No antibody response in acral cutaneous manifestations associated with COVID‐19?

Editor,

Skins symptoms during COVID‐19 have been recently described, but their relation to SARS‐CoV‐2 is unclear while results for real‐time reverse transcriptase polymerase chain reaction (rRT‐PCR) testing were variable. ¹ , ² , ³ Recalcati et al. ² reported 14 cases of patients with skin symptoms consistent with previous described COVID‐19 lesions, but all the patients were tested negative. They asked for a serology to validate the hypothesis that these lesions are related to COVID‐19. ²

We identified ten patients (median age 27 years) with acral cutaneous manifestations suggestive of COVID‐19 and serological assay, rRT‐PCR on nasopharyngeal swab (n = 10), skin biopsy (n = 3) with PCR (n = 4) on histological material were performed. All patients had acral chilblain‐like lesions (Fig. 1d). Two patients had non‐specific symptoms (asthenia, shiver, conjunctivitis and headache) 6–7 days before skin lesions. The cutaneous lesions consisted in erythemato‐violaceous, infiltrated papules or macules, located on the dorsum or the tips of the toes, associated with a mild swelling. They were slightly painful or pruriginous. A bullous evolution occurred in five patients (Fig. 1f). The dorsal aspect of the forefoot (Fig. 1f), the lateral sides of the feet or the heel were also frequently involved. One patient displayed similar lesions on the soles (Fig. 1a). These cutaneous manifestations affected both feet except in one patient. Two patients displayed fingers associated lesions. All of them had favourable outcome without specific treatment within 2–4 weeks. Skin biopsy showed a superficial and deep perivascular and perisudoral infiltrate of lymphocytes and histiocytes (Fig. 1b,e). The infiltrate was slightly lichenoid. In one biopsy, parietal fibrinoid necrosis was seen in a deep dermal arteriole (Fig. 1c). In another one, oedema of the papillary dermis was obvious and histiocytoid cells and caryoclasia accompanied lymphocytes in the dermis (Fig. 1g).

Figure 1.

Acral cutaneous manifestation and associated histological findings in three patients. (a) Chilblain‐like lesions of the tips of the toes with associated lesions on the soles. (b) Superficial and deep perivascular and perisudoral lymphoide infiltrates (HPS). (c) Parietal fibrinoid necrosis in a deep dermal arteriole (HE&S). (d) Violaceous chilblain‐like lesions. (e) Superficial and deep perivascular lymphoide infiltrates slightly lichenoid (HE&S). (f) Chilblain‐like lesions with vesciculo‐bullous lesion and forefoot involvement. (g) Oedema of the papillary dermis, lymphocytes, histiocytes and histiocytoid cells infiltrates with caryoclasia (HE&S). (h–j) Immunohistochemistry staining: histiocytoid cells marked with myeloperoxydase (h), anti CD163 (i), and not CD15 (j)

Immunohistochemistry showed a massive infiltrate of both CD4⁺ and CD8⁺ T cell, some being granzyme B⁺, and of CD68⁺ CD163⁺ CD15⁻ myeloid precursors cells (histiocytoid cells; Fig. 1i,j) that expressed myeloperoxydase in one patient (Fig. 1h), as described in the histiocytoid Sweet Syndrome. ⁴

Real‐time reverse transcriptase‐PCR for SARS‐CoV‐2 on skin biopsies and nasopharyngeal swabs were all negative. SARS‐CoV‐2‐specific IgA and IgG antibodies (EUROIMMUN, Luebeck, Germany) were undetectable in all patients. Complete blood count, hepatic and kidney functions, C‐reactive protein, immunoglobulins blood levels, cryoglobulinaemia, complement system exploration and antiphospholipid antibodies were normal, and HBV, HCV and HIV serology were negative.

Most of dermatological manifestations during the COVID‐19 involved the cutaneous microvascular system with acral eruption with possible bullous evolution, chilblain‐like lesions, transient livido reticularis and acrocyanosis. ¹ , ² , ³ , ⁵ Because endothelial cells express ACE2, a receptor for SARS‐CoV‐2, microvascular lesion is consistent with pathophysiology of COVID‐19. While evidence of SARS‐CoV‐2 in the lung during the acute phase has been provided through electron microscope, immunohistochemical staining and rRT‐PCR, only inflammatory lesions were found in other organs and tissues. ⁶ In support, none of our patients were positive for SARS‐CoV‐2 on rRT‐PCR on skin biopsy nor had detectable anti‐SARS‐CoV‐2 antibodies, despite an overall sensitivity of serological assay above 80%. ⁷ We propose that these skin lesions could be due to cytotoxic CD8 T cells, locally recruited to kill some infected keratinocytes and/or endothelial cells. Accordingly, SARS‐CoV‐2 proteins have been previously evidenced in a COVID‐19 patient with similar cutaneous manifestations. ⁸ During COVID‐19, lower levels of specific antibodies have been reported in patients with mild compared to severe disease ⁹ suggesting that T‐cell exhaustion and viral‐associated immunosuppression may dampen the production of SARS‐CoV‐2 specific antibodies. ¹⁰ Inability of the host immune system during mild form of the disease to completely clear the virus may contribute to explain these delayed cutaneous lesions without detectable antibody production.

Conflict of interest

We declare no conflicts of interest.