From the Journals

More data needed to better understand COVID-19 skin manifestations



An erythematous rash was the most common cutaneous manifestation in patients with COVID-19, followed by chilblain-like lesions and urticaria-like lesions in a systematic review of mostly European studies.

Qing Zhao, MD, Xiaokai Fang, MD, and their colleagues at the Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, in Jinan, China, reported the results of a literature review of 44 articles published through May 2020 that included 507 patients with cutaneous manifestations of COVID-19. The review was published in the Journal of The European Academy of Dermatology and Venereology.

Nearly all of the patients (96%) were from Europe, and more than half were women (60%), with an average age of 49 years. Most patients had multiple skin symptoms, with the most common being erythema (44%), chilblain-like lesions (20%), urticaria-like lesions (16%), vesicular manifestations (13%), livedo/necrosis (6%), and petechiae (almost 2%). The authors described erythema as being present in specific sites, such as the trunk, extremities, flexural regions, face, and mucous membranes. Slightly less than half of all patients had significant pruritus.

Data on systemic COVID-19 symptoms were available for 431 patients and included fever in about two-thirds of patients and cough in almost 70%, with dyspnea in almost half of patients. Almost 60% had fatigue, and almost 60% had asthenia. Information about the onset of skin symptoms was available in 88 patients; of these patients, lesions were seen an average of almost 10 days after systemic symptoms appeared and, in almost 15%, were the first symptoms noted.

Histopathologic exams were done for only 23 patients and, in all cases, showed “inflammatory features without specific pathological changes, such as lymphocyte infiltration.” In one study, reverse transcription polymerase chain reaction testing of skin biopsy specimens tested negative for SARS-CoV-2.

Expression of ACE2, the receptor of SARS-CoV-2, in the skin was evaluated in six of the studies. “Higher ACE2 expression was identified in keratinocytes, mainly in differentiating keratinocytes and basal cells compared to the other cells of skin tissues,” the authors wrote. These results were confirmed with immunohistochemistry, which, they said, found “ACE2-positive keratinocytes in the stratum basal, the stratum spinosum, and the stratum granulosum of epiderma.” They added that this provides evidence “for percutaneous infection or the entry of virus into patients through skin tissues,” but cautioned that more research is needed.

The authors acknowledged that there are still many unanswered questions about COVID-19, and that more clinical data and research are needed, to improve the understanding of the cutaneous manifestations associated with COVID-19.

Dr. Alisa N. Femia

In an interview, Alisa N. Femia, MD, director of inpatient dermatology in the department of dermatology at New York University, said that the cutaneous signs described in the review align well with what she has seen in patients with COVID-19.

At this point, it is unclear whether cutaneous manifestations of COVID-19 are a result of SARS-CoV-2 invading the skin or an immune response related to SARS-CoV-2, noted Dr. Femia, who was not involved in the research. One method of entry could be through transmitting virus present on the skin to another part of the body where infection is more likely.

While it is possible COVID-19 could be contracted through the skin, she noted, it is much more likely an individual would be infected by SARS-CoV-2 through more traditionally understood means of transmission, such as through respiratory droplets in person-to-person contact. “I think we are far away from drawing that conclusion, that one could touch a surface or a person who has COVID and contract it through their skin,” Dr. Femia said. “The skin has a lot of other ways to protect against that from occurring,” she added.

“SAR-CoV-2 obviously enters through the ACE2 receptor, which is fairly ubiquitous, and it has been seen in keratinocytes,” she said. “But the skin is one of our biggest barriers ... and further, studies to date have shown that that receptor is expressed in relatively low levels of the keratinocytes.”

Pathogenesis of different cutaneous manifestations may be different, Dr. Femia said. For example, urticaria and morbilliform eruption were described by the authors of the review as more benign eruptions, but pathogenesis may differ from that of so-called COVID toes and from the pathogenesis of purpura and ulcerations seen in patients with more severe disease, she noted. It is plausible, she added, that purpura and ulcerations may be a “direct invasion of SARS-CoV-2 into endothelial cells,” which creates secondary processes “that ultimately destroy the skin.”

Urticaria and morbilliform eruptions, on the other hand, “are more simply that the immune system is recognizing COVID, and in doing so, is also recognizing some antigens in the skin and creating a hypersensitive response to the skin” and has “nothing to do with the SARS-CoV-2 virus actually being in that location,” she said.

It is important to differentiate between patients who have skin manifestations attributed to COVID-19 and those with manifestations independent of COVID-19, which is difficult, Dr. Femia noted. A patient with COVID-19 and a cutaneous manifestation may be having a reaction to a medication. “It’s important to have a critical eye and to remember that, when we see these manifestations, we should always be investigating whether there was an alternative cause so that we can better learn what exactly we should be attributing to this infection,” she said

Dr. Adam Friedman, professor and interim chief of dermatology, George Washington University, Washington, DC

Dr. Adam Friedman

Adam Friedman, MD, professor and interim chair of dermatology at George Washington University, Washington, said the authors of the review had presented interesting work, but made some “assumptions that need to be proven.” Dr. Friedman also was not involved in the research, but agreed in an interview with the assessment that it is unlikely SARS-CoV-2 would penetrate the skin. While some viruses – such as the poxvirus that causes molluscum contagiosum and the herpes simplex virus – invade keratinocytes specifically, there is a particular clinical phenotype that results that is associated with changes in the epidermis. However, “the skin manifestations of COVID-19 do not fit with direct skin invasion, [but] rather the immune response to systemic disease,” he said.

“[I]n terms of systemic invasion through the skin, it is possible, but this study certainly doesn’t show that. The presence/expression of ACE2 in the epidermis doesn’t translate to route of infection,” Dr. Friedman said..

The study received financial support from Shandong First Medical University, the Innovation Project of Shandong Academy of Medical Sciences and the Shandong Province Taishan Scholar Project. The authors report no relevant financial disclosures. Dr. Femia and Dr. Friedman had no relevant financial disclosures.

SOURCE: Zhao Q et al. J Eur Acad Dermatol Venereol. 2020 Jun 28. doi: 10.1111/jdv.16778.

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