The coronavirus disease 2019 (COVID-19) or coronavirus-2 (SARS-CoV-2) has been declared a global pandemic by the World Health Organization and has affected millions of people worldwide. Reference Cucinotta and Vanelli1 Initially, it was thought that COVID-19 was primarily an acute respiratory syndrome; however, with time, multisystem involvement has been increasingly recognised. In contrast to adults, COVID-19 in children usually leads to a mild illness and few children have been reported to have severe manifestations. However, children may develop a post-infectious cytokine storm, possibly due to the activation of macrophages. Reference Mehta, McAuley, Brown, Sanchez, Tattersall and Manson2 The condition has been termed “multisystem inflammatory syndrome in children (MIS-C)” or “pediatric multisystem inflammatory syndrome (PMIS)” and it is characterised by a hyperinflammatory syndrome with multi-organ dysfunction. Diagnostic criteria have been developed by different health organisations. 3–5
At the beginning of the COVID-19 outbreak, several centres in the United States of America and Europe reported cases of MIS-C including cardiac involvement. Reference Toubiana, Poirault and Corsia6–Reference Ouldali, Pouletty and Mariani8 Variable cardiac manifestations were reported. Reference Sperotto, Friedman, Son, VanderPluym, Newburger and Dionne9 However, most reports or series of MIS-C cases documented that median age was greater than 5 years, and some researchers have considered the age at presentation as one of the differentiating features from Kawasaki disease. Reference Toubiana, Poirault and Corsia6,Reference Ramcharan, Nolan and Lai10,Reference Consiglio, Cotugno and Sardh11 Only limited reports have documented MIS-C under the age of 5 years. Reference Dufort, Koumans and Chow12 In the current report, we present a series of MIS-C cases below the age of 5 years with an emphasis on cardiac involvement.
Subject and methods
This study is a retrospective analysis of a series of MIS-C patients admitted between May and November 2020 from a single centre. The research was approved by the IRB (Institutional Research Board) of the faculty of medicine, Mansoura University. Cases were children of up to 5 years of age with MIS-C who fulfilled the MIS-C case definition of the Royal College of Pediatrics and Child Health (RCPCH) criteria with cardiac clinical, laboratory, or echocardiographic findings as evidence of cardiac disease. Data were collected retrospectively included patients’ demographics, clinical presentations, laboratory results, and echocardiographic findings. Moreover, data on the course of the disease, treatments, and outcomes were evaluated.
Case definition of MIS-C according to the RCPCH
1. A child presenting with persistent fever more than 38.5°C, inflammation (neutrophilia, elevated CRP, and lymphopenia), and evidence of single- or multi-organ dysfunction (shock, cardiac, respiratory, renal, gastrointestinal, or neurological disorder) with additional features. This may include children fulfilling full or partial criteria for Kawasaki disease. 2. Exclusion of any other microbial cause, including bacterial sepsis, staphylococcal or streptococcal shock syndromes, infections associated with myocarditis such as enterovirus, and 3. SARS-CoV-2 polymerase chain reaction testing may be positive or negative. 5
Transthoracic echocardiogram of two cases ( a ) Short parasternal view and a five-chamber view showing multiple coronary aneurysms are seen affecting left main coronary artery and its major branches; ( b ) short parasternal and five-chamber view showing diffuse ectatic dilatation of right coronary artery. LAD: left anterior descending artery, LC: left main coronary, LCX: left circumflex, RC: right coronary artery.
Laboratory investigations
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Basic investigations were performed: complete blood count (CBC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), serum ferritin, and troponin I.
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Nose and throat swab viral polymerase chain reaction for SARS-CoV-2 was performed for all patients. Moreover, cases were tested for immunoglobulin M (IgM), and immunoglobulin G (IgG) to viral spike glycoprotein using an enzyme-linked Immunosorbent Assay (ELISA) test.
Electrocardiogram
At the initial presentation, 12-lead electrocardiogram was performed to exclude arrhythmia or conduction abnormality. It was repeated whenever required during the admission, especially if attacks of arrhythmias were suspected on monitoring.
Echocardiographic findings
Detailed transthoracic echocardiography for all the included children was performed using the Philips Epiq C7 X-matrix (Philips Medical Systems, Bothell, WA, United States of America; 2014). Images were recorded from the standard echocardiographic views, apical four-chamber, three-chamber, two-chamber, and parasternal short-axis and long-axis views based on the recommendations of the American Society of Echocardiography. Reference Lopez, Colan and Frommelt13 For each patient, the following parameters were fulfilled:
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Left ventricular systolic function was estimated through the assessment of fractional shortening using M-mode. Function was categorised according to fractional shortening as normal (28–45%), borderline (26–27%), mild (20–25%), moderate (15–19%), or severe reduction (≤14%). Reference Tissot, Singh and Sekarski14
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Coronary artery assessment with measurements of internal lumen diameter with the determination of z-scores of the right coronary artery, main left coronary artery, and its branches left circumflex and left anterior descending artery. Coronary aneurysm was defined using the American Heart Association z-score classification: no involvement (<2); dilation only (≥2 to <2.5); small aneurysm (≥2.5 to <5); medium aneurysm (≥5 to <10 and absolute dimension <8 mm); and giant aneurysm (≥10 or an absolute dimension ≥8 mm). Reference McCrindle, Rowley and Newburger15
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Presence of mitral or tricuspid valvular regurgitation.
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Presence of pericardial effusion.
Management
Patients with coronary artery involvement were treated with intravenous immunoglobulins at a dose of 2 g/kg and high-dose aspirin at a dose of 80–100 mg/kg/d. In patients with persistent fever or worsening inflammatory markers after 48 hours, the second dose of intravenous immunoglobulin was given. Thromboprophylaxis with antiplatelet therapy or anticoagulation was based on the extent of coronary involvement. A similar dose of intravenous immunoglobulin was given in cases of myocarditis. Moreover, inotropes (e.g., milrinone or dobutamine) were given in the cases of left ventricle dysfunction. In case of borderline or residual systolic function impairment by discharge, angiotensin-converting enzyme inhibitors were prescribed.
Statistical analysis
All statistical analyses were performed using SPSS software (version 25, IBM Corp., Armonk, NY, United States of America). Results are presented as mean ± SD or median (IQR), while categorical variables are presented as frequencies and percentages.
Results
Out of 16 patients with MIS-C under the age of 5 years, 10 (62.5%) had evidence of cardiac involvement. Table 1 demonstrates the demographic characteristics, clinical presentation, and laboratory findings of the study cohort. The median age at presentation was 12 months (IQR: 4.5–27 months, range 35 days to 4.5 years). Most cases were males (80% of cases) and the majority of patients (90%) were previously healthy with no comorbidities. One patient had unoperated transposition of the Great Arteries with ventricular septal defect. All patients presented with a fever, while gastrointestinal manifestations including vomiting and/or diarrhoea were present in six patients (60%). Mucocutaneous manifestations of Kawasaki-like disease were present in eight patients (80%). Variable respiratory symptoms were found in four patients (40%); of those, only one patient had positive polymerase chain reaction for COVID-19 in addition to pleural effusion and pulmonary infiltrations on CT chest consistent with category 6 of COVID-19 Reporting and Data (CO-RAD) System. Furthermore, an infant with Kawasaki-like disease had gangrenous toes, lymphadenopathy, and shock on admission. It was noticeable that all patients had a significant rise in C-reactive protein, Erythrocyte sedimentation rate, and serum ferritin levels with leucocytosis; however, leucopenia was not evident in our cohort with a median of 2.45 103/μL and only three patients (30%) had a mild decrease in the lymphocytic count for age. Serology for SARS-CoV-2 was positive in all cases for the combined IgG and IgM. One patient had positive SARS-CoV-2 polymerase chain reaction.
Demographics, clinical presentations, and basic laboratory results of MIS-C cases under the age of 5 years with cardiac findings.
* Data are expressed as median (interquartile range) or frequencies (percentage).
CRP = C-reactive protein; ESR = Erythrocyte sedimentation rate; Hgb = hemoglobin; PCR = polymerase chain reaction; TLC = total leucocytic count.
The details of cardiac diagnoses including echocardiographic findings and serum troponin I level in cases of MIS-C under 5 years of age are shown in Table 2. The children were categorised according to their cardiac diagnosis: five in isolated coronary arterial disease (50%), two in combined coronary artery disease with myopericarditis(20%), one in myopericarditis(10%), and one in arrhythmia(10%). Variable coronary involvements were detected in seven patients including ectatic dilatation in at least one coronary artery in four cases, a small aneurysm in one case, moderate fusiform aneurysm with ectasia in another case, and multiple large aneurysms in one case. Coronaries affected included isolated right coronary artery in two cases, both main coronaries in two cases, right coronary with left main and left anterior descending involvement in two cases, and left main with left anterior descending and left circumflex in one patient. Regarding systolic myocardial impairment, four cases had low fractional shortening with three of those with mildly reduced function and one patient who had severe myocarditis with acute heart failure and severe reduction of fractional shortening (14%) and ejection fraction (31%). Troponin was increased in four cases in which systolic function was below normal and troponin was borderline in one case presenting with arrhythmia. A child in the series had moderate pericardial effusion with mild mitral regurgitation but without tamponade and did not require extensive intervention. No cases presented with more than mild atrioventricular valves regurgitation.
Details of cardiac diseases in MIS-C cases of the study.
ECG = electrocardiogram; FS = fractional shortening; LAD = left anterior descending; LCA = left coronary artery; LCX = left circumflex; LV = left ventricle; RCA = right coronary artery.
Management and outcome of MIS-C cases under 5 years of age with cardiovascular involvement are presented in Table 3. Intravenous immunoglobulin was given to cases with coronary artery disease or myocarditis, while inotropes were used in 40% of cases. Discharge cardiac medication was needed in seven cases; five cases with an antiplatelet dose of aspirin and /or warfarin, one case received aspirin with angiotensin-converting enzyme inhibitor, and one patient on angiotensin-converting enzyme inhibitor alone. The median duration of hospitalisation was 7 days (6–14) and two patients died despite extensive inotropic and ventilatory support. The rest of the patients were discharged home clinically well with normalisation of systolic function within a week in half of all affected cases. All had a clinical review 1 week and 1 month after discharge with a repeat electrocardiogram and echocardiogram. There were no new coronary changes or functional deterioration with an improvement of coronary abnormalities in most cases, but the persistence of aneurysms in two cases (33% of survivors with residual coronary disease) at the one-month follow-up. All cases with coronary abnormalities had a long-term follow-up plan in the paediatric cardiology clinic and CT angiogram.
Management and outcome of MIS-C cases under the age of 5 years with cardiac involvement.
* Data are expressed as median (interquartile range) or frequencies (percentage).
ACEIs = angiotensin-converting enzyme inhibitors; ASA = acetyl salicylic acid.
Discussion
MIS-C related to COVID- 19 is now a well-described syndrome, especially in school-aged children and adolescents. Reference Jiang, Tang and Levin16 MIS-C includes many forms of cardiac involvement including cardiac dysfunction, pericardial effusion, and coronary abnormalities. Nevertheless, limited reports have described cases under the age of 5 years, especially from a cardiac perspective. In the current series, variable cardiac disorders are described in this younger patient population.
Dufort et al reported a large case series of MIS-C cases from New York, 31 were under 5 years of age. In contrast to our series in which we have one case with CHD, 22 of their series had pre-existing comorbidities, especially obesity in 10 out of 31 cases. Reference Dufort, Koumans and Chow12 In the current work, most of the patients were males, a finding that is consistent with most MIS-C series of older children. Reference Toubiana, Poirault and Corsia6,Reference Ramcharan, Nolan and Lai10 However, in the current work, the male to female ratio of 8:2 is significantly higher. In a study of MIS-C cases with acute cardiac decompensation with only one case was under the age of 5 years, males comprised 51% of cases. Reference Belhadjer, Méot and Bajolle17
Fever, which is a common presentation of MIS-C, was documented in all our cases, consistent with previous reports on MIS-C. Reference Ramcharan, Nolan and Lai10,Reference Ahmed, Advani and Moreira18 Fever was followed by the presence of atypical Kawasaki-like mucocutaneous manifestations (60%) and gastrointestinal symptoms in half of our cases. In the Ramcharan et al series, 87% of cases with cardiac findings had gastrointestinal symptoms, and nearly half the cases with Kawasaki-like features. Reference Ramcharan, Nolan and Lai10
Cardiac involvement in MIS-C in our series was 62.5% which compares with the Verdoni et al series reporting 60%, Reference Verdoni, Mazza and Gervasoni7 while cardiac findings approached 100% in the Ramcharan et al cohort with 93% of them diagnosed with coronary artery involvements, although only one with aneurysms. Moreover, they documented a high incidence of atrioventricular valve regurgitation, documented in 13 of 15 cases with a median age of 8.8 years. Reference Ramcharan, Nolan and Lai10 In Matsubara et al’s series, coronary involvement in MIS-C patients (median age 11.4 years) was 4% with one case of coronary ectasia and no documented aneurysms, while coronary aneurysms were present in 8.8% of Feldestien et al series. Reference Matsubara, Kauffman and Wang19,Reference Feldstein, Tenforde and Friedman20 In another large MIS-C cohort from the United States of America, aneurysms were found in 13.4% of cases with regression in 79.1% by 1 month and in 100% by 3 months; therefore, they suggested that rapid resolution of coronary aneurysm might be due to vasodilatation rather than destruction by inflammatory cells. Reference Feldstein, Rose and Horwitz21 However, this theory does not explain the presence of significant-sized aneurysms which is clearly a result of more than a simple vascular dilatation. In the Dufort et al MIS-C cases under the age of 5 years, myocarditis occurred in 39% with coronary involvement in 13% but with no details on the cardiac outcome of the cohort. Reference Dufort, Koumans and Chow12 In the current series, we had a comparable rate of myocarditis; however, coronary involvement was higher reaching 70% of cases with cardiac disorders.
Cardiac troponin I could be a useful marker in detecting cardiac involvement in children with MIS-C. The level indicating cardiac diseases is above 0.045 ng/ml in children aged less than 3 months and above 0.005 ng/ml for children aged greater than 3 months. Reference Dionne, Kheir, Sleeper, Esch and Breitbart22 In our series, 40% of cases had a high troponin value for age.
The recovery of myocardial systolic function in our series reached 100% of surviving cases within 1 month. Similarly, all cases with reduced fractional shortening were normalised before discharge with a median of 3 days in another series from the United Kingdom Reference Ramcharan, Nolan and Lai10 , while the recovery was 71% within 7 days in a series of MIS-C with acute heart failure and a median age of 10 years. Reference Belhadjer, Méot and Bajolle17 Furthermore, it was described that left ventricle ejection fraction in MIS-C was decreased in 34.2% of cases in a large series from the United States of America with a median age of 9.7 years with 91% of them having normal functions within a month and 99.4% normalised within 3 months of follow-up. Reference Feldstein, Rose and Horwitz21 Thus, the resolution of myocardial dysfunction is expected when the acute decompensation stage is aggressively managed.
The length of hospital stay in our series was comparable to the average of MIS-C cases described in a meta-analysis by Ahmed et al Reference Ahmed, Advani and Moreira18 Nevertheless, mortality is considered higher in our series with 20% of cases with cardiac involvement and about 12.5% of total MIS-C under the age of 5 years in our centre. In the cases of under the age of 5 years, series by Dufort et al mortality was only 3%, while it was 1.9% in a higher median age cohort by Feldestien et al and no mortality was reported in the series of cardiac decompensated MIS-C series by Belhadjer et al Reference Belhadjer, Méot and Bajolle17 This could be due to the unavailability of extracorporeal membrane oxygenation in our centre as an advanced management step for acute decompensation of severe cases.
One of the limitations of the current work is that we did not document details of diastolic function or strain to detect subclinical myocardial injury. Another limitation is the descriptive study design and lack of comparative statistics with Kawasaki cases in the same age group. However, our series demonstrates that cardiac complications could be significant even in the younger age group with a median age of 12 months. Thus, the exclusion of this paediatric age category from COVID-19 vaccine trials should be reconsidered due to the severity, mortality, and persisting cardiac implications. Moreover, long-term follow-up is required for resolving cases with cardiac MRI and advanced echocardiographic modalities to enhance the understanding of MIS-C cardiac effects.
Conclusion
MIS-C associated with COVID-19 under the age of 5 years has the potential for cardiac manifestations, including mortality or long-term morbidities such as coronary aneurysms even in previously healthy children.
Acknowledgements
None.
Financial support
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of interest
None.
Ethics standards
The authors assert that all work comply with the ethical standards of the relevant national guidelines on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008, and the study was reviewed and approved by the IRB (Institutional Research Board) of Mansoura University, Faculty of Medicine.
