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      Multisystem Inflammatory Syndrome in U.S. Children and Adolescents

      research-article
      , Ph.D., , Ph.D., , M.D., , M.D., , M.P.H., , M.D., , M.D., M.P.H., , M.D., M.P.H., , M.D., , M.D., , M.D., , M.D., M.P.H., , M.D., , M.D., , M.D., M.P.H., , M.D., , M.D., , M.D., M.P.H., , M.D., , M.D., Ph.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , D.O., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., Ph.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., M.P.H., , M.D. , , M.D. *
      The New England Journal of Medicine
      Massachusetts Medical Society
      Keyword part (code): 5Keyword part (keyword): DermatologyKeyword part (code): 5_1Keyword part (keyword): Dermatology General , 5, Dermatology, Keyword part (code): 5_1Keyword part (keyword): Dermatology General, 5_1, Dermatology General, Keyword part (code): 8Keyword part (keyword): NephrologyKeyword part (code): 8_4Keyword part (keyword): Chronic Kidney Disease , 8, Nephrology, Keyword part (code): 8_4Keyword part (keyword): Chronic Kidney Disease, 8_4, Chronic Kidney Disease, Keyword part (code): 10Keyword part (keyword): Emergency MedicineKeyword part (code): 10_1Keyword part (keyword): Emergency Medicine General , 10, Emergency Medicine, Keyword part (code): 10_1Keyword part (keyword): Emergency Medicine General, 10_1, Emergency Medicine General, Keyword part (code): 12Keyword part (keyword): Pulmonary/Critical CareKeyword part (code): 12_1Keyword part (keyword): Pulmonary/Critical Care General , 12, Pulmonary/Critical Care, Keyword part (code): 12_1Keyword part (keyword): Pulmonary/Critical Care General, 12_1, Pulmonary/Critical Care General, Keyword part (code): 14Keyword part (keyword): CardiologyKeyword part (code): 14_1Keyword part (keyword): Cardiology General , 14, Cardiology, Keyword part (code): 14_1Keyword part (keyword): Cardiology General, 14_1, Cardiology General, Keyword part (code): 18Keyword part (keyword): Infectious DiseaseKeyword part (code): 18_6Keyword part (keyword): Viral Infections , 18, Infectious Disease, Keyword part (code): 18_6Keyword part (keyword): Viral Infections, 18_6, Viral Infections, Keyword part (code): 19Keyword part (keyword): Allergy/ImmunologyKeyword part (code): 19_1Keyword part (keyword): Allergy/Immunology General , 19, Allergy/Immunology, Keyword part (code): 19_1Keyword part (keyword): Allergy/Immunology General, 19_1, Allergy/Immunology General

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          Abstract

          Background

          Understanding the epidemiology and clinical course of multisystem inflammatory syndrome in children (MIS-C) and its temporal association with coronavirus disease 2019 (Covid-19) is important, given the clinical and public health implications of the syndrome.

          Methods

          We conducted targeted surveillance for MIS-C from March 15 to May 20, 2020, in pediatric health centers across the United States. The case definition included six criteria: serious illness leading to hospitalization, an age of less than 21 years, fever that lasted for at least 24 hours, laboratory evidence of inflammation, multisystem organ involvement, and evidence of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on reverse-transcriptase polymerase chain reaction (RT-PCR), antibody testing, or exposure to persons with Covid-19 in the past month. Clinicians abstracted the data onto standardized forms.

          Results

          We report on 186 patients with MIS-C in 26 states. The median age was 8.3 years, 115 patients (62%) were male, 135 (73%) had previously been healthy, 131 (70%) were positive for SARS-CoV-2 by RT-PCR or antibody testing, and 164 (88%) were hospitalized after April 16, 2020. Organ-system involvement included the gastrointestinal system in 171 patients (92%), cardiovascular in 149 (80%), hematologic in 142 (76%), mucocutaneous in 137 (74%), and respiratory in 131 (70%). The median duration of hospitalization was 7 days (interquartile range, 4 to 10); 148 patients (80%) received intensive care, 37 (20%) received mechanical ventilation, 90 (48%) received vasoactive support, and 4 (2%) died. Coronary-artery aneurysms (z scores ≥2.5) were documented in 15 patients (8%), and Kawasaki’s disease–like features were documented in 74 (40%). Most patients (171 [92%]) had elevations in at least four biomarkers indicating inflammation. The use of immunomodulating therapies was common: intravenous immune globulin was used in 144 (77%), glucocorticoids in 91 (49%), and interleukin-6 or 1RA inhibitors in 38 (20%).

          Conclusions

          Multisystem inflammatory syndrome in children associated with SARS-CoV-2 led to serious and life-threatening illness in previously healthy children and adolescents. (Funded by the Centers for Disease Control and Prevention.)

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          Most cited references35

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          Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

          Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
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            Clinical Characteristics of Coronavirus Disease 2019 in China

            Abstract Background Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients. Methods We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. Results The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Conclusions During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.)
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              Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

              Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
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                Author and article information

                Journal
                N Engl J Med
                N. Engl. J. Med
                nejm
                The New England Journal of Medicine
                Massachusetts Medical Society
                0028-4793
                1533-4406
                29 June 2020
                29 June 2020
                : NEJMoa2021680
                Affiliations
                From the COVID-19 Response, Centers for Disease Control and Prevention (L.R.F., E.B.R., J.P.C., M.W.T., M.M.P.), and the Division of Critical Care Medicine, Department of Pediatrics (K.M.T.), the Department of Pediatrics, Division of Infectious Diseases (P.J.), and the Department of Pediatrics, Division of Cardiology (M.E.O.), Emory University School of Medicine, Atlanta; Public Health Service Commissioned Corps, Rockville (L.R.F., E.B.R., M.M.P.), and the Department of Anesthesiology and Critical Care Medicine, Division of Pediatric Anesthesiology and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore (B.J.R.) — both in Maryland; the Department of Pediatrics, Division of Pediatric Critical Care, Bristol-Myers Squibb Children’s Hospital, Robert Wood Johnson Medical School, Rutgers University (S.M. Horwitz), the Department of Pediatrics, Division of Population Health, Quality, and Implementation Sciences (PopQuIS), Rutgers Robert Wood Johnson Medical School (L.C.K.), New Brunswick, the Department of Pediatrics, Division of Pediatric Cardiology, Children’s Hospital of New Jersey, Newark Beth Israel, Newark (R.F.W.), the Division of Hospital Medicine, Department of Pediatrics, Hackensack University Medical Center, Hackensack (K.N.C.), and the Division of Pediatric Critical Care, Department of Pediatrics, Saint Barnabas Medical Center, Livingston (S.J.G.) — all in New Jersey; the Department of Anesthesiology, Critical Care and Pain Medicine (M.M.N., A.G.R.), the Division of Immunology (M.B.F.S.), and the Department of Cardiology (J.W.N.), Boston Children’s Hospital, and the Departments of Pediatrics (M.B.F.S., J.W.N., A.G.R.) and Anaesthesia (A.G.R.), Harvard Medical School, Boston, and the Department of Pediatrics, Pediatric Critical Care, Baystate Medical Center, Springfield (K.L.M.) — both in Massachusetts; the Department of Pediatrics, Division of Pediatric Critical Care Medicine, Central Michigan University, Detroit (S.M. Heidemann, A.A.M.); the Pediatric Critical Care Division, Maria Fareri Children’s Hospital at Westchester Medical Center and New York Medical College, Valhalla (A.R.S., S.L.), Pediatric Critical Care Medicine, Department of Pediatrics, Icahn School of Medicine at the Mount Sinai Kravis Children’s Hospital (S.P.Z., J.G.), the Division of Pediatric Infectious Diseases, Departments of Pediatrics and Microbiology, New York University Grossman School of Medicine (A.J.R.), Pediatric Critical Care, New York City Health and Hospitals, Kings County Hospital (M.A.K., H.A.), the Division of Pediatric Critical Care, Department of Pediatrics, SUNY Downstate Health Sciences University (S.D.), and the Department of Pediatrics, Division of Pediatric Critical Care, Maimonides Children’s Hospital (A.D.), New York — all in New York; the Division of Critical Care, Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia (J.C.F.); the Department of Pediatrics, Division of Critical Care, Yale University School of Medicine, New Haven (J.S.G., A.G.), and the Division of Critical Care, Connecticut Children’s, Hartford (R.M.P., C.L.C.) — both in Connecticut; the Department of Pediatrics, Section of Critical Care Medicine, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora (A.B.M.); the Division of Pediatric Critical Care Medicine, Department of Pediatrics, Advocate Children’s Hospital, Chicago (V.H., S.R.); the Department of Pediatrics, Division of Pediatric Rheumatology, MetroHealth Medical Center, Case Western Reserve University (H.B.), and the Division of Pediatric Hospital Medicine, Rainbow Babies and Children’s Hospital (A.L.), Cleveland; the Department of Pediatrics, Division of Cardiology, Louisiana State University Health Sciences Center and Children’s Hospital of New Orleans, New Orleans (T.T.B.); the Department of Pediatrics, Division of Pediatric Critical Care Medicine, University of Washington, Seattle (L.S.S.); the Pediatric Critical Care Division, Department of Pediatrics, University of Texas Health Science Center at Houston, Houston (A.C.M.); the Department of Pediatrics, Department of Microbiology, Division of Infectious Diseases, University of Mississippi Medical Center, Jackson (C.V.H.); and the Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville (N.B.H.).
                Author notes
                Address reprint requests to Dr. Patel at the Influenza Division, Centers for Disease Control and Prevention, 1600 Clifton Rd., MS H24-7, Atlanta, GA 30329, or at mpatel@ 123456cdc.gov ; or to Dr. Randolph at Division of Critical Care Medicine, Boston Children’s Hospital, Bader 634, Boston, MA 02115, or at adrienne.randolph@ 123456childrens.harvard.edu .
                [*]

                Complete lists of members of the Overcoming COVID-19 Investigators and the CDC COVID-19 Response Team are provided in the Supplementary Appendix, available at NEJM.org.

                Drs. Feldstein and Rose and Drs. Patel and Randolph contributed equally to this article.

                Author information
                http://orcid.org/0000-0002-4071-0280
                http://orcid.org/0000-0001-9690-5493
                http://orcid.org/0000-0001-5349-5260
                Article
                NJ202006293830402
                10.1056/NEJMoa2021680
                7346765
                32598831
                62ef4de5-c082-41b8-a2e9-1b7481430d81
                Copyright © 2020 Massachusetts Medical Society. All rights reserved.

                This article is made available via the PMC Open Access Subset for unrestricted re-use, except commercial resale, and analyses in any form or by any means with acknowledgment of the original source. These permissions are granted for the duration of the Covid-19 pandemic or until revoked in writing. Upon expiration of these permissions, PMC is granted a license to make this article available via PMC and Europe PMC, subject to existing copyright protections.

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