key: cord-0756930-mm68dmdj
authors: Drago, Francesco; Broccolo, Francesco; Ciccarese, Giulia
title: PITYRIASIS ROSEA, PITYRIASIS ROSEA-LIKE ERUPTIONS AND HERPES ZOSTER IN THE SETTING OF COVID-19 AND COVID-19 VACCINATION
date: 2022-01-31
journal: Clin Dermatol
DOI: 10.1016/j.clindermatol.2022.01.002
sha: 94dc6b3ad06db0fa1e5a9dd64c7105280d7d75e7
doc_id: 756930
cord_uid: mm68dmdj

Pityriasis rosea (PR), pityriasis rosea like eruptions (PR-LEs) and herpes zoster (HZ) have been frequently reported during COVID-19 or following COVID-19 vaccination. PR is a self-limiting exanthematous disease and HZ a treatable condition, therefore their occurrence does not require discontinuation of the vaccination schedule. PR-LE is a hypersensitivity reaction and, therefore, less predictable in its course. In case of booster dose, the clinical manifestation may not recur, may be different from PR-LE or may present with systemic symptoms. However, also in the case of PR-LE, the possibility of mild and predominantly cutaneous adverse events should not discourage all eligible candidates to receive and complete the COVID-19 vaccination programme since such adverse reaction represent a small risk considering the possible severe and fatal outcome of COVID-19. We emphasize the relevance of looking for any viral reactivation in SARS-CoV-2 infected patients with skin eruptions; the search for viral reactivations could be useful not only for distinguishing between PR and PR-LE but also because viral reactivations may contribute to patient's systemic inflammation and influence the course of the disease.

Numerous skin manifestations have been reported during Coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 1,2 . Pityriasis rosea (PR) and pityriasis rosea-like eruptions (PR-LEs) have been repeatedly described 1 and authors have recorded a fivefold increase in the number of PR cases during the pandemic 2 . PR and PR-LE have also been frequently described following different COVID-19 vaccines [3] [4] [5] [6] . Furthermore, an increase of herpes zoster (HZ) cases and other viral reactivations in COVID-19 patients and HZ following COVID-19 vaccinations have been reported 1 . These observations raise many critical issues, namely: a) Is it possible to distinguish between PR and PR-LE? b) Can SARS-CoV-2 infection trigger viral reactivations? c) Why do PR, PR-LE and Herpes zoster (HZ) occur following COVID-19 vaccination?

PR is a common, self-limiting exanthematous disease associated with the endogenous systemic reactivation of human herpesvirus 6 (HHV-6) and/or HHV-7. The disease typically begins with a single, erythematous plaque followed by a secondary eruption with lesions on the cleavage lines of the trunk (configuration as a "theatre curtain"). In the classic form of PR, duration may vary from 2 weeks to a few months 7 . Although some authors have not been able to demonstrate this association, the relationship of PR with systemic active HHV-6 and HHV-7 infection is based on many and consistent observations. Several studies have identified HHV-6 and HHV-7 DNA by polymerase chain reaction (PCR) and real-time calibrated quantitative-PCR in plasma, peripheral blood mononuclear cells (PBMCs) and skin samples of patients with PR 8 ; mRNA expression and specific antigens have been documented in PR skin lesions by in situ hybridization and immunohistochemistry respectively 8, 9 . Furthermore, plasma load of HHV-6 and HHV-7, a direct marker of viral replication, is associated with the development of systemic symptoms as well as with a significant reduction of the humoral neutralizing antibodies, further supporting that PR is associated with the endogenous reactivation of HHV-7 or HHV-6 infection 8 . Herpesvirus virions in various stages of morphogenesis were detected by electron microscopy in PR skin lesions 10 and in the supernatant of co-cultured PBMCs of PR patients 8 . Lastly, the increased levels of interferon (IFN) α, IL-17, IFN-, vascular endothelial growth factor (VEGF), and CXCL10 in the sera of PR patients could again support a viral role in PR pathogenesis 11 . The fact that other authors reported contradictory results in their studies on PR is likely to be attributed to the sensitivity and specificity of the methods used. Sampling the patient in the acute phase or in convalescence, for example, is not immaterial, and the type of biologic material studied (PBMCs, plasma, tissue) and its combination with the method of study are of paramount importance.

Conversely, PR-LE is not a true form of PR and, although it is often difficult to distinguish clinically the two eruptions, PR-LE has a completely different pathogenesis. Unlike PR, PR-LE is not associated with HHV-6 and or -7 systemic reactivation but it has a pathogenesis more similar to that of other drug eruptions 12, 13 . PR-LE can be compared to PR just as morbilliform drug eruptions to measles. Clinical, histopathologic, and, primarily, virologic criteria have been proposed for distinguishing between the two forms (Table I) 

PR, PR-LE and HZ have also been described following COVID-19 vaccination 3-6, 14 .

Furthermore, PR and PR-LE have been reported following influenza, diphtheria, tuberculosis, poliomyelitis, tetanus, yellow fever, hepatitis A, rabies, Japanese encephalitis and human papilloma virus vaccines. Usually, PR develops a few weeks after vaccination whereas PR-LE after a few days. This different latency is due to the time required for HHV-6 or -7 reactivation resulting in PR longer than the immunological hypersensitivity reaction originating PR-LE 42, 43 . Unfortunately, also in PR and PR-LE cases occurring following COVID-19 vaccination the markers of HHV-6 and-7 systemic reactivation, such as detection of HHV 6/7 DNA in plasma and detection of positive IgM antibodies against HHV-6/7 in serum, have never been investigated 44 . VZV and HSV reactivations accounted from 3 to 14% of cutaneous reactions after mRNA COVID-19 and Oxford/AstraZeneca AZD1222 vaccines in a large case series of subjects 45, 46 . VZV reactivation was more frequent after BNT162b2 (Pfizer) vaccination and in men. The time elapsed before a viral reactivation was on average 7 days and reactivation was more frequent after the first dose than after the second (63% versus 37% of cases) 45, 46 . The pathogenesis of HZ, PR and PR-LE after vaccination is unknown.

Generally, adverse events following immunization may be fortuitous or closely 

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