Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents in New York City | Adolescent Medicine | JAMA | JAMA Network
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Table 1.  Demographics, Clinical Characteristics, Treatment, and Outcomes of Patients With COVID-19–Related Multisystem Inflammatory Syndrome in Children (N = 17)
Demographics, Clinical Characteristics, Treatment, and Outcomes of Patients With COVID-19–Related Multisystem Inflammatory Syndrome in Children (N = 17)
Table 2.  Laboratory, Echocardiogram, and Imaging Characteristics of COVID-19–Related Multisystem Inflammatory Syndrome in Children (N = 17)
Laboratory, Echocardiogram, and Imaging Characteristics of COVID-19–Related Multisystem Inflammatory Syndrome in Children (N = 17)
1.
Castagnoli  R, Votto  M, Licari  A,  et al.  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children and adolescents: a systematic review.   JAMA Pediatr. Published online April 22, 2020. doi:10.1001/jamapediatrics.2020.1467PubMedGoogle Scholar
2.
Tagarro  A, Epalza  C, Santos  M,  et al.  Screening and severity of coronavirus disease 2019 (COVID-19) in children in Madrid, Spain.   JAMA Pediatr. Published online April 8, 2020. doi:10.1001/jamapediatrics.2020.1346PubMedGoogle Scholar
3.
Riphagen  S, Gomez  X, Gonzalez-Martinez  C, Wilkinson  N, Theocharis  P.  Hyperinflammatory shock in children during COVID-19 pandemic.   Lancet. 2020;395(10237):1607-1608. doi:10.1016/S0140-6736(20)31094-1PubMedGoogle ScholarCrossref
4.
McCrindle  BW, Rowley  AH, Newburger  JW,  et al; American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Council on Cardiovascular Surgery and Anesthesia; and Council on Epidemiology and Prevention.  Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association.   Circulation. 2017;135(17):e927-e999. doi:10.1161/CIR.0000000000000484PubMedGoogle ScholarCrossref
5.
Li  Y, Zheng  Q, Zou  L,  et al.  Kawasaki disease shock syndrome: clinical characteristics and possible use of IL-6, IL-10 and IFN-γ as biomarkers for early recognition.   Pediatr Rheumatol Online J. 2019;17(1):1. doi:10.1186/s12969-018-0303-4PubMedGoogle ScholarCrossref
6.
Chen  G, Wu  D, Guo  W,  et al.  Clinical and immunological features of severe and moderate coronavirus disease 2019.   J Clin Invest. 2020;130(5):2620-2629. doi:10.1172/JCI137244PubMedGoogle ScholarCrossref
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    Research Letter
    June 8, 2020

    Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents in New York City

    Author Affiliations
    • 1Department of Pediatrics, Columbia University Irving Medical Center, New York, New York
    JAMA. 2020;324(3):294-296. doi:10.1001/jama.2020.10374

    Severe coronavirus disease 2019 (COVID-19) has been reported rarely in children.1,2 International data suggest the development of a proinflammatory syndrome with features of Kawasaki disease (KD) or toxic shock syndrome (TSS) in children, possibly related to COVID-19.3

    Methods

    Patients were included if they (1) were 21 years or younger; (2) were hospitalized at Columbia University Irving Medical Center/New York-Presbyterian Morgan Stanley Children’s Hospital in New York City between April 18 and May 5, 2020; (3) presented with a clinical syndrome characterized by prolonged fever, systemic inflammation, shock, end-organ dysfunction, or symptoms reminiscent of KD or TSS; and (4) had evidence of recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. SARS-CoV-2 infection was determined by reverse transcriptase–polymerase chain reaction (RT-PCR) of nasopharyngeal swabs or positive serology. Serology testing was done using a New York State Department of Health–approved combined assay for IgM and IgG antibodies against SARS-CoV-2 spike trimer or nucleocapsid protein (96% specificity, 93% sensitivity). Admission testing included hematologic parameters, chemistries, co-infections, and inflammatory markers along with assessments of cardiac function (electrocardiograms, transthoracic echocardiograms). The Columbia University ethics committee approved the study with a waiver of informed consent.

    Results

    Among 17 patients (8 male; median age, 8 years [range, 1.8-16 years]) (Table 1), most were white (n = 12) and previously healthy (mild asthma in 3). All patients had fever (median duration, 5 days). Fourteen had gastrointestinal symptoms, with 1 showing acute ileocolitis on imaging. Mucocutaneous findings were common (rash [n = 12], conjunctivitis [n = 11], and lip redness/swelling [n = 9]). Three patients were hypoxic at presentation, and 13 had shock. Fourteen had abnormal chest radiograph findings, most commonly bilateral, interstitial opacities. Eight met criteria for KD and 5 for incomplete KD.4

    Eight patients tested positive for SARS-CoV-2 by RT-PCR and the other 9 by serology. Levels of inflammatory markers were elevated in all patients, and most had lymphopenia (n = 12), bandemia (n = 11), elevated troponin T level (n = 14), and elevated N-terminal pro–brain-type natriuretic peptide (NT-proBNP) level (n = 15). Studies suggesting co-infections were infrequent (n = 3) (Table 2). Serum IL-6 level was elevated in 16. Cytokine profiling in 8 patients showed elevated IL-2R, IL-18, and CXCL 9 levels in all and mildly increased IFN-γ (n = 3) and IL-8 (n = 2) levels in some. TNF-α, IL-1b, Il-2, IL-4, IL-5, and IL-13 levels were normal. Fifteen patients required pediatric intensive care unit admission; vasoactive support was required in 10. Of 9 patients with hypoxia, none required mechanical ventilation.

    Fourteen patients received steroid treatment, either with methylprednisone (dose range, 2-30 mg/kg per day) or hydrocortisone (dose, 2 mg/kg per day); 1 received prednisone. Thirteen patients received intravenous immunoglobulins (dose range, 2-4 g/kg), including 3 patients who did not receive steroids and 8 who met criteria for KD. One patient received tocilizumab.

    Electrocardiograms of 16 patients showed nonspecific ST/T-wave abnormalities in 10 and attenuated QRS voltage in 1. Dysrhythmias were noted in 3 (premature ventricular contractions, nonsustained ventricular tachycardia, and sinus bradycardia). Admission echocardiograms showed normal to mildly decreased left ventricular function (n = 11) or moderate or more ventricular dysfunction (n = 6). All patients had normal coronary arteries by measurement, though coronary arteries were described as prominent or echogenic in 7. Most patients had improved function on follow-up echocardiogram (range, 2-18 days from admission)—12 with normal and 1 with mildly decreased function. One patient (aged 4 years) had a medium-sized aneurysm (z score, 5.2) of the left anterior descending coronary artery. This patient presented with fever, diarrhea, and shock, with no additional features of KD. Admission testing revealed lymphopenia (absolute lymphocyte count, 540/μL); elevated levels of proBNP (44 677 pg/mL), ferritin (1195.0 ng/mL), and D-dimer (1.39 μg/mL [7.61 nmol/L]); normal troponin T level (19 ng/L); and thrombocytopenia (105 × 103/μL). Thirteen days later, thrombocytosis developed (maximum, 671).

    By May 20, after a mean total length of hospital stay of 7.1 (range, 3-18) days, all patients had been discharged home with no fatalities.

    Discussion

    This study describes 17 previously healthy children and adolescents who developed an inflammatory phenotype related to COVID-19. Features overlapped with, but were distinct from, those of KD and TSS. The observed pattern of cytokine expression suggests an interferon signaling component, along with IL-6 and IL-10 production, seen in KD5 and acute pulmonary COVID-19 infection. The lack of elevated TNF-α or IL-13 levels may differ from acute pulmonary COVID infections.6 The occurrence of abnormal cardiac findings suggests the need for long-term surveillance. Limitations include the small number of patients, short follow-up period, and the inability to establish causality.

    Section Editor: Jody W. Zylke, MD, Deputy Editor.
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    Article Information

    Corresponding Author: Eva W. Cheung, MD, Divisions of Cardiology and Critical Care, Department of Pediatrics, Columbia University Irving Medical Center, 3959 Broadway, CHN 2 North, New York, NY 10032 (ec2335@cumc.columbia.edu).

    Accepted for Publication: May 27, 2020.

    Published Online: June 8, 2020. doi:10.1001/jama.2020.10374

    Author Contributions: Drs Cheung and Zachariah had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Cheung and Zachariah contributed equally to the authorship of this article.

    Concept and design: All authors.

    Acquisition, analysis, or interpretation of data: Cheung, Zachariah, Gorelik, Boneparth, Orange, Milner.

    Drafting of the manuscript: Cheung, Zachariah, Gorelik, Boneparth, Milner.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Cheung, Zachariah.

    Administrative, technical, or material support: Zachariah, Gorelik, Orange.

    Supervision: Kernie, Orange, Milner.

    Conflict of Interest Disclosures: Dr Orange reported receiving personal fees from ADMA Biologics, CSL Bhering, Gigagen, Grifols, and Takeda. No other disclosures were reported.

    Additional Contributions: Candace Johnson, MD, Kara Gross-Margolis, MD, Irene Lytrivi, MD, Angela Chan, MD, and Brian Jonat, MD, MPH (Department of Pediatrics, Columbia University Irving Medical Center), contributed to data collection and analysis and editing assistance for this letter. Eldad A. Hod, MD (Department of Pathology and Cell Biology, Columbia University Irving Medical Center), contributed to data collection and writing of the manuscript. None of these individuals were compensated for their contributions.

    References
    1.
    Castagnoli  R, Votto  M, Licari  A,  et al.  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children and adolescents: a systematic review.   JAMA Pediatr. Published online April 22, 2020. doi:10.1001/jamapediatrics.2020.1467PubMedGoogle Scholar
    2.
    Tagarro  A, Epalza  C, Santos  M,  et al.  Screening and severity of coronavirus disease 2019 (COVID-19) in children in Madrid, Spain.   JAMA Pediatr. Published online April 8, 2020. doi:10.1001/jamapediatrics.2020.1346PubMedGoogle Scholar
    3.
    Riphagen  S, Gomez  X, Gonzalez-Martinez  C, Wilkinson  N, Theocharis  P.  Hyperinflammatory shock in children during COVID-19 pandemic.   Lancet. 2020;395(10237):1607-1608. doi:10.1016/S0140-6736(20)31094-1PubMedGoogle ScholarCrossref
    4.
    McCrindle  BW, Rowley  AH, Newburger  JW,  et al; American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Council on Cardiovascular Surgery and Anesthesia; and Council on Epidemiology and Prevention.  Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association.   Circulation. 2017;135(17):e927-e999. doi:10.1161/CIR.0000000000000484PubMedGoogle ScholarCrossref
    5.
    Li  Y, Zheng  Q, Zou  L,  et al.  Kawasaki disease shock syndrome: clinical characteristics and possible use of IL-6, IL-10 and IFN-γ as biomarkers for early recognition.   Pediatr Rheumatol Online J. 2019;17(1):1. doi:10.1186/s12969-018-0303-4PubMedGoogle ScholarCrossref
    6.
    Chen  G, Wu  D, Guo  W,  et al.  Clinical and immunological features of severe and moderate coronavirus disease 2019.   J Clin Invest. 2020;130(5):2620-2629. doi:10.1172/JCI137244PubMedGoogle ScholarCrossref
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