-19 spike proteins but negative to the excipient polyethylene glycol 2000. These results further solidified the influence of the COVID-19 vaccine on the patient's clinical presentation. Although the mechanisms underlying these reactions are still being investigated, it is likely that they result from the host's immune response to viral particles, such as spike proteins or vaccine components, rather than a direct viral attack.[2,3] Among them, cutaneous lymphomatoid reactions have rarely been described in post-COVID-19 vaccination scenarios, especially the generalized form.[4] LeWitt et al. and Sernicola et al. each reported a case with clinical manifestations of pityriasis lichenoides and varioliformis acuta-like eruptions after BioNTech COVID-19 vaccine and histopathologic findings in both cases revealed cutaneous lymphomatoid reactions.[4,5] Notably, there have been limited reports of new-onset bullous pemphigoid following COVID-19 infection,[6,7] with one of the cases experiencing concomitant psoriasis exacerbation.[7] These cases, including our own, ruled out changes in medications, particularly anti-diabetic drugs. Interestingly, Ruffo di Calabria et al. reported a case of abrupt resolution of LPP after COVID-19 infection.[8] The patient had lichen planus diagnosed 2 months before contracting COVID-19. During the course of the COVID-19 infection, the patient developed blisters and was diagnosed with LPP. These skin lesions subsided along with the preexisting lichen planus post-COVID-19 resolution. Conversely, our patient exhibited a prolonged course despite systemic steroid treatment. Our case highlights the heterogeneous skin manifestations following both COVID-19 vaccination and infection. Cutaneous and lymphomatoid reactions postvaccination and LPP post-COVID-19 infection are infrequently reported phenomena. Furthermore, the underlying pathway of lymphomatoid reactions involves cell-mediated immunity, while LPP is associated with autoantibody-mediated immunity. The distinct skin presentations in these cases indicate the involvement of different immune pathways in the induction of cutaneous reactions. Further research is required to elucidate the mechanisms underlying these phenomena. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Data availability statement Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. Financial support and sponsorship Nil. Conflicts of interest Dr. Yu-Hung Wu and Dr. Chun-Bing Chen, editorial members at Dermatologica Sinica, had no role in the peer review process of or decision to publish this article. The other authors declared no conflicts of interest in writing this paper.