Multisystem Inflammatory Syndrome in Children, Chile, May–August 2020

We describe 26 children with multisystem inflammatory syndrome associated with coronavirus disease in the pediatric intensive care unit of Roberto del Río Hospital (Santiago, Chile). In total, 10 (38.5%) children required mechanical ventilation; 13 (50.0%) required inotropic support. In addition, 18 (69.2%) patients had echocardiographic abnormalities. No patients died.

O n March 11, 2020, the World Health Organization declared a coronavirus disease (CO-VID-19) pandemic. Acute respiratory failure is the most common complication of COVID-19 in adults (1); as of February 2021, COVID-19 has been associated with 2.4 million deaths according to the World Health Organization (https://www.who. int/publications/m/item/weekly-epidemiologicalupdate---23-february-2021). Most children and adolescents with COVID-19 have mild disease that does not require medical intervention (2).
In April 2020, a total of 8 previously healthy children with hyperinfl ammatory shock in the United Kingdom tested positive for antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19 (3). Consequently, the Royal College of Pediatrics and Child Health proposed the diagnosis of multisystem infl ammatory syndrome associated with COVID-19 in children (MIS-C), defi ned as a persistent fever, infl ammation, and evidence of organ dysfunction, after the exclusion of any other microbial cause, with or without PCR confi rmation of SARS-CoV-2 infection (4). On May 14, 2020, the US Centers for Disease Control and Prevention issued an advisory for MIS-C; the same day, the World Health Organization also issued a report with a case defi nition of MIS-C (https://emergency.cdc.gov/han/2020/han00432. asp). Researchers have since reported similar cases in the United States (5) and Europe (6)(7)(8)(9). The signs and symptoms of MIS-C can resemble Kawasaki disease, toxic shock syndrome, hemophagocytic lymphohistiocytosis, and macrophage activation syndrome (10).
Few publications on COVID-19 in children (11) and MIS-C (12) have reviewed cases in Latin America. We describe the clinical characteristics, treatment, and results of a cohort of children admitted to the pediatric intensive care unit (PICU) with MIS-C in a tertiary hospital in Chile.

The Study
We analyzed patients with MIS-C treated in the PICU of Roberto del Río Hospital (Santiago, Chile) during May 11-August 30, 2020 ( Figure). We used the case defi nition of MIS-C proposed by the Ministry of Public Health of Chile (13).
We collected demographic data, medical history, clinical symptoms, and physical examination fi ndings, as well as results of imaging, cardiac, and laboratory tests conducted during the patient's stay in the emergency room and PICU. We also analyzed data on treatment, complications, outcome, and length of PICU and total hospital stay. The institutional ethics committee of Roberto del Rio Hospital approved the study protocol. We described categorical variables with absolute frequencies and percentages; we described continuous variables with medians and IQRs.

Figure.
Treatment algorithm for children with multisystem inflammatory syndrome associated with COVID-19, Chile, May-August 2020. †Prophylactic anticoagulation was considered if D-dimer was >1,000 ng/dL or progressively increasing: treatment was 1 mg/kg/d of low molecular weight heparin (Enoxaparin). When thrombosis was suspected or confirmed, the dose was increased to 1 mg/kg every 12 hours and adjusted with anti-Xa factor activity. ‡Favorable response was considered absence of fever for 48 hours, hemodynamic stability, and improvement of inflammatory parameters. AAS, acetylsalicylic acid; APTT, activated partial thromboplastin time; COVID-19, coronavirus disease; CRP, C-reactive protein; IVIG, intravenous immunoglobulin; KD, Kawasaki disease; MIS-C, pediatric inflammatory multisystem syndrome temporally associated with coronavirus disease; PCT, procalcitonin; pro-BNP, pro-brain natriuretic peptide; PT, prothrombin time; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
In total, 18 (69.2%) patients had echocardiographic abnormalities (Table 1), including 5 (19.2%) patients who met the criteria for Kawasaki disease with coronary artery abnormalities. The median duration of PICU stay was 5 days (IQR 2-7 days). None of the patients died.

Conclusions
We describe 26 MIS-C patients in the PICU of Roberto del Río Hospital in Chile. In this hospital, the maximum incidence of MIS-C occurred ≈4 weeks after the peak of COVID-19 cases in adults, as described in the literature (5)(6)(7)(8)(9).
The median age of the cohort in our study was 6.5 years, lower than usually reported for patients with MIS-C (8-9 years) (5); 2 patients were neonates. Slightly more than half (61.5%) of patients met criteria for typical or atypical Kawasaki disease.
Nearly all (84.6%) patients had laboratory-confirmed SARS-CoV-2 infection. However, whereas many (57.6%) had antibodies against SARS-CoV-2, only 7 (26.9%) tested positive by PCR. These findings suggest that MIS-C might be caused by a hyperinflammatory response after asymptomatic SARS-CoV-2 infection, rather than direct cell injury from active viral replication. Although the syndrome's pathophysiology has been correlated with the cytokine storm described in adults with severe COVID-19 (13), the mechanisms of MIS-C remain unclear.
Similar to previous reports (5-9), our results showed almost all patients had cardiovascular involvement: 92% had shock and 50% required vasoactive support. Although Roberto del Río Hospital is a Intensive care unit Leukocytes, mm 3 10,540.0 (7,400.0-15,900.0) NA 4,500-11,000 Lymphocytes, mm 3 1,080.0 (732.5-2,579. national reference center for ECMO, none of the patients in this cohort required extracorporeal supportive treatment; in contrast, Radia et al. (15) found that 4% of patients with MIS-C needed ECMO. This difference might be attributable to early immunotherapy. Approximately two thirds (69.2%) of patients had echocardiographic abnormalities. The most frequent (26.9%) anomaly was left ventricular dysfunction with or without pericardial effusion. In all affected patients, cardiac function recovered before discharge from the PICU. Only 5 (19.2%) of our patients had coronary abnormalities: 4 had a coronary dilatation (Z-score of ≈2.5-2.8) and 1 had a medium coronary aneurysm (Zscore of 6). The frequency of coronary involvement is also consistent with previous reports (5)(6)(7)(8)(9).
We treated nearly all children with intravenous immunoglobulin (76.9%) or corticosteroids (88.5%). Treatment seemed to improve symptoms and decrease inflammatory responses, similar to findings in Europe and the United States (5-9). According to our treatment protocol, we administered tocilizumab to 3 (11.7%) children; we administered infliximab to 1 (3.8%) child with a medium coronary aneurysm. The main limitations of this study are small sample size and descriptive, nonrandomized design.
In conclusion, we described 26 children with MIS-C in Chile. Our findings were similar to those reported in other countries. Most patients had echocardiographic abnormalities, and half required vasoactive drug support. We administered immunomodulatory therapy to most patients. Clinical trials and long-term follow-up are needed to elucidate the mechanisms of various treatments and potential sequelae of this condition.