Ten Things to Know About MIS-C
First identified in April 2020, Multisystem Inflammatory Syndrome in Children (MIS-C) is a systemic inflammatory syndrome associated with exposure to SARS-CoV-2. With a higher incidence in Black and Hispanic/Latino children, the mechanism of this post-viral syndrome is still unknown to date. Children may require hospitalization, and possibly critical care. Cardiac involvement is common. Children generally make a complete recovery with low rates of morbidity and death, although long-term sequelae are unknown. The following are ten things to know about MIS-C.
- Epidemiology: The incidence of MIS-C is 316 per 1 million SARS-CoV-2 infections in those <21 years of age (about 1 per 3000). Median age is 9 years old, and 75% of cases have no prior comorbidities. Highest incidences are in Black and Hispanic/Latino children, with the incidence in Blacks not explainable by COVID-19 rates.1-4
- Clinical features: MIS-C occurs in those <21 years following a recent SARS-CoV-2 infection. Diagnostic criteria include fever >24 hours, at least two different organ systems involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, or neurological), without plausible alternative diagnosis. In over 50% of patients, at least five organ systems have been involved.5,6
- Laboratory findings: Acute phase reactants, including C-reactive protein, are often markedly elevated, with evidence of recent SARS-CoV-2 infection by reverse transcription polymerase chain reaction (RT-PCR), serology, or antigen test or known COVID-19 exposure within 4 weeks prior to the onset of symptoms (note: vaccinated individuals with no prior infection will have positive anti-spike IgG antibodies but not anti-nucleocapsid IgG antibodies). Troponin and BNP/NT-Pro BNP are often also markedly elevated. It is important to trend cardiac biomarkers as cardiac involvement may worsen during the course of the illness.5,6
- Echocardiogram: Up to 40% of cases will exhibit left ventricular systolic and/or diastolic dysfunction. Mitral regurgitation is present in approximately 30%, and pericardial effusion in approximately 20%. Coronary artery dilation is seen in approximately 13% of cases and can occur even after MIS-C treatment.3,7-9
- Electrocardiogram (ECG): Abnormal ECG changes may be seen in approximately 35% of cases. These include ST or T wave abnormalities and transient QTc prolongation. First and second-degree atrioventricular block have been reported but are often transient.10,11
- Treatment: Current accepted therapy is based on experience with Kawasaki disease. Intravenous immunoglobulin (IVIG) is most often used, and glucocorticoids have been shown to aid cardiac recovery. Some report treating mild cases with glucocorticoids alone. In severe cases, immune modulators such as anakinra and tocilizumab have been helpful. Due to the risk of thrombosis with MIS-C, prophylactic anticoagulation while hospitalized is common and aspirin may be prescribed for 6 weeks. Those with documented coronary dilation are treated according to Kawasaki disease therapeutic guidelines.5,12
- Short-term outcomes: About 65% of patients require critical care, with almost half requiring inotropic support. Median total length of hospital stay is approximately 5 days. Fortunately, children tend to respond well to treatment. As of October 2021, the overall mortality reported to the Centers for Disease Control and Prevention (CDC) is 0.9%, which appears to be decreasing over time. Demographic risk factors for severe outcomes include older age, male sex, and non-Hispanic Black race/ethnicity.3,7,13-15
- Medium-term outcomes: Echocardiograms are often performed to evaluate for ventricular dysfunction, coronary dilation and to assess myocardial strain. Within a few days to weeks after diagnosis, nearly all who have had ventricular dysfunction have recovered and coronary ectasia and small aneurysms have regressed. In children with severe cardiac involvement during acute presentation, magnetic resonance imaging (MRI) findings at follow-up tend to improve. However, some symptoms may persist for months, including neurologic abnormalities, muscle weakness, easy fatigability, anxiety, emotional lability and postural orthostatic tachycardia syndrome (POTS). Longer-term follow-up studies to assess the natural history of this disease process are ongoing.9,15,16
- Vaccination recommendations: Patients with a history of MIS-C have high levels of antibody titers to SARS-CoV-2, but it is unclear how long these antibodies last and confer protection. Recurrent SARS-CoV-2 infection and MIS-C is possible but rare. Data on the safety and efficacy of COVID-19 vaccines in children who have had MIS-C are limited, but experts believe that the benefits of vaccination outweigh the risks. Those with MIS-C are generally advised to wait at least 90 days after their acute illness to ensure adequate cardiac recovery prior to receiving a COVID-19 vaccine.17-19
- MIS-A: Although less common than in children, multisystem inflammatory syndrome can occur in adults (>21 years of age), a condition referred to as MIS-A. Its diagnostic criteria include: a) fever >24 hours or within the first 3 days of hospitalization, b) laboratory evidence of inflammation, c) laboratory evidence of current or past SARS-CoV-2 infection, d) and meeting at least three of six clinical criteria, one of which must be primary. The primary criteria are: a) severe cardiac involvement, b) rash and non-purulent conjunctivitis. Secondary criteria include: a) new-onset neurologic signs and symptoms, b) shock or hypotension not attributable to other causes, c) abdominal pain, vomiting, or diarrhea, d) thrombocytopenia (platelet count <150,000/ microliter).20-24
- Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem inflammatory syndrome in US children and adolescents. N Engl J Med 2020;383:334-46.
- Payne AB, Gilani Z, Godfred-Cato S, et al. Incidence of multisystem inflammatory syndrome in children among US persons infected with SARS-CoV-2. JAMA Netw Open 2021;4:e2116420.
- Son MBF, Murray N, Friedman K, et al. Multisystem inflammatory syndrome in children—initial therapy and outcomes. N Engl J Med 2021;385:23-34.
- Stierman B, Abrams JY, Godfred-Cato SE, et al. Racial and ethnic disparities in multisystem inflammatory syndrome in children in the United States, March 2020 to February 2021. Pediatr Infect Dis J 2021;40:e400-06.
- McArdle AJ, Vito O, Patel H, et al. Treatment of multisystem inflammatory syndrome in children. N Engl J Med 2021;385:11-22.
- Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease 2019 (COVID-19) (CDC website). 2020. Available at: https://emergency.cdc.gov/han/2020/han00432.asp. Accessed 10/15/2021.
- Feldstein LR, Tenforde MW, Friedman KG, et al. Characteristics and outcomes of US children and adolescents with multisystem inflammatory syndrome in children (MIS-C) compared with severe acute COVID-19. JAMA 2021;325:1074-87.
- Gaitonde M, Ziebell D, Kelleman MS, et al. COVID-19-related multisystem inflammatory syndrome in children affects left ventricular function and global strain compared with Kawasaki disease. J Am Soc Echocardiogr 2020;33:1285-87.
- Matsubara D, Kauffman HL, Wang Y, et al. Echocardiographic findings in pediatric multisystem inflammatory syndrome associated with COVID-19 in the United States. J Am Coll Cardiol 2020;76:1947-61.
- Regan W, O'Byrne L, Stewart K, et al. Electrocardiographic changes in children with multisystem inflammation associated with COVID-19: associated with coronavirus disease 2019. J Pediatr 2021;234:27-32.
- Valverde I, Singh Y, Sanchez-de-Toledo J, et al. Acute cardiovascular manifestations in 286 children with multisystem inflammatory syndrome associated with COVID-19 infection in Europe. Circulation 2021;143:21-32.
- Henderson LA, Canna SW, Friedman KG, et al. American College of Rheumatology clinical guidance for multisystem inflammatory syndrome in children associated with SARS–CoV‐2 and hyperinflammation in pediatric COVID‐19: version 2. Arthritis Rheumatol 2021;73:e13-e29.
- Abrams JY, Oster ME, Godfred-Cato SE, et al. Factors linked to severe outcomes in multisystem inflammatory syndrome in children (MIS-C) in the USA: a retrospective surveillance study. Lancet Child Adolesc Health 2021;5:323-31.
- Kaushik S, Aydin SI, Derespina KR, et al. Multisystem inflammatory syndrome in children associated with severe acute respiratory syndrome coronavirus 2 infection (MIS-C): a multi-institutional study from New York City. J Pediatr 2020;224:24-29.
- Penner J, Abdel-Mannan O, Grant K, et al. 6-month multidisciplinary follow-up and outcomes of patients with paediatric inflammatory multisystem syndrome (PIMS-TS) at a UK tertiary paediatric hospital: a retrospective cohort study. Lancet Child Adolesc Health 2021;7:473-82.
- Farooqi KM, Chan A, Weller RJ, et al. Longitudinal outcomes for multisystem inflammatory syndrome in children. Pediatrics 2021;Jul 15:[Epub ahead of print].
- Gargano JW, Wallace M, Hadler SC, et al. Use of mRNA COVID-19 vaccine after reports of myocarditis among vaccine recipients: update from the Advisory Committee on Immunization Practices—United States, June 2021. MMWR Morb Mortal Wkly Rep 2021;70:977-82.
- Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Approved or Authorized in the United States (CDC website). 2021. Available at: https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html#CoV-19-vaccination. Accessed 10/15/2021.
- Rostad CA, Chahroudi A, Mantus G, et al. Quantitative SARS-CoV-2 serology in children with multisystem inflammatory syndrome (MIS-C). Pediatrics 2020;Sep 2:[Epub ahead of print].
- Davogustto GE, Clark DE, Hardison E, et al. Characteristics associated with multisystem inflammatory syndrome among adults with SARS-CoV-2 infection. JAMA Netw Open 2021;4:e2110323.
- Morris SB, Schwartz NG, Patel P, et al. Case series of multisystem inflammatory syndrome in adults associated with SARS-CoV-2 infection—United Kingdom and United States, March–August 2020. MMWR Morb Mortal Wkly Rep 2020;69:1450-56.
- Most ZM, Hendren N, Drazner MH, Perl TM. Striking similarities of multisystem inflammatory syndrome in children and a myocarditis-like syndrome in adults: overlapping manifestations of COVID-19. Circulation 2021;143:4-6.
- Multisystem Inflammatory Syndrome in Adults (MIS-A) Case Definition (CDC website). 2021. Available at: https://www.cdc.gov/mis/mis-a/hcp.html. Accessed 10/15/2021.
- Vogel TP, Top KA, Karatzios C, et al. Multisystem inflammatory syndrome in children and adults (MIS-C/A): case definition & guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine 2021;39:3037-49.
Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Congenital Heart Disease and Pediatric Cardiology, COVID-19 Hub, Noninvasive Imaging, Pericardial Disease, Prevention, Valvular Heart Disease, Vascular Medicine, Implantable Devices, EP Basic Science, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Congenital Heart Disease, CHD and Pediatrics and Arrhythmias, CHD and Pediatrics and Imaging, CHD and Pediatrics and Prevention, CHD and Pediatrics and Quality Improvement, Magnetic Resonance Imaging, Mitral Regurgitation
Keywords: Child, Young Adult, COVID-19, COVID-19 Vaccines, SARS-CoV-2, Immunoglobulins, Intravenous, C-Reactive Protein, Glucocorticoids, Interleukin 1 Receptor Antagonist Protein, Follow-Up Studies, Atrioventricular Block, Mucocutaneous Lymph Node Syndrome, Pericardial Effusion, Dilatation, Pathologic, African Americans, Hispanic Americans, Length of Stay, Platelet Count, Acute-Phase Proteins, Mitral Valve Insufficiency, Muscle Weakness, Postural Orthostatic Tachycardia Syndrome, Ethnic Groups, Acute Disease, Coronary Vessels, Dilatation, Reverse Transcription, Electrocardiography, Thrombosis, Magnetic Resonance Imaging, Aneurysm, Ventricular Dysfunction, Hypotension, Thrombocytopenia, Long QT Syndrome, Risk Factors, Inflammation, Exanthema, Abdominal Pain, Diarrhea, Anxiety, Vomiting, Vaccination, Critical Care, Centers for Disease Control and Prevention, U.S., Myocardial Infarction, Polymerase Chain Reaction, Anticoagulants, Biomarkers, Pediatrics
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