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Cardiovascular magnetic resonance imaging in children with pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 and heart dysfunction

  • Luis M. Prieto
    Correspondence
    Corresponding author. Luis M. Prieto, Pediatric Infectious Diseases Unit, Department of Pediatrics, Hospital Universitario 12 de Octubre, Madrid, Spain.
    Affiliations
    Pediatric Infectious Diseases Unit, Department of Pediatrics, Hospital Universitario 12 de Octubre, Madrid, Spain

    Pediatric Research and Clinical Trials Unit (UPIC), Instituto de Investigación Sanitaria Hospital 12 de Octubre (IMAS12), Madrid, Spain

    Fundación para la Investigación Biomédica del Hospital 12 de Octubre, Madrid, Spain

    RITIP (Traslational Research Network in Pediatric Infectious Diseases), Spain
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  • Belén Toral
    Affiliations
    Pediatric Heart Institute, Department of Pediatrics, Hospital Universitario 12 de Octubre, Madrid, Spain
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  • Ana LLorente
    Affiliations
    Pediatric Intensive Care Unit, Department of Pediatrics, Hospital Universitario 12 de Octubre, Madrid, Spain
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  • David Coca
    Affiliations
    Department of Pediatric Radiology, Hospital Universitario 12 de Octubre, Madrid, Spain
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  • Daniel Blázquez-Gamero
    Affiliations
    Pediatric Infectious Diseases Unit, Department of Pediatrics, Hospital Universitario 12 de Octubre, Madrid, Spain

    Pediatric Research and Clinical Trials Unit (UPIC), Instituto de Investigación Sanitaria Hospital 12 de Octubre (IMAS12), Madrid, Spain

    Fundación para la Investigación Biomédica del Hospital 12 de Octubre, Madrid, Spain

    RITIP (Traslational Research Network in Pediatric Infectious Diseases), Spain
    Search for articles by this author
Published:October 10, 2020DOI:https://doi.org/10.1016/j.cmi.2020.10.005
      To the Editor,
      The coronavirus disease 2019 (COVID-19) appears to affect proportionally fewer children than adults and with a less severe clinical presentation. However, during the COVID-19 pandemic, a new childhood disorder has emerged worldwide characterized by fever, elevated inflammatory markers, and organ dysfunction [
      • Whittaker E.
      • Bamford A.
      • Kenny J.
      • Kaforou M.
      • Jones C.E.
      • Shah P.
      • et al.
      Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2.
      ,
      • Feldstein L.R.
      • Rose E.B.
      • Horwitz S.M.
      • Collins J.P.
      • Newhams M.M.
      • Son M.B.F.
      • et al.
      Multisystem inflammatory syndrome in U.S. Children and adolescents.
      ]. A case definition was published in April 2020 by The Royal College of Paediatrics and Child Health in the United Kingdom, and was named “pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)”, or PIMS-TS. World Health Organization (WHO) and the U.S. Centers for Disease Control and Prevention (CDC) have subsequently also published their own case definitions.
      We describe the recent experience with five patients affected by this condition from April 28 to May 11, 2020. All were previously healthy children, with a median age of 7 years old, [interquartile range (IQR), 5-12 years]. They presented at admission with fever, tachycardia and hypotension. The median white cell count was 9100 cells/mm3 (IQR: 7700-9660) and the median lymphocytes count was 1700 cells/mm3 (IQR: 610-1760). Other ancillary tests revealed elevated cardiac biomarkers [median troponin T was 66.6 ng/l (IQR: 3.2-75.2) and NT-proBNP of 14,407 pg/ml (IQR: 3988–16,150)], and markedly increased inflammatory biomarkers like C-reactive protein and procalcitonin [10.2 mg/dl (IQR: 9.4-26.9) and 10.5 ng/ml (IQR: 3.4-14.8), respectively]. The median ferritin was 421 μg/l (IQR: 369-639) and the median interleukin 6 was 63.5 pg/ml (IQR: 27.2-216.2). The echocardiography revealed mild to moderate heart dysfunction in all of the patients (Table 1). All of them had a positive serology against SARS-CoV-2 (Ig anti receptor-binding domain) and met criteria for PIMS-TS according to UK, WHO and CDC definitions.
      Table 1Demographic, clinical characteristics, ancillary tests, treatmenta and outcomes of children with PIMS-TS and heart dysfunction
      VariablePatient 1Patient 2Patient 3Patient 4Patient 5
      Demographics and epidemiology
      Age (years)695712
      SexMaleMaleFemaleFemaleMale
      EthnicitySub-Saharan AfricanArabicHispanicCaucasianCaucasian
      Medical historyHealthyPsoriasisHealthyHealthyTonsillectomy
      Family cluster of SARS-CoV-2 infectionNoYesYesYesYes
      Signs and symptoms at admission
      Temperature (°C)40.338.540.239.340.7
      Days of fever before admission (>38°C)57565
      RashYesYesYesNoYes
      Distribution of the rashThorax, arms and legsHands and feetPalms, thorax and legsPalms
      ConjunctivitisYesYesYesYesNo
      LymphadenitisNoNoNoNoNo
      LipsNormalCracked lipsNormalNormalNormal
      TongueNormalNormalNormalNormalNormal
      Abdominal painYesYesYesYesYes
      DiarrheaNoYesYesYesYes
      CoughNoNoNoNoYes
      Oxygen saturation (%)8797959895
      Heart rate (bpm)125182130116112
      Blood pressure (mmHg)86/4475/4288/4690/5087/38
      Image and heart evaluation
      Chest X-raysMild left pulmonary infiltrateNormalNormalNormalNormal
      Echocardiography (at admission
      • Mild systolic disfunction (LVEF 52%)
      • Moderate systolic disfunction (LVEF 40%)
      • Moderate systolic disfunction (LVEF:40%)
      • Moderate systolic disfunction (LVEF: 40%)
      • Mild systolic disfunction (LVEF 50%)
      • Diastolic dysfunction
      • Diastolic dysfunction
      • Diastolic dysfunction
      • Normal coronary arteries: LCA 2.7mm (z score +0.2) and RCA 2.5mm (z score +0.4).
      • Normal coronary arteries: LCA: 3,8mm (z score +0.6), RCA: 3,4mm (z score +0.5).
      • Normal coronary arteries: LCA 2,4mm (z score -1.6) and RCA 2,3mm (z score -1).
      • Normal coronary arteries: LCA 2,8mm (z score 0), LAD 2,8mm (z score: +1.5) and RCA 2.5mm (z score 0).
      • Severe mitral regurgitation and moderate tricuspid regurgitation
      • Normal coronary arteries: LCA 2,9mm (z score +1.4), LAD 2,2mm (z score +1), RCA 2,7mm (z score +1.5).
      Electrocardiogram
      • Normal
      • Repolarization abnormalities
      • Normal
      • Repolarization abnormalities
      • Normal
      TreatmentDopamineDopamineCeftriaxoneCeftriaxoneNorepinephrine
      NorepinephrineCefotaximeClindamycinIVIG (2gr/kg)Amoxicillin-clavulanate
      CeftriaxoneIVIG (2 gr/kg)IVIG (2gr/kg)Steroids (2 mg/kg)IVIG (2gr/kg)
      IVIG (2 gr/kg)Steroids (2 mg/kg)
      Steroids (2 mg/kg)
      Hydroxychloroquine
      Azithromycin
      PICU admissionYesYesYesNoYes
      Respiratory support/oxygen therapyBiPAPNasal cannulaNasal cannulaNasal cannula
      Outcome
      EchocardiographyComplete resolution of abnormalities on day 7 of admission. LVEF 70%. Normal coronary arteries.Complete resolution of abnormalities on day 5 of admission. LVEF 55%. Normal coronary arteries.Evaluation on day 6 of admission. Mild tricuspid regurgitation. Resolution of mitral regurgitation. LVEF 60%. Normal coronary arteriesComplete resolution of abnormalities on day 5 of admission. LVEF 70%. Normal coronary arteriesComplete resolution of abnormalities on day 8 of admission. LVEF 70%. Normal coronary arteries
      Cardiovascular Magnetic ResonanceLVEF 60% (EDV 76 ml/m2)

      RVEF 57% (EDV 84 ml/m2)

      No myocardial edema or enhancement abnormalities
      LVEF 65% (EDV 78 ml/m2)

      RVEF 69% (EDV 83 ml/m2)

      No myocardial edema or enhancement abnormalities
      LVEF 57% (EDV 70 ml/m2)

      RVEF 57% (EDV 73 ml/m2). Mild trycuspid regurgitation.

      No myocardial edema or enhancement abnormalities
      LVEF 66% (EDV 64 ml/m2)

      RVEF 67% (EDV 63 ml/m2)

      No myocardial edema or enhancement abnormalities
      LVEF 66% (EDV 64 ml/m2)

      RVEF 67% (EDV 63 ml/m2)

      No myocardial edema or enhancement abnormalities
      BiPAP, Bilevel Positive Airway Pressure; LAD, Left Anterior Descending; EDV, End-Diastolic Volume; IVIG, Intravenous Immunoglobulin; LCA: Left Coronary Artery; LVEF, Left Ventricular Ejection Fraction; ND, not done; PICU, Pediatric Intensive Care Unit;; RCA: Right Coronary Artery; RVEF: Right Ventricular Ejection Fraction.
      Z-score for coronary artery diameters was assessed according to: Dallaire F, Dahdah N. New equations and a critical appraisal of coronary artery Z scores in healthy children. J Am Soc Echocardiogr. 2011 Jan; 24:60-74. https://doi.org/10.1016/j.echo.2010.10.004.
      They received IGIV, and in three cases steroids were added because of persistent fever 48 hours after IVIG administration. They were discharged home with total recovery of the heart function.
      The exact mechanisms of how SARS-CoV-2 causes this transient myocardial dysfunction in children with PIMS-TS are not well understood. During the last decade, cardiovascular magnetic resonance imaging (CMRI) has become the diagnostic tool of choice for patients with evidence for acute nonischemic myocardial injury, including myocarditis. The largest pediatric study assessing the role of CMRI in myocarditis included 143 children and young adults up to 21 years old. CMRI abnormalities were identified most commonly with late gadolinium enhancement. Based on CMRI features 117 children (82%) were interpreted as positive for myocarditis, 18 as negative (13%) and equivocal in 7 (5%) [
      • Banka P.
      • Robinson J.D.
      • Uppu S.C.
      • Harris M.A.
      • Hasbani K.
      • Lai W.W.
      • et al.
      Cardiovascular magnetic resonance techniques and findings in children with myocarditis: a multicenter retrospective study.
      ].
      CMRI allows for targeting several features of myocardial injury: inflammatory hyperemia and edema, necrosis/scar, contractile dysfunction and pericardial effusion. CMRI is also a predictor of functional and clinical recovery. In summary, on the basis of available research, CMRI allows for a robust assessment of the extent of injury and dysfunction in clinically acute scenarios of myocardial injury [
      • Canter C.E.
      • Simpson K.E.
      Diagnosis and treatment of myocarditis in children in the current era.
      ]. However, the diagnostic value of echocardiography for myocardial injury is limited by the fact that many patients with less severe disease have a normal echocardiogram and the highly variable echocardiographic findings lack specificity.
      A cardiovascular magnetic resonance imaging (CMRI) was performed after discharge [median day after admission: +16, (9-17)]. The protocol performed included steady-state free precession cine 2D sequences (short axis, 4, 3 and 2 Chamber views); study of edema (Inversion Recovery sequence in short axis), hyperemia and capillary leak (early gadolinium enhancement) and myocyte necrosis and fibrosis (late gadolinium enhancement). Both ventricles had normal function and no edema or abnormalities in early and late gadolinium enhancement were observed in any cases.
      CMRI did not show any myocardial damage in this series. CMRI is considered a highly sensitive technique to evaluate myocardial injury. Although the number of patients in this series was small, heart dysfunction did not seem secondary to myocardial viral injury in these children. An alternative hypothesis is that the exaggerated inflammatory response observed in these children with PIMS-TS could be the cause of the heart dysfunction [
      • Imazio M.
      • Klingel K.
      • Kindermann I.
      • Brucato A.
      • De Rosa F.G.
      • Adler Y.
      • et al.
      COVID-19 pandemic and troponin: indirect myocardial injury, myocardial inflammation or myocarditis?.
      ]. The rapid recovery of the heart function after immunomodulatory treatment and the absence of myocardial abnormalities in CMRI support this hypothesis. Studies to further elucidate the cause of myocardial dysfunction in children with multisystem inflammatory syndrome related to COVID-19 are warranted.

      Author contributions

      LP, DB, AL, DC and BT had full access to all of the data in the study and take the responsibility for the integrity of the data and the accuracy of the data analysis. ALL authors contributed equally in writing the paper and approved the final manuscript as submitted.

      Transparency declaration

       Potential conflicts of interest

      No conflicts of interest.

       Funding

      There was not funding source for any of the authors.

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