key: cord-0790438-fpk1iexu authors: Sethuraman, Usha; Kannikeswaran, Nirupama; Ang, Jocelyn; Singer, Adam; Miller, Jason; Haddad, Rita; Stankovic, Curt title: Multisystem inflammatory syndrome in children associated with novel coronavirus SARS-CoV-2: Presentations to a pediatric emergency department in Michigan date: 2020-10-24 journal: Am J Emerg Med DOI: 10.1016/j.ajem.2020.10.035 sha: c38a6bcd88e5f9df306746de2b710a0df901d511 doc_id: 790438 cord_uid: fpk1iexu The SARS-CoV-2 is a respiratory virus of the coronavirus family responsible for a global pandemic since December 2019. More than 35 million people have been affected with the novel coronavirus disease (COVID-19), with more than one million deaths worldwide. Michigan was one of the top three states in the United States that was severely affected by the SAR-CoV-2 pandemic with more than 7000 deaths in adults and greater than 145,000 confirmed infections. However, compared to adults, the majority of children until recently were either asymptomatic or had a mild illness with SARS-CoV-2. Recently, a rare but potentially serious presentation associated with SARS-CoV-2 called multisystem inflammatory syndrome in children (MIS-C) has been recently reported and the Centers for Disease Control (CDC) released a case definition for the same. We report the clinical and laboratory presentations and outcomes of 34 children with MIS-C who were evaluated within a 12 week period at a pediatric emergency department (PED) of single institution in Michigan. These cases presented approximately three weeks after the peak of adult SAR-CoV-2 related deaths occurred in the state. While many children presented with clinical characteristics similar to incomplete Kawasaki disease (KD), they also exhibited certain unique features which differentiated MIS-C from KD. The information presented below will aid clinicians with early recognition, evaluation and management of MIS-C in the emergency department. The coronavirus disease pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has become the most far-reaching health threat of this century, with more than 39 million infected individuals and 1.1 million deaths worldwide 1 . The United States has been one of the most severely affected countries with 2.3 million infected cases and more than 200,000 deaths 2 . Michigan was one of the states in the country that was significantly impacted by the pandemic with more than 7000 deaths and 150,000 confirmed infections. Compared to adults, until recently children were rarely severely affected by this disease with more than 90% being either asymptomatic or with mild disease. 3 However, recent reports from Europe described a pediatric multisystem inflammatory syndrome resembling incomplete Kawasaki Disease (KD) in children. 4, 5 The CDC recently named this entity as MIS-C and formulated a case definition. 6 Since then, additional reports of MIS-C from Europe and the US have been published. 7, 8, 9 The objective of this report was to describe the initial clinical and laboratory features of MIS-C in a cohort of 34 children at presentation to a pediatric emergency J o u r n a l P r e -p r o o f department (PED) of a single institution in Michigan. All of these children met the CDC MIS-C definition and presented to our PED approximately three weeks after the peak of adult COVID-19 cases in our state. Methods: This study was performed at a level one pediatric trauma center with more than 85,000 visits per year. Our hospital is located in Detroit, Michigan which experienced high mortality rates in adults from SARS-CoV-2 infection. We performed a retrospective chart review of thirty four children ≤ 21 years of age who presented to our PED, met the CDC definition of MIS-C (Supplemental Table 1 ) and required treatment with intravenous immunoglobulin between April 16, 2020 and July 07, 2020. Data on patient demographics, clinical features, laboratory parameters including COVID-19 testing (reverse transcriptase polymerase chain reaction from nasopharyngeal swabs-RT-PCR and/or IgG serology), management and outcomes were abstracted. Descriptive statistics was used to summarize patient and laboratory characteristics. We used percentages, and means with standard deviation to describe normally distributed variables and median and interquartile ranges for those that were not normally distributed. This study was approved by our institutional review board under expedited review with waiver of informed consent. The demographics and clinical features of this cohort of children at presentation to the PED are noted in Table 2 . The majority were African American, older than 5 years of age, and many had at least one prior health care visit in the preceding 48 hours. Comorbidities occurred in more than one third of the children with asthma being the most common. Fever ≥ 2 days, gastrointestinal symptoms (vomiting, abdominal pain or diarrhea) anorexia and rash were the most common symptoms, while respiratory symptoms were rare. While generalized abdominal J o u r n a l P r e -p r o o f tenderness was elicited in 44.4% of patients, specific right lower quadrant tenderness was present in two patients that resulted in a work up for appendicitis which was found to be negative. Shock (persistent hypotension requiring > 20ml/kg fluids or need for vasopressors) occurred more than one third of the patients overall, with 10 (29%) requiring vasopressor addition (dopamine or epinephrine) in the PED. Elevated inflammatory markers such as C-reactive protein (CRP), ferritin and D-dimer were noted in the majority of children with MIS-C while elevation of transaminases and hypoalbuminemia were less common at presentation (Table 3 ). Patients had significant cardiac involvement at presentation with abnormalities noted in 33% of electrocardiograms (EKG) and more than 60% of echocardiograms (Supplemental Table 4 ). Further, of the patients with elevated troponin who also had an EKG (n=18) or ECHO (n=17) performed, 50% and 88.2% were abnormal respectively. Table 5 . Our case series of 34 children from a single institution is one of the largest reports in the US of MIS-C temporally associated with SARS-CoV2 that predominantly resulted in myocardial injury. Our report parallels that of those reported from both Europe and other parts of United 8 This could be reflective of the population race and ethnicity distribution in our PED which is predominantly non Hispanic, African American. Further, compared to other reports, children in our series were slightly younger the reasons for which are unclear. In contrast to adults, the clinical features of COVID-19 in children had previously been mild with most presenting with fever and respiratory symptoms. Critical illness was rare and usually secondary to respiratory illness without cardiac involvement. 3 In contrast, most of the children in our cohort with MIS-C required admission to the intensive care unit for circulatory and hemodynamic support given their significant myocardial injury involvement. Some children with MIS-C presented with similar clinical and laboratory features as incomplete KD. 10 However, notable differences that distinguished MIS-C from incomplete KD included older age, predominantly gastrointestinal symptoms and more shock and myocardial injury at presentation. 8, 9, 11, 12 The most striking occurrence in our cohort was the myocardial injury associated with MIS-C. While reports of troponin elevation in KD have conflicted, more than half of our patients with MIS-C had an elevated troponin associated with myocardial injury at presentation. 13, 14 Many children in our cohort had myocardial dysfunction with predominantly LV dysfunction and 3 children had coronary dilation at presentation, suggesting a rapid and severe inflammation with a predilection for the heart. Further, the majority of those who did not have myocardial dysfunction in the PED developed worsening myocardial function later in their course. In fact, the myocardial involvement in our children bears similarity to that seen in adult acute COVID-19 cardiovascular syndrome which presents with reduced left ventricular ejection fraction in the absence of obstructive coronary artery disease. 15 Although the exact reason for this myocardial involvement is unclear in children, in adults it has been hypothesized to be secondary to acute coronary syndrome, microvascular ischemic injury, myocarditis or cytokine dysregulation. A striking feature was that most children with MIS-C had lymphopenia which has been reported commonly in adults with severe COVID-19. 16 Postulated reasons for this lymphopenia in COVID-19 include direct cell lysis due to interaction with the expressed ACE 2 receptor on cell surface and apoptosis caused by circulating cytokines. 17 The hyponatremia observed in a large proportion of MIS-C at presentation was likely secondary to dehydration, renal or cardiac failure. While hyponatremia has been described as a predictor of poor outcome in both COVID- 19 and KD, its role as a prognosticator in MIS-C is unclear. 18, 19 Further, while elevated D dimer J o u r n a l P r e -p r o o f levels have been associated with treatment resistant KD, its significance in cardiac involvement in MIS-C is unclear. 20 Lastly, a recent report describes a MIS-A (multisystem inflammatory syndrome in adults) which clinical features very similar to the MIS-C in children thus suggesting a possible common pathophysiology that warrants further investigation. 21 Certainly, as the pandemic continues, it is critical for emergency department providers to recognize the various clinical presentations of MIS-C and its serious cardiovascular complications. A more comprehensive evaluation may be warranted in any child presenting with a fever in combination with a rash, conjunctivitis or gastrointestinal symptoms regardless of COVID-19 exposure. Laboratory investigation should include an evaluation of markers for inflammation and myocardial injury including a troponin level, an EKG and an echocardiogram. Clinicians should also anticipate sudden clinical deterioration in these children and consider early critical care unit admission. Clinicians need to be on high alert for MIS-C in previously healthy children. Since many of these children present with myocardial injury and recover completely with timely treatment, institution of a standardized screening protocol in the emergency department may facilitate the early identification and evaluation of these children. Evidence of increased inflammation and myocardial injury should prompt immediate admission to the pediatric critical care unit to optimize management and prevent morbidity and mortality. 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