key: cord-0724501-k0euj0h8
authors: Naka, Fludiona; Melnick, Laura; Gorelik, Mark; Morel, Kimberly D.
title: A Dermatologic Perspective on Multisystem Inflammatory Syndrome in Children
date: 2020-11-26
journal: Clin Dermatol
DOI: 10.1016/j.clindermatol.2020.11.005
sha: 632304db0a816ba3db7da9cbbe0f14cf40f9098e
doc_id: 724501
cord_uid: k0euj0h8

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, skin eruptions, neck stiffness, and gastrointestinal manifestations with pronounced abdominal pain. Shock and organ dysfunction on presentation are frequent but inconsistent, while respiratory distress is typically, and notably, absent. We have reviewed the recent published data aiming to better understanding MIS-C, with a focus on its mucocutaneous manifestations.

SARS-CoV-2 is a novel coronavirus which originated in Wuhan, China, in December of 2019. 1 This virus causes a severe respiratory distress syndrome among several other severe manifestations. 1 Starting in early 2020, the virus spread rapidly worldwide, compelling the World Health Organization (WHO) to declare a global pandemic on March 11, 2020 . To date,

there are over 15 million cases with over half a million deaths due to COVID-19, globally.

Children make up a small percentage of these cases. According to the CDC Morbidity and Mortality Weekly Report, published April 6, 2020, 2,572 (1.7%) of roughly 150, 000 known cases of COVID-19 infection in the US were among children < 18 years. 2 This is consistent with a review of over 72,000 COVID-19 cases performed by the Chinese Center for Disease Control and Prevention, which revealed that < 1% of infected patients were children under the age of 10. 3 Infected children tend to be completely asymptomatic or exhibit mild symptoms. [4] [5] [6] [7] [8] While the majority of children with COVID-19 are asymptomatic or have mild manifestations, a small percentage require hospitalization and intensive care for shock and multi-organ failure due to the emerging multisystem inflammatory syndrome. 7-10 On May 14, 2020, two months after the WHO declaration of a global pandemic, the Centers for Disease Control (CDC) released a health advisory about Multisystem Inflammatory Syndrome in Children associated with COVID-19.

Multisystem inflammatory syndrome in children describes an emergent childhood inflammatory disorder, with similarities to Kawasaki"s disease (KD), Kawasaki disease shock syndrome (KDSS), Toxic Shock Syndrome (TSS), and Macrophage Activating Syndrome (MAS). Due to its recent nascence, the constellations of manifestations defining MIS-C can be found under a number of names, such as Pediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2 (PIMS-TS), Kawasaki-like disease, or Toxic shocklike syndrome, among others. [11] [12] Altogether, there are now approximately 1000 cases of MIS-C documented worldwide. 13 As the spotlight shines on this new inflammatory disease, we are beginning to have 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 symptoms. 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, 14-21 Importantly, diagnostic criteria for this condition are generally very broad, and thus there is 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, and Ashkenazi Jewish. 15, 19, [23] [24] Most patients were treated with IVIG +/-systemic steroids. Most 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 exception of one report, 20 all the other case series revealed 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 non-specific maculopapular eruption, 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 identified children who met criteria for MIS-C and described the cutaneous symptoms that they presented. The following descriptive terminology was used to describe the skin findings: "conjunctivitis" "rash" "red/cracked lips" lips/oral cavity changes" "cheilitis" "extremity changes" "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: "polymorphous" "general" "variable" "skin desquamation" "diffuse" "non-specific" or simply "rash." Refer to Table 3 .

A targeted surveillance for MIS-C at multiple pediatric health centers across the United States was conducted 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 nonspecific rash, 55% bilateral conjunctivitis, 42% oral mucosal changes, and 37% peripheral extremity changes. 24 A review of over 191 potential MIS-C cases of hospitalized children reported to the New York State Department of Health, indicated 95 met criteria for MIS-C. 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 were: conjunctivitis 27% -93%, oral mucosal changes 25% -87%, rash 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 sound similar to other diseases, specifically Kawasaki Disease (both typical and atypical). There should be a wide differential diagnosis, when seeing a child with a mucocutaneous eruption the differential diagnosis also includes the following: Stevens Johnson Syndrome/Toxic Epidermal Identifying the similarities and differences between these entities is crucial in distinguishing them and making the correct diagnosis.

From a clinical perspective, a subset of patients with MIS-C show features that are similar to Kawasaki disease, including mucocutaneous findings. The question arises as to whether these two syndromes represent a single entity, rather than completely separate conditions. Kawasaki shock syndrome, which is a known variant of Kawasaki disease, as well as severe Kawasaki disease, both recapitulate many of the more common features found in MIS-C, such as shock, pro-inflammatory state and pathology, and some of the hematologic disturbances, such as thrombocytopenia, which at first glance appear unique to MIS-C. A reasonable argument can be made that MIS-C represents a severe Kawasaki spectrum.

Many of the demographic features of the disease differ, such as age (mean age 8-12 years old in MIS-C versus the rarity of Kawasaki cases in children older than five years of age). The absence of predilection for Asian populations being affected in MIS-C is also contrary to what one might see in KD. 34 For instance, only 1 of 17 children diagnosed with MIS-C in NYC was of Asian descent. 23 The most common cardiac abnormality associated with MIS-C is left ventricular dysfunction/myocarditis, unlike coronary artery abnormalities in KD. 16 Thirty five percent of children who met criteria for MIS-C at Columbia University Irving Medical Center/New York-Presbyterian Morgan Stanley Children"s Hospital in New York City had moderate left ventricular dysfunction, while only one child developed a medium-size aneurysm. 23 Coronary aneurysms t are observed in other vasculitis syndromes, such as Takayasu arteritis and polyarteritis nodosa, 35 but rarely are they seen in association with other viral and infectious conditions. 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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