A retrospective cohort study was conducted at a tertiary pediatric referral center. Patients were identified from the electronic database of pediatric patients with confirmed COVID-19 seen between 19 April, and 31 October, 2020, at the Department of infectious diseases. This study was approved by the institutional research board.

Of the 533 children aged <18 years with COVID-19, 25 (4.7%) met the diagnostic criteria for MIS-C. In addition, 75 patients were included as controls. Median age of cases was 104 months (IQR 61-126) vs 78 months (IQR 18-139) in the control group. Underlying diseases were more commonly observed in the control group (n=52; 69%) than in MIS-C patients (n=7; 28%) Underlying diseases were cancer (18 controls; 24%), solid organ trans-plantation (18 controls; 24%), genetic disorders (4 controls; 5%), neurological disorders (4 controls; 5%, and 3 cases; 12%), congenital disorders (3 controls; 4%), obesity (3 controls; 4%), recurrent wheezing (3 cases; 12%), chronic renal failure (1 case; 4%), and others (15 controls; 20%).

Clinical manifestations of MIS-C patients and controls are shown in Table I. Nine MIS-C patients (36%) vs one control (1.3%) required intensive care unit (ICU) admission. Eight MIS-C patients (32%) had cardiac abnormalities consisting of myocarditis (n=3), pericarditis (n=1), left ventricular dysfunction (n=3) and coronary dilatation (n=1). Lymphopenia and thrombo-cytopenia were more common in MIS-C patients than controls. Median (IQR) CRP was 139 (122-248) mg/L, BNP 1116 (183-4857) pg/mL, troponin 2.5 (<1.5-79) ng/L, and ferritin 339 (191-611) ng/mL in MIS-C patients. At onset, PCR for SARS-Co-V2 was positive in 15 MIS-C patients (60%) and in all of those in the control group. IgM antibodies were positive in seven MIS-C patients (28%) and six controls (8%), while IgG antibodies were positive in 24 MIS-C patients (96%) and 22 controls (29%). In one MIS-C patient with a history of close contact with COVID-19 one month previously, both the PCR and antibody test were negative. All MIS-C patients received IVIG, associated with steroids in 15 (60%). Median　(IQR) length of hospital stay was 10 days (9-12) in cases vs 8 (4-11) days in controls (P=0.006) (Table II).

In our series all MIS-C patients were older than 2 years, which is in agreement with previous finding that MIS-C does not affect infants younger than 1 year [1-8]. Potential age-related variability among MIS-C patients may result from differences in SARS-CoV-2 infection due to the likelihood of exposure or to differential nasal expression of angiotensin-converting enzyme 2, the entry receptor for SARS-CoV-2 [2-6]. Inequalities in access to health care, genetics-related risks, or overcrowding might be lines for future research. In our study, living with a person with COVID-19 and overcrowded living condi-tions were significantly associated with MIS-C in univariate analysis.

Several studies evaluating patients with MIS-C have found high rates of comorbidities [8,13,14]. In our series comorbidities were less frequently observed in MIS-C patients than in controls. A recent meta-analysis concluded that cancer patients undergoing treatment were not at a higher risk of developing more severe COVID-19 disease; however, the role of comorbidities in patients with COVID-19 needs further exploration [15]. Most MIS-C patients had a previous or concurrent laboratory-confirmed SARS-CoV-2 infection, supporting the hypothesis that MIS-C is an immune-mediated post-infectious synd-rome related to SARS-CoV-2 infection [6-11]. In our series, gastrointestinal symptoms were more frequent in MIS-C patients than in controls. Fever was observed in all MIS-C patients but not in all controls [8]. Similar to other series, shock and acute heart failure were more frequent in MIS-C patients than in controls [13].

MIS-C is associated with heart complications and inflammatory disorders triggered by SARS-CoV-2 with features similar to KD suggesting that this virus might be acting as an immunological trigger causing similar immune- mediated injury to the heart and coronary arteries comparable to KD [13]. Cardiovascular involvement was common in our MIS-C patients but not seen in any of the controls.

Low lymphocyte count, associated with poor outcome, was more common in MIS-C patients than in controls [14]. Levels of acute-phase reactants (CRP and PCT), may be high in patients with MIS-C [5,8]. Similar to other studies, all MIS-C patients received IVIG and combination with steroids in some of them [8]. As in previous studies on COVID-19 in children, ICU admission was more frequent in MIS-C patients [7-8], but no deaths were reported.

In conclusion SARS-CoV-2 associated MIS-C was more common in children older than 2 years and in those with lymphopenia or thrombocytopenia. The presence of underlying diseases seems to decrease the likehood to develop MIS-C; however, further studies are needed to confirm this observation and rule out that it was an incidental association in this study.

Ethics clearence: Hospital Juan P Garrahan; No. 1294, dated October 11, 2020.

Contributors: MTR: conceptualized the study design; analyzed and interpreted the results, and wrote the manuscript; GP, MMK, AAP, MP, CG, NB, AB: recruited patients, collected demographic and clinical data analyzed and interpreted the results; RL,RB: conceptualized the study design- analyzed and interpreted the results, and commented on and revised the manuscript. All authors approved the final version of manuscript, and are accountable for all aspects related to the study.

Funding: None; Competing interest: None stated.