Introduction

Multisystem inflammatory syndrome in children (MIS-C) is a novel condition identified following the SARS-CoV-2 pandemic. In this paper, the clinical pattern of MIS-C in children from urban Haryana is described. The objectives of the present study were: (1) evaluation of clinical and laboratory characteristics of hospitalized MIS-C patients, including disease severity, therapeutic interventions, and outcomes; (2) comparison of patients with and without severe disease, and with and without cardiac involvement; and (3) identification of risk factors for severe MIS-C.

Material and Methods

A retrospective multicentric observational study was conducted in 6 tertiary-care hospitals in urban Haryana. Hospitalized patients (age < 18 y) fulfilling the WHO-MIS-C criteria were included [1]. Those with concomitant infections were excluded. Demographic details, symptomatology, laboratory investigations, treatment, and outcomes were noted. Cardiac abnormality was defined as elevated N-terminal-pro-B-type brain natriuretic peptide (NT-proBNP), presence of moderate/higher valvular regurgitation, pericardial effusion, ejection fraction < 50%, dilated coronary segment with referenced z score > 2, or arrhythmias [2]. Patients with/without cardiac abnormalities were compared.

Disease severity was graded as follows: mild MIS-C—no vasoactive support, mild/no respiratory support, and minimal organ injury; moderate MIS-C—significant oxygen supplementation (> 5 L/min or high-flow nasal cannula), minimal vasoactive support [vasoactive infusion score (VIS) < = 10], and mild/isolated organ injury; severe MIS-C—noninvasive/invasive ventilation support, VIS > = 10, moderate/severe organ injury (including moderate-to-severe ventricular dysfunction) [3]. Patients with/without severe disease were compared.

Data were reported as mean ± SD (if normally distributed) or median (IQR) and counts/percentages (categorical variables). Chi-square and student independent t-tests were used for comparison of categorical and continuous variables, respectively. Nonparametric variables between groups were compared using Mann–Whitney U test. Risk factors for cardiac involvement and severe MIS-C were independently identified using univariate analysis. Multivariate analysis was done using forward LR method. A p < 0.05 was considered significant. SPSS version 24 was used.

Results

From June 2020 to February 2021, 53 patients satisfied the WHO-MIS-C criteria. Five were excluded (positive dengue-NS1 antigen/IgM-ELISA). Eight (16.7%) had history of SARS-CoV-2 infection/contact. Forty-five (93.8%) had positive SARS-COVID-IgG antibodies. Thirty-eight patients (79.2%) were at/above 75th centile; 21 (55%) were > 90th centile of weight for age. Two had underlying chronic neurological problems, rest were healthy.

Fever (n = 48, 100%), gastrointestinal (n = 40, 83%), and mucocutaneous (n = 24, 50%) symptoms were common. Fever duration was 3–7 d in 28 (58.3%) and > 1 wk in 14 patients (29.2%). Unusual presentations were: status epilepticus (n = 2), bilateral lower limb weakness (n = 1), diabetic ketoacidosis (n = 1), hyperlipasemia (n = 1).

Seventeen patients had mild MIS-C, 8 had moderate, and 23 had severe MIS-C. Thirty-three (68.8%) patients required respiratory support. One patient required ECMO. Four patients required renal-replacement therapy (Table 1).

Table 1 Patients characteristics according to cardiac involvement and severity of the disease
Full size table

Thirty-eight patients (80.9%) received intravenous immunoglobulin (IVIG). A combination of steroids ± IVIG was used in 44 (91.7%) patients. No patient received interleukin-1–receptor antagonists.

Forty-five patients (93.8%) recovered and 3 died (6.4%). All 3 had shock (VIS: 40–140) and platelet count < 25000/µL at admission.

Cardiac abnormalities group (n = 30): Twenty-six patients (54.2%) had abnormal ECHO, while 4 (8.3%) had isolated raised NT-proBNP levels. Eleven (42.3%) had low ejection fraction and 10 (20.8%) had coronary aneurysms. Pericardial effusion and mitral regurgitation were seen in 6 patients (23%).

Patients with and without cardiac abnormalities had significant differences in NT-proBNP, procalcitonin, sodium, albumin, and incidence of thrombocytopenia (Table 1).

On univariate analysis, shock, hypoalbuminemia, hyponatremia, high NT-proBNP, and thrombocytopenia were identified to be significant risk factors for cardiac involvement (Supplementary Tables S1 and S2). Multivariate analysis was inconclusive.

Severe MIS-C group (n = 23): Median age was higher (12 vs. 7 y; p = 0.034). Median NT-proBNP, incidence of thrombocytopenia, and hypoalbuminemia were significantly higher. No difference was seen in incidence of cardiac abnormalities in patients with severe and mild/moderate MIS-C (73.9% vs. 52%, p = 0.117).

On univariate analysis, significant risk factors for severe MIS-C were age > 9.5 y, shock, high NT-proBNP, thrombocytopenia, hypoalbuminemia, and high ferritin > 380.5 ng/mL (Supplementary Tables 1 and 2). NT-proBNP > 1286.5 pg/mL [OR (95% CI): 20.49 (1.81–231.58), p = 0.015] and platelet count ≤ 119500/microliter [OR (95% CI): 21.59 (1.29–360.56), p = 0.032] were significant on multivariate analysis.

Discussion

The observations on the clinical presentation of MIS-C, in the present study, appear consistent with previous reports [4, 5]. Fever, gastrointestinal, and mucocutaneous symptoms were common. Epidemiological history was positive in less than 20% patients; hence, antibody screening is important in a suspected case.

Due to incomplete data on BMI, weight for age was used, which if > 75th and 90th centile identifies overweight and obese children, respectively [6]. A predominance of overweight children was observed. Obesity has been previously reported to be associated with MIS-C, especially severe disease [5].

Features of Kawasaki disease (KD) and MIS-C may have some overlap, but there are distinctions. While thrombocytosis is characteristic of KD, thrombocytopenia is seen in MIS-C. A high incidence of gastrointestinal symptoms (> 80%) was observed, which could be a clue favoring MIS-C in a patient with fever and/or KD-like symptoms. Older age is another distinguishing point. Similar to the present study, previous reports have also described higher median age in MIS-C (6–11 y) [3, 7].

Cardiac involvement is a prominent feature of MIS-C. The incidence of cardiac abnormalities in the present study was 54.2%, similar to other reports [2, 8]. Cardiac involvement was associated with vasoactive infusion requirement and thrombocytopenia, similar to a study by Pignatelli et al. [2].

It was observed that hypoalbuminemia, high NT-proBNP, and thrombocytopenia were common associations with cardiac involvement and severe MIS-C. Severity of thrombocytopenia correlated with disease severity. NT-proBNP > 1286.5 pg/mL predicted severe MIS-C. Both thrombocytopenia and high NT-proBNP appear to have an important role in early sick patient identification. Presence of such deranged parameters warrants intensive monitoring. This is relevant for triaging patients in resource-limited settings.

Interestingly, coronary aneursyms developed more in patients with mild/moderate MIS-C rather than severe disease. This is perhaps because the KD-like phenotype of MIS-C is less likely to have multiorgan involvement.

IVIG and steroids are the mainstay of treatment. Combination therapy is probably better than IVIG alone, as it improves recovery time and decreases complications [9, 10]. In the present cohort, steroids (alone/combined) were used more frequently than IVIG. High cost and limited availability lead to restricted IVIG use.

Conclusion

MIS-C is a possibility in any child with unexplained fever, even if epidemiological history is absent. Specific laboratory and cardiac evaluation establish early diagnosis. High NT-proBNP and thrombocytopenia predict severe disease.