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Cutaneous Manifestations of COVID-19: Characteristics, Pathogenesis, and the Role of Dermatology in the Pandemic

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References

Urticarial Rash
Urticarial lesions represent approximately 7% to 19% of reported COVID-19–associated rashes.9,13,14 Urticarial rashes in patients testing positive for SARS-CoV-2 primarily occur on the trunk.14 The urticaria, which typically last about 1 week,14 are seen most frequently in middle-aged patients (mean/median age, 42–48 years)13,14 and are associated with pruritus, which has been reported in 74% to 92% of patients.13,14 Urticarial lesions typically do not precede other symptoms of COVID-19 and are nonspecific, making them less useful diagnostically.14

Urticaria appears to be associated with more severe COVID-19 illness in several studies, but this finding may be confounded by several factors, including older age, increased tobacco use, and polypharmacy. Of 104 patients with reported urticarial rash and suspected or confirmed COVID-19 across 3 studies, only 1 death was reported.9,13,14

The histopathologic appearance is that of typical hives, demonstrating a perivascular infiltrate of lymphocytes and eosinophils with edema of the upper dermis.9,19

Morbilliform Eruption
Morbilliform eruption is a commonly reported morphology associated with COVID-19, accounting for 20% to 47% of rashes.9,13,14 This categorization may have limited utility from a diagnostic and prognostic perspective, given that morbilliform eruptions are common, nonspecific, and heterogenous and can arise from many causes.9,13,14 Onset of morbilliform eruption appears to coincide with14 or follow13,20,21 the development of other COVID-19–related symptoms, with 5% of patients reporting morbilliform rash as the initial manifestation of infection.13,14 Morbilliform eruptions have been observed to occur in patients with more severe disease.9,13,14

Certain morphologic subtypes, such as erythema multiforme–like, erythema elevatum diutinum–like, or pseudovesicular, may be more specific to COVID-19 infection.14 A small case series highlighted 4 patients with erythema multiforme–like eruptions, 3 of whom also were found to have petechial enanthem occurring after COVID-19 diagnosis; however, the investigators were unable to exclude drug reaction as a potential cause of rash in these patients.22 Another case series of 21 patients with COVID-19 and skin rash described a (primarily) petechial enanthem on the palate in 6 (28.5%) patients.23 It is unclear to what extent oral enanthem may be underrecognized given that some physicians may be disinclined to remove the masks of known COVID-19–positive patients to examine the oral cavity.

The histologic appearance of morbilliform rash seen in association with COVID-19 has been described as spongiotic with interface dermatitis with perivascular lymphocytic inflammation.9,21

COVID Toes, Pseudochilblains Rash, Perniolike Rash, and Acral Erythema/Edema
Of all the rashes associated with COVID-19, COVID toes, or pseudochilblains rash, has perhaps attracted the most attention. The characteristic violaceous erythema on the fingers and/or toes may be itchy or painful, presenting similar to idiopathic cases of pernio (Figure 1).14 The entity has been controversial because of an absence of a clear correlation with a positive SARS-CoV-2 polymerase chain reaction test or antibodies to the virus in a subset of reported cases.24,25 Onset of the rash late in the disease course, generally after symptom resolution in mild or asymptomatic cases, may explain the absence of viral DNA in the nasopharynx by the time of lesion appearance.14,26 Seronegative patients may have cleared SARS-CoV-2 infection before humoral immunity could occur via a strong type 1 interferon response.25

Cutaneous Manifestations of COVID-19

Figure 1. COVID toes/pseudochillblains rash.

Across 3 studies, perniolike skin lesions constituted 18% to 29% of COVID-19–associated skin findings9,13,14 and persisted for an average of 12 to 14 days.13,14 Perniolike lesions portend a favorable outcome; patients with COVID toes rarely present with systemic symptoms or laboratory or imaging abnormalities9 and less commonly require hospitalization for severe illness. Perniolike lesions have been reported most frequently in younger patients, with a median or mean age of 32 to 35 years.13,14

Histology demonstrates lichenoid dermatitis with perivascular and periadnexal lymphocytic infiltrates.9 Notably, one study observed interface dermatitis of the intraepidermal portion of the acrosyringium, a rare finding in chilblain lupus, in 83% of patients (N=40).25 Direct immunofluorescence demonstrates a vasculopathic pattern, with some patients showing deposition of IgM or IgG, C3, and fibrinogen in dermal blood vessels. Vascular C9 deposits also have been demonstrated on immunohistochemistry.9 Biopsies of perniolike lesions in COVID-19 patients have demonstrated the presence of SARS-CoV-2 RNA,27 have identified SARS-CoV-2 spike protein in endothelial cells on immunohistochemistry, and have visualized intracytoplasmic viral particles in vascular endothelium on electron microscopy.28

Livedoid Rash/Retiform Purpura
Netlike purpuric or violaceous patches signifying vessel damage or occlusion have been seen in association with COVID-19, constituting approximately 6% of COVID-19–associated skin findings in 2 studies.13,14 Livedoid rash (Figure 2) and retiform purpura (Figure 3) are associated with older age and occur primarily in severely ill patients, including those requiring intensive care. In a registry of 716 patients with COVID-19, 100% of patients with retiform purpura were hospitalized, and 82% had acute respiratory distress syndrome.13 In another study, 33% (7/21) of patients with livedoid and necrotic lesions required intensive care, and 10% (2/21) died.14

Cutaneous Manifestations of COVID-19

Figure 2. Fixed livedo reticularis associated with COVID-19.

Cutaneous Manifestations of COVID-19

Figure 3. Retiform purpura associated with COVID-19.

Livedoid lesions and retiform purpura represent thrombotic disease in the skin due to vasculopathy/coagulopathy. Dermatopathology available through the American Academy of Dermatology registry revealed thrombotic vasculopathy.13 A case series of 4 patients with livedo racemosa and retiform purpura demonstrated pauci-inflammatory thrombogenic vasculopathy involving capillaries, venules, and arterioles with complement deposition.29 Livedoid and retiform lesions in the skin may be associated with a COVID-19–induced coagulopathy, a propensity for systemic clotting including pulmonary embolism, which mostly occurs in hospitalized patients with severe illness.30

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