key: cord-0759915-i7lb36k9 authors: Tabaac, Sydney; Kothari, Poonam; Cassidy-Smith, Tara title: Multisystem Inflammatory Syndrome in Children date: 2020-11-05 journal: J Emerg Med DOI: 10.1016/j.jemermed.2020.10.009 sha: 1b713e0027dc585d173acb8afce2ee4974b36db1 doc_id: 759915 cord_uid: i7lb36k9 BACKGROUND: As the number of coronavirus disease 2019 (COVID-19) cases increases globally, more cases of a rare COVID-19–associated disease process are being identified in the pediatric population. This syndrome is referred to as multisystem inflammatory syndrome in children (MIS-C). Clinical manifestations of the syndrome vary and include one or a combination of the following: vasodilatory shock, cardiogenic shock, Kawasaki-like disease, cytokine storming, coronary artery dilatation, and aneurysms. CASE REPORT: This case report describes the presentation, findings, workup, and treatment for a 9-year-old boy diagnosed with MIS-C. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS? It is important to recognize MIS-C, as it shares many of the same features as other disease processes, for example, Kawasaki disease and toxic shock syndrome, but has different complications if left untreated. During a short 10-day period, the South Thames Retrieval Service in London, UK, began to identify an unparalleled group of cases within the pediatric population. These cases began to arise in mid-April 2020, during which a cluster of pediatric patients presented with hyperinflammatory shock. During these 10 days, 8 children were identified and presented with disease characteristics similar to Kawasaki disease or toxic shock syndrome. The symptoms that presented included 4 to 5 days of fever, rash, conjunctivitis, peripheral edema, myalgias, vomiting, and diarrhea. Each of the 8 patients was found to have multisystem organ involvement that eventually progressed to shock. All 8 patients tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies, and it is believed that this is a new disease process affecting previously healthy, asymptomatic children with the virus (1, 2) . Since then, many cases have been identified, mainly throughout Europe. More recently, cases have appeared throughout the United States, specifically prevalent in New York. The current term for this disease process is multisystemic inflammatory syndrome in children (MIS-C). Both the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) have provided definitions for MIS-C. The CDC provides the following definition: An individual younger than 21 years presenting with fever (fever $ 38.0 C for $ 24 h, or report of subjective fever lasting $ 24 h), laboratory evidence of inflammation (including but not limited to one or more of the following: elevated C-reactive protein, erythrocyte sedimentation rate, fibrinogen, procalcitonin, D-dimer, ferritin, lactic acid dehydrogenase, interleukin 6, or neutrophils; reduced lymphocytes and low albumin), and evidence of clinically severe illness requiring hospitalization, with multisystem (two or more) organ involvement RECEIVED: 29 June 2020; FINAL SUBMISSION RECEIVED: 15 September 2020; ACCEPTED: 4 October 2020 (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, or neurologic); No alternative plausible diagnoses; and Positive for current or recent SARS-CoV-2 infection by reverse transcription polymerase chain reaction (PCR), serology, or antigen test; or coronavirus disease 2019 (COVID-19) exposure within the 4 weeks prior to onset of symptoms (3) . WHO has provided the following definition in which all criteria must be met: Age 0 to 19 years old; Fevers for at least 3 days; Clinical signs of multisystem involvement, at least two of the following: rash, bilateral nonpurulent conjunctivitis or mucocutaneous inflammation, hypotension or shock, cardiac dysfunction, pericarditis, valvulitis or coronary abnormalities, evidence of coagulopathy, and acute gastrointestinal symptoms; Elevated markers of inflammation; No other obvious microbial cause of inflammation; and Evidence of COVID-19 or likely contact (4). On May 19, 2020, a 9-year-old boy presented to the pediatric emergency department with multiple systemic symptoms. His mother reported that 6 days prior to arrival, the patient developed a subjective fever associated with erythematous, cracked lips. The patient presented to an urgent care clinic on day 3 with a fever and sore throat. There, he was tested for both COVID-19 and strepto-coccal pharyngitis and was empirically started on amoxicillin. The following day, the patient developed an erythematous rash on the left lower extremity, which then spread diffusely throughout the body. The rash began to improve after about 24 to 48 h. Mother reported that on day 5, the testing from the urgent care resulted, and the patient was found to be negative for both COVID-19 and streptococcal pharyngitis. The amoxicillin was discontinued. Given persistent fevers, with a maximum temperature of 104 F, the mother brought the patient to an outside hospital emergency department on day 5 and again on day 6. At that time, the patient began complaining of diffuse abdominal pain associated with vomiting and nonbloody diarrhea. His mother reported that plain films of the chest and abdomen obtained at the outside hospital were unremarkable. The patient was discharged with the diagnosis of a viral syndrome. On day 7, the patient presented to our emergency department. On presentation, the patient had symptoms of fatigue and continued abdominal pain, vomiting, and diarrhea. On this day he denied any fevers, urinary symptoms, bloody stool, conjunctival injection, cough or shortness of breath. His mother noted that rash was much improved. Of note, the patient's mother reported that the boy's father was presumed to be positive for COVID-19 three weeks prior. On physical examination, the patient was afebrile, tachycardic with a heart rate of 118 beats/min, mildly tachypneic with a respiratory rate of 24 breaths/min, had a normal blood pressure of 112/55 mm Hg, and was saturating 100% on room air. He appeared to be drowsy and was moaning in discomfort. Significant examination findings included strawberry tongue without oropharyngeal exudates, erythema, or swelling. He had no conjunctival injection. Lungs were clear to auscultation. The abdomen was soft with diffuse tenderness, worse in the right lower S. Tabaac et al. quadrant but was non-peritoneal. A rash was noted on the bilateral lower extremities (Figure 1) , which was much improved compared with photos taken by his mother on days prior. Given the presentation and examination, there was concern for MIS-C associated with SARS-CoV-2 infection. Other disease processes remained on the differential, such as Kawasaki disease, mononucleosis, viral or bacterial gastroenteritis, toxic shock syndrome, staphylococcal scalded skin syndrome, and appendicitis. Initial workup included a complete blood count, basic metabolic panel, erythrocyte sedimentation rate, C-reactive protein, liver function test, Monospot test, point-ofcare COVID-19 test, electrocardiogram (Figure 2) , and a 20 mL/kg IV fluid bolus. The patient was negative for both heterophile antibodies and point-of-care COVID-19. Given multiple laboratory abnormalities, additional laboratory tests were ordered, which included COVID-19 PCR, high-sensitivity (hs) troponin, NT-pro-BNP, coagulation studies, D-dimer, ferritin, interleukin 6 ( Table 1) , and urinalysis ( Table 2 ). In addition, chest xray study and computed tomography (CT) abdomen/ pelvis with contrast were ordered. The chest x-ray study was negative for acute cardiopulmonary disease and the CT abdomen/pelvis was equivocal for appendicitis. Two hours after the initial presentation, on repeat examination the patient became hypotensive with increased work of breathing. He developed a fever of 102 F (38.9 C) and was hypotensive with systolic blood pressure 84 mm Hg. Given the fever and hypotension, blood cultures and lactate were ordered. The initial lactate was 2.3 mmol/L and blood cultures had no growth after 5 days. The patient was also covered with antibiotics, which included vancomycin and ceftriaxone, as well as clindamycin for possible toxic shock syndrome. The pediatric infectious disease physician was consulted and agreed with the suspicion for MIS-C. The infectious disease consultant advised us to be judicious with fluid administration, as case reports revealed decompensation in the setting of aggressive fluid resuscitation in patients with suspected myocarditis. The patient had already received two 20-mL/kg fluid boluses, thus further administration of fluids was held. The CDC guidelines also recommend drawing a lactate dehydrogenase, albumin, and procalcitonin, however, these were not drawn in this patient and retrospectively should have been. Soon after, an elevated hs-troponin and an elevated pro-BNP resulted, which were indicative of possible myocarditis. Point-of-care ultrasound was used to evaluate cardiac function and showed a decreased ejection fraction. Given the acuity of the patient's condition and his potential need for multidisciplinary specialists (including pediatric nephrology, cardiology, rheumatology, hematology, and oncology), the patient was transferred to a dedicated children's hospital for higher level of care. After being transferred, the patient's COVID-19 PCR resulted and was positive. While in the pediatric intensive care unit, the patient received one dose of i.v. immunoglobulin with resolution of the fever and was subsequently placed on a short course of oral steroids. He never required vasopressor support. Because of his age (younger than 12 years) and given the reports of coagulopathy associated with MIS-C, he was started on low-dose aspirin. Patients 12 years and older are started on enoxaparin. Echocardiogram revealed an enlarged left ventricle without any decreased ejection fraction or thrombus. His creatinine returned to normal within 2 to 3 days. His abdominal pain improved without further intervention as well. His clinical course was otherwise unremarkable and he was discharged on low-dose aspirin and a steroid taper. The clinical course for pediatric patients infected with COVID-19 is most often benign. It is important to identify the rare cases of MIS-C, as it presents similarly to other disease processes, but results in serious morbidity and mortality, given the risk of myocarditis and heart failure. It may present with features similar to Kawasaki disease, toxic shock syndrome, or many other disease processes; however, as in this case, along with other case series, specific features can aid in differentiating. Based on this case and other case series, specific features include cardiac dysfunction, enteropathy, and a relative thrombocytopenia (5) . More specifically, a positive COVID-19 test will further distinguish MIS-C from these other disease processes. All of these features were demonstrated in our case and aid in distinguishing MIS-C from other disease processes. Currently, multiple children's hospitals have created their own individual guidelines for treatment of MIS-C. Most guidelines recommend a multidisciplinary approach when deciding when and which treatments to start and include a combination of the following: broadspectrum antibiotics for patients who present in shock and those for whom sepsis may be of concern; i.v. immunoglobulin with or without steroids in those with shock; and, depending on their illness severity, aspirin with or without anticoagulation if not contraindicated. Antivirals are not routinely recommended, as this syndrome is thought to be a post-infectious inflammatory process. Some guidelines also recommend considering the use of immunosuppressive drugs like anakinra and tocilizumab (1, 6) . This new disease process or syndrome, MIS-C, is becoming more prevalent or is at least being diagnosed more readily within the pediatric population as the COVID-19 pandemic continues to be a global crisis. MIS-C appears to be related to SARS-CoV-2 infection. The clinical presentation can be confused with Kawasaki disease, toxic shock syndrome, and many other disease entities. It is important to distinguish MIS-C as its own disease process, given the association with myocarditis. Further studies are required to better understand this disease process to facilitate prevention and evidence-based treatment guidelines. Children's Hospital of the King's Daughters. CKHD Treatment Guideline for COVID-19 in Children Hyperinflammatory shock in children during COVID-19 pandemic Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19). CDC Health Alert Network. 2020. Available at: emergency.cdc.gov/han/2020/han00432 Multisystem inflammatory syndrome in children and adolescents temporally related to COVID-19 Multisystem inflammatory syndrome in children during the COVID-19 pandemic: a case series Multisystem inflammatory syndrome (MIS-C) clinical pathway-emergency, ICU and inpatient. The Children's Hospital of Philadelphia