key: cord-0722477-05k1f12k
authors: Ganatra, B.; Amarnani, R.; Alfallouji, Y.; Dear, K.; Twigg, E.; Westwood, J.‐P.; Goulden, B.; Morris, V.; Hillman, T.; Goolamali, S.; Sidwell, R.; Ellery, P.; Kravvas, G.; Bunker, C.
title: Patient characteristics in tardive Covid‐19 pseudoperniosis – a case series of 16 patients
date: 2021-08-19
journal: Clin Exp Dermatol
DOI: 10.1111/ced.14891
sha: 0cb744b9f03cf99802bb6606711451f916b9fbd7
doc_id: 722477
cord_uid: 05k1f12k

Although chilblain‐like lesions (CLL) or pseudoperniosis (PP) in association with acute COVID‐19 infection is a well‐described phenomenon, frequently lasting 12‐15 days and usually resolving with no long‐term sequelae, a number of patients with delayed or late‐onset, protracted, Covid‐related PP of varying severity have recently been encountered. We describe a series of 16 such cases. We have termed the phenomenon tardive Covid‐19 pseudoperniosis (TCPP). The onset of symptoms was variably related to assumed, prior Covid infection. Symptoms in all patients persisted beyond 2 months. In nine patients, fingers were the initial site of involvement, and ten out of 16 had eventual involvement of all acral sites. Most patients reported a prior history of cold intolerance during the winter months without having any known autoimmune connective tissue disorders (CTD). Positive autoimmune serological markers and an arachnodactyloid phenotype were observed in some patients and may represent risk factors. Underlying CTD, anorexia, or sickle cell trait may also predispose to prolonged PP.

Classic perniosis (chilblains) present as cold-induced, erythematous, or violaceous skin lesions typically involving the fingers and/or toes, and are associated with oedema, itching, pain, burning, blisters, or ulceration. Acute pseudoperniosis (PP) has a recognised, but initially contentious, association with COVID-19 dating from the beginning of the pandemic. Whilst it resembles classic perniosis, it tends to occur in younger, often otherwise healthy patients, sometimes without a clear history of COVID-19, and without cold precipitation 1,2,3 . These lesions usually last 12-15 days and resolve without long-term sequelae 4, 5 . However, in the early months of 2021, patients with delayed and long-lasting manifestations began to emerge 3 . We describe our experience of 16 such cases.

Sixteen patients with PP were reviewed by our outpatient dermatology service between February and June 2021.

The median age of presentation was 29.5 years with a male to female ratio of 1:2.2.

Based on their background, patients could be divided in three categories.

One category (n=4) comprised those with known connective tissue disorders (CTD) such as chilblain lupus (n=2), juvenile psoriatic arthritis (n=1) or Raynaud's phenomenon with ANA positivity (n=1). Another (n=10) consisted of those with primary Raynaud's phenomenon with negative ANA (n=1), Raynaud's phenomenon associated with anorexia nervosa (n=1), as well as cool peripheries, acrocyanosis or occasional chilblains during winter months (n=8). The third (n=2) category comprised those without a background of autoimmune disorders who also denied prior symptoms of cold intolerance Most patients, 87.5% (n=14) developed painful PP associated with digital oedema, cool peripheries, and acrocyanosis. The initial clinical manifestations and site of involvement were reported as erythema, swelling and PP of the fingers in 56.2% (n=9) of the toes in 31.2% (n=5), differing degrees of desquamation in 56.2% (n=9), and acrocyanosis of the heels or forefeet in 12.5% (n=2). Ten patients (62.5%) had eventual involvement of all acral sites (Figures 1 & 2) .

This article is protected by copyright. All rights reserved Nailfold dermoscopy was performed in 12 patients and demonstrated dilated or abnormally shaped capillary loops in seven patients. Most of these patients (5/7, 75%) were also found to have a positive low titre ANA. A significant number of the patients (12) were also noted to have an arachnodactyloid phenotype with long, spindly fingers and toes.

Of those with no known CTD, six were newly found to have raised autoimmune markers.

All three patients who underwent skin biopsies had findings that were in keeping with classic perniosis, such as vacuolar interface dermatitis, mild oedema, erythrocyte extravasation in the papillary dermis, and a moderate cuffed perivascular and peri-eccrine lymphocytic infiltrate in the superficial and deep dermis. In one patient, dermal vessels displayed endothelial swelling with focal fibrinoid necrosis and areas with fibrin microthrombi. 

This article is protected by copyright. All rights reserved Four patients (25%) experienced complete or almost complete resolution of symptoms, whilst the rest remain under ongoing review and active treatment.

A detailed breakdown of individual patient characteristics, interventions, and outcomes is given in Table 1 .

Acral PP (also known as 'pseudo-chilblains', 'chilblain-like lesions (CLL)', and 'Covid toes') has become a well-recognised acute entity. Initially contentious, several global case series have demonstrated this to be a predominant dermatological manifestation of COVID-19 disease. In contrast to idiopathic or secondary perniosis, this has largely been described in children or young adults with no exposure to cold temperatures and is largely of short duration (up to 3 weeks), with less than 10% of patients having lesions lasting more than 60 days 3, 5 .

It is noteworthy that PP is commonly seen alongside minimal or no COVID-19 symptoms and is usually associated with negative SARs-CoV-2 tests 3, 6, 7 .

Clinical features include acral areas of painful, burning, or itchy erythema, oedema, vesicles, pustules, or purpura 1 , with a lack of cold exposure necessity being a distinguishing feature from idiopathic or secondary perniosis.

Unlike the above well-described and acute PP, our cohort of patients has a protracted (median duration of symptoms of 191 days), and usually delayed, presentation that is typically associated with profound acrocyanosis. This presentation has been called 'long COVID-19 PP', but we prefer and promulgate the term 'tardive COVID-19 PP (TCPP)'. Patients with TCPP represent a new phenomenon that is part of the post-COVID-19 syndrome, with risk factors and pathophysiology that are not yet fully understood 7, 8 .

This article is protected by copyright. All rights reserved To our knowledge, our experience represents the largest series of patients with such tardive skin sequalae related to the COVID-19 pandemic yet to be reported.

Our data indicate that likely predisposing factors for developing TCPP include young age, a preceding history of cold intolerance and an arachnodactyloid phenotype. Anorexia, CTDs, or sickle cell trait may also predispose to prolonged TCPP. In addition, low titre ANA positivity, the presence of cryoglobulins, or low complement levels may represent further risk factors, even in the absence of any known CTD. The UK experienced very cold weather during the months of the last winter and early spring. Prolonged low temperatures are also likely to have contributed to the symptoms that our patients experienced.

Histologically, pseudo-chilblains have the same histopathologic features as idiopathic and CTDrelated chilblains 5 .

Various theories have been proposed for the mechanism that leads to the development of PP.

According to one prevailing notion, higher levels of IFN-α are observed in patients with PP compared with other COVID-19 patients 9 . High levels of IFN-α are also seen in type 1 interferonopathies (where severe chilblains can be a hallmark of disease) and are thought to drive the development of chilblains and to also contribute to the inhibition of viral particles, thus explaining why patients with PP frequently have clinically milder disease and negative COVID-19 tests 9 .

According to another theory, SARS-CoV-2 immunohistochemical positivity in endothelial cells, and the presence of coronavirus particles in the cytoplasm of endothelial cells on electron microscopy suggest the SARS-CoV-2 virus as a direct cause of endothelial damage and thrombosis 10 .

Our case series highlight the emerging importance of delayed and persistent PP and acrocyanosis as a manifestation of the long-COVID-19 syndrome. Recognition of this entity and adoption of early and appropriate management 2 can lead to better outcomes and minimise morbidity. 

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Long COVID in the skin: a registry analysis of COVID-19 dermatological duration

Stay at home: guidance for households with possible or confirmed coronavirus (COVID-19) infection

COVID toes"): Histologic, immunofluorescence, and immunohistochemical study of 17 cases

Dermatologic manifestations of COVID-19: a comprehensive systematic review

The spectrum of COVID-19-associated dermatologic manifestations: An international registry of 716 patients from 31 countries

COVID-19 rapid guideline: managing the long-term effects of COVID-19

Clinical, Laboratory, and Interferon-Alpha Response Characteristics of Patients With Chilblain-like Lesions During the COVID-19 Pandemic

SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultrastructural study of seven paediatric cases