One-Year Outcomes of Critical Care Patients Post–COVID-19 Multisystem Inflammatory Syndrome in Children | Critical Care Medicine | JAMA Pediatrics | JAMA Network
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Figure.  Time to First Evidence of Normalization
Time to First Evidence of Normalization

For UK patients with pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 or multisystem inflammatory syndrome in children presenting with echocardiographic evidence of functional problems, aneurysms, or subjectively bright coronaries. Patients with no evidence of normalization are denoted by a diamond at the time of their last abnormal echocardiogram.

Table.  Resolution of Echocardiographic and Laboratory Parameters in Patients Admitted to UK Pediatric Intensive Care Units With Post–SARS-CoV-2 Inflammatory Shock
Resolution of Echocardiographic and Laboratory Parameters in Patients Admitted to UK Pediatric Intensive Care Units With Post–SARS-CoV-2 Inflammatory Shock
1.
Whittaker  E, Bamford  A, Kenny  J,  et al; PIMS-TS Study Group and EUCLIDS and PERFORM Consortia.  Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2.   JAMA. 2020;324(3):259-269. doi:10.1001/jama.2020.10369PubMedGoogle ScholarCrossref
2.
Davies  P, Lillie  J, Prayle  A,  et al.  Association between treatments and short-term biochemical improvements and clinical outcomes in post-severe acute respiratory syndrome coronavirus-2 inflammatory syndrome.   Pediatr Crit Care Med. 2021;22(5):e285-e293. doi:10.1097/PCC.0000000000002728PubMedGoogle ScholarCrossref
3.
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(5):323-331. doi:10.1016/S2352-4642(21)00050-XPubMedGoogle ScholarCrossref
4.
Feldstein  LR, Tenforde  MW, Friedman  KG,  et al; Overcoming COVID-19 Investigators.  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(11):1074-1087. doi:10.1001/jama.2021.2091PubMedGoogle ScholarCrossref
5.
Penner  J, Abdel-Mannan  O, Grant  K,  et al; GOSH PIMS-TS MDT Group.  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;5(7):473-482. doi:10.1016/S2352-4642(21)00138-3PubMedGoogle ScholarCrossref
6.
Davies  P, Evans  C, Kanthimathinathan  HK,  et al.  Intensive care admissions of children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in the UK: a multicentre observational study.   Lancet Child Adolesc Health. 2020;4(9):669-677. doi:10.1016/S2352-4642(20)30215-7PubMedGoogle ScholarCrossref
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    1 Comment for this article
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    Difficulties in Distinguishing MIS-C from Kawasaki Disease
    Anne Rowley, M.D. | Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago
    Most pediatricians who have cared for children with Kawasaki Disease (KD) and MIS-C recognize that sometimes the two conditions can be difficult to distinguish, particularly if a child with KD has co-incidental or prior infection with SARS-CoV-2. It is very interesting that in this study, all the distinguishing features between children with persisting aneurysms and children in whom aneurysms resolved were those that would be more consistent with a diagnosis of KD than with a diagnosis of MIS-C. These include lower CRP values, higher lymphocyte count, higher platelet count, and lower troponins.
    Many lines of evidence now suggest that
    KD and MIS-C are entirely different disorders, with different pathogenesis. The timing of coronary artery dilation in the two conditions is particularly disparate, with coronary dilation occurring in the acute febrile phase of MIS-C, while coronary dilation in KD often occurs 2-3 weeks after fever onset, when the patient appears clinically well (1). In the US, children with MIS-C have almost universally had resolution of coronary artery dilation within weeks to months after the illness (2).
    It seems possible that the children with persisting aneurysms in this report actually had KD.

    1. McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, treatment, and long-term management of Kawasaki disease. Circulation. 2017;135:e927-e999.
    2. Feldstein LR, Rose EB, Horwitz SM et al. Multisystem Inflammatory Syndrome in US Children and Adolescents. JAMA 2021;325(11):1074-1087.
    CONFLICT OF INTEREST: None Reported
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    Research Letter
    August 30, 2021

    One-Year Outcomes of Critical Care Patients Post–COVID-19 Multisystem Inflammatory Syndrome in Children

    Author Affiliations
    • 1Paediatric Critical Care, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom
    • 2Paediatric Intensive Care, Great Ormond Street Hospital, London, United Kingdom
    • 3Paediatric Intensive Care, Evelina Children’s Hospital, London, United Kingdom
    • 4Paediatric Intensive Care, Birmingham Children’s Hospital, Birmingham, United Kingdom
    JAMA Pediatr. Published online August 30, 2021. doi:10.1001/jamapediatrics.2021.2993

    Medium- to long-term outcomes of the novel pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS)1 or multisystem inflammatory syndrome in children (MIS-C) are unknown. Short-term, 40-day, and 6-month outcomes have been published previously.2-5

    Methods

    We collected follow-up data for the previously published multicenter national critical care cohort admitted to the hospital prior to May 10, 2020.6 Data from critical care readmissions and outpatient follow-up clinics up to April 2021 (1 year postadmission) were collected. Monitoring frequency was at the discretion of each unit. The project was classified as a service evaluation by the Nottingham Research and Innovation team (reference 20-235C), and ethics approval and informed consent were not required as per the UK Health Research Authority. The study team analyzed routinely collected deidentified data submitted by clinicians from the participating centers. Definitions of cardiological normal values were locally defined. Descriptive statistics were used.

    Results

    Data were available from 68 of 76 patients (89%) of the initial surviving cohort. Six-month outcomes of 18 of these patients have been published previously.5 There were no deaths, and 2 patients (3%) had critical care readmission. Both readmissions were unrelated to complications of PIMS-TS or immunomodulatory therapy. Median length of hospital stay was 10 days (interquartile range [IQR], 7 to 14 days) and none needed respiratory support postdischarge.

    Outcome data are presented in the Table. It is possible that for many patients whose blood test results did not normalize, lack of repeated tests, rather than failure to normalize, may be contributory. Only 2 of 65 test results (3%) for C-reactive protein, 2 of 59 test results (3%) for D-dimer, and 1 of 60 test results (2%) for troponin were abnormal when tested more than 50 days postadmission. All results for blood tests performed for levels of lymphocytes, neutrophils, platelets, creatinine, ferritin, and alanine transaminase more than 50 days postadmission were normal. Although resolution to normality for D-dimer, ferritin, and troponin was demonstrated in fewer patients, fewer patients had serial monitoring of these parameters.

    Echocardiographic outcomes are shown in the Table and Figure. For abnormal data, the date of the last test is shown as a diamond in the Figure. Of those patients who presented with aneurysms, 14 of 19 had resolution, and of those who presented with subjectively “bright” coronary arteries, 9 of 10 had resolution and 1 patient progressed to having unresolved coronary artery aneurysms (albeit the latest follow-up echocardiography was 86 days postadmission). All patients who presented with impaired function without aneurysm recovered by day 74.

    All 6 patients (9%) with ongoing echocardiographic abnormalities had aneurysmal changes, with latest echocardiograms between days 86 and 336 postadmission. At presentation, these 6 patients had a median (interquartile range [IQR]) C-reactive protein level of 22.1 mg/dL (6.6-36.9 mg/dL), compared with 25.8 mg/dL (18.2-32.3 mg/dL) (to convert to milligrams per liter, multiply by 10) for those without aneurysmal changes at follow-up, a lymphocyte count of 1100/µL (600-3300/µL) vs 900/µL (500-1400/µL) ( to convert to ×109/L, multiply by 0.001), and platelet count of 217 ×103/µL (128-368 ×103/µL) vs 151 ×103/µL (85-198×103/µL) (to convert to ×109/L, multiply by 1). Surprisingly, median troponin levels were significantly lower in the group with aneurysm (0.06 ng/mL [0.02-0.418 ng/mL] vs 0.157 ng/mL [0.033-0.81 ng/mL] [to convert to micrograms per liter, multiply by 1]; P = .02). All 6 received intravenous immunoglobulin, compared with 46 of 62 of the other patients; 5 of 6 received steroids vs 46 of 62; and 1 of 6 received a biologic agent vs 13 of 62. According to the case reports, 5 of the 6 were Afro-Caribbean boys and 1 was a White girl, with an age range of 0 to 13 years (median, 8.75 years).

    Discussion

    Interpretation is limited by the small numbers, lack of consistent follow-up protocol, and hospital-wide readmission data, but is strengthened by a nationwide data set. While the majority of the units have established a consistent multidisciplinary follow-up protocol, this analysis is restricted to one of the earliest reported cohorts of patients worldwide, when the presence of such an entity was becoming apparent.

    Although our data identify a group of patients with a risk of significant long-term morbidity, it is reassuring that the majority of patients had good outcomes with no significant medium- or long-term sequelae.

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    Article Information

    Accepted for Publication: June 17, 2021.

    Published Online: August 30, 2021. doi:10.1001/jamapediatrics.2021.2993

    Corresponding Author: Patrick Davies, MRCPCH, Paediatric Critical Care Unit, Nottingham Children’s Hospital, Derby Road, Nottingham NG7 2UH, United Kingdom (patrick.davies@nuh.nhs.uk).

    Author Contributions: Dr Davies had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Davies, du Pré, Kanthimathinathan.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Davies, du Pré.

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

    Statistical analysis: Davies.

    Administrative, technical, or material support: Davies, Lillie.

    Other—suggestions re: analysis and presentation of data: Kanthimathinathan.

    Conflict of Interest Disclosures: None reported.

    Additional Contributions: We acknowledge the contribution and collaboration of the following in the collection of this data, and for the creation of the initial cohort: Claire Evans, MRCPCH, Andrew Prayle, PhD, and Harish Vyas, DM, Paediatric Critical Care Unit, Nottingham Children’s Hospital, Nottingham, UK; Joseph Brierley, MRCPCH, and Mae Johnson, FRCA, Paediatric Intensive Care Unit, Great Ormond Street Hospital, London, UK; Gareth Waters, FRCA, and Benedict Griffiths, MBBS, Paediatric Intensive Care Unit, Evelina Children’s Hospital, London, UK; Zoha Mohammad, MRCPCH, Paediatric Intensive Care Unit, Leicester Royal Infirmary, Leicester, UK; Akash Deep, MRCPCH, Paediatric Intensive Care Unit, King’s College Hospital, London, UK; Stephen Playfor, DM, Paediatric Intensive Care Unit, Royal Manchester Children’s Hospital, Manchester, UK; Davinder Singh, MRCPCH, Paediatric Intensive Care Unit, Leeds Royal Infirmary, Leeds, UK; David Inwald, PhD, Paediatric Intensive Care Unit, Addenbrooke’s Hospital, Cambridge, UK; Michelle Jardine, MSc, Paediatric Critical Care Unit, Children’s Hospital for Wales, Cardiff, UK; Oliver Ross, FRCA, Paediatric Intensive Care Unit, Southampton Children’s Hospital, Southampton, UK; Nayan Shetty, MRCPCH, Paediatric Intensive Care Unit, Alder Hey Children’s Hospital, Liverpool, UK; Mark Worrall, MBChB, Paediatric Intensive Care Unit, Royal Hospital for Children, Glasgow, UK; Ruchi Sinha, MRCPCH, Paediatric Intensive Care Unit, St Mary’s Hospital, London, UK; Ashwani Koul, DNB(MD), Paediatric Critical Care Unit, John Radcliffe Hospital, Oxford, UK; Elizabeth Whittaker, PhD, Paediatric Infectious Diseases Department, Imperial College Healthcare NHS Trust, London UK; Barnaby R. Scholefield, PhD, Paediatric Intensive Care Unit, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UK and Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK; Padmanabhan Ramnarayan, Children’s Acute Transport Service, Great Ormond Street Hospital NHS Foundation Trust and NIHR Biomedical Research Centre, London, UK.

    References
    1.
    Whittaker  E, Bamford  A, Kenny  J,  et al; PIMS-TS Study Group and EUCLIDS and PERFORM Consortia.  Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2.   JAMA. 2020;324(3):259-269. doi:10.1001/jama.2020.10369PubMedGoogle ScholarCrossref
    2.
    Davies  P, Lillie  J, Prayle  A,  et al.  Association between treatments and short-term biochemical improvements and clinical outcomes in post-severe acute respiratory syndrome coronavirus-2 inflammatory syndrome.   Pediatr Crit Care Med. 2021;22(5):e285-e293. doi:10.1097/PCC.0000000000002728PubMedGoogle ScholarCrossref
    3.
    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(5):323-331. doi:10.1016/S2352-4642(21)00050-XPubMedGoogle ScholarCrossref
    4.
    Feldstein  LR, Tenforde  MW, Friedman  KG,  et al; Overcoming COVID-19 Investigators.  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(11):1074-1087. doi:10.1001/jama.2021.2091PubMedGoogle ScholarCrossref
    5.
    Penner  J, Abdel-Mannan  O, Grant  K,  et al; GOSH PIMS-TS MDT Group.  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;5(7):473-482. doi:10.1016/S2352-4642(21)00138-3PubMedGoogle ScholarCrossref
    6.
    Davies  P, Evans  C, Kanthimathinathan  HK,  et al.  Intensive care admissions of children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in the UK: a multicentre observational study.   Lancet Child Adolesc Health. 2020;4(9):669-677. doi:10.1016/S2352-4642(20)30215-7PubMedGoogle ScholarCrossref
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