A Review of Pityriasis Rosea in Relation to SARS-CoV-2/COVID-19 Infection and Vaccination

Pityriasis rosea (PR) is an acute exanthematous disease, commonly preceded by a primary solitary herald patch followed by the onset of smaller scaly papulosquamous lesions within days to weeks. The exact cause of PR remains unclear; however, rash eruptions are thought to be associated with systemic reactivation of human herpesvirus 6 and 7 (HHV-6/7). Several cutaneous manifestations, including PR, have been reported secondary to SARS-CoV-2 infection and/or COVID-19 vaccination. The purpose of this review is to synthesize available data regarding PR in close association with SARS-CoV-2/COVID-19 infection and/or vaccination. A total of 154 patients were included in this study with 62 females and 50 males. PR was reported to occur more commonly in association with SARS-CoV-2/COVID-19 vaccination (102, 66.2%) than during infection (22, 42.3%) or post-infection (30, 57.7%). Interestingly, only 7.1% of patients were tested for concomitant HHV-6/7 past or current infection, with 4.2% testing positive or reporting a history of roseola infantum. While rare, clinicians should be aware of the possibility of patients developing PR associated with SARS-CoV-2/COVID-19 infection and/or vaccination, among other cutaneous reactions. Future studies exploring the link between PR and SARS-CoV-2/COVID-19 infection and/or vaccination would be beneficial, including direct examination of tissue and serological studies for evidence of COVID-19-induced HHV‐6/7 reactivation.


Introduction And Background
Pityriasis rosea (PR) is an acute exanthematous disease, commonly preceded by a primary solitary herald patch followed by the onset of smaller finely scaly erythematous macules or plaques distributed along the trunk and limbs within days to weeks [1]. The exact cause of PR has not been identified; however, epidemiological and clinical features suggest an infective etiology [2]. Several cutaneous manifestations, including PR, have been reported secondary to SARS-CoV-2 infection and/or COVID-19 vaccination [3]. The purpose of this review is to synthesize available data regarding reports of PR eruptions in close association with SARS-CoV-2/COVID-19 infection and/or vaccination.

Review
We searched PubMed for studies reporting PR cases in relation to SARS-CoV-2/COVID-19 infection and/or vaccination on February 5, 2022. Of the 59 screened studies, 34 met the inclusion criteria, yielding a total of 154 patients ( Figure 1). The quality of evidence of the included studies was established using criteria from the 2009 Oxford Levels of Evidence, presented in Table 1.    Table  2).
PR is theorized to be a result of the reactivation of HHV-6 or HHV-7 [13,37]. Manifestations of PR classically arise with an initial solitary plaque called the "herald patch," often on the patient's trunk. In the following days to weeks, the rash generalizes, commonly throughout the trunk and upper arms. This is termed the second eruption, which consists of multiple, discrete, scaly oval plaques and patches along skin cleavage lines [38]. Our data regarding PR in close association with SARS-CoV-2/COVID-19 infection and/or vaccination revealed the appearance of a herald patch in only 36.4% of cases. Alternatively, PR-like eruptions (PR-LE) are typically associated with medications or vaccines. PR-LE do not typically present with a herald patch and instead tend to appear with confluent lesions, intense pruritus, and eosinophilia on histology [13,15]. This atypical presentation is more consistent with the PR described by the literature in association with SARS-CoV-2/COVID-19 infection and/or vaccination; several reports included in this study demonstrated PR with the absence of a herald patch, presence of pruritus, involvement of atypical sites, papulovesicular rash, and associated chilblain-like lesions. Although the presentation of COVID-19-related PR may be considered atypical, the majority of cases included in this study exhibited susceptibility to conventional supportive therapy with reported resolution of symptoms.
The cases described in this literature review had features of both PR and PR-LE, with neither form presenting more commonly in association with COVID-19 infection or vaccination. Thus, patients who develop a rash after SARS-CoV-2/COVID-19 infection and/or vaccination may present with either PR or PR-LE. Nearly all of the patients included in this review reported resolution of symptoms with supportive therapy, suggesting that either rash eruption should not hinder the continuation of the vaccination series. While the etiology of PR in relation to SARS-CoV-2/COVID-19 infection and/or vaccination remains unknown, of the cases included in this literature review that reported positive or negative serologies, 63.4% of cases described positive HHV-6/7 serologies, a past history of roseola infantum, or contact with a person who had roseola infantum. This supports the theory that SARS-CoV-2/COVID-19 infection and/or vaccination may lead to the reactivation of HHV-6/7 viruses. Català et al. [11] propose that the mechanisms of this reactivation may be due to a strong specific immune response against SARS-CoV-2/COVID-19 infection or the S protein from vaccines diverting cell-mediated control of another latent virus.
Limitations of this study include the disparateness of the reported data among different manuscripts, as well as the potential exclusion of relevant articles secondary to the search strategy.

Conclusions
While rare, clinicians should be aware of the possibility of patients developing PR or PR-LE associated with SARS-CoV-2/COVID-19 infection and/or vaccination, among other cutaneous reactions. The management of PR and PR-LE can likely remain supportive as most patients included in this study reported complete resolution of symptoms; however, clinical judgment and patient comfort should ultimately guide this decision. We would like to emphasize that we believe that the protective benefits provided by the SARS-CoV-2/COVID-19 vaccination against infection, hospitalization, and possible death far outweigh the risks of acquiring such cutaneous reactions. Future studies exploring the link between PR and SARS-CoV-2/COVID-19 infection and/or vaccination would be beneficial, including direct examination of tissue and serological studies for evidence of COVID-19-induced HHV-6/7 reactivation.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.