COVID-19 and skin U10.-

Last updated on: 10.12.2021

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History
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In December 2019, China reported the first cases of the 2019 coronavirus disease (COVID-19). In March 2020, this infectious disease was classified as a global pandemic by the World Health Organization. The disease caused by severe acute respiratory syndrome - coronavirus 2 (SARS-CoV-2) has become a pandemic (WHO declaration in March 2019). SARS-Cov-2 is a single-stranded RNA virus, a beta-coronavirus composed of 16 non-structural proteins that have specific roles in coronavirus replication. To date, the disease has resulted in approximately 85 million confirmed cases (and rising) and caused nearly 1.8 million associated deaths worldwide. The COVID-19 pandemic is undoubtedly the most serious health and socioeconomic crisis of our time.

Definition
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In December 2019, China reported the first cases of the 2019 coronavirus disease (COVID-19). In March 2020, this infectious disease was classified as a global pandemic by the World Health Organization. The disease caused by severe acute respiratory syndrome - coronavirus 2 (SARS-CoV-2) has become a pandemic (WHO declaration in March 2019).

SARS-Cov-2 is a single-stranded RNA virus, a beta-coronavirus composed of 16 non-structural proteins that have specific roles in coronavirus replication. To date, the disease has resulted in approximately 85 million confirmed cases (and rising) and caused nearly 1.8 million associated deaths worldwide. The COVID-19 pandemic is undoubtedly the most serious health and socioeconomic crisis of our time.

The most common symptoms of the disease are cough and fever. More than 80% of patients have asymptomatic to moderate disease. 15% develop severe pneumonia and 5% develop multiple organ failure.

Increasingly, dermatologic abnormalities are being observed in association with COVID-19. This is of particular interest as dermatological symptoms can also occur in asymptomatic or low-symptomatic patients (Gaspari V et al. 2020). This is epidemiologically even more important as this oloeigo or asymptomatic patient group represents by far the largest group of COVID-19 patients. Thus, special attention must be paid to the monitoring signs of the skin in order to initiate the important and necessary medical and organizational measures for a possible COVID-19 infection in this patient group as well.

Classification
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Basically, skin changes in viral infections(viral exanthems) and thus also in COVID-19 can be classified as follows:

  • Generalized or localized rashes of different clinical symptoms and morphology induced directly (infectious exanthema) or indirectly (parainfectious exanthema) by viruses. The clinic of infectious viral exanthema is an expression of a defined pathogen (e.g. varicella, measles; rubella, etc.).
  • Parainfectious viral exanthemas (e.g. Gianotti-Crosti syndrome; unilateral laterothoracic exanthema; postherpetic erythema multiforme, morbilliform exanthema in infectious mononucleosis) may be caused by different pathogens or by drugs. They are usually pathogen-unspecific. For example, 13 different types of viruses are known to trigger Gianotti-Crosti syndrome.
  • A special role is played by the (parainfectious) multisystemic inflammatory syndrome in connection with COVID-19. Epidemiological data show that COVID-19 apparently occurs less frequently in children and, above all, has a milder course. In 2020, a frequently severe clinical picture was described in children and adolescents with a phenotype similar to Kawasaki syndrome. Dermatological findings included maculo-papular exanthema, concunctivitis, cheilites, palmar erythema, and hand and foot edema with severe febrile general symptoms (Pouletty M et al 2020).
  • Drug-induced exanthema, with viral infection playing an initiating role.

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Currently, in addition to COVID-19-associated exanthema, vasculitic skin lesions have been described (Drerup, K.A. et al 2021)

Exanthematous vasculitic skin lesions:

  • Vesicular, possibly pruritic exanthema, occurring before other COVID-19 symptoms in 15% of cases.
  • Maculopapular, often pruritic exanthema usually together with other COVID-19 symptoms, especially in more severe courses.
  • Urticarial, highly pruritic exanthema, usually concomitant with other symptoms

Acral vasculitic skin changes

  • Livedo, purpura or necrotic skin changes, especially in older patients with severe disease at the same time as the first symptoms, high mortality of up to 10%.
  • Chilblain-like skin changes

Occurrence/Epidemiology
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The mean age of patients with COVID skin lesions is 49.03 years (5-91years); w:m=6:4. Skin lesions appeared on average 9.92 days (1-30) after the onset of systemic symptoms (Zhao Q et al. 2020). Importantly, skin changes can occur in otherwise oligo- or asymptomatic patients.

Pathophysiology
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The pathology of COVID-19 is multifactorial: state of hypercoagulability, damage to lung tissue, involvement of the neurological and/or gastrointestinal tract, a monocyte/macrophage activation syndrome culminating in excessive cytokine secretion, the so-called "cytokine storm", which can lead to exacerbation of the infectious event and death. Associated with this are alterations in various genes (IFNAR2, IFNAR2, IFNAR2, IFNAR2). This is associated with alterations in various genes(IFNAR2, OAS1, TYK2, DPP9 and CCR2) associated with innate immune defense.

These systemic conditions may be associated with multiform cutaneous lesions that also show different inflammatory patterns at the histopathological level. The cutaneous lesions may be associated with different multisystemic manifestations (Criado PR et al. 2020).

Clinical features
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Spanish dermatologists have worked out five characteristic clinical patterns on the basis of a larger collective (Catalá Gonzalo A et al. 2020). In addition, there is a 6th category with other skin changes that have been reported casuistically.

  • Maculopapular exanthema (21.3% of COVID skin lesions). They most frequently affected middle-aged adults (mean age 53.2 years): patients presented with varying degrees of morbilliform exanthema of the skin, sometimes with hemorrhagic as well as punctate or extensive redness. These lesions were also observed in severe courses of Covid-19 disease in which several drugs were used. Thus it cannot be excluded, according to the Spanish dermatologists, that these skin reactions are expression of a drug side effect. The purpuric vasculitic exanthemas also belong to the maculopapular exanthemas which can also take on a vesiculous aspect in case of strong exudation. Underlying them is a leukocytoclastic vasculitis (Camprodon Gómez M et al 2020).
  • Chilblain lupus-like changes (COVID-19 chilblains; blue-toe syndrome):Acral, painful livid-red swellings ( pseudo-frost bumps) were the most frequently identified lesions, accounting for 40.4% of all COVID skin symptoms (Daneshgaran G et al. 2020, Le Cleach L et al.2020). The frostbump-like changes, usually asymmetrical on the hands (fingers) and feet (toes), occurred predominantly in younger female patients (58.5% affected females between 18-39years, mean age 23.2 years) (Daneshgaran G et al. 2020) with lower COVID-19 symptomatology. They formed later in the course of the disease and persisted for an average of 12.7 days. In about one-third of affected individuals, the skin lesions were painful or caused pruritus (Daneshgaran G et al. 2020). Histopathologically, varying degrees of lymphocytic vasculitis are found, ranging from endothelial swelling and endotheliitis to fibrinoid necrosis and microthrombotic phenomena. Furthermore, superficial and deep perivascular lymphocytic infiltrates with paracellular accentuation and mild vacuolar interface damage are detectable. In some cases, SARS-CoV-2 immunohistochemistry was positive in endothelial cells and epithelial cells of eccrine glands. Electron microscopically, coronavirus particles were found in the cytoplasm of endothelial cells by one group of authors (Colmenero I et al. 2020). However, this seems to be rather a rarity (Herman A et al. 2020; Le Cleach L et al. 2020). Although the clinical and histopathological features are similar to other forms of chilblains, the presence of viral particles in the endothelium and the histological evidence of vascular damage support a causal relationship of the lesions with SARS-CoV-2. It is likely that viral-induced endothelial damage is important in the pathogenesis of the acral "frostbite-like" changes.
  • Urticaria/angioedema: Urticarial, mostly pruritic, exanthems affected 10.9% of COVID skin lesions. They affected adult patients (mean age 38.3 years). They were associated with a severe course of Covid 19 disease in some studies. The trunk was mainly affected. More rarely, facial angioedema occurs in the context of a manifest COVID-19 infection (Najafzadeh M et al. 2020).
  • Vesicular exanthema: Primary vesicular exanthema affected 13.0% of COVID skin lesions. They occurred in middle-aged adults (mean age 48.3 years). In these patients, chickenpox-like, vesicular, pruritic exanthema occurred on the trunk and extremities. Sometimes a hemorrhagic component may also occur. Middle-aged patients were affected. The lesions persisted detectably for an average of 10.4 days (Marzano AV et al. 2020).
  • Livedovasculitis (livedo racemosa ): These skin manifestations with their characteristic saturated red or even hemorrhagic lightning figures were rare. They are probably due to microthrombotic processes and vascular damage. The skin lesions occurred mainly on the trunk and extremities and accounted for 4% of the COVID skin lesions. Livedovasculitides occurred mainly in severe courses and in elderly patients (mean age 77.5 years) and were associated with concomitant non-cutaneous COVID-19 symptoms in 60% of cases (Daneshgaran G et al. 2020). Mortality in this group was 10%. The extent to which these are directly viral triggered, or occur in the context of viral induced immunological dysfunction is as yet unclear. The livedovasculitides were histologically based on occlusive vasculitis of medium-sized skin vessels (Daneshgaran G et al 2020).

Other skin manifestations:

Note(s)
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In summary, skin changes in the context of a COVID infection are to be regarded as monitoring signs for this viral infection. This applies especially to varicelliform exanthema. Acral COVID chilblains can be indicative and prognostic markers for the severity of the disease. Thus, "COVID toes" are frequently found in children and asymptomatic patients!

The rare livedovaculitis should be considered as a potential correlate to disease severity. The same seems to be true for angioedema.

It is important for health care professionals to become familiar with COVID skin changes in order to assess these monitorable symptoms early.

Literature
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  1. Brin C et al (2020) An Isolated Peculiar Gianotti-Crosti Rash in the Course of a COVID-19 Episode. Acta Derm Venereol 100:adv00276.
  2. Camprodon Gómez M et al (2020) Leucocytoclastic vasculitis in a patient with COVID-19 with positive SARS-CoV-2 PCR in skin biopsy. BMJ Case Rep 13:e238039.
  3. Catalá Gonzalo A, Galván Casas C (2020) COVID-19 and the skin. Actas Dermosifiliogr 111:447-449.
  4. Chicharro P et al (2021) SDRIFE-like rash associated with COVID-19, clinicopathological correlation. Australas J Dermatol 62: 88-89.
  5. Colmenero I et al (2020) SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultrastructural study of seven paediatric cases. Br J Dermatol 183:729-737.
  6. Criado PR et al. (2020) Are the cutaneous manifestations during or due to SARS-CoV-2 infection/COVID-19 frequent or not? Revision of possible pathophysiologic mechanisms. Inflamm Res 69:745-756.
  7. Daneshgaran G et al (2020) Cutaneous manifestations of COVID-19: An evidence-based review. Am J Clin Dermatol 21:627-639.
  8. Dominguez-Santas M et al (2020) Cutaneous small-vessel vasculitis associated with novel 2019 coronavirus SARS-CoV-2 infection (COVID-19). J Eur Acad Dermatol Venereol 34:e536-e537.
  9. Estébanez A et al (2020) Cutaneous manifestations in COVID-19: a new contribution. J Eur Acad Dermatol Venereol 34:e250-e251.
  10. Gaspari V et al. (2020) COVID-19: how it can look on the skin. Clinical and pathological features in 20 COVID-19 patients observed in Bologna, north-eastern Italy. J Eur Acad Dermatol Venereol 34:e552-e553.
  11. Gianotti R et al. (2020) Histopathological Study of a Broad Spectrum of Skin Dermatoses in Patients Affected or Highly Suspected of Infection by COVID-19 in the Northern Part of Italy: Analysis of the Many Faces of the Viral-Induced Skin Diseases in Previous and New Reported Cases. Am J Dermatopathol 42:564-570.
  12. Gottlieb M et al (2020) Dermatologic manifestations and complications of COVID-19. Am J Emerg Med 38:1715-1721.
  13. Herman A et al (2020) Evaluation of chilblains as a manifestation of the COVID-19 pandemic. JAMA Dermatol 156:998-1003.
  14. Klejtman T (2020) Skin and COVID-19. J Med Vasc 45:175-176.
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  16. Le Cleach L et al. (2020) Most chilblains observed during the COVID-19 outbreak occur in patients who are negative for COVID-19 on polymerase chain reaction and serology testing. Br J Dermatol 183:866-874.
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Last updated on: 10.12.2021