COVID‐19‐associated cutaneous manifestations: does human herpesvirus 6 play an aetiological role?

Dear Editor, Recently, during the development of the coronavirus disease 2019 (COVID‐19) pandemic, several publications have warned of possible cutaneous manifestations in association with this novel coronavirus (SARS‐CoV‐2). In our hospital, we have created a multidisciplinary unit with a specific protocol to attend to patients with these manifestations.

For this study, we included patients who, during the development of the pandemic, were clinically suspected and/or microbiologically confirmed to have COVID‐19 and also had a recent‐onset skin rash (within the last 4 weeks). All patients underwent biochemistry, haematimetry and serology for parvovirus B19 and for human herpesvirus (HHV)‐6, in addition to other serologies and a coagulation study according to clinical manifestations. Based on the findings of these tests, we randomly selected 12 hospitalized patients, of a similar median age, with COVID‐19 but without cutaneous manifestations, and we requested HHV‐6 serology. The SARS‐CoV‐2 antibody assay was Roche’s Elecsys® Anti‐SARS‐CoV‐2 (Roche, Basel, Switzerland) and the HHV‐6 antibody assay was ELISA‐VIDITEST anti‐HHV‐6 IgM (Vidia, Prague, Czech Republic). The protocol was approved by the Aragon Ethical Committee for Clinical Research.

In total, 53 patients were included between 1 May 2020 and 31 October 2020. Overall, 20 (38%) patients had a positive COVID‐19 test and the remaining patients had symptoms suggestive of COVID‐19. Unexpectedly, 12 of 53 patients presented IgM serology and/or seroconversion to IgG of HHV‐6; the other 41 patients were negative for IgM of HHV‐6. Of these 12 patients, only four (33%) tested positive for SARS‐CoV‐2 [for these 12 patients, the median delay between first symptoms and polymerase chain reaction (PCR) or serology was 3 days and 27·5 days, respectively]. Characteristics of these patients are summarized in Table 1. In the COVID‐19 control group, two patients had positive IgM for HHV‐6. Statistical analysis performed using Pearson’s χ²‐test did not show significant differences between the proportion of patients who were positive for HHV‐6 (12 of 53 vs. two of 12) in both groups (P = 0·64). For the same period of the previous year, 175 HHV‐6 IgM serologies were requested, of which only three were positive (all three in children).

Table 1.

Characteristics of the patients with positive serology for human herpesvirus (HHV)‐6

Patient no.	Sex, age (years)	Medical history	Clinical pattern	Location	Symptoms suggestive of COVID‐19	COVID‐19 testa	HHV‐6 serology	Coagulation studyb	Histology	Other findings
1	F, 14	–	Perniosis‐like	Feet	Fever	Negative (serology)	IgM+, IgG+	–	–
2	M, 4	–	Perniosis‐like	Hands and feet	Fever	Negative (PCR, serology)	IgG+ (seroconversion)	Normal	–	Brother with the same symptoms
3	M, 32	HIV	Maculopapular	Trunk, UP, LE, hands, palms or soles, mucous, genitals	Dyspnoea, general malaise/myalgia/asthaenia	Negative (serology)	IgM+, IgG+	–	Vacuolar interface dermatitis and inflammatory perivascular and interstitial infiltrate	Suspicion of toxicoderma owing to recent change of antiretroviral
4	M, 33	–	Maculopapular, pityriasis rosea‐like	Trunk, UP, LE, hands, feet, palms and soles, head	–	Negative (PCR, serology)	IgM+, IgG+	–	Vacuolar interface dermatitis with keratinocyte necrosis	Syphilis serology: negative
5	F, 29	–	Livedoid	UP, LE, hands, feet	Fever, myalgia, headache	Negative (PCR, serology)	IgM+, IgG+	Normal	Dermal oedema and ectasia of the superficial plexus capillaries
6	F, 4	–	Vesicular	Trunk, UP, LE, head, mucous	Fever, digestive symptomsc	Negative (serology)	IgM+, IgG+	–	–	VZV: IgG+, IgM− (vaccinated)
7	M, 50	–	Maculopapular	UP, LE	–	Negative (serology)	IgM+	–	–
8	M, 3	–	Perniosis‐like	Hands	Fever, digestive symptoms	Negative (serology)	IgM+, IgG+	Normal	–	Sister with same symptoms and inflammation and erythema of the helix
9	F, 48	–	Maculopapula and seborrhoeic dermatitis	Trunk, UP, head	Fever, general malaise/myalgia/asthaenia, headache, anosmia/ageusia	Positive PCR of nasopharyngeal swab, serology IgG+	IgM+, IgG+	–	–
10	F, 50	SLE	Worsening of SCLE	Trunk	General malaise/myalgia/asthaenia, anosmia/ageusia	Positive PCR of nasopharyngeal swab	IgM+, IgG+	Normal	Interface dermatitis consistent with SCLE
11	M, 49	Knee arthroscopic surgery with osteosynthesis material	Urticarial	Trunk, UP, LE, head	Fever, dyspnoea	Serology IgM+ (with negative PCR and without seroconversion)	IgM +, IgG+	–	Urticaria vasculitis	Normal complement levels
12	F, 45	Bronchial asthma	Maculopapular, erythema multiforme‐like	Trunk, UP, LE	Fever, dyspnoea, general malaise/myalgia, digestive symptoms	Positive PCR of nasopharyngeal swab, serology IgG+	IgM+, IgG+	–	–

M, male; F, female; UP, upper extremities; LE, lower extremities; PCR, polymerase chain reaction; VZV, varicella zoster virus; SLE, systemic lupus erythematosus; SCLE, subacute cutaneous lupus erythematosus. ^aKit, S/S. ^bInternational normalized ratio, prothrombin time, cephalin time, activated partial thromboplastin time, partial thromboplastin time, derived fibrinogen, D‐dimer, lupus anticoagulant, anticardiolipin, anti‐beta‐2 glycoprotein, antithrombin III, homocysteine and protein C and S. ^cNausea, vomiting, diarrhoea.

Galván Casas et al. described the following five clinical patterns of cutaneous manifestations associated with SARS‐CoV‐2: acral areas of erythema with vesicles or pustules (pseudochilblain), other vesicular eruptions, urticarial lesions, maculopapular eruptions and livedo or necrosis.¹ Various hypotheses about the mechanisms inducing the different cutaneous lesions have been proposed. These include immunological responses, hypercoagulability state, drug reactions, a direct cytopathic effect of SARS‐CoV‐2 or the role of the receptor of SARS‐CoV‐2, i.e. angiotensin‐converting enzyme 2, which was found to be expressed on the skin, mainly on keratinocytes.² Alternatively, the role of other viruses, particularly those belonging to the Herpesviridae family,² has been suggested, especially in vesicular eruptions, erythema multiforme lesions and pityriasis rosea.³, ⁴ In fact, recent reports refer to the increase in frequency of pityriasis rosea after the occurrence of the COVID‐19 pandemic.⁴, ⁵ In one case the reactivation of HHV‐6 was demonstrated by PCR,³ and a case of coreactivation of herpes simplex virus 1 and varicella zoster virus in a critically ill patient with COVID‐19 was also reported.⁶ In this regard, we want to highlight the finding of positive IgM serology for HHV‐6 in our series of patients. Cutaneous diseases that have been associated with HHV‐6 infection include roseola infantum, pityriasis rosea, Gianotti–Crosti syndrome, drug reaction with eosinophilia and systemic symptoms or thrombocytopenic purpura, among others.⁷ Nevertheless, an aetiological association between HHV‐6 infection and a cutaneous disease is complicated by the ubiquity and nearly universal prevalence of the virus. In addition, several samples over time are needed to demonstrate seroconversion, which is considered an indispensable requirement to prove the active pathological role of the virus.⁷ However, serology as a diagnostic procedure has disadvantages and limitations, such as a lack of interpretation for the diagnosis of reactivations or cross‐reactivity with other betaherpesviruses.⁸ As our patients do not share clinical characteristics, and the difference in the proportion of both groups is not statistically significant, it is very difficult to be sure that HHV‐6 has played an aetiological role in the development of cutaneous manifestations. However, it is even more difficult to attribute cutaneous manifestations to SARS‐CoV‐2 given the negative results of several microbiological tests, even repeatedly, in some of these patients. Thus, we want to emphasize the finding of a positive serology for HHV‐6 in different clinical patterns described in association with COVID‐19. We suggest that SARS‐CoV‐2 could cause the reactivation of other viruses, such as HHV‐6, which could be responsible for some cutaneous manifestations initially related to COVID‐19. The main limitation of our study is that only 38% of the patients were positive for SARS‐CoV‐2 (33% in the HHV‐6 group). Therefore, more studies are necessary to demonstrate the association between SARS‐CoV‐2 and HHV‐6, and its possible aetiological role in COVID‐19‐associated cutaneous manifestations.

Author Contribution

Isabel Abadías‐Granado: Conceptualization (equal); Data curation (equal); Investigation (lead); Methodology (equal); Writing‐original draft (lead). Alba Navarro‐Bielsa: Data curation (equal); Formal analysis (lead); Writing‐original draft (equal). Ana M. Morales‐Callaghan: Conceptualization (equal); Data curation (equal); Investigation (equal); Methodology (lead); Writing‐review & editing (equal). Lourdes Roc: Data curation (equal); Validation (lead). Catalina C. Suso‐Estívalez: Conceptualization (equal); Data curation (equal); Investigation (equal); Methodology (equal). Marina Povar‐Echeverría: Conceptualization (equal); Data curation (equal); Investigation (equal); Methodology (equal). Yolanda Gilaberte: Conceptualization (lead); Investigation (equal); Methodology (equal); Resources (lead); Supervision (lead); Writing‐review & editing (lead).