Introduction

Pityriasis lichenoides (PL) is a spectrum of histopathologically and clinically overlapping dermatological conditions, the two main types being pityriasis lichenoides et varioliformis acuta (PLEVA) and pityriasis lichenoides chronica (PLC) [1, 2]. PLEVA onsets acutely/subacutely with the eruption of polymorphous lesions ranging from macules, to hemorrhagic papules, to ulcers [1, 2]. PLEVA may involve burning, pruritus, and occasionally constitutional symptoms, and typically resolves within weeks to months [1, 2]. PLC onsets insidiously, is typically asymptomatic, and may relapse and remit for years [1, 2]. PLC is characterized by reddish-brown maculopapules containing centrally located micaceous scales [1, 2]. Both PLEVA and PLC lesions can leave hyper or hypopigmented pox-like scars [1, 2].

PL is diagnosed clinically, supported by skin biopsy demonstrating interface dermatitis and dense and diffuse lymphocytic infiltrate [1, 2]. Gradual acute and chronic type histopathological differences exist between PLEVA and PLC [1, 2]. Evidence on the treatment of PL is limited; however, a systematic review by Bellinato et al. (2019) recommended narrow-band ultraviolet B phototherapy (nb-UVB-PT) as first-line therapy and oral erythromycin or methotrexate with or without topical corticosteroids (TCS) as second-line therapies [3].

Recently, cases of PL following SARS-CoV-2 infection/vaccination have been reported, but not yet comprehensively reviewed. Cases of other dermatoses following SARS-CoV-2 infection/vaccination have been reviewed [4•]. Therefore, this review comprehensively summarizes PL cases following SARS-CoV-2 infection/vaccination to guide its diagnosis and management.

Methods

PubMed, Embase, and Web of Science were comprehensively searched in October of 2022 using the following: (“pityriasis lichenoides” OR “pityriasis lichenoides et varioliformis acuta” OR “PLEVA” OR “pityriasis lichenoides chronica” OR “mucha habermann”) AND (“covid” OR “SARS” OR “coronavirus”). Following PRISMA guidelines, title/abstract screening, full-text screening, and data extractions were completed in duplicate (Fig. 1) [5]. Articles reporting new-onset or exacerbation of PL following SARS-CoV-2 infection/vaccination were included.

Fig. 1
figure 1

Search strategy employed to identify cases of pityriasis lichenoides following SARS-CoV-2 infection and/or vaccination

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Results

Thirteen articles, comprising 14 cases of PL following SARS-CoV-2 infection/vaccination, were included [6–15, 16•, 17, 18•]. The mean age of those affected was 41.4 years (median 41.0 years, range 6.0–81.0 years) and 64.3% of those affected were male. Of these cases, ten (71.4%) were PLEVA/ “PLEVA-like” and four (28.6%) were PLC. Thirteen cases (92.9%) were new-onset, while one (7.1%) was an exacerbation of previous PL disease. The majority of cases (N = 9, 64.3%) were associated with SARS-CoV-2 vaccination, while four (28.6%) were associated with SARS-CoV-2 infection. One case (7.1%) followed infection, and recurred following subsequent vaccination. The majority of vaccine-associated cases (n = 8/10, 80%) followed the Pfizer-BioNTech vaccine, while one (10.0%) followed the Oxford-AstraZeneca vaccine and one (10.0%) followed the Sinopharm vaccine. Additionally, 40.0% (n = 4/10) following vaccination followed the first dose, while 40% (n = 4/10) followed the first dose, with worsening after the second, and 20% (n = 2/10) followed the second dose. Latency period ranged from 5 days to 1 month overall and for cases following vaccination, and 10 to 17.5 days for cases following infection. The mean latency period was 13.8 days overall and for cases following infection, and 13.7 days for cases following vaccination. The most common lesion location was the limbs, affected in 11 cases (78.6%), followed by the torso affected in ten (71.4%), the face/scalp affected in three (21.4%), and finally the neck affected in one (7.1%). Cases’ scores on Naranjo’s Adverse Drug Reaction Probability Scale (ADRPS) averaged 6.3 and ranged from 5.0 to 8.0 [19].

Two patients (14.3%) received no treatment, and treatment use was not reported in two cases (14.3%). However, all four of these cases (100.0%) reported complete resolution at unspecified time points.

One patient (7.1%) received oral corticosteroids with complete resolution at 1 month. Oral corticosteroids with TCS were used in two cases (14.3%) with complete resolution at 1 and 5 months. Oral azithromycin with TCS was used in one case (7.1%) with marked improvement at 5 months. Oral doxycycline with TCS was used in one case (7.1%) with no improvement at 1 month. Oral doxycycline was used alone in two cases (14.3%), with one reporting complete resolution at 3 months, while the other did not report follow-up. Topical fusidic acid with TSC and nb-UVB-PT was used in one case (7.1%) with complete resolution at 10 weeks, while oral azithromycin with TCS and topical immunosuppressant was used in one case (7.1%) with marked improvement at 2 months. Finally, nb-UVB-PT was used alone in one case (7.1%) with complete resolution at 2 months. Results are summarized in Table 1.

Table 1 Summary of cases reporting pityriasis lichenoides following SARS-CoV-2 infection and/or vaccination (TCS, topical corticosteroid; nb-UVB-PT, narrow-band ultraviolet B phototherapy)
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Discussion

While the etiology of PL remains unknown, proposed mechanisms of disease include immune-mediated hypersensitivity vasculitis, inflammatory response to T-cell dyscrasia, or infectious or drug-related hypersensitivity reaction [2]. The latter is supported by the fact that many viruses (e.g., human immunodeficiency virus, Epstein-Barr, varicella-zoster, parvovirus B19, cytomegalovirus, and adenovirus) and vaccinations (measles, mumps, and rubella (MMR); tetanus; diphtheria; influenza; and human papilloma virus) have been linked to PL [1, 2, 20,21,22,23]. While the link between vaccinations/infections and PL is not fully understood, it is thought that viral antigens serve as an epidermal target, and PL is the cutaneous manifestation of this cytotoxic hypersensitivity [5].

While this review cannot determine causality, Naranjo’s ADRPS suggests SARS-CoV-2 may be a “probable” cause of PL [19]. However, this scale is not well validated [24, 25]. These cases could also be due to chance coincidence, as many people have been infected with, or vaccinated for, SARS-CoV-2, and not been affected by PL. If this association is in fact not due to chance, causality still cannot be established, and the risk of PL with SARS-CoV-2 is likely extremely small and at this time should not deter individuals from receiving vaccination. More infection/vaccination challenge may lead to more evidence into the relationship between SARS-CoV-2 and PL, and the etiology of PL in general.

It is of the utmost importance that possible side effects of vaccines are reported. These can be reported via platforms such as the Vaccine Adverse Event Reporting System (VAERS) (co-sponsored by the Food and Drug Administration (FDA) and the CDC), and the Canadian Adverse Events Following Immunization Surveillance System [26, 27]. Additionally, these platforms perform active surveillance of case reports from health professionals, health facilities, and publications in scientific journals [28]. These reports are considered a “signal,” or a “preliminary indication of a product-related issue” [28]. Signals are then evaluated to determine their validity [28]. This may include conducting vaccine studies, for example, via case-crossover designs which are used to study transient effects on the risk of acute events, and involves the patient acting as his or her own control [29]. A cohort study published by Akpandak et al. (2022) assessed whether vaccination against SARS-CoV-2 was associated with an increased risk of herpes zoster infection [30]. No increased risk was found [30]. This is an example of a signal derived from case reports that was not supported by properly conducted epidemiological studies, suggesting the initial reports were coincidental. However, should vaccine studies suggest increased risk or causality, this can lead to regulatory action including but not limited to re-assessment of risk/benefit profiles of vaccines, the dissemination of risk alerts to healthcare professionals and consumers, and even market withdrawals [28].

This article highlights the importance of clinicians taking a thorough SARS-CoV-2 infection/vaccination history for new or exacerbated PL. Additionally, this article provides preliminary insight into the risk window for PL in relationship to SARS-CoV-2 vaccination. The risk window is the period of time in which subjects are considered to be at an increased risk of adverse events following vaccination [31]. Based on the latency period determined in this study, which ranged from 5 days to 1 month following vaccination, with a mean of 13.7 days, the risk window is likely confined to approximately 1 month following vaccination.

The treatment of PL is not well established, and varied among these cases, as did follow-up periods making comparisons difficult. However, considering that at the time of follow-up, 12/14 patients (85.7%) had either marked improvement or complete resolution of lesions, clinicians should provide their patients with reassurance, in addition to nb-UVB-PT or oral erythromycin or methotrexate with or without TCS, as suggested by Bellinato et al. [3].

Small sample sizes, likelihood of unreported cases, and lack of controlled studies are limitations of this review.

Conclusion

In conclusion, 14 cases of PL following SARS-CoV-2 infection/vaccination were identified. Although this review does not prove causality, the case reports observed a temporal association and in one case PL occurred after natural SARS-CoV-2 infection, and recurred with subsequent vaccination, suggesting an association. However, these cases could be due to chance coincidence, and if they are not, the risk of developing PL following SARS-CoV-2 infection/vaccination is likely still extremely minimal. This review adds to the growing body of evidence suggesting the etiology of PL to be an infectious or drug-related hypersensitivity reaction. Therefore, clinicians including dermatologists should inquire about recent SARS-CoV-2 infection/vaccination when diagnosing a new or exacerbated case of PL. Additionally, given that the majority of patients experienced marked improvement or complete resolution of lesions at the time of follow-up, clinicians should provide reassurance to those affected.