key: cord-1028636-5ukzsnnq
authors: Blondiaux, Eléonore; Parisot, Pauline; Redheuil, Alban; Tzaroukian, Lucile; Levy, Yaël; Sileo, Chiara; Schnuriger, Aurélie; Lorrot, Mathie; Guedj, Romain; Ducou le Pointe, Hubert
title: Cardiac MRI of Children with Multisystem Inflammatory Syndrome (MIS-C) Associated with COVID-19: Case Series
date: 2020-06-09
journal: Radiology
DOI: 10.1148/radiol.2020202288
sha: c9a3355e7b0ff589d0ad050c047db6d3c04ccdc1
doc_id: 1028636
cord_uid: 5ukzsnnq

This case series examines cardiac MRI findings in four children and adolescents admitted to intensive care in April 2020 for multisystem inflammatory syndrome and Kawasaki disease-like features related to COVID-19. Acute myocarditis occurred less than 1 week after onset of fever and gastrointestinal symptoms. Physical examination showed rash and cheilitis/conjunctivitis. All patients recovered after intravenous immunoglobulin therapy. SARS-CoV-2 RT-PCR was negative on nasopharyngeal, stool, and respiratory samples and was positive on serology. Cardiac MRI showed diffuse myocardial edema on T2-STIR sequences and native-T1 mapping, with no evidence of late gadolinium enhancement suggestive of replacement fibrosis or focal necrosis. These findings favor post-infectious myocarditis in children and adolescents with COVID-19.

The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appears to affect fewer children than adults, with less severe presentation, and rapid recovery in most children (1) . However, recent publications have reported multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease-like features related to COVID-19 in children (2) (3) (4) . This case series examines the cardiac MRI findings in four children and adolescents with MIS-C and Kawasaki-disease like features associated with COVID-19 who were referred to our intensive care unit (ICU).

This study was approved by our institutional review board (CRM-2005-087) with a waiver of informed consent because of the retrospective nature of the study. In April 2020, we identified 8 children and adolescents with Kawasaki-like disease. Four had myocarditis and were consecutively admitted to our ICU with signs of cardiogenic and/or septic shock syndrome. All four underwent transthoracic echocardiography and cardiac MRI. The clinical course, laboratory data and cardiac imaging findings were retrospectively reviewed. The four patients who were not included in this study were not admitted to our ICU and did not undergo cardiac MRI. They were less than 6 years old and had a favourable outcome: 3 patients (5 months, 6 months and 3 years old) had 4 to 5 major diagnostic criteria for Kawasaki disease, without myocarditis, and one patient (5 years old) had rash and myocarditis and was transferred to another hospital.

Pathogen identification involved RT-PCR in nasopharyngeal swabs (technique Seegene® tested once in patients 1 and 2, tested twice in patient 3, technique Anatolia geneworks® in patient 4) and in stool samples (technique Anatolia geneworks® in patients 2 and 3) and serology for SARS-I n P r e s s 

Image analysis was performed with consensus by 2 radiologists (EB, AR) with 10 and 20 years, respectively, of experience in cardiac MRI. Endocardial and epicardial contours of the left ventricle (LV) and endocardial contour of the right ventricle (RV) were manually traced on enddiastole and end-systole phases by using Medis Suite 3.1.16.2 (Medis Medical Imaging Systems, Leiden, The Netherlands). Native-T1 maps were calculated on basal and mid-LV short-axis slices.

Apical slices were not analyzed because of motion artifacts. Regions of interest were drawn on T1 and T2 images on the septal, inferior and lateral walls of the LV. Myocardial hyperemia was defined as T1 relaxation time > 1058 ms according to (5) . Myocardial edema was defined as signal intensity ratio of myocardium to skeletal muscle ≥ 2.0 on T2 weighted imaging(6) or T2 relaxation time >50 ms. These thresholds were compatible with the local experience of cardiac MRI in I n P r e s s children on the same magnet with the same pulse sequences.

Patient characteristics of the four children and adolescents are in Table 1 

Electrocardiography revealed ST segment depression in patient 2 and decreased T-wave amplitude in inferior leads in patient 3. Initial transthoracic echocardiography showed severely decreased LV ejection fraction (LVEF) in one patient (LVEF < 30%) and low-normal LVEF in three patients (LVEF > 50%), although the four patients had transient systolic dysfunction (Table E1 Supplemental data). The initial LVEF was low-normal in patients 2, 3 and 4 due to marked vasoplegia with decreased afterload.

The myocardium appeared echogenic on 2D echocardiography in patient 2 and normal in the other patients. Three patients showed global or septal hypokinesia. Patients 1 and 3 showed functional mitral regurgitation related to LV dilatation. LV diastolic function was not impaired. Three I n P r e s s patients had moderate pericarditis. Coronary artery diameters were normal, without coronary artery dilatation or aneurysm at initial and follow-up echocardiography.

The patients tested positive for COVID-19 (IgG 4/4 and IgM 1/4), and all tested negative for SARS-Cov-2 on RT-PCR in nasopharyngeal swabs and respiratory and stool samples. Serology for other viral agents was negative in all patients except patient 2, for whom the blood PCR and serology for Epstein-Barr showed an acquired immunity (viral reactivation).

Chest CT revealed typical COVID-19 opacities in patient 3 as described in (7): peripheral, posterior, multilobar and bilateral distribution of a combination of ground-glass opacities and consolidations, especially in the lower lobes. Chest CT was normal in the other patients.

The cardiac MRI findings are in Table 2 . Three patients (patients 2, 3 and 4) underwent cardiac MRI during the acute phase, whereas in patient 1, cardiac MRI was performed during the recovery phase. In patients 2, 3 and 4, mean global values for T1-mapping were increased >1100 ms. T2mapping was not contributive in patients 2 and 3 because of motion artifacts. T2-STIR sequences showed diffuse myocardial signal hyperintensity of the LV, suggesting interstitial edema, in patients 2, 3 and 4 (Figure 2 ). This finding was confirmed by signal intensity ratio of myocardium to infraspinatus muscle ≥2.0 in these three patients and by T2 relaxation >50 ms in patient 4. For patient 1, who underwent cardiac MRI at 14 days after hospital discharge, native-T1 values were normal (1050 ms), and T2-STIR sequences did not reveal edema, confirmed by normal T2 mapping values. None of the patients showed late gadolinium enhancement.

On follow-up echocardiography, all patients recovered normal ventricular function and kinetics in 48 hours to 5 days. No pericardial effusion was found (supplemental data, Table E1 ). Therapies included inotropic support (3/4), volume expanders (3/4), mechanical ventilation (1/4), intravenous immunoglobulin (4/4), and steroids (3/4) ( Table 1) . None required extracorporeal membrane oxygenation.

All four patients showed rapidly progressive clinical and hemodynamic improvement and were discharged from the hospital at 13 to 23 days after symptom onset. Patient 3 stayed for 8 days in the pediatric department after the ICU because of pancreatitis presumably related to COVID-19.

We report cardiac MRI findings for four children and adolescents admitted to our ICU for Current evidence suggests COVID-19 infection in children and adolescents is associated with I n P r e s s toxic shock syndrome and Kawasaki disease-like symptoms together with cardiac inflammation (4, 8) . This new entity, called MIS-C for multisystem inflammatory syndrome in children, shares similarities with Kawasaki disease with different clinical signs and outcome. Kawasaki disease is an autoimmune systemic disease characterized by systemic inflammation in all medium-sized arteries during the acute febrile phase (9) that affects predominantly children < 5 years of age. In our series, patients were older, from 8 to 12 years old (9) . In Kawasaki disease, a prominent feature is the appearance of coronary artery dilatation or aneurysm(9), which was not evidenced in our series.

In our institution, children with myocarditis admitted to the ICU undergo cardiac MRI as a clinical routine protocol to document the diagnosis and to assess the severity of myocarditis (10).

We found MRI signs of diffuse myocardial edema and hyperemia without evidence of focal myocardial necrosis/fibrosis, contrary to recent published data for adults with myocarditis related to COVID-19 (11, 12) . Our findings are consistent with histopathological analysis of hearts with Kawasaki disease, which demonstrated little evidence of myocardial cell degeneration or necrosis but mainly cell infiltration of macrophages and neutrophils in myocardial interstitium (13) . Our findings might be explained by the difference between viral myocarditis and post-infectious myocarditis related to MIS-C in COVID-19. Viral myocarditis results from injury by virus infiltration and immune response to this injury. As in Kawasaki disease, the MIS-C myocarditis corresponds to an inflammatory infiltration of the interstitial myocardium. A potential mechanism for myocardial manifestations of Kawasaki disease is the occurrence of a cytokine storm syndrome. Rowley et al. suggested that the immunologic cascade of Kawasaki disease is due to infection with an RNA virus that enters through the upper respiratory tract (14) . SARS-CoV-2 could be a candidate for such an inflammatory response in MIS-C.

Regarding the outcome, myocarditis resolved rapidly in our series as demonstrated by normal echocardiographic follow-up and cardiac MRI findings in patient 1, as in Kawasaki disease, in which myocardial inflammation peaks 10 days after disease onset and disappears gradually after I n P r e s s 20 days (15) . We did not find complications such as circulatory failure in the acute phase, development of artery aneurysm as in Kawasaki disease or resistance to intravenous immunoglobulin (16) .

Our case series had limitations. First, we did not examine the coronary artery with MR angiography sequences. Instead, we used echocardiography in accordance with international recommendations of evaluation of the coronary artery. In the initial phase of Kawasaki disease, coronary artery abnormalities are usually screened by transthoracic echocardiography (17) with quantitative assessment of luminal dimensions several times during the acute and the recovery phases (9) . Second, our patients might not reflect the entire spectrum of patients with myocarditis related to COVID-19 because of referral bias related to ICU admission. Finally, there are known issues with native-T1 such as variation in sequences, different sensitivities to T2 effects, lack of standardization and normal values, and partial dependence on heart rate.

In conclusion, this case series illustrates cardiac MRI findings in children and adolescents admitted to the ICU with myocarditis and MIS-C related to COVID-19. In our series, the most common findings were age > 5 years, increased levels of brain natriuretic peptide and troponin I, echocardiography changes with transient systolic dysfunction associated with cardiac MRI signs of diffuse myocardial edema and hyperemia without evidence of focal myocardial necrosis or replacement fibrosis. All patients recovered rapidly, with no evidence of coronary artery dilatation or aneurysm. The pathophysiology of MIS-C is still unexplained, but our cardiac MRI findings support the hypothesis of an immune response to an antigen rather than a direct complication secondary to SARS-CoV-2 infection.

We are grateful to Aurélie Jouve who took the greatest care of the children undergoing cardiac MRI and their parents.

Atypical presentation of covid-19 in young infants

Covid-19 and kawasaki disease: Novel virus and novel case

Hyperinflammatory shock in children during covid-19 pandemic

Acute heart failure in multisystem inflammatory syndrome in children (mis-c) in the context of global sars-cov-2 pandemic

Normal myocardial native t1 values in children using single-point saturation recovery and modified look-locker inversion recovery (molli)

Cardiovascular magnetic resonance in nonischemic myocardial inflammation: Expert recommendations

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Pediatric myocarditis protocol: An algorithm for early identification and management with retrospective analysis for validation

Cardiac involvement in a patient with coronavirus disease 2019 (covid-19)

Covid-19-related myocarditis in a 21-year-old female patient

Histopathological characteristics of myocarditis in acute-phase kawasaki disease

Ultrastructural, immunofluorescence, and rna evidence support the hypothesis of a "new" virus associated with kawasaki disease

Cmr evaluation of cardiac involvement during the convalescence of kawasaki disease

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I n P r e s s I n P r e s s