key: cord-0825479-4i3buv2d
authors: Akl, J.; El‐Kehdy, J.; Salloum, A.; Benedetto, A.; Karam, P.
title: Skin Disorders associated with the COVID‐19 Pandemic: A Review
date: 2021-06-02
journal: J Cosmet Dermatol
DOI: 10.1111/jocd.14266
sha: abe1420243b1662348e7a21e017f836d8186bd29
doc_id: 825479
cord_uid: 4i3buv2d

In December 2019, a new coronavirus has emerged out of China, the SARS‐Cov‐2 virus, causing a disease known as COVID‐19, which steadily has progressed into a pandemic. This coronavirus affects many organs, including the skin, whose manifestations are a consequence of the disease itself, as well as the preventative measures taken to avoid the infection. This paper reviews the cutaneous manifestations which currently have been encountered during this pandemic. A search was conducted on PubMed, and all relevant articles were included. The results show the occurrence of many cutaneous findings, ranging from those related to the infection itself and to various dermatitides related to the use of personal protective equipment (PPE) utilized by healthcare workers while attending to infected patients. Recognizing these findings is important for the accurate diagnosis of those infected with COVID‐19 as well as the prompt treatment of the side effects caused by PPE that might further impair the effectiveness of healthcare workers.

This article is protected by copyright. All rights reserved Another commonly reported skin manifestation is a herpetiform or vesicular eruption similar to what is seen in Herpesviridae infections. 4 It has been described in multiple reports [32] [33] [34] [35] as a vesicular rash, sometimes associated with pustular or papular lesions.

The distribution was either generalized or localized, with lesions of different stages in the generalized form, and monomorphic, same-age lesions in the localized form, mostly limited to the chest area. In a few cases, palms and soles were affected. 34 According to the reports, it was mostly seen in middle-aged and older adults, although one case of an 8-year-old girl was reported. [32] [33] [34] The most common extracutaneous associated symptoms with herpetiform or vesicular eruptions were pneumonia, fever, cough, headache, and weakness. The rash appeared after the COVID-19 diagnosis, confirmed by nasopharyngeal swab PCR testing , with a latency period averaging 2 weeks, but reaching up to a month. In the majority of patients, the vesicular rash was pruritic. 33, 34 In a report of three cases where a skin biopsy was done around 6-10 days after the onset of the rash, the most common features were intraepidermal vesiculation, dyskeratosis, acantholysis, suprabasal clefting, mild dermal inflammatory infiltrates, and dermal eosinophils. Direct Immunofluorescence (DIF) done on one of the specimens was negative. 36

An additional cutaneous finding associated with infection with the SARS-Cov-2 virus is the urticariform rash. Multiple reports describe patients who presented with pruritic urticariform lesions (Fig.1&2) , and who were found to be positive by PCR for COVID-19 infection. 37-41 The most common extracutaneous finding was fever. Other symptoms including malaise, myalgias, cough, rhinorrhea, and dyspnea were also commonly reported. These symptoms occurred concomitantly with the cutaneous eruption or preceding it. 37,39-41 Additionally, in some cases, the urticaria was associated with angioedema, affecting the eyelids, lips and hands. 40,41 The mainstay of treatment was oral antihistamines, with marked improvement or even resolution of symptoms. One patient also received favipiravir and hydroxychloroquine in addition to antihistamines, as a treatment for his [39] [40] [41] None of the reported patients had a skin biopsy and therefore no histopathological studies were done of these urticariform eruptions.

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A few case reports also identified patients with either a petechial or a purpuric rash in PCR-confirmed cases of COVID-19 (Fig. 3,4,5) . [42] [43] [44] [45] [46] Interestingly, one of the cases was initially attributed to Dengue fever, but was later found to be related to a COVID-19

infection. 42 Both necrotic and non-necrotic purpura were evident in patients with The purpura was described in a few reports as being retiform and associated with hemorrhagic blisters, or evolving from petechiae into hemorrhagic bullae and necrotic plaques. 22, 46 The petechial rash was most commonly preceded by respiratory symptoms, including pleuritic chest pain and shortness of breath, by around a few days to one week. 43, 44, 46 Patients affected included children as well as adults. 43, 44, 46 In the majority of the reported cases, the rash affected the lower extremities. 43, 46 In one case, the affected areas included the flexures and the lower part of the abdomen in addition to the lower extremities. 44 Histopathological studies on skin biopsies from the lesions showed a wide array of different findings, ranging from superficial perivascular lymphocytic infiltrate with red blood cell extravasation and absence of thrombotic vasculopathy, to small vessel vasculitis and vasculopathy. DIF studies showed deposition of IgM, C3, and fibrinogen in dermal blood vessel walls. 22, 44, 46 

Livedo and necrotic lesions appeared in elderly patients with COVID-19, and in those with more severe disease. 47 These occurred anytime during the course of the disease. In one report, the prevalence of livedo and/or necrotic lesions among COVID-19 patients was 6%. 48 The pathophysiology behind these was most probably the major systemic occlusive vascular disease that occurred in the patients.

This article is protected by copyright. All rights reserved Additional skin manifestations related to this viral infection include erythema multiforme (EM)-like lesions that were described as fixed targetoid or annular plaques with a dusky center, affecting the extremities and trunk in most cases, and generally affecting the face and mucous membranes. 11, [49] [50] [51] [52] [53] This was seen in both children and adults, with the mean age in adulthood being around 66 years of age. 51, 53 The rash mostly followed the viral symptoms by an average of two to three weeks. 51 Histological examination of skin biopsies from these lesions showed mild to moderate epidermal spongiosis, erythrocyte extravasation in the dermis, dilated vessels with neutrophil predominance, as well as a perivascular and interstitial lymphocytic infiltrate. 51 In most of these cases, testing for Herpes Simplex Virus by PCR and/or Mycoplasma pneumoniae by serologies was found to be negative. 51, 53 

Another skin manifestation is the pityriasis-rosea (PR) or PR-like eruption. The eruption was described by multiple reports to be pruritic and consisting of oval or round shaped, erythematous and scaly, patches or plaques, with a surrounding collarette of scale. [54] [55] [56] [57] [58] Most of the patients reported to have PR-like eruption were healthy young adults aged between 23 to 26 years old, with one report of a 39 year old patient. [54] [55] [56] [57] The rash was noted a few days after the onset of COVID-19 symptoms, which were most commonly cough and fever, and up to 6 weeks following them. 54, 55 In a few cases, patients were asymptomatic with a PR-like eruption, who were later found to have a positive SARS-Cov-2 PCR test. 57 Laboratory evaluation with a complete blood count and basic metabolic panels were normal in most of the patients, except for one who was found to have lymphopenia. [54] [55] [56] [57] No histopathological studies on skin biopsies were reported.

Patients were treated with either monotherapy or a combination of anti-histamines and/or topical steroids, with notable improvement. 54,56,57

This article is protected by copyright. All rights reserved Data about pruritus in this pandemic is still scarce, but it is an important symptom that occurs either alone or with the multitude of dermatoses encountered, and significantly affects the quality of life of patients. No studies have assessed the epidemiological characteristics of pruritus related to the pandemic, but according to one report, the underlying causes of itching are multiple, and can be classified into three major groups:

itch related to the viral-induced or viral-related dermatoses, pruritus secondary to chemical use and PPE wear, and finally, that related to psychosocial stress resulting from the pandemic. 59 (Fig. 6,7,8,9 ,10)

One important syndrome encountered during this pandemic with temporal association with the virus is the multi-system inflammatory syndrome in children (MIS-C), also known as Kawasaki-disease-like syndrome, described in multiple reports to involve numerous organ systems, and characterized by fever, hemodynamic instability, lymphadenopathy, gastrointestinal symptoms, conjunctivitis, and variable mucocutaneous manifestations, including lip and tongue mucositis, cheilitis, palmoplantar erythema, and several types of cutaneous manifestations like urticariform, purpuric, targetoid or morbilliform rashes. [60] [61] [62] It affects children in the majority of cases, except for one case report in an adult. [60] [61] [62] [63] Laboratory findings in these patients show elevated inflammatory markers and lymphopenia and other cytopenias. 62, 64 Many treatments are given to these patients, including antibiotics, immunomodulators, corticosteroids, and supportive care. 60-64

Refer to Table 1 

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Multiple reports have described anagen and telogen effluvium in patients with PCR-confirmed SARS-Cov-2 infection. These entities affected white, middle-aged adults with a mean age of 48 years old, who were mostly women, and the majority of whom were febrile and many had other dermatologic findings. These patients also received multiple treatments, including paracetamol, corticosteroids, antivirals, antimalarials, antibiotics, and immunomodulators. The onset of hair findings followed that of the viral symptoms by 30 to 60 days, with a mean latency of 57 days. [65] [66] [67] Hair shedding was severe in most of the cases, as assessed by the Sinclair Shedding Scale, and the disease sometimes remained active one month later. 66 Most of these patients were prescribed topical minoxidil, although some received oral nutricosmetics or platelet-rich plasma injections. 65, 66 

Even though both androgenetic alopecia and grey hair were not induced by COVID-19, they were both found to be risk factors for a more severe course of the infection. [68] [69] [70] Most hospitalized patients were found to have male-pattern alopecia, with a total frequency of around 70%, higher in males than in females, whose median ages were 62.5 years and 71 years respectively. 68, 70 Similarly, grey hair was also found to be a severity factor in both males and females. 69

Apart from the skin manifestations directly related to the virus itself, other dermatitides related to the use of PPE and to hygiene measures, as well as to the treatment of COVID-19 were reported.

This article is protected by copyright. All rights reserved risk factors included female sex, age (young adults), severity of the epidemic in the workplace, working in a hospital (nurse, intern, resident, pharmacist,..), and regular hand washing, especially when it exceeded 10 times per day. 79, 81 Additionally, the type of mask, especially the N95 and FFP2/3 respirators led to more pressure-related symptoms than others. 71

An array of skin manifestations secondary to infection with the SARS-Cov-2 virus are described, some of which are not different from those seen in other viral infections. These include the urticariform, vesicular, and erythematous eruptions. 1 However, some skin findings were rather specific to COVID-19 infection, and not commonly seen with other viral infections, such as the chilblains described in many reports. This finding was encountered in a younger population, and hypothesized to be a late manifestation of the viral infection, where the immune system targets the skin vasculature. 6, 9, 11 A similarly-presenting finding were the acro-ischemic lesions. Some reports considered them similar and did not differentiate between the two. In other reports, however, it was shown that acro-ischemic lesions occurred in an older population than the chilblains, and portended a worse prognosis to the patients who presented with them, as compared to those who presented with chilblains. 22 They were seen in severely ill patients, in whom D-dimer levels and prothrombin time were elevated and indicated a poorer prognosis. However, the underlying pathophysiology of such lesions could not be fully attributed to a coagulation disorder, and the possibility of a hypersensitivity reaction remains possible. 82 Furthermore, the underlying pathogenesis of the petechial rash in SARS-CoV-2 was described to be similar to the exanthem seen in Parvovirus B19 infection, where viral proteins in the dermal vessel wall as well as extravasated red blood cells lead to the petechial and purpuric findings. 44 One important syndrome to recognize is the multisystem inflammatory syndrome, that is mostly seen in children, but has also been reported in adults. Timely diagnosis of this severe syndrome

This article is protected by copyright. All rights reserved is important because it affects multiple organ systems and can lead to many complications, including kidney injury, myocardial injury, hypercoagulability and respiratory distress. 62 It is hypothesized to be caused by a hyper-inflammatory response with cytokines Il-6 and Il-8 the major contributors. 64 It was initially thought to be related to Kawasaki disease, but has recently been classified as a different novel, post-viral syndrome that is usually seen up to a month after contracting COVID-19 syndrome, regardless of whether they were symptomatic.

Moreover, despite the association of itch with multiple factors of the pandemic, including the dermatoses encountered, the psychological stress sustained, and the use of harsh chemicals and many irritants, and its substantial effect on the patients' quality of life, the data available concerning it are still very limited. 59 Finally, as seen with many other viral infections and systemic illnesses, both hair and nails can be affected. A few isolated reports of nail involvement were described, and findings included leukonychia and onychomadesis, and a distinctive feature described as the red half moon nail sign. Its underlying pathogenic mechanism is not known yet, but it has been hypothesized to be related to microvascular injury and coagulopathy. 83 As for the hair findings, telogen effluvium, which follows systemic stressors by 2-3 months, is an expected finding after the massive stress that patients with COVID-19 experience, on both the physiologic and the psychologic levels. 65 However, the association of androgenetic alopecia and grey hair with a more severe course of COVID-19 infection was surprising, and it paves the way to new possibilities in treatment modalities using anti-androgens. 68, 69 The SARS-CoV-2 virus requires a transmembrane protein for infectivity, the transcription of which is regulated by the androgen receptor, which makes it a reasonable therapeutic, and even prophylactic option. 69 Nevertheless, it is to be noted that, despite the multiple skin findings that have been either hypothesized or confirmed related to COVID-19 infection, multiple characteristics of these findings are yet to be defined. For instance, prevalence studies for these findings are still missing, as well as inquiries into the underlying pathophysiology that is leading to some of these COVID-related exanthems. Additionally, many of these patients have received numerous

This article is protected by copyright. All rights reserved medications and treatments, and the possibility of these treatments being a causative or exacerbating factor should be considered when applicable.

Due to the increased use of personal protective equipment and the enhanced hygiene measures, especially among healthcare workers, it is not unusual to encounter skin disorders either as a result of such habits or exacerbated by them.

Skin disorders resulting from the use of protective measures, such as gloves, goggles, and gowns are attributed to multiple factors, including what was termed as the "hyper-hydration effect", which was seen after prolonged wearing of the occlusive gear trapping moisture, and, along with friction, also leading to defects in skin barrier and increased susceptibility to contact dermatitis. 75, 78 Excessive handwashing may also lead to irritant contact dermatitis. 78 An additional finding is folliculitis resulting most likely from occlusion secondary to PPE use. 3 An important notion concerning the aforementioned mechanisms is the increase in the risk of skin damage with the increased duration of PPE use, as multiple studies have shown. 3,75,76,79 , Also noted is an exacerbation of pre-existing skin diseases, with an increased rate of flares in acne, rosacea, and seborrheic dermatitis. The basis of such exacerbations might be multifactorial, including, but not limited to, an increase in psychological stress and obstruction of the skin by protective equipment use. 2, 3 Lastly, considering all these findings, it is important for persons at risk, most notably healthcare workers, to follow a few instructions in order to avoid such consequences. For example, they should avoid using very hot water, refrain from prolonged glove wearing, moisturize frequently to maintain the skin barrier, and the reasonable use of alcoholic hand sanitizers. 76, 84 

In conclusion, during this pandemic that has affected most of the world, many skin diseases have emerged. Ranging from skin findings secondary to the viral infection to consequences of PPE wear and hygiene measures, as well as exacerbations of pre-existing skin diseases, these dermatological outcomes are important to be distinguished and treated for multiple reasons. First, skin findings related to the disease itself can guide us in the diagnosis, especially when other This article is protected by copyright. All rights reserved 

Chilblain-like lesions: a case series of 41 patients during the COVID-19 pandemic

COVID-19) infection-induced chilblains: A case report with histopathologic findings. JAAD Case Rep

Chilblains-like dermatologic manifestation of COVID-19 diagnosed by serology via multidisciplinary virtual care

Acral cutaneous lesions in the Time of COVID-19

Pernio-like skin lesions associated with COVID-19: a case series of 318 patients from 8 countries

Two cases of COVID-19 presenting with a clinical picture resembling chilblains: first report from the Middle East

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

Chilblain-like lesions during COVID-19 epidemic: a preliminary study on 63 patients

Chilblains in children in the setting of COVID-19 pandemic

Accepted Article This article is protected by copyright. All rights reserved

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

Histologic features of long-lasting chilblain-like lesions in a paediatric COVID-19 patient

Chilblain-like lesions on feet and hands during the COVID-19 Pandemic

Acro-ischemia in hospitalized COVID-19 patients

Skin signs resembling vascular acrosyndromes during the COVID-19 outbreak in Italy

Acro-ischemia and COVID-19 infection: clinical and histopathological features

Clinical and histological characterization of late appearance maculopapular eruptions in association with the coronavirus disease 2019. A case series of seven patients

Cutaneous lesions in a patient with COVID-19: are they related?

Diffuse cutaneous manifestation in a new mother with COVID-19 (SARS-Cov-2)

All rights reserved 26. Hunt M, Koziatek C. A Case of COVID-19 Pneumonia in a Young Male with Full Body Rash as a Presenting Symptom

Morbilliform exanthem associated with COVID-19

Acute maculopapular eruption in Covid-19 patient: A case report

Unexpected Presentation of COVID-19 in a 38-Year-Old Male Patient: A Case Report

Maculopapular rash as initial manifestation of SRAS-coronavirus-2 infection

Cutaneous Clinico-Pathological Findings in three COVID-19-Positive Patients Observed in the Metropolitan Area of

Varicella-like exanthem associated with COVID-19 in an 8-year-old girl: A diagnostic clue?

Varicella-like exanthem as a specific COVID-19-associated skin manifestation: Multicenter case series of 22 patients

Clinical and histological characterization of vesicular COVID-19 rashes: a prospective study in a tertiary care hospital

COVID-19: how it can look on the skin. Clinical and pathological features in twenty COVID-19 patients observed in Bologna, northeastern Italy

Retiform purpura as a dermatological sign of covid-19 coagulopathy

A dermatologic manifestation of COVID-19: Transient livedo reticularis

Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases

Comment on: Cutaneous manifestations in COVID-19: a first perspective. Safety concerns of clinical images and skin biopsies

SARS-CoV-2 infection presenting as a febrile rash

Erythema multiforme-like eruption in patients with COVID-19 infection: clinical and histological findings

A fatal case of COVID-19 infection presenting with an erythema multiforme-like eruption and fever

Erythema multiforme and Kawasaki disease associated with COVID-19 infection in children

Pityriasis rosea as a cutaneous manifestation of COVID-19 infection

Pityriasis rosea and COVID-19

Pityriasis rosea-like eruption revealing COVID-19

Pityriasis Rosea in Otherwise Asymptomatic Confirmed COVID-19 Positive Patients: A Report of Two Cases. JAAD Case Rep

Pityriasis rosea Gibert type rash in an asymptomatic patient that tested positive for COVID-19

Itch in the era of COVID-19 pandemic: An unfolding scenario

Severe manifestations of SARS-CoV-2 in children and adolescents: from COVID-19 pneumonia to multisystem inflammatory syndrome: a multicentre study in pediatric intensive care units in Spain

Mucocutaneous disease and related clinical characteristics in hospitalized children and adolescents with COVID-19 and multisystem inflammatory syndrome in children

The Natural History of SARS-Cov-2 Related Multisystem Inflammatory Syndrome in Children (MIS-C): A Systematic Review

Adult Inflammatory Multi-System Syndrome Mimicking Kawasaki Disease in a Patient With COVID-19

Multisystem inflammatory syndrome in children related to COVID-19: A New York City experience

Telogen effluvium associated with COVID-19 infection

SARS-CoV-2-induced telogen effluvium: a multicentric study

COVID-19 related anagen effluvium

Androgenetic alopecia present in the majority of patients hospitalized with COVID-19: The "Gabrin sign

A preliminary observation: Male pattern hair loss among hospitalized COVID-19 patients in Spain -A potential clue to the role of androgens in COVID-19 severity

Personal Protective Equipment (PPE) in COVID 19 Pandemic: Related Symptoms and Adverse Reactions in Healthcare Workers and General Population

Skin damage among health care workers managing coronavirus disease-2019

Increased Prevalence of Face Mask-Induced Itch in Health Care Workers

Accepted Article This article is protected by copyright. All rights reserved

Iatrogenic dermatitis in times of COVID-19: A pandemic within a pandemic

Skin Reactions to Non-glove Personal Protective Equipment: An Emerging Issue in the COVID-19 Pandemic

Consensus of Chinese experts on protection of skin and mucous membrane barrier for health-care workers fighting against coronavirus disease 2019

Changing gears: Medical gloves in the era of coronavirus disease 2019 pandemic

Challenges of COVID-19 pandemic for dermatology

Adverse Skin Reactions Among Healthcare Workers During the Coronavirus Disease 2019 Outbreak: A Survey in Wuhan and Its Surrounding Regions

Effect of face mask on skin characteristics changes during the COVID-19 pandemic

Occupational-Related Contact Dermatitis: Prevalence and Risk Factors Among Healthcare Workers in the Al'Qassim Region, Saudi Arabia During the COVID-19 Pandemic

Characterization of acute acro-ischemic lesions in non-hospitalized patients: a case series of 132 patients during the COVID-19 outbreak

The red half-moon nail sign: a novel manifestation of coronavirus infection

Rational hand hygiene during COVID-19 pandemic

Letter from the Editor: Occupational skin disease among healthcare workers during the Coronavirus (COVID-19) epidemic

A distinctive skin rash associated with coronavirus disease 2019?

Transverse leukonychia (Mees' lines) nail alterations in a COVID-19 patient

Beau's Lines and Leukonychia in a COVID-19

Beau lines associated with COVID-19

Onychomadesis following COVID-19 infection: Is there a relationship?

COVID-19 and nail manifestation: be on the lookout for the red half-moon nail sign

The red half-moon nail sign: a novel manifestation of coronavirus infection

Transverse orange nail lesions following SARS-CoV-2 infection

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This article is protected by copyright. All rights reserved

This article is protected by copyright. All rights reserved Accepted Article