A clinical, histopathological and laboratory study of 19 consecutive Italian paediatric patients with chilblain‐like lesions: lights and shadows on the relationship with COVID‐19 infection

Abstract

Background Acral chilblain-like lesions are being increasingly reported during COVID-19 pandemic. However, only few patients proved positivity for SARS-CoV-2 infection. The relationship between this skin manifestation and COVID-19 infection has not been clarified yet. Objective To thoroughly characterize a prospective group of patients with chilblain-like lesions and to investigate the possible relationship with SARS-CoV-2 infection. Methods Following informed consent, patients underwent (i) clinical evaluation, (ii) RT-PCR and serology testing for SARS-CoV-2, (iii) digital videocapillaroscopy of finger and toe nailfolds, (iv) blood testing to screen for autoimmune diseases and coagulation anomalies, and (v) skin biopsy for histopathology, direct immunofluorescence and, in selected cases, electron microscopy. Results Nineteen patients, all adolescents (mean age: 14 years), were recruited. 11/19 (58%) of them and/or their cohabitants reported flu-like symptoms one to two months prior to skin manifestation onset. Lesions were localized to toes and also heels and soles. Videocapillaroscopy showed pericapillary oedema, dilated and abnormal capillaries, and microhaemorrhages both in finger and toe in the majority of patients. Major pathological findings included epidermal basal layer vacuolation, papillary dermis oedema and erythrocyte extravasation, perivascular and perieccrine dermal lymphocytic infiltrate, and mucin deposition in the dermis and hypodermis; dermal vessel thrombi were observed in two cases. Blood examinations were normal. Nasopharyngeal swab for SARS-CoV-2 and IgG serology for SARS-CoV-2 nucleocapsid protein were negative. Importantly, IgA serology for S1 domain of SARS-CoV-2 spike protein was positive in 6 patients and borderline in 3. Conclusions Chilblain-like lesions during COVID-19 pandemic have specific epidemiologic, clinical, capillaroscopic and histopathological characteristics, which distinguish them from idiopathic perniosis. Though we could not formally prove SARS-CoV-2 infection in our patients, history data and the detection of anti-SARS-COV-2 IgA strongly suggest a relationship between skin lesions and COVID-19. Further investigations on the mechanisms of SARS-CoV-2 infection in children and pathogenesis of chilblain-like lesions are warranted.

Perniosis during the COVID‐19 pandemic: Negative anti‐SARS‐CoV‐2 immunohistochemistry in six patients and comparison to perniosis before the emergence of SARS‐CoV‐2

“…The lack of SARS-CoV-2 nucleocapsid staining, the older average age of patients in this cohort, the absence of a history of autoimmune disease, and the fingers being affected more than the toes would all support that these cases represent a manifestation of idiopathic perniosis rather than perniosis secondary to direct infection of the skin by SARS-CoV-2. This conclusion is in line with the absence of detectable SARS-CoV-2 by PCR testing of lesional PDC tissue 14,15 and negative IgM and IgG SARS-CoV-2 serologic studies in this series and others, [1][2][3][4]22 but conflicts with reports of positive immunohistochemical staining for the spike protein in PDC. 16,17 IgM and IgG serologies may not be the best way to test for COVID -19, with evidence that IgA serologies may be better in detecting relatively asymptomatic patients in later stages of the disease.…”

“…16,17 IgM and IgG serologies may not be the best way to test for COVID -19, with evidence that IgA serologies may be better in detecting relatively asymptomatic patients in later stages of the disease. 2,23 Similarly, the negative nucleocapsid staining in this series vs spike protein staining in the literature deserves further study and warrants continued validation of different antibodies in the skin. typically present on acral sites, and none of these patients had known CLL.…”

“…1,3,7 The observation that the majority of reported individuals have been negative for detectable SARS-CoV-2 from nasopharyngeal swabs has precluded drawing a direct link between this manifestation and COVID-19. 1,2,4 However, the typical manifestation of lesions at least 1 week after any systemic symptoms (when present), as well as other observations summarized in Tables 1 and 3 ,7-9 suggests that perniosis-like lesions are somehow related to the COVID-19 pandemic. 8 Diagnostic criteria suggested for classic perniosis include the presence of persistent, localized erythema and swelling on acral sites with at least one of the following: (a) onset in November to March in the Northern hemisphere, (b) typical histopathology (eg, dermal edema and superficial plus deep perivascular lymphocytes), or (c) response to conservative treatments (eg, warming).…”

“…Skin findings resembling perniosis or chilblains, most commonly affecting children's toes, have been reported from geographic areas where COVID-19 has been prevalent. [1][2][3][4] Soles and heels, as well as fingers, 4,5 can be involved. 1,3,6 Affected individuals may manifest mild fever or respiratory symptoms in the weeks preceding the skin lesions.…”

“…1,4,7 While cases have fulfilled the suggested diagnostic criteria for perniosis, cases continue to present after March, 2020, and the purpuric and eroded lesions reported in the literature would not be expected to resolve with warming. 2,7,8 Additionally, although thrombi have been described in idiopathic perniosis and perniosis in the setting of systemic disease, 11,12 thrombi present in perniosis lesions during the COVID-19 pandemic have been proposed as a distinctive finding. 13 There are several possible explanations for the apparent increase in perniosis during the COVID-19 pandemic (henceforth abbreviated PDC for ease of discussion).…”