Negative SARS‐CoV ‐2 antibodies in patients with positive immunohistochemistry for spike protein in pityriasis rosea‐like eruptions

Pityriasis rosea-like eruptions (PR-LE) have been recently associated with COVID-19 infection and vaccines. Negative SARS-CoV-2 PCR and serology have been reported in patients with skin manifestations, suggestive of COVID-19 with positive immunohistochemistry (IHQ) for SARS-CoV-2 spike protein in skin biopsies.1-3 SARS-CoV-2 IHQ studies in biopsies of PR-LE are limited to a case report.4 Herein, we report on 3 patients with PR-LE with positive IHC for SARS-CoV-2 spike protein and negative serology. Three patients were evaluated between January and May 2021, and none of them had received COVID-19 vaccines at the time of evaluation or biopsy. IHQ with SARS-CoV/SARS-CoV-2 was performed on all cases [SARS-CoV/SARS-CoV-2 (COVID-19) spike antibody (1A9), dilution 1:100, lot no.43943, GTX632604; GeneTex Inc., Irvine, CA, USA]. The clone employed has shown specific immunoreactivity.5 We performed positive controls on placental tissue of postpartum women with SARS-CoV-2 infection, and negative controls on normal skin and in 7 skin biopsies with a pityriasis rosea diagnosis from 2019. The first case is a 22-year-old man with a 7-day history of a papulosquamous rash on his trunk, arms and legs (Fig. 1a), and petechiae in the feet dorsum. He referred fatigue, sore throat and close contact with a person diagnosed with COVID-19. IHC for SARS-CoV/SARS-CoV-2 spike protein was positive on the endothelium. IgG antibody testing for SARS-CoV-2 spike and nucleocapsid protein were both negative 5 months after the initial diagnosis. The second case is a 26-year-old woman with a 2-week history of a disseminated rash on her trunk and arms. She referred headache and sore throat 2 weeks prior. IHC for SARS-CoV/SARS-CoV-2 spike protein was positive on the endothelium. IgG antibody testing for SARS-CoV-2 spike and nucleocapsid protein were both negative 5 months after the initial diagnosis. The third case is a 31-year-old woman with a 1-month history of a disseminated rash on her trunk and arms. She referred headache during the last month. IHC for SARS-CoV/SARS-CoV-2 spike protein was positive on the endothelium and perivascular lymphocytes (Fig. 1d). IgG antibody testing for SARS-CoV-2 spike protein was negative 3 weeks after the initial evaluation. All the biopsy specimens presented acanthosis, focal parakeratosis, mild spongiosis, extravasated erythrocytes and a superficial perivascular lymphocytic infiltrate in the dermis (Fig. 1c). Minimal neutrophils were present in the stratum spinosum similar to another case reported.6 Due to the clinical features, evolution, histological findings and lack of human herpesvirus 6 (HHV-6) and 7 testing, we diagnosed the patients as having PR-LE.7 All three patients were treated with topical corticosteroids, and the rash resolved after 1 week without recurrence; the first patient received his first dose and the third patient received two doses of the COVID-19 vaccine without adverse events. The relationship between pernio and other cutaneous findings in COVID-19 has been challenging and complex. In SARS-CoV-2-associated perniosis, recent hypotheses have postulated that a robust innate and intrinsic immune activity driven by interferon-1 may explain the negative serological and PCR testing as it may drive viral clearance without inducing detectable antibody production.8, 9 If a similar immunological cascade happens in other COVID-19-associated manifestations, it warrants further investigation, but may explain the negative testing in the patients reported herein. More studies with IHC analysis of skin biopsies and lymphocyte assays for SARS-CoV-2-reactive T cells are necessary to clarify the relationship between SARS-CoV-2 and skin manifestations.9 Limitations of our report include the lack of HHV-6/7 investigation and the possibility of cross-reaction with other antigens or viruses. In conclusion, IHQ for SARS-CoV-2 may represent an important tool in the diagnosis of COVID-19 PR-LE especially in patients with negative serology or PCR. The prognosis of the dermatosis seems similar to other causes of PR-LE. The patients in this manuscript have given written informed consent to the publication of their case details. None to declare. None. The data that support the findings of this study are available from the corresponding author upon reasonable request. The data that support the findings of this study are available from the corresponding author upon reasonable request.