Clinical and Histopathological Features and Potential Pathological Mechanisms of Skin Lesions in COVID-19: Review of the Literature

In recent weeks, several reports have emerged of skin lesions with different clinical presentations in COVID-19 cases. All dermatologists should be aware of these cutaneous lesions, which may be early clinical symptoms of infection. We reviewed the literature on cutaneous manifestations in the PubMed database from December 2019 and June 2020. From the cases described as case reports or series in 57 recent articles, it appears that skin lesions (i) are highly varied, (ii) may not be related to the severity of the condition and (iii) resolve spontaneously in a few days. The frequency of these lesions in COVID-19 patients varies between 1.8% and 20.4%. The major clinical forms described were maculopapular eruptions, acral areas of erythema with vesicles or pustules (pseudochilblain), urticarial lesions, other vesicular eruptions and livedo or necrosis. The lesions were mainly localized in the trunk and extremities. The majority of patients were male, aged between 4.5 and 89 years. A minority of the patients were children presenting with acral, chilblain-like lesions, papulo-vesicular eruptions or Kawasaki disease-like pediatric inflammatory multisystem syndrome. The mean duration of the lesions was a few days, but some lasting as little as 20 min and others as long as four weeks have been reported. The mean latency time in the majority of cases was between 1 and 14 days; however, in some patients, lesions appeared 2 to 5 days before the onset of COVID-19 symptoms. The histopathological features of these lesions also vary, corresponding to the diversity of clinical manifestations. These features underline the nature of epidermal and dermal vascular lesions—and in severe cases, microvascular injury and thrombosis—associated with COVID-19, and provide important clues to their pathological mechanisms.


Introduction
In recent weeks, there have been several published reports of COVID-19 cases with skin lesions with different clinical presentations; all dermatologists should be aware of these clinical signs. In patients with COVID-19, aggravation of previous skin lesions have been noted, and allergic reactions to the different medications used for treatment may occur. However, recently, there have been reports of skin lesions that may correspond to cutaneous manifestations of SARS-CoV-2 [1].
The characteristics of skin lesions in patients with COVID-19, as described recently in case reports or case series, are summarized in the Table 1  . According to these publications, in which the majority of reported patients had Fitzpatrick skin types I-III [59], the skin manifestations of COVID-19 are highly varied and nonspecific, are not necessarily related to the severity of the condition and resolve spontaneously in a few days. Sebopsoriasis (n = 1), facial herpes (n = 1), exanthem (n = 9), acral vasculitic eruption (n = 6), urticaria (n = 2) and varicelliform rash (n = 1).    We still have a lot to learn about the cutaneous manifestations associated with this disease, and there are currently more questions than answers. It is still unclear what percentage of COVID-19 patients develops cutaneous eruptions. Although 20.4% of patients (18 out of 88) in an Italian cohort developed cutaneous abnormalities [24], they were present in only 1.8% (2 out of 1099 patients) in a Chinese cohort [10].

Methods
A literature search using the following strategy was performed on the PubMed database to identify eligible articles: (COVID* or coronavirus* or SARS-CoV-2*) and (dermatol* or skin* or cutaneous*). The publication date was limited to December 2019 onward. A total of 112 papers were identified in the initial search. Abstracts and full-texts of all articles were then reviewed. Reports on different cutaneous manifestations associated with COVID-19 were included in this review (67 in total, 57 of which are listed in Table 1).
The lesions are mainly localized in the trunk and extremities (hands and feet), sparing the face; however, lesions located on the face, neck, mouth and axillary folds have also been reported.
The majority of patients were male, aged between 4.5 and 89 years. A minority of patients were children (between 4.5 and 14 years) presenting with acral, chilblain-like lesions, papulo-vesicular eruptions on the trunk or pediatric inflammatory multisystem syndrome.
The mean duration of the lesions was a few days, but some lasting as little as 20 min and others as long as four weeks have been reported. The mean latency time (i.e., time to develop skin lesions after the appearance of the first typical symptoms of COVID-19) in the majority of cases was between 1 and 14 days; however, in some patients, lesions appeared 2 to 5 days before the onset of COVID-19 symptoms.
In the table, we have classified all reported cases according to the time of occurrence of skin lesions. In some patients, lesions appeared 2 to 5 days before the onset of COVID-19 symptoms; one such case involved an 8 year-old. The types of skin lesions in these patients were similar to those appearing up to 7 days after the onset of the first symptoms of COVID-19; this is consistent with a viral rash. In contrast, lesions appearing beyond the 7th day of ongoing COVID-19 are more vascular in nature.
COVID-19 is less frequent in children than adults (<1%), with a milder course; however, cases of pediatric inflammatory multisystem syndrome with features resembling atypical Kawasaki disease occurring several weeks after SARS-CoV-2 infection have recently been reported in children in the UK, as well as in Italy, France, Switzerland and the USA (Kawa-COVID-19) [57]. Clinical presentation includes fever, variable rash, conjunctivitis and abdominal pain, progressing to hemodynamic shock with severe myocardial involvement. Severe disease, with the need for intensive care due to myocarditis, occurred in almost half of all reported cases, with a higher risk of poor outcome for patients older than 5 years of age, and particularly for teenagers. A recent study from Italy reported a 30-fold increase in the rate of Kawasaki-like presentation during the COVID-19 pandemic among children; in many cases, nasopharyngeal swabs taken from these children were negative for COVID-19, and the association with COVID-19 infection is unclear [44].

Histopathological Features
Histopathological features have been reported in only a minority of patients in these articles ( Table 1).

Maculopapular Eruptions
Maculopapular eruptions show superficial perivascular dermatitis with slight lymphocytic exocytosis, swollen thrombosed vessels with neutrophils, eosinophils and nuclear debris/superficial and deep perivascular dermatitis with cuffs of lymphocytes surrounding blood vessels in a vasculitic pattern/superficial perivascular vesicular dermatitis, focal acantholytic suprabasal clefts, dyskeratotic and ballooning herpes-like keratinocytes and swollen vessels with dense lymphocyte infiltration mixed with rare eosinophils in the dermis.

Urticarial Lesions
Urticarial lesions show perivascular infiltrate of lymphocytes, some eosinophils and upper dermal edema. Urticarial vasculitis lesions show blood extravasation and neutrophilic perivascular inflammation with prominent karyorrhexis, some macrophages with a cytoplasm full of nuclear debris and endothelial swelling, necrosis and fibrin deposition. Some urticarial lesions show slight vacuolar-type interface dermatitis with occasional necrotic keratinocytes with no eosinophils, consistent with an erythema multiforme-like pattern.

Acral Chilblain-Like Lesions
In acral chilblain-like lesions, a diffuse dense lymphoid infiltrate of the superficial and deep dermis, as well as hypodermis, with a prevalent perivascular pattern and signs of endothelial activation, are observed.

Purpuric and Livedoid Lesions
Purpuric and livedoid lesions show thrombogenic vasculopathy accompanied by striking and extensive deposition of C5b-9 and C4d within the microvasculature.

Pityriasis Rosea-Like Lesions
In pityriasis rosea-like lesions, there is mild diffuse spongiosis in the epidermis and rounded spongiotic vesicles containing aggregates of lymphocytes and Langerhans cells, as well as mild papillary edema and lymphohistiocytic infiltrate in the dermis.

Kawasaki-Like Lesions
In Kawasaki-like lesions, findings consistent with leukocytoclastic vasculitis, including necrosis of the epidermis and most of the dermis with extravasation of erythrocytes and fibrin thrombi in the capillaries, as well as infiltration of neutrophils with nuclear debris in vessel walls, and C3 and IgA deposition in a vascular pattern in direct immunofluorescence, are observed.

Subcutaneous Lesions
Subcutaneous lesions show a predominantly lobular panniculitis with lymphocytes, histiocytes and many eosinophils, consistent with an eosinophilic panniculitis.

Pustular Lesions
Pustular lesions show a subcorneal pustule with mild focal acanthosis and spongiosis, neutrophilic exocytosis, sparse keratinocyte necrosis and a perivascular lymphocytic infiltrate with rare neutrophils and eosinophils, consistent with acute generalized exanthematous pustulosis.
In a recent report, the postmortem histology of COVID-19 patients revealed lymphocytic endotheliitis in lung, heart, kidney, liver and small intestine, a pathological picture reminiscent of what is seen in skin lesions, suggesting that SARS-CoV-2 infection facilitates the induction of endothelial inflammation in several organs as a direct consequence of viral involvement and of host inflammatory response [61].
The histopathological features of these lesions also vary, corresponding to the diversity of clinical manifestations. In maculopapular lesions, it is sometimes quite difficult to differentiate a drug reaction from a viral infection. However, the presence of multinucleated ballooning cells suggests a cytopathic effect, lending weight to the hypothesis that the lesions are due to COVID-19. For varicella-like acantholytic lesions, Grover's disease should be eliminated by the presence of endothelial swelling and vascular damage or extensive epidermal necrosis, and a herpes infection by immunohistochemistry and cultures. The histology of chilblain lesions are quite characteristic, with dermal edema and deep lymphocytic vasculitis, and purpuric and livedoid lesions show vascular thrombosis. In Kawasaki-like lesions and urticarial vasculitis, leukocytoclastic vasculitis is observed. Other lesions such as urticaria, pityriasis rosea-like, subcutaneous and pustular lesions do not seem to be specific. These features underline the nature of epidermal (acantholysis, multinucleated ballooning keratinocytes, dyskeratosis, necrosis) and dermal vascular (lymphocytic vasculitis, endotheliitis) lesions-and in severe cases, microvascular injury and thrombosis-associated with COVID-19, and provide important clues to their pathological mechanisms.

Potential Pathological Mechanisms
The pathological mechanisms of skin lesions in COVID-19 patients remain poorly understood. Cutaneous manifestations in COVID-19 may be classified into two major groups regarding their pathomechanisms [62]: (1) clinical features similar to viral exanthems (an immune response to viral nucleotides) (2) cutaneous eruptions secondary to systemic consequences caused by COVID-19 (especially vasculitis and thrombotic vasculopathy).
The possible actions of SARS-CoV-2 on human skin and the resulting potential dermatological manifestations can be summarized as follows [63].
SARS-CoV-2 is a single-stranded RNA virus composed of 16 nonstructural proteins (NSP 1-16) with specific roles in the replication of coronaviruses (CoVs). For example, NSP3 has the ability to block the host's innate immune response and promote cytokine expression, while NSP5 can inhibit interferon (IFN) signaling, and NSP16 avoids MAD5 (melanoma differentiation-associated gene 5) recognition, depressing innate immunity.

Some studies have shown direct T cell viral infection by the detection SARS-like viral particles and SARS-CoV-2 RNA in T lymphocytes.
In a subset of patients, overactive immune responses may induce immunopathological conditions, or "cytokine storm" (i.e., an increase in pro-inflammatory cytokines, in particular, IL-6); these cytokines could reach the skin and stimulate dermal dendritic cells, macrophages, mast cells, lymphocytes and neutrophils, and promote eruptions such as erythema, urticarial lesions, vesicles and others (JAK inhibitors for IL-6).
Complement activation (C5b-9 and C4d) by SARS-CoV-2 spike glycoproteins has been shown in retiform purpura [18]. In pseudochilblain and purpuric lesions, an obliterative microangiopathy consisting of endothelial and intensive myointimal growth with complement activation has been observed. This mechanism, together with increased vascular permeability, could contribute to obliterative vascular lumen and hemorrhage in COVID-19 patients [64].
Aerosolized uptake of SARS-CoV-2 leads to infection of the functional receptor angiotensin-converting enzyme (ACE) type II (ACE2)-expressing target cells such as alveolar type 2 or other unknown target cells. ACE2 is present in the skin in the basal layer of the epidermis, in endothelial cells of dermal blood vessels and in eccrine adnexal tissue [65]; a direct pathogenic effect of the virus in the epidermis via ACE2, leading to acantholysis and dyskeratosis, has been proposed [58]. COVID-19-endotheliitis via ACE2 could explain the systemic impaired microcirculatory function in different vascular beds and their clinical sequelae in patients with COVID-19 [62]. SARS-CoV-2 was shown to be absent in only four studied lesional skin biopsy samples (Table 1). However, in two recent reports, its presence was confirmed by immunohistochemistry in the endothelial cells of chilblain lesions, suggesting a causal relationship between the lesions and SARS-CoV-2 [66,67]. In one of them SARS-CoV-2 particles were found in the cytoplasm of endothelial cells by electron microscopy [66]. Endothelial damage induced by the virus could be the key mechanism in the pathogenesis of COVID-19 chilblains, and perhaps also in a group of patients severely affected by COVID-19 presenting with microangiopathic damage [66].
In order for the virus to attach (spike protein, S) to ACE2, activation by TMPRSS2, a type II transmembrane serine protease, is needed. The TMPRSS2 gene is located on human chromosome 21; one of its significant features is that several androgen receptor elements (AREs) are located upstream of the transcription start site. The first intron COVID-19 could affect males more than females due to the relationship between TMPRSS2 and androgen levels; the greater prevalence of COVID-19 in males in Spain offers a potential clue to the role of androgens in increasing COVID-19 severity, due to the higher prevalence of androgenetic alopecia among patients [9].
A better understanding of the clinical, histopathological and pathogenetic aspects of COVID-19 in different organs, including skin, will help guide early diagnoses and treatment of this new and fatal human disease with intriguing cutaneous manifestations.