key: cord-0981448-b5imlmto authors: Agnihothri, Ritesh; Fox, Lindy P. title: Clinical Patterns and Morphology of COVID-19 Dermatology date: 2021-05-31 journal: Dermatol Clin DOI: 10.1016/j.det.2021.05.006 sha: cd75b43d3b20daf388ea2b503608e2157bb6ec55 doc_id: 981448 cord_uid: b5imlmto Coronavirus disease 2019 (COVID-19), an emergent disease caused by severe acute respiratory syndrome cornonavirus 2 (SARS-CoV-2), has rapidly spread throughout the globe since its discovery in December 2019. Although first appreciated to cause pneumonia, numerous organ systems are now known to be involved. The objective of this article is to review the broad spectrum of cutaneous manifestations reported in association with SARS-CoV-2 infection. The most commonly reported cutaneous manifestations associated with COVID-19 infection include pernio (chilblain)-like acral lesions, morbilliform (exanthematous) rash, urticaria, vesicular (varicella-like) eruptions, and vaso-occlusive lesions (livedo racemosa, retiform purpura). It is important to consider SARS-CoV-2 infection in the differential diagnosis of a patient presenting with these lesions in the appropriate clinical context, as cutaneous manifestations may be present in otherwise asymptomatic individuals, or present prior to developing other symptoms of infection. With increased access to diagnostic testing, we are beginning to understand the utility and limitations of currently available assays. Overall, pernio-like lesions are typically seen in patients with relatively mild COVID-19 disease courses and resolve within 2-8 weeks (median 12 days in lab-confirmed cases). 32,36,37 However, persistent and recurrent lesions have been reported. Recent data illustrates a subset of patients with "long Covid" in the skin who had dermatological signs of COVID-19 that persisted longer than 60 days, including seven of 103 cases of pernio. 37 Recurrent pernio-like lesions in the absence of reinfection have also been noted, with patients who complained of pernio in the fall experiencing an absence of symptoms in the summer, despite surges of COVID-19 infections in the warmer months. 24 Of note, pernio lesions in type I interfernopathies are also known to flare with cold exposure. 38 There are increasing number of reports suggesting a direct association between pernio-like lesions and SARS-CoV-2. Positive anti-SARS-CoV-2 immunostaining and viral spike protein have been demonstrated in lesional skin biopsy specimens (endothelial cells and eccrine glands) in adult and pediatric patients with pernio-like lesions. [39] [40] [41] However, due to lack of specificity, some authors have suggested these findings be interpreted with caution. [42] [43] [44] The pathogenesis of pernio-like lesions is not well understood but is thought to be predominantly an inflammatory process similar to idiopathic and autoimmune-related chilblains. The striking similarity of pernio-like lesions to those observed in type 1 interferopathies (i.e. Aicardi-Goutieres syndrome and STING-associated vasculopathy) has raised the suspicion of the important role of interferon (IFN) despite the absence of other manifestations of interferonopathies in patients with COVID-19 infection. [45] [46] [47] One group demonstrated induction of the type I IFN pathway in lesional sections of COVID-19-associated chilblain-like lesions. 48 Type I interferon is known to have an important role in the pathogenesis of lupus erythematosus. 49,50 Furthermore, interferons are also thought to induce microangiopathic changes contributing to development of chilblains lupus. 46, 47 J o u r n a l P r e -p r o o f As mounting evidence suggests a direct association with SARS-CoV-2, pernio-like lesions are currently believed to represent a postviral or late-onset finding after COVID-19 infection, especially in those who can mount a robust IFN response. In a report by Freeman et al., 80 out of 318 cases developed pernio-like lesions after the onset of other symptoms of COVID-19 infection; a similar finding has been noted in at least one other study. 9,32 Conversely, pernio-like lesions have also been reported to occur concurrently with RT-PCR test positivity. 32,51 Negative nasopharyngeal reverse-transcription polymerase chain reaction (RT-PCR) or anti-SARS-CoV-2 serologies in many patients 52-58 created uncertainty early in the pandemic regarding the precise relationship. 39,57-60 Indeed, some patients who were RT-PCR negative after developing pernio, were later found to have positive COVID-19 antibodies (immunoglobulin M, G, or A). 24, 26, 32, 61, 62 What was initially surprising, however, was that serological testing for IgM or IgG antibodies was often negative. There is increased understanding of this mechanism: I. Early in the pandemic, interpretation of RT-PCR/antibody results in patients with skin rash and probable COVID-19 was difficult due to lack of understanding of timing and antibody kinetics. Much of the available antibody data was drawn from patients with more severe illness as widespread testing was not available. IV. The kinetics of early interferon production may determine overall COVID-19 disease severity and antibody production. Interferons are early antiviral response proteins that interfere with intracellular viral replication, recruit other cells for antiviral response, and cause "flu-like symptoms" such as fever and muscle pain. It is thought that robust production of interferon-I is associated with early viral control, suppressed antibody response, and mild COVID-19 infection. This may be an additional explanation for why some patients fail serologic detection. 70 Conversely, patients with severe COVID-19 have notably depressed/absent interferon responses or interferon deficiency that can lead to severe, life-threatening COVID-19 infection. [71] [72] [73] [74] Several authors hypothesize that chilblains, specifically, could be the cutaneous expression of a strong type I interferon response. [75] [76] [77] [78] This could therefore explain the absence of antibodies in patients with chilblains. There is a correlation between severity of COVID and timing of appearance of COVID-antigen-specific CD4 T-cells in circulation. Patients with early expansion of antigen-specific CD4 T-cells (2 days after symptom onset) seem to have mild COVID and those have late response (CD4 appearance >20 days after symptoms) have severe disease, suggesting that an early CD4 T-cell response is important in fighting SARS-CoV- Morbilliform (maculopapular) eruptions frequently arise as a result of viral infections or adverse drug reactions, and are the most commonly reported cutaneous manifestation of COVID-19 with a prevalence as high as 47%. 7,9,23,28,81 Predominantly involving the trunk, the rash has been noted either at disease onset, or more frequently, after hospital discharge, with a reported median duration of 7 Urticaria (hives) is a common feature among COVID-19 patients who experienced rashes. Acute urticaria, defined as a self-limited lesion lasting less than 6 weeks, has been reported as a presenting sign of COVID-19 infection, although it can also occur later in the disease course. 7,9,23,28,45 COVID-associated urticaria has also been reported to present with fever as an early prodromal sign in otherwise asymptomatic individuals. [86] [87] [88] Acute urticaria can be triggered by infections, medications, insect bites/stings, and type I immune reactions. It has been hypothesized that viral IgM/IgG can cross-react with mast cell IgE and cause mast cell degranulation, which could explain urticaria in the setting of COVID-19 infection. 89 It is important to note that urticaria is also a possible side effect for numerous medications used to treat COVID-19. 85 Despite more than 3.85 million testing positive for COVID-19 since the onset of the pandemic, 115 and are the 7 th most common extrapulmonary manifestation. 116 There are several case reports and case series of various cutaneous eruptions in COVID positive children. Children with COVID-19 and skin manifestations carry an overall better prognosis than those without. 117 reticulated exanthems similar to erythema infectiosum. 127 In addition, distal extremity changes, oral mucous membrane changes, conjunctivitis, and purpura are reported. 128 The molecular mechanisms underlying the relationship between COVID-19 and MIS-C are poorly understood. There are increasing numbers of adults being reported to have COVID-19-associated MIS-C, characterized by multiorgan dysfunction (particularly cardiac) in the absence of severe respiratory illness. 129, 130 infection. [142] [143] [144] While cases of LR were grouped with more severe necrosis in a major early study, 9 more recent reports estimate that this manifestation was present in 3.5% of patients. 28 Fixed livedo racemosa, retiform purpura, and necrotic vascular lesions Vaso-occlusive lesions (livedo racemosa, thrombotic retiform purpura, and acral ischemia) have been noted in elderly, critically ill patients with severe COVID-19 infection. 9,28,145 These clinical entities exist at the opposite end of the disease severity spectrum compared to perniosis, which occurs in those with mild or asymptomatic disease. Patients with this clinical finding have been noted to have markedly elevated D-dimer levels and disseminated intravascular coagulation. 8, 145 Skin biopsy of a COVID patient with retiform purpuric patches showed multiple occlusive thrombi in most small vessels of the superficial and mid-dermis. 146 Direct immunofluorescence in this patient was notable for IgM, C3 and C9 deposition within dermal vessel walls. 146 In a subsequent study of a series of COVID patients with retiform purpura, terminal complements C5b-9 and other complement components were found in the microvasculature. This may be suggestive of systemic complement activation and pathophysiology similar to atypical hemolytic uremic syndrome or other microthrombotic syndromes. 145 Pauci-J o u r n a l P r e -p r o o f inflammatory purpuric (most often on buttocks) pressure ulcers have also been noted in several critically ill COVID patients with limited mobility, incontinence, and malnutrition. 147 Histopathology of these purpuric pressure ulcers were consistent with pressure necrosis (epidermal necrosis, eccrine gland necrosis); SARS-CoV-2 RNA in-situ hybridization of all four skin biopsies was negative. The reported patients did not have any laboratory evidence of coagulopathy such as disseminated intravascular coagulation. 147 It is important to recognize that this clinical finding is distinct from the thrombotic vasculopathy noted by Magro et al. 145 In a recent review of the literature, vaso-occlusive lesions were found to be the least commonly Transient "rash" (morphology not described) in babies born to mothers with COVID-19. 163 Mottling noted in a neonate with sepsis and +COVID-19. 164 J o u r n a l P r e -p r o o f As the novel SARS-CoV-2 virus rapidly spread throughout the world, the scientific and medical community has worked with remarkable pace to understand its full clinical effects. Early in the pandemic, scarcity of diagnostic assays limited our ability to confirm infection in patients presenting with an array of cutaneous manifestations. The majority of young patients presenting with pernio-like lesions had mild clinical courses, which precluded them from having access to COVID-19 testing early in the pandemic when diagnostic resources were limited. Viral infections are known to produce a variety of clinical findings due not only to their direct action on human cells, but also to the host immune response and resulting inflammatory cascade. Further complicating the clinical picture, patients with COVID-19 infections were often treated with a multitude of medications, many of which can be associated with the reported cutaneous manifestations. Now with relative widespread availability of RT-PCR assays and serologic testing, we are beginning to understand the utility and limitations of testing (including timing in relation to a patient's infection course and imperfect sensitivities and specificities of available tests). 63, 165 It is now understood that a negative swab or antibody test at one point in time does not necessarily rule out SARS-CoV-2 as a causative agent. 165 Data derived from a UK COVID Symptoms Study app suggest that those with cutaneous rash are more likely to test positive for SARS-CoV-2 (odds ratio 1.67). 166 Although less prevalent than fever, the authors also found rash to be more specific for COVID-19 infection, which lends support to the diagnostic value of cutaneous manifestations of SARS-CoV-2 infection. 166 The most commonly reported cutaneous manifestations associated with COVID-19 infection include pernio-like, urticarial, morbilliform, and retiform purpura. 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