Skin is a potential host of SARS-CoV-2: A clinical, single-cell transcriptome-profiling and histologic study.

To the Editor: The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide. The lung is the main target organ of SARS-CoV-2; however, extrapulmonary virus distribution has been observed. Skin manifestations, including skin rashes, morbilliform exanthema and chilblains,2, 3, 4 have recently been reported as possible presentations in patients with COVID-19. However, the number of such cases has been relatively small, and whether SARS-CoV-2 might infect injured skin and cause COVID-19 is still unknown. We therefore examined whether the skin is a potential host of SARS-CoV-2 by analyzing clinical, histologic, and single-cell transcriptome data.

This retrospective analysis included 3128 patients with laboratory-confirmed COVID-19. Data were collected from the Shanghai Public Health Clinical Center and Wuhan Leishenshan Hospital. Skin rashes were present in 52 patients (1.66%). Among them, obvious skin lesions were present in 17 patients (0.54%) before the other symptoms of COVID-19 and in 35 (1.12%) in the early stages of the COVID-19 infection (Fig 1 , A and Supplemental Table I, available via Mendeley at https://data.mendeley.com/datasets/scvph5w5jr/1). The skin rashes were urticarial in 52 patients (52%), followed by papules (15%), erythema and papules (14%), scratch (10%), rhagades (6%), and chilblains (4%).

Fig 1

A, Presentation of skin rashes associated with patients with SARS-CoV-2. Left, Localized erythema and papule rash involving the hands. Center, Urticarial rash involving the back. Right, Papular rash on the breast. B, Uniform Manifold Approximation and Projection (UMAP) plot shows the expression levels of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine proteases (TMPRSSs) family genes in skin cells. Coexpression was found in cells in the skin granulosum. C, ACE2 expression in human skin tissue and immunofluorescent staining of viral nucleocapsid protein (NP) in skin tissue from a healthy patient (lower, normal) and a patient with COVID-19 (upper, infected). Scale bar = 50 μm. DAPI, 4′, 6-diamidino-2-phenylindole.

Among the 52 patients with skin rashes, 21 patients were treated with oral corticosteroid (prednisone, 10 mg thrice daily), and the average time for skin rash recovery was 4.2 ± 2.3 days. This was significantly shorter than 8.3 ± 5.1 days in patients who were not treated with corticosteroid (Supplemental Table II). Although the use of corticosteroids in treatment of patients with COVID-19 remains controversial, our data suggested that skin lesions are associated with COVID-19 and that corticosteroid therapy is effective.

To further investigate the association of SARS-CoV-2 and skin rashes present in patients with COVID-19, we performed single-cell RNA sequencing with keratinocytes from normal human skin. The data showed that angiotensin-converting enzyme 2, the viral host cellular receptor, was highly and specifically expressed in the granulosum of the skin, whereas transmembrane serine proteases were relatively scattered in all keratinocytes and melanocytes, and in duct, Schwann, and neurocyte cells. The coexpression of angiotensin-converting enzyme 2 and transmembrane serine proteases was particularly found in the granulosum (Fig 1, B). Nucleocapsid protein was expressed in cytoplasm of epidermis from patients with COVID-19 but was not detected in normal skin tissue (Fig 1, C). These data suggested that the skin is a potential host of SARS-CoV-2. Although this hypothesis needs further study, it is intriguing to conjecture that SARS-CoV-2 may directly infect the keratinocytes in the injured skin (Fig 2 ).

Fig 2

The potential risk of SARS-CoV-2 transmission via wounded skin causing COVID-19. ACE2, Angiotensin-converting enzyme 2; TMPRSS, transmembrane serine proteases.

In summary we noted in 52 patients with COVID-19, that skin manifestation can be present before the onset of fever or can coexist with fever and that angiotensin-converting enzyme 2 and transmembrane serine proteases were coexpressed in stratum granulosum keratinocytes. These findings highlight the potential risk of SARS-CoV-2 transmission via wounded skin in those with skin manifestations of the disease. Hence, recognition of skin lesions associated with COVID-19 by dermatologists and other health care professionals is essential.