key: cord-0951467-t8pltw5x
authors: Novak, N; Peng, WM; Naegeli, MC; Galvan, C; Kolm‐Djamei, I; Brüggen, MC; Cabanillas, B; Schmid‐Grendelmeier, P; Catala, A
title: SARS‐CoV‐2, COVID‐19, skin and immunology ‐ what do we know so far?
date: 2020-07-13
journal: Allergy
DOI: 10.1111/all.14498
sha: 7ee89c960ffc62cf9b0d1cb19555470567507f51
doc_id: 951467
cord_uid: t8pltw5x

The pandemic condition Coronavirus‐disease (COVID‐19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) can take asymptomatic, mild, moderate, and severe courses. COVID‐19 affects primarily the respiratory airways leading to dry cough, fever, myalgia, headache, fatigue, and diarrhea and can end up in interstitial pneumonia and severe respiratory failure. Reports about the manifestation of various skin lesions and lesions of the vascular system in some subgroups of SARS‐CoV‐2 positive patients as such features outside the respiratory sphere, are rapidly emerging. Vesicular, urticarial and maculopapular eruptions as well as livedo, necrosis and other vasculitis forms have been reported most frequently in association with SARS‐CoV‐2 infection. In order to update information gained, we provide a systematic overview of the skin lesions described in COVID‐19 patients, discuss potential causative factors and describe differential diagnostic evaluations. Moreover, we summarize current knowledge about immunologic, clinical and histologic features of virus‐ as well as drug‐induced lesions of the skin and changes to the vascular system in order to transfer this knowledge to potential mechanisms induced by SARS‐CoV‐2.

The story behind the virus with the crown Coronaviruses belong to a large group of related viruses, named coronavirus family, which can infect humans and animals and lead to diseases of the airways, the gut, liver, and the nervous system. Some members of coronavirus family may infect the upper airways with rather mild courses and others -as severe acute respiratory syndrome coronavirus SARS-CoV-2 -may affect the lower respiratory airways with pneumonia and fatal courses ( Table 1 ) (1) (2) (3) .

Belonging to the -Coronavirus genus, SARS-CoV-2 is the pathogen that causes the new infectious respiratory disease, termed as coronavirus disease , which was reported to have emerged in December 2019, in Wuhan (Hubei province, China) first (or supposedly even earlier) and turned rapidly to be a global pandemic (2) . SARS-CoV-2 displays 79% nucleotide identity with SARS-CoV and 51.8% nucleotide identity with MERS-CoV, but most importantly shares 96% identity across the entire genome with a bat coronavirus, which is supposed to be the natural origin of SARS-CoV-2 (1, 4, 5).

As other coronaviruses, SARS-CoV-2 is an enveloped, positive-sense single-stranded RNA virus with spikes that protrude from the virus surface resembling a crown or "corona" (Fig. 1 ). Most importantly, the spike (S) protein of coronaviruses is essential for viral infection of host cells.

During the virus entry procedure, the S protein engages its cellular receptor, angiotensinconverting enzyme 2 (ACE2), which facilitates viral attachment to the cell surface of target cells.

As a next step, the engaged S protein is further primed by the cellular serine protease (Transmembrane Protease Serine 2) TMPRSS2, which mediates membrane fusion and viral entry into the cells ( Fig. 1 ) (6) (7) (8) (9) (10) . ACE2 is expressed on the apical surface of the epithelial cells that line conducting airways, as well as alveolar epithelial cells. ACE2 is cleaved from the surface of epithelia by shedding. Soluble ACE2 is catalytically active, interferes with epithelial cell signaling and has protective defense function. Importantly, as the efficiency of ACE2-S interaction largely determines SARS-CoV transmissibility (11) (12) (13) , the expression of ACE2 receptors represents a major risk factor for the vulnerability to SARS-CoV-2 infection. In humans, the ACE2 receptors are expressed by CD8 + T cells (14), resting and activated natural killer (NK) cells (14), alveolar epithelial cells of type II (15) , vascular endothelial cells, macrophages, monocytes and adipocytes

This article is protected by copyright. All rights reserved (16) . The nose and the nasal epithelium play an important role for infection and viral spreading (17, 18) . High ACE2 expression has also been demonstrated on epithelial cells of the oral mucosa, in particular the tongue, so that this receptor might provide an entry route for the virus and designates the oral cavity as a potential organ at high risk for viral spreading from one individual to the other (19) . Tissue distribution of the ACE2 gene includes the small intestine, testis, kidneys, heart, thyroid, and adipose tissue with relatively high expression (16) . It has been recently demonstrated that the inflammatory cytokines interferon (IFN)-α2 and IFN-γ increase the expression of ACE2 and is supposed that tissue inflammation may modulate the receptor expression and thereby change the risk of immune cells to be infected by SARS-CoV-2 (18) . So far, a positive correlation of ACE2 gene expression to CD8 + cells in the skin has been shown 16).

Binding of SARS-CoV-2 to ACE2 downregulates its expression and impacts thereby on its main function, the regulation of the renin-angiotensin system. This downregulation leads to a dysregulation of the balance of soluble factors, electrolytes, blood pressure combined with an increase of vascular permeability and lung inflammation (1). Usually, virus-specific T cells recruited to the site of inflammation eliminate the virus with neutralizing antibodies generated from B cells and macrophages and prevent thereby virus spreading in an immunocompetent individual (1, 20) . However, inflammation-induced cell death of infected cells and damagereleased molecular patterns might induce proinflammatory cytokines and chemokines and recruitment of inflammatory cells to the lung (Fig. 2) (21) . In patients with severe COVID-19, HLA class II expression is downregulated and type I interferon driven signatures are reduced in peripheral blood cells, i.e. monocytes and changes in the function of natural killer cells occur, a mechanism which mirrors evasion of SARS-CoV-2 from innate immune sensing and defense (22) .

In parallel, inflammatory programs in macrophages resident in the lung are induced. Thus, the lung tissue damage caused by SARS-CoV-2 infection and replication, may thereby destroy stepwise the lung structure with the development of pulmonary fibrosis by transformation of adipocytes into myofibroblasts (23) . The knowledge accumulated from SARS and MERS, together with current clinical observations from COVID-19 patients, suggest that type-I IFN-mediated antiviral responses and activation of both CD4 + Th1 and CD8 + cytotoxic T lymphocytes (CTLs) result in viral clearance in SARS-CoV-2 infected subjects with mild symptoms. However, insufficient initiation of antiviral immune responses, increased production of inflammatory Accepted Article cytokines, as well as lung infiltration of monocytes and neutrophils, contribute to a cytokine storm in severe patients (24, 25) . Moreover, the cytokine storm elicited from the overproduction of pro-inflammatory mediators such as interleukin (IL)-1, IL-6, IL-12, and tumor necrosis factor (TNF)-α, not only leads to increased vascular permeability and inflammation in the lung (24, 25) but may reach other organs through the vascular system. In the worst case, this might induce injury of multiple other organs including the cardiac, renal or hepatic system (Fig. 2) (1). This cascade of events might lead despite intensive care and a lot of other measures initiated, to fatal courses and death, in particular in elderly patients and individuals with pre-existing diseases.

Transmission of SARS-CoV-2 is mediated mainly via respiratory droplets from an infected person (26, 27) . Of note, SARS-CoV-2 positive patients emit respiratory droplets in high numbers during speaking, which remain in the air up to 8-14 minutes (28) . The average incubation time until the onset of COVID-19 is 4-11 days (29) . The immune responses resulting from SARS-CoV-2 infection vary broadly and range from asymptomatic courses, over mild, moderate to severe courses with a need for hospitalization and intensive care. Typical symptoms of COVID-19 include dry cough, fever, myalgia, headache, anosmia and ageusia (30) . Depending on the severity of the disease, even other organ systems such as the gastrointestinal tract, the liver, the renal system as well as the cardiac system might be involved and become symptomatic as well (Fig. 3 ).

Comorbidities, gender and senescence of the immune system Comorbidity rate increases the rate of mortality of COVID-19 with cardiovascular diseases, hypertension, poorly controlled diabetes mellitus and obesity being major risk factors (31) (32) (33) .

Since adipocytes express ACE2 and might serve as a reservoir for SARS-CoV-2, this fact might explain in part the higher risk of obese patients and obesity being a predictor for mortality among COVID-19 patients (23, 34) .

This article is protected by copyright. All rights reserved Altered immune function and impaired defense against infectious pathogens and modulations of the innate as well as the adaptive immune system underlie the higher risk for severe courses of patients with diabetes mellitus (32) . On the other handside, COVID-19 impacts also on preexisting diabetes mellitus with alterations of the glucose metabolisms, which lead to severe metabolic complications (35) . Endothelial dysfunction, which goes along with aging, decline of sex hormones, increased number of endothelial microparticles, an inflammatory immune state and reactive oxygen species, might among other factors represent a risk factor for patients with cardiovascular diseases (36) . SARS-Cov-2 might also enter cardiomyocytes, which express ACE2 and induce myocardial damage (37) .

Senescence of the immune system with lower antigen response of T and B cells from elder individuals as well as weaker effector functions and limited number of CD8 + memory cells capable to react do different pathogens might among other factors play a role for attenuated virus clearance and lower number of anti-inflammatory cytokines and mediators, innate immune regulatory proteins or regulatory cell mechanisms in higher age groups (38, 39) .

One reason besides a higher number of comorbidities and drugs take in the group of elder patients might be that ACE2 expression increases with age (40).

In a study on patients with asthma, male gender, African Americans race and history of diabetes mellitus, was associated with higher expression of ACE2 and TMPRSS2 in sputum cells of patients with asthma (41) .

Higher expression of ACE2 and CD147 related genes in bronchial biopsies, bronchoalveolar lavage or peripheral blood cells was observed in patients with asthma, COPD, hypertension and obesity, as well as in smokers and males (42) .

Circulating plasma levels of ACE2 have been demonstrated to be higher in men with heart failure than in women and might indicate higher tissue expression of the SARS-CoV-2 entry receptor in man as a risk factor for more fatal courses of COVID-19 (43) . The expression of ACE2 in the myocard is regulated by androgen in mouse models (44, 45) . Male mice with hypertension had

This article is protected by copyright. All rights reserved higher ACE2 expression, which was reduced after orchiectomy. These data indicate that testosterone might negatively impact on the risk for COVID-19 (44, 45) .

Whether gender differences in terms of nature and frequency of the skin lesions exist, needs to be elucidated in further studies.

However, several gender differences in relation to virus responses and responses to viral vaccines have been described in the past. These include higher susceptibility of men to infectious diseases or stronger antibody titers inducible by several different types of vaccines in women as opposed to men (46, 47) . Moreover, plasmacytoid dendritic cell-mediated type I IFN responses have been demonstrated to be stronger in women than in men, another factor of putative importance for viral clearance even in the context of SARS-CoV-2 infections (46, 47) . Higher susceptibility, need for hospitalization, longer duration of the disease and higher rate of mortality in men versus women has been also described for other virus infections such as with influenza virus (48) . Together, these observations point to SARS-CoV-2 specific as well as general differences in viral immunity in man versus women.

Patients with blood group A type are more susceptible to severe courses of COVID-19 and association with genetic variations in a gene cluster on chromosome 3p21.31 detected in a genome wide association study of severe COVID-19 cases with respiratory failure imply a genetic risk of this group. In the same study, a protective effect in blood group 0 type was observed (49) .

Another reason might be the presence of allelic variants interfering with the binding of the Sprotein of SARS-CoV-2 to ACE2 and putative protection of the carriers from SARS-CoV-2 infection (50) . In contrast, higher allele frequencies of variants in the ACE2 coding gene region, which go along with higher ACE2 expression in the tissue, have been observed in populations from east Asia (51) and might indicated a specific risk, related to ethnic groups.

Besides the typical symptoms described above, more and more reports about skin lesion and lesions of the vascular system observed in patients tested positive for SARS-CoV-2 and patients suspected to be infected by SARS-CoV-2 are coming up in countries all over the world (52) (53) (54) (55) .

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The percentage of patients with skin lesions varies from lower than 1% to up to 20% of all SARS-CoV-2 patients and has to be estimated exactly in systematic studies on this issue.

The spectrum of skin lesions in SARS-CoV-2 patients described and published so far contain skin lesions occurring in other infectious and viral diseases such as maculopapular-exanthema, vesicular exanthema or urticarial eruptions (52, (56) (57) (58) (59) (60) (61) . Furthermore, the skin lesions might also be related to virus induced or indirectly induced vascular dysfunctions, such as livedo reticularis, petechiae or cutaneous acro-ischemia (52) (53) (54) (55) (56) (57) 62) . Chilblain lesions have been described as well (63-65) but a direct relation to SARS-CoV-2 infection is questionable. Considering frequency, most reports exist on maculopapular exanthema/vesicular exanthema and urticarial lesions (56) . 2. Maculopapular exanthema manifests together with COVID-19 symptoms, often in more severe cases with a mortality rate up to 2%, lasts 7-9 days and is in over 50% of the cases accompanied by itch (Fig. 4B ).

3. Urticarial eruptions occur at the same time as other symptoms in more severe COVID-19 cases are accompanied by itching and last 6-8 days (Fig. 4C ). 4 . Livedo or necrosis and other vasculitis forms tend to occur in older and more severe cases, with relatively high mortality (up to 10%) and the onset was together with COVID-19 symptoms (Fig. 4D ).

5. Chilblain was observed in younger patients with mild or even asymptomatic courses or negative SARS-CoV-2 testing, the onset is late, duration 12-14 days and in one third are the lesions accompanied by pain and itch (28, 29) (Fig. 4E ).

Since it is quite difficult to verify, in which context the skin lesions occur in terms of SARS-CoV-2 infections, we would like to summarize in the next few sections current knowledge about the

This article is protected by copyright. All rights reserved pathophysiologic background of virus-induced and drug-induced lesions of the skin and the vascular system.

Viral exanthema is defined as a skin rash, which is sometimes associated with an enanthem and goes along with fever and other systemic symptoms (66, 67) . In this context, it is important to notice that also the ACE2 receptor has been described to be expressed in the oral cavity (15) (68). Nucleotide testing of tissue specimens is highly sensitive and specific, but stability of samples and RNA, contamination, and other issues may occur and limit information gained, so that even part of smear taken from the mouth remain false negative (67).

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Although skin biopsies are rarely taken from viral skin lesions, because the features observed are mostly not very specific, biopsies might be an option to differentiate viral exanthema from druginduced exanthema in COVID-19 patients, in these cases it is essential to do the differential diagnosis and rule out the pharmacological cause.

To distinguish infectious exanthema from exanthema induced by drug-hypersensitivity reactions, histologic features and immunologic changes in the skin might help to diagnostically differentiate both entities.

Immunologic features of maculopapular virus exanthema known so far are summarized in Fig.   5A . Typical histologic features of infectious exanthema induced by viremia or dissemination of infectious agents through the blood are shown in Table 2 and Fig. 6A . 

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Urticaria and acute urticarial rashes go along with up to 50% of all cases with infections of the upper respiratory tract (75) and are most often mediated by complement activation and serum sickness induced by viral antigens or secondary mechanisms, due to the interaction of the immune system with viral antigens. This could be also the case in part of the SARS-CoV-2 positive patients with urticarial eruptions (Fig. 7) .

Infectious diseases are the cause of over 20% of cutaneous vasculitis (76) . Most of them have a self-limiting course, but the involvement of other organs is possible.

Vasculitis can affect small, medium and large vessels (Fig. 8 ). Mechanisms might be type III or immune complex-mediated reactions to viral antigens or part of viral antigens. In this context, large immune complexes might precipitate and accumulate within vessels, a process leading to vascular injury (Fig. 8A ) (77) . Histologic features of vasculitis are an inflammatory infiltrate in wall of dermal or subcutaneous vessels (which can be neutrophilic, lymphocytic or granulomatous), red blood cell extravasation, variable fibrinoid necrosis of vessel walls, and nuclear debris. Cell-mediated hypersensitivity, in which exposure to viral antigens induce recruitment of lymphocytes, which release proinflammatory cytokines and further attract macrophages and more lymphocytes leading to tissue damage of the vessels, has also been described as a pathway in some infectious vasculitis types (Fig. 8B) .

Furthermore, abnormal immune regulation including different expression of adhesion molecules and cytokines in vascular endothelium by different virus-related processes as well as direct endothelial cell invasion of the virus (Fig. 8C ) or direct stimulation of the immune system by infectious agents might take place (78) .

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Whether and which kind of virus induced mechanisms of infectious vasculitis play a major role in SARS-CoV-2 vascular lesions is unclear, but immune complex mediated mechanisms are likely to be of relevance.

Furthermore, since ACE2 expression has been described for endothelial cells (79, 80) , it is quite speculative but still conceivable at this time point -but even possible -that the virus directly interacts with endothelial cells leading to tissue damage and the resulting skin lesions.

In children an association of COVID-19 with Kawasaki-like disease with mucocutaneous involvement, polymorphic rash, erythema of the palms and soles, firm induration of hands or feet, or both besides other symptoms of Kawasakis disease has been postulated (81).

Kawasaki disease is classified a systemic vasculitis of medium size vessels (Fig. 8) and pathogens including different virus types have been suspected as one causative factor in a rather multifactorial pathogenesis. Further studies are needed to demonstrate a correlation of Kawasaki disease with SARS-CoV-2 in larger patient groups and time courses.

Skin manifestations, such as urticaria, psoriasis, autoimmune diseases, or others, might result from the SARS-CoV-2 related reactivation or aggravation of pre-existing skin diseases.

Idiopathic chilblain or also called acro-ischemic lesions, presenting as violaceous, infiltrated painful and sometimes even pruritic plaques on erythematous skin with predilection on the back of the toes or feet has been described to occur in a special group of SARS-CoV-2 positive, suspected patients as well as asymptomatic or non-infected patients (Fig. 4F ) (82, 83) . Histologic features of these lesions were typical for a lymphocytic vasculitis, with a superficial and deeper lymphocytic infiltration around vessels and close to eccrine glands, a papillary edema, vacuolar degeneration of the basal layer as well as lymphocytic exocytosis to the epidermis. Red cell extravasation as well as focal thrombosis in papillary dermal capillaries as well as vessels of the reticular dermis were described in some reports as well (64, 84, 85 

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Cutaneous drug reactions are classified into immediate and nonimmediate drug hypersensitivity reactions. The latter have been subclassified into 5 groups based on the type of immune mechanisms in the foreground ( Table 3) . Part of the skin and vascular lesions are most likely related to drug hypersensitivity reactions.

Urticaria and urticarial rashes belong at least in part to cutaneous type I (IgE-mediated) drughypersensitivity reactions (Table 3 ) (Fig. 7) . Other mechanisms involved in drug induced urticarial rashes are direct mast cell activation, immune complex formation/precipitation (Fig. 7) and

activation of complement during serum sickness or interaction with metabolic pathways of drugs such as arachidonic acid metabolism (88) . Urticaria or urticarial rashes in SARS-CoV-2 patients could be drug induced, induced by viral RNA or a mixture of both. Infection-associated reactivation or exacerbation of pre-existing urticaria might be possible as well.

In general, about 7% of hospitalized patients develop drug hypersensitivity reactions of variable severity, and exanthema occurs in 2-3% of these cases (89, 90) .

Both, drugs and metabolites of drugs might elicit exanthematous drug-hypersensitivity reactions (Table 4) .

Maculopapular exanthema with eosinophilia has been described in COVID-19 patients (91) .

Some skin lesions observed in COVID-19 patients might result from cutaneous type IV (T-cell mediated) drug hypersensitivity reactions. Typical immunologic characteristics of maculopapular eruptions are summarized in Figure 5B (type IVb) and 5C (type IVc) and histologic features are summarized in Table 5 and shown in Figure 6B . 

This article is protected by copyright. All rights reserved extravasation of red blood cells and dilatation of blood vessels. It is often impossible to histologically distinguish viral and drug induced exanthema. Lichenoid -and less frequentlyspongiotic or psoriasiform pattern of reactions may be related to maculopapular drug reactions.

Sometimes even systemic eosinophilia and elevated CRP levels might occur (92) . Typical immunologic characteristics of maculopapular eruptions are summarized in Figure 5B (type IVb) and 5C (type IVc) and histologic features are summarized in Table 5 and shown on Figure 6B .

There are COVID-19 positive cases severe cutaneous adverse drug reactions including DRESS (drug reaction with eosinophilia and systemic symptoms) described, which is a severe cutaneous drug reaction with non-specific histologic findings ( Figure 9A and B). The diagnosis is based on a combination of clinical symptoms and laboratory parameters including frequently occurring hepatic abnormalities, eosinophilia and exanthema with facial swelling and lymphadenopathy (93) . The culprit drug should be stopped immediately upon identification.

Drug hypersensitivity reactions with changes of the vasculature or vascular pathways such as vasculitis, livedo racemosa or purpura represent a proportion of 10-20% of cutaneous reactions to drugs and can occur relatively late (7-14 days) during or even after drug exposure, but the time of onset to the related drug varies and depending on the causative drug (94) .

Numerous drugs can induce vasculitis, which manifests primarily as cutaneous vasculitis, mediated as III hypersensitivity reactions (Table 3) , i.e. immune complex deposits with antigen excess in arteries, arterioles, venules or capillaries (Fig. 8) . It is of notice that some drugs might also induce antibody production (78) .

Drug-induced vasculitis includes leukocytoclastic or hypersensitivity vasculitis, necrotizing vasculitis, Panarteritis-nodosa like vasculitis and others (78) .

Histologic features of vasculitis are an inflammatory infiltrate in the wall of dermal or subcutaneous vessels (which can be neutrophilic, lymphocytic or granulomatous), red blood cell extravasation, variable fibrinoid necrosis of vessel walls and nuclear debris (94) .

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The number of drugs, which have been reported to be applied to COVID-19 patients all over the world is high and ranges from specific antiviral drugs, antiphlogistics, antibiotics, anti-coagulants, immunosuppressive as well as immunoregulatory drugs. All of these drugs are approved and 

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The authors declare no conflict of interest.

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