key: cord-308046-y9kui730
authors: Naka, Fludiona; Melnick, Laura; Gorelik, Mark; Morel, Kimberly D.
title: A Dermatologic Perspective on Multisystem Inflammatory Syndrome in Children()()
date: 2020-09-23
journal: Clin Dermatol
DOI: 10.1016/j.clindermatol.2020.09.003
sha: 
doc_id: 308046
cord_uid: y9kui730

As of May 2020, an emerging immune-mediated syndrome primarily affecting children has been detected primarily in Europe and the United States. The incidence of this syndrome appears to mirror the initial infectious assault, with a delay of several weeks. This syndrome has been termed multisystem inflammatory syndrome in children (MIS-C), and is observed in association with the coronavirus disease 2019 (COVID-19). The phenotypes of presentation include several characteristic features, including prolonged fever, eruption, neck stiffness and gastrointestinal manifestations with pronounced abdominal pain. Shock and organ dysfunction on presentation are frequently but inconsistent, while respiratory distress is typically, and notably, absent. We have reviewed recently published data aiming to better understanding MIS-C, with a focus on its mucocutaneous manifestations. • Mucocutaneous manifestations of MIS-C: conjunctivitis, oral mucosal changes, rash. • The rash of MIS-C is typically diffuse and non-specific. • Mucocutaneous manifestations of MIS-C are more common in younger children. • KD and MIS-C differ in mean age of onset, race predilection, and associated symptoms.

documented worldwide. 13 As the spotlight shines on this new inflammatory disease, we are beginning to get more clarification of its clinical presentation and pathogenesis.

Both the CDC and the WHO have released their own MIS-C diagnostic criteria to help clinicians in making such diagnosis. Table 1 and Table 2 review these criteria in detail. The main clinical manifestations that both groups focus on include fever for over 24 hours, laboratory evidence of inflammation, two or more organ involvement (commonly GI, followed by cardiac and renal), mucocutaneous findings, and either a positive test or exposure within four weeks of clinical manifestations. A negative COVID PCR does not rule out this diagnosis. Because MIS-C is thought to be an immune-mediated secondary response to the virus, COVID PCRs are usually negative at the time of the illness, and antibodies are positive in the majority of cases. 11, [14] [15] [16] [17] [18] [19] [20] [21] Because diagnostic criteria for this condition are generally very broad, there is a significant challenge in identifying which patients falling under these diagnostic criteria are 'true' MIS-C. 22 Demographic data of children with MIS-C from thirteen recent large case series are summarized in Table 3 . The size of these studies ranges from eight to 186 children. We recap patient mean/median age, sex, cutaneous signs/symptoms, SARS-CoV-2 testing method, treatments, and outcome. Fever and GI symptoms were the top two most common systemic signs/symptoms seen in children who met criteria for MIS-C. The majority of patients were previously healthy. The two most common comorbidities were asthma and obesity. The median age of children with MIS-C was between 8-12 years old. Boys were equal or more prevalent in all but two publications. In the US studies, the majority of the children affected were black non-Hispanic, Hispanic or Latino, or Ashkenazi Jewish. 15, 19, [23] [24] Most patients were treated with IVIG +/-systemic steroids. The majority of patients had a negative COVID PCR at the time of diagnosis, likely because the disease tends to present 4-6 weeks after the viral infection. With the J o u r n a l P r e -p r o o f Journal Pre-proof exception of one report, 20 all other case series found that patients were more likely to have positive antibodies as compared to PCR. COVID PCR positivity ranged from 13% -50%, while antibody positivity ranged from 75%-100%. 10-12, 14-21, 23-24 Mucocutaneous Manifestations of MIS-C While mucocutaneous manifestations are not very common among children with COVID-19 at large, they are among the top clinical manifestations in children with MIS-C, making them important to identify and recognize these in an attempt to understand the disease.

Most of the clinical information to date comes from small descriptive studies, such as case series and case reports. Documented cutaneous findings reported in children with COVID-19 include non-specific maculopapular eruptions, followed by chilblain-like or pernio-like acral lesions, urticarial lesions, livedo reticularis, papulovesicular or varicella-like lesions, petechiae or dengue-like lesions, and erythema multiforme-like lesions. [25] [26] [27] [28] [29] [30] [31] [32] [33] Multiple larger case series published in the recent months 10-12, 14-21, 23-24 focus on characterizing and understanding MIS-C. Each case series has identified children who met criteria for MIS-C and described the cutaneous findings with which they presented. The following descriptive terminology was used to describe the skin findings: "conjunctivitis," "eruption," "red/cracked lips," lips/oral cavity changes," "cheilitis," "extremity changes," or "hand/feet edema". Most of the studies did not provide photos of the eruption and did not attempt to describe it. Others that did, used the following non-descriptive terminology: J o u r n a l P r e -p r o o f Journal Pre-proof "polymorphous," "general," "variable," "skin desquamation," "diffuse," "non-specific," or simply "eruption." Refer to Table 3 .

The investigators of one of the major series conducted targeted surveillance for MIS-C at multiple pediatric health centers across the United States and identified 126 children who met criteria for MIS-C. Mucocutaneous findings were identified in 74% of children who met criteria for MIS-C. Of these, 59% had non-specific eruption, 55% bilateral conjunctivitis, 42% oral mucosal changes, and 37% peripheral extremity changes. 24 In a review of over 191 potential MIS-C cases of hospitalized children reported to the New York State Department of Health, 95 met criteria for MIS-C. They found that 60% of children who met criteria for MIS-C had a diffuse non-specific eruption, while 56% had conjunctivitis and 27% oral mucosal changes. 19 Looking at all the thirteen-case series presented in Table 3 , the percentage of children diagnosed with MIS-C who developed mucocutaneous findings included: conjunctivitis 27% -93%, oral mucosal changes 25% -87%, eruption 47% -81%, and hand/feed erythema and edema 27% -68%. Table 4 summarizes the top mucocutaneous manifestations of children with MIS-C. 10-12, 14-21, 23-24 The skin findings associated with MIS-C tend to be more common in younger children and decrease with age. 87% of children between 0-5 years old had mucocutaneous findings, compared to only 61.5% of those 13-20 years old. 19

As we discuss the various mucocutaneous manifestations associated with MIS-C, many sounds similar to other diseases, specifically Kawasaki Disease (both typical and atypical); however, a wide differential diagnosis consideration is needed, when seeing a child with a 36 The presence of an aneurysm itself is not a defining feature that would necessitate relating the two syndromes. Table 5 

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