COVID-19 and skinU10.-

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.

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

SARS-Cov-2 is a single-stranded RNA virus, a betacoronavirus consisting of 16 non-structural proteins that have specific roles in the replication of coronaviruses. To date, the disease has led to around 85 million confirmed cases (and rising) and caused almost 1.8 million related deaths worldwide. The COVID-19 pandemic is undoubtedly the most serious health and socio-economic crisis of our time.

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

Dermatological abnormalities are increasingly being observed in connection with COVID-19. This is of particular interest as dermatological symptoms can also occur in asymptomatic or less symptomatic patients (Gaspari V et al. 2020). This is all the more important epidemiologically as this oligo- or asymptomatic patient group makes up by far the largest group of COVID-19 patients. It is therefore important to pay particular attention to the monitoring signs of the skin in order to initiate the important and necessary medical and organizational measures with regard to a possible COVID-19 infection in this patient group as well.

Skin changes in viral infections(viral exanthema) and therefore 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 exanthema (e.g. Gianotti-Crosti syndrome; unilateral laterothoracic exanthema; postherpetic erythema multiforme, morbilliform exanthema in infectious mononucleosis) - these can 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 (parainfectious) multisystemic inflammatory syndrome in connection with COVID-19. Epidemiological data show that COVID-19 appears to occur 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. Dermatologically, maculo-papular exanthema, conjunctivitis, cheilitis, palmar erythema and hand and foot oedema were seen with severe febrile general symptoms (Pouletty M et al. 2020).
• Drug-induced exanthema, with the viral infection playing an initiating role.

_______________________________________________________________________________________________

In addition to COVID-19-associated exanthema, vasculitic and non-vasculitic skin changes are currently described (Drerup, K.A. et al 2021)

Exanthematic skin changes:

• vesicular, possibly itchy exanthema, which occurs before other COVID-19 symptoms in 15% of cases
• maculopapular, often itchy exanthema, usually together with other COVID-19 symptoms, especially in more severe cases
• urticarial, very itchy exanthema, usually simultaneously with other symptoms

Acral vasculitic skin changes:

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

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.

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

These systemic conditions may be associated with multifaceted cutaneous lesions that also show different patterns of inflammation at the histopathologic level. The skin changes may be associated with different multisystemic manifestations (Criado PR et al. 2020).

Spanish dermatologists have identified five characteristic clinical patterns based on 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 commonly affected middle-aged adults (mean age 53.2 years): The patients showed varying degrees of morbilliform exanthema of the skin, sometimes with hemorrhagic and punctiform or extensive redness. These lesions were also observed in severe courses of Covid-19 disease in which several drugs were used. According to the Spanish dermatologists, it cannot therefore be ruled out that these skin reactions are an expression of a drug side effect. Maculopapular exanthema also includes purpuric vasculitic exanthema, which can also take on a vesicular aspect if there is heavy exudation. They are based on 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 frostbite-like changes, which usually occur asymmetrically on the hands (fingers) and feet (toes), occur predominantly in younger female patients with fewer COVID-19 symptoms (58.5% affected women between 18 and 39 years of age, average age 23.2 years) (Daneshgaran G et al. 2020). They only developed later in the course of the disease and persisted for an average of 12.7 days. In around a third of those affected, the skin changes were painful or caused itching (Daneshgaran G et al. 2020). Histopathologically, there are varying degrees of lymphocytic vasculitis, ranging from endothelial swelling and endotheliitis to fibrinoid necrosis and microthrombotic phenomena. Furthermore, superficial and deep perivascular lymphocytic infiltrates with paraeccrine accentuation and slight vacuolar interface damage are detectable. In some cases, SARS-CoV-2 immunohistochemistry was positive in endothelial cells and epithelial cells of the eccrine glands. One group of authors found coronavirus particles in the cytoplasm of endothelial cells using electron microscopy (Colmenero I et al. 2020). However, this appears to be 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 the endothelial damage induced by the virus is important in the pathogenesis of the acral "chilblain-like" changes.
• Urticaria/angioedema: Urticarial, mostly itchy exanthema affected 10.9% of COVID skin lesions. Adult patients were affected (average age 38.3 years). In some studies, this was associated with a severe course of Covid-19 disease; the trunk was mainly affected; less frequently, 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). These patients showed chickenpox-like, vesicular, itchy exanthema on the trunk and extremities. In some cases, a hemorrhagic component may also be present. The lesions persisted for an average of 10.4 days (Marzano AV et al. 2020).
• Livedovasculitis (livedo racemosa): These skin manifestations with their characteristic rich red or hemorrhagic flashes were rare. These are probably microthrombotic processes and vascular damage. The skin lesions occurred mainly on the trunk and extremities and affected 4% of COVID skin lesions. Livedovasculitis occurred mainly in severe cases and in older patients (average age 77.5 years) and was associated with non-cutaneous COVID-19 symptoms in 60% of cases (Daneshgaran G et al. 2020). The mortality rate in this group was 10%. The extent to which these are directly virally triggered or occur as part of a virally induced immunological dysfunction is still unclear. The livedovasculitis was histologically based on occlusive vasculitis of medium-sized skin vessels (Daneshgaran G et al. 2020).

Other skin manifestations:

• Erythema multiforme: Multiforme exanthema was rare and affected 3.7% of COVID skin lesions, but mainly children (mean age 12.2 years).
• Gianotti-Crosti syndrome (Brin C et al. (2020)
• Leukocytoclastic vasculitis with hemorrhagic patches, including hemorrhagic vesicles and blisters; signs of isomorphism with streak-like lesions in scratch marks (Camprodon Gómez M et al. (2020)
• Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) Criado PR et al. (2020)
• Acral peeling skin syndrome (Rotulo GA et al. 2020)
• SDRIFE (Chicharro P et al. 2021)
• Pityriasis lichenoides chronica, also after COVID vaccination (Drago F et al. 2022)

In summary, skin changes in the context of a COVID infection are to be regarded as monitoring signs of this viral infection. This applies in particular to varicelliform exanthema. Acral COVID chilblains can be indicative and prognostic markers for the severity of the disease. For example, "COVID toes" are often found in children and asymptomatic patients!

The rare livedovasculitis is a potential correlate of the severity of the disease. The same appears to be true for angioedema.

It is important for healthcare professionals to familiarize themselves with COVID skin changes in order to be able to assess these monitoring symptoms at an early stage.

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.
15. Kluger N (2020) Que nous apprend la pandémie de COVID-19 à nous et sur nous, les dermatologues? Ann Dermatol Venereol 147:413-417.
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.

17. Lipsker D (2020) . Paraviral eruptions in the era of COVID-19: Do some skin manifestations point to a natural resistance to SARS-CoV-2? Clin Dermatol 38:757-761.

18. Muskaan Sachdeva et al (2020) Cutaneous manifestations of COVID-19: report of three cases and a review of literature. J Dermatol Sci 98:75-81.

19. Marzano AV et al (2020) Varicella-like exanthem as a specific COVID-19-associated skin manifestation Multicenter case series of 22 patients. J Am Acad Dermatol 83:280-285.
20. Najafzadeh M et al (2020) Urticaria (angioedema) and COVID-19 infection. J Eur Acad Dermatol Venereol 34:e568-e570.
21. Nasiri S et al (2020) Urticarial vasculitis in a COVID-19 recovered patient. Int J Dermatol 59:1285-1286.
22. Pistorius MA et al (2020) Chilblains and COVID19 infection: Causality or coincidence? How to proceed? J Med Vasc 45:221-223.
23. Pouletty M et al (2020) Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort. Ann Rheum Dis 79:999-1006.
24. Recalcati S (2020) Cutaneous manifestations in COVID-19: a first perspective. J Eur Acad Dermatol Venereol 34:e212-e213.
25. Rotulo GA et al (2020) Giant urticaria and acral peeling in a child with coronavirus disease 2019. J Pediatr S0022-3476(20): 31311-1.
26. Wang L et al (2020) Review of the 2019 novel coronavirus (SARS-CoV-2) based on current evidence. Int J Antimicrob Agents 55:105948. - PMC - PubMed.
27. Whittaker E et al (2020) Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporarily Associated With SARS-CoV-2. JAMA 324: 259-269.
28. Wollina U et al (2020) Cutaneous signs in COVID-19 patients: A review. Dermatol Ther 33:e13549.
29. Zhao Q et al (2020) COVID-19 and cutaneous manifestations: a systematic review. J Eur Acad Dermatol Venereol 34:2505-2510.
30. Drerup, K.A. et al (2021) SARS-CoV-2 - an update on skin manifestations, predictive markers, and cutaneous vaccine reactions. Dermatologist 72, 929-932. https://doi.org/10.1007/s00105-021-04881-7.