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

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References

Multisystem Inflammatory Disease in Children

A hyperinflammatory syndrome similar to Kawasaki disease and toxic shock syndrome associated with mucocutaneous, cardiac, and gastrointestinal manifestations has been reported following COVID-19 infection.31 This syndrome, known as multisystem inflammatory syndrome in children (MIS-C), predominantly affects adolescents and children older than 5 years,11 typically occurs 2 to 4 weeks after infection, and appears to be at least 100-times less common than COVID-19 infection among the same age group.31 Sixty percent31 to 74%11 of affected patients have mucocutaneous involvement, with the most common clinical findings being conjunctival injection, palmoplantar erythema, lip hyperemia, periorbital erythema and edema, strawberry tongue, and malar erythema, respectively.32

Because this condition appears to reflect an immune response to the virus, the majority of cases demonstrate negative SARS-CoV-2 polymerase chain reaction and positive antibody testing.33 Although cutaneous findings are similar to those seen in Kawasaki disease, certain findings have been noted in MIS-C that are not typical of Kawasaki disease, including heliotrope rash–like periorbital edema and erythema as well as erythema infectiosum–like malar erythema and reticulated erythematous eruptions.32

The course of MIS-C can be severe; in one case series of patients presenting with MIS-C, 80% (79/99) required intensive care unit admission, with 10% requiring mechanical ventilation and 2% of patients dying during admission.31 Cardiac dysfunction, coagulopathy, and gastrointestinal symptoms are common.11,31 It has been postulated that a superantigenlike region of the SARS-CoV-2 spike protein, similar to that of staphylococcal enterotoxin B, may underlie MIS-C and account for its similarities to toxic shock syndrome.34 Of note, a similar multisystem inflammatory syndrome associated with COVID-19 also has been described in adults, and it too may present with rash as a cardinal feature.35

Pathophysiology of COVID-19: What the Skin May Reveal About the Disease

The diverse range of cutaneous manifestations in COVID-19 reflects a spectrum of host immunologicresponses to SARS-CoV-2 and may inform the pathophysiology of the disease as well as potential treatment modalities.

Host Response to SARS-CoV-2
The body’s response to viral infection is 2-pronged, involving activation of cellular antiviral defenses mediated by type I and III interferons, as well as recruitment of leukocytes, mobilized by cytokines and chemokines.36,37 Infection with SARS-CoV-2 results in a unique inflammatory response characterized by suppression of interferons, juxtaposed with a rampant proinflammatory cytokine and chemokine response, reminiscent of a cytokine storm. Reflective of this imbalance, a study of 50 COVID-19 patients and 20 healthy controls found decreased natural killer cells and CD3+ T cells in COVID-19 patients, particularly severely or critically ill patients, with an increase in B cells and monocytes.38 This distinctive immune imbalance positions SARS-CoV-2 to thrive in the absence of inhibitory interferon activity while submitting the host to the deleterious effects of a cytokine surge.36

Type I Interferons
The perniolike lesions associated with mild COVID-19 disease14 may represent a robust immune response via effective stimulation of type I interferons (IFN-1). Similar perniolike lesions are observed in Aicardi-Goutières syndrome37 and familial chilblain lupus, hereditary interferonopathies associated with mutations in the TREX1 (three prime repair exonuclease 1) gene and characterized by inappropriate upregulation of IFN-1,39 resulting in chilblains. It has been suggested that perniolike lesions in COVID-19 result from IFN-1 activation—a robust effective immunologic response to the virus.14,26,40

On the other end of the spectrum, patients with severe COVID-19 may have a blunted IFN-1 response and reduced IFN-1–stimulated gene expression.36,38 Notably, low IFN-1 response preceded clinical deterioration and was associated with increased risk for evolution to critical illness.38 Severe disease from COVID-19 also is more commonly observed in older patients and those with comorbidities,1 both of which are known factors associated with depressed IFN-1 function.38,41 Reflective of this disparate IFN-1 response, biopsies of COVID-19 perniosis have demonstrated striking expression of myxovirus resistance protein A (MXA), a marker for IFN-1 signaling in tissue, whereas its expression is absent in COVID-19 livedo/retiform purpura.27

Familial chilblain lupus may be effectively treated by the Janus kinase inhibitor baricitinib,39 which inhibits IFN-1 signaling. Baricitinib recently received emergency use authorization by the US Food and Drug Administration for treatment of severe COVID-19 pneumonia,42,43 hinting to disordered IFN-1 signaling in the COVID-19 pathophysiology.

The impaired IFN-1 response in COVID-19 patients may be due to a unique characteristic of SARS-CoV-2: its ORF3b gene is a potent IFN-1 antagonist. In a series of experiments comparing SARS-CoV-2 to the related virus severe acute respiratory disease coronavirus (which was responsible for an epidemic in 2002), Konno et al44 found that SARS-CoV-2 is more effectively able to downregulate host IFN-1, likely due to premature stop codons on ORF3b that produce a truncated version of the gene with amplified anti–IFN-1 activity.

Cytokine Storm and Coagulation Cascade
This dulled interferon response is juxtaposed with a surge of inflammatory chemokines and cytokines, including IL-6, IL-8, IL-10, and tumor necrosis factor α, impairing innate immunity and leading to end-organ damage. This inflammatory response is associated with the influx of innate immune cells, specifically neutrophils and monocytes, which likely contribute to lung injury in COVID-19 acute respiratory distress syndrome.38 It also is thought to lead to downstream activation of coagulation, with a high incidence of thrombotic events observed in patients with severe COVID-19.1 In a retrospective study of 184 intensive care patients with COVID-19 receiving at least standard doses of thromboprophylaxis, venous thromboembolism occurred in 27% and arterial thrombotic events occurred in 3.7%.45

Livedo racemosa and retiform purpura are cutaneous markers of hypercoagulability, which indicate an increased risk for systemic clotting in COVID-19. A positive feedback loop between the complement and coagulation cascades appears to be important.13,14,29,46-48 In addition, a few studies have reported antiphospholipid antibody positivity in hospitalized COVID-19 patients.49,50

The high incidence of coagulopathy in severe COVID-19 has prompted many institutions to develop aggressive prophylactic anticoagulation protocols. Elevation of proinflammatory cytokines and observation of terminal complement activation in the skin and other organs has led to therapeutic trials of IL-6 inhibitors such as tocilizumab,51 complement inhibitors such as eculizumab, and Janus kinase inhibitors such as ruxolitinib and baricitinib.42,48

COVID Long-Haulers
The long-term effects of immune dysregulation in COVID-19 patients remain to be seen. Viral triggering of autoimmune disease is a well-established phenomenon, seen in DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome and other dermatologic diseases, raising the possibility that dermatologists will see a rising incidence of cutaneous autoimmune disease in the aftermath of the pandemic. Disordered interferon stimulation could lead to increased incidence of interferon-mediated disorders, such as sarcoidosis and other granulomatous diseases. Vasculitislike skin lesions could persist beyond the acute infectious period. Recent data from a registry of 990 COVID-19 cases from 39 countries suggest that COVID-19 perniolike lesions may persist as long as 150 days.52 In a time of many unknowns, these questions serve as a call to action for rigorous data collection, contribution to existing registries for dermatologic manifestations of COVID-19, and long-term follow-up of COVID-19 patients by the dermatology community.

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