Cardiac Manifestations in Multi-System Inflammatory Syndrome in Children Temporally Associated with SARS-CoV-2 Infection

INTRODUCTION

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to over 6 million fatalities worldwide^[1] and was officially classified as a pandemic on March 11, 2020, by the World Health Organization (WHO).^[2] Predominant symptoms included fever, cough, fatigue, and dyspnea, with less frequently reported gastrointestinal manifestations such as diarrhea. The elderly population, aged 65 years or older, faced an elevated risk of developing severe SARS-CoV-2 infection due to a higher prevalence of established comorbidities.^[3] While younger adults were also hospitalized for severe illness, the occurrence was significantly lower.^[4] Compared to infected adults, most infected children exhibited a less severe clinical course and presented with milder symptoms.^[5,6] Asymptomatic infections were also observed with inconsiderable frequency.^[5] However, reports emerged from COVID-19 epicenters across Europe documenting clusters of pediatric hospitalizations associated with a severe Kawasaki-like disease and hyperinflammatory shock syndrome.^[7,8] The clinical symptoms included pyrexia (>38.5°C) and asthenia. Prevalent gastrointestinal manifestations were abdominal pain, vomiting, and diarrhea. All individuals exhibited a pronounced inflammatory condition, as indicated by elevated levels of C-reactive protein (CRP) and D-dimer. This syndrome was characterized by a temporal correlation with a recent SARS-CoV-2 infection, evidenced by a history of close contact and positive serology.^[9] The predominant cardiac involvement ranged from mild-to-severe reduced left ventricular (LV) ejection, arrhythmias, pericardial effusion, coronary artery dilatations, or aneurysms to cardiogenic shock.^[10] This emerging syndrome was categorized as “Multisystem inflammatory syndrome in children (MIS-C)” by the US Centers for Disease Control and Prevention (CDC)^[11] and WHO^[12] and as “Pediatric multisystem inflammatory syndrome temporally associated with COVID-19” by the Royal College of Pediatrics and Child Health.^[13] The most frequent therapies for MIS-C include immunoglobulins, vasoactive agents, and corticosteroids.^[14] In the present study, we delineate the cardiovascular and clinical manifestations, laboratory findings, and cardiac imaging results of MIS-C observed at our center during a 1-year time frame. The aim of the present study was to assess the cardiac manifestations (by echocardiogram) and laboratory markers due to MIS-C and to analyze the outcome and follow-up changes at 2 weeks and 6 weeks.

MATERIAL AND METHODS

The present study was a descriptive study and was conducted at the Department of Pediatrics, PSG Institute of Medical Science and Research, Coimbatore, for a period of 1 year. The study was initiated after obtaining approval from the Institutional Human Ethics Committee, Ref: PSG/IHEC/2020/Appr/Exp/285, dated December 18, 2020.

The study population included patients diagnosed with MIS-C. As per the CDC, MIS-C was defined as any person below 21 years presenting with fever >38.0°C for more than 24 h, inflammation, severe illness requiring hospitalization, involvement of more than 2 organs after ruling out other differential diagnoses, and positive for SARS-CoV-2 or has recently been in contact with a suspected or confirmed COVID-19 case.^[14]

Children with known congenital or acquired cardiac diseases and who were already on cardiotoxic medications such as chemotherapy and immunomodulators were excluded from the study.

A convenient sampling method was used for the study. Considering an absolute error of 5% and a death rate of 1.7% from previous studies,^[15] the present study included 34 patients with MIS-C diagnosed during the study period. The formula for sample size calculation for an unknown population was used as follows-

Sample size = Z2 × p(1-p)/e²

The names of the patients were masked in the study, and each patient was allocated a case number. The cardiac status, including heart rate, blood pressure, cardiovascular system findings, perfusion status, and signs of pericardial/pleural effusion at the time of presentation, were clinically assessed and noted. Biochemical markers such as D-dimer, creatine phosphokinase (CPK), CPK-MB, Troponin T, and N-terminal pro-brain natriuretic peptide (NT-Pro BNP) values were also noted. A standard 12 lead electrocardiogram (ECG) was used, and findings such as normal sinus rhythm, sinus tachycardia, arrhythmias, heart block, or any other abnormal findings suggestive of myocarditis or pericarditis were noted. The cardiac status of the children was assessed clinically, and normalization of previously elevated biochemical markers was confirmed during the follow-up.

RESULTS

A total of 34 MIS-C patients were included in this study. The median age of the population was 6.5 years, with IQR 3–10. Among the study subjects, 23 (67.6%) were male. The baseline characteristics of the study subjects, along with the abnormal cardiovascular findings, are presented in Table 1.

Among the laboratory markers, NT-Pro BNP, Troponin-T, CPK-total, CPK-MB, and D-dimer, D- dimer was elevated in 28 (82.4%) patients [Table 1].

Out of 34 MIS-C patients, 15 had ECG, and abnormalities were noted in eight children. The most common abnormality noted were sinus tachycardia, sinus bradycardia, and non-specific T wave changes. Since a majority of the children had predominantly echocardiographic abnormality than rhythm abnormality. So ECG was not done for all children recruited in this study.

Among the 34 patients, 27 (79.4%) had abnormal echocardiograms. The abnormalities noted were coronary abnormalities such as dilation and aneurysm, chamber dilatation, valvular regurgitation, decreased LV function, and pericardial effusion [Table 2].

Among the coronary abnormalities, isolated aneurysms were seen in 5 (14.7%) patients, and 7 (20.6%) patients had both dilation and aneurysm. Among 12 patients with coronary abnormalities, the left anterior descending artery (LAD) (9/12) was the most involved artery, followed by the left main coronary artery (LMCA) (5/12). The aneurysms were mostly small aneurysms; only one patient had a moderate aneurysm of LMCA [Table 2].

In our study, 55.8% need pediatric intensive care unit (PICU) care, with a median length of PICU stay was 2.8 days (1–4) and a median length of hospital stay is 5.9 days (5–7).

MIS-C patients were followed up at 2 weeks and 6 weeks after discharge; 26 (76.4%) patients had follow-up data, remaining eight patients had not turned up for follow-up. Among the 27 patients with abnormal echocardiograms, 20 (58.8%) patients had follow-up echocardiograms. Among the patients who had been followed up with echocardiogram, 8 (23.5%) patients had two follow-ups at 2 weeks and 6 weeks after discharge, 8 (23.5%) patients had only one follow-up at 2 weeks after discharge, and 7 (20.5%) patients had only one follow-up at 6 weeks after discharge.

Analyzing the follow-up echocardiogram at 2 weeks after discharge, only one patient had persistence of coronary aneurysm at 2 weeks, which resolved subsequently at 6 weeks follow-up. All other abnormalities noted at admission in all patients were resolved at 2 weeks follow-up. At 6 weeks follow-up after discharge, all had normal echocardiograms and their previous abnormalities were resolved completely.

Scatter plot diagram of Z-score values of coronary arteries at admission were noted [Figure 1]. A Z-score of above 2 is abnormal, as is seen in Figure 1; a significant number of patients had abnormal Z-score at admission; however, only one had persistence of coronary abnormality at 2 weeks, and all Z-scores were normal at 6 weeks. Among the 34 patients, only 6 (17.6%) patients had repeat cardiac biochemical markers, and all six patients had normal values during follow-up at 2 weeks. As most of the children at the time of discharge, their biomarkers levels came back to normal, and only children with high levels were repeated during follow-up. The eight patients who have been missing during follow-up were contacted through telephone and their clinical well-being was confirmed.

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Figure 1:

Z-scores of coronary arteries at admission. LMCA: Left main coronary artery, LAD: Left anterior descending, LCX: Left circumflex artery, RCA: Right coronary artery.

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The patients received various treatments, including intravenous immunoglobulin (IVIG), steroids, aspirin, and different cardiac drugs. IVIG was given at a dose of 2 g/kg for children presented with cardiac manifestations alone (18/34). Steroids doses were given as a pulse dose of about 30 mg/kg in 7 (20.6%) patients and as 2 mg/kg in 22 (64.7%) patients. Although oxygen requirement was present in some (20.5%) patients, none of them were mechanically ventilated.

DISCUSSION

There are limited studies focusing solely on the cardiac manifestations along with the follow-up data in MIS-C, especially in India. Our study has evaluated the cardiac manifestations due to MIS-C by echocardiogram and the outcome and follow-up changes at 2 weeks, 6 weeks, and till the end of the study period. All the MIS-C patients included in the study were previously healthy children. The median age of our population was 6.5 years. Similar to this, other studies^[18,19] have also demonstrated that MIS-C patients are usually older compared to classical Kawasaki disease, as described in various reports.^[20] In the present study, the median day of illness of patients at admission was 5 days. The median pulse rate was 118 beats/min, and systolic and diastolic blood pressure was 97 mmHg and 60 mmHg, respectively. These values are similar to those reported by Matsubara et al., where the median pulse rate was 116 beats/min, and systolic and diastolic blood pressure were 99 mmHg and 56 mmHg, respectively.^[20]

Clinically, cardiac manifestations were assessed with abnormal cardiovascular findings, congestive hepatomegaly, and the presence of shock. Abnormal cardiovascular findings were present in 11.7%, and congestive hepatomegaly was present in 11.8%. In our study, we have used CDC guidelines to diagnose MIS-C; we have reported 7 (20.6%) patients who presented with shock requiring fluid resuscitation and inotropes to recover. However, the incidence of cardiogenic and vasoplegic shock was observed in 40–80%of MIS-C cases in the literature. Campanello et al.,^[14] in their study, found that all patients presented with cardiovascular manifestations and among the patients who presented with shock, none required inotropic support. We had only 15 patients with ECG data; among them, 8 (23.5%) had abnormal findings. Commonly noticed abnormalities were nonspecific T wave inversion, sinus tachycardia, sinus bradycardia, and QT prolongation. Regan et al., in their study, reported 67% of children with ECG abnormalities, and the most frequent findings were low QRS amplitude and transient T- wave inversion.^[21] In our study, 27 (79.4%) patients with MIS-C had echocardiographic abnormalities; this is similar to reports of 75% of patients with echocardiographic abnormalities among MIS-C patients in a study by Kelly et al.;^[22] In their study, the most common echocardiographic abnormality was reduced LVEF, noted in 58% patients. However, in our study, we have reported abnormal LV function in 13 (38.2%) patients with MIS-C.

Large case series in the literature have reported coronary artery abnormalities in approximately 13–26% of MIS-C patients.^[23] In our study, using z-scores of 2–2.5 as dilation and ≥2.5 as an aneurysm, we have found 12 (35.2%) patients of MIS- C with coronary artery abnormalities. In our study, 26 (76.4%) patients had follow-up. We have follow-up at 2 weeks and 6 weeks after discharge. Analyzing the follow-up, only one child had a persistence coronary aneurysm at 2 weeks that too resolved at 6 weeks. All other abnormalities in other children had been resolved.

Among the laboratory markers, D- dimer was elevated in 28 (82.4%) patients. Similarly, a study by Dufort et al. reported elevated D-dimer in 91% of patients. However, the same study reported elevated troponin in 71% of patients, in contrast to our study, where we found troponin elevation in only 9 (26.5%) patients.^[24]

The treatment of MIS-C has evolved over time. Children presenting with only fever, rash, and systemic inflammation without any signs of other organ damage require only close monitoring in an outpatient setting. However, close clinical follow-up must be ensured.^[25] In the present study, oxygen requirement was present in 7 (20.5%) patients, but none were mechanically ventilated. However, Dhanalakshmi et al.^[10] found a significant number of children (57%) developed hypotension, requiring admission to the PICU for vasoactive medications. Angurana et al. showed that most cases (85%) required PICU admission where they received nasal prong oxygen (40%), noninvasive (22.5%) and invasive (22.5%) ventilation, and vasoactive drug support (72.5%).^[26].In our study, 55.8% of patients required admission to the PICU; in a similar study conducted in the United States in 2020, the majority of the patients (63.9%) had to be admitted to the intensive care unit (ICU).^[27] In the present study, the various drugs given to our patients were immunoglobulin (52.9%) and steroids (64.7%). IVIG and glucocorticoids are considered the line agents for the treatment of MIS-C.^[28] Both these therapies are the most frequently used immunomodulatory medications in MIS-C patients reported to date.^[28,29] Evidence suggests that early initiation of IVIG and glucocorticoids in patients may potentially reduce ICU admissions and length of hospital stay.

The strength of this study is patient selection criteria as per CDC guidelines, and cardiac dysfunction not considered as mandatory criteria for MIS-C diagnosis. This could probably eliminate selection bias and our study had the opportunity to include patient spectrum from mild disease to severe disease. Moreover, echocardiography was performed by a single cardiologist to avoid observer bias. However, one limitation of this study was that children only under the age of 18 years were included; this might have resulted in the exclusion of MIS-C patients older than 18 years of age. Furthermore, it was a single-center study with medium sample size and follow-up data of few patients are lacking.

CONCLUSION

Cardiac manifestations in MIS-C are one of the most crucial and common systems to be involved which determines the severity and the prognosis in MIS-C patients. Our study suggests that prompt anti-inflammatory and multitarget therapy can potentially result in a favorable outcome, preventing further complications. However, further studies with larger sample sizes and longer follow-up periods are necessary to evaluate the long-term outcome for MIS-C patients.