Systemic inflammatory syndrome in children during COVID-19 pandemic in Ceará state, northeastern Brazil: an observational study

Abstract In this study, we report the occurrence of multisystemic inflammatory syndrome among 64 children (2 deaths) with recent severe acute respiratory syndrome-related coronavirus 2 (SARS-COV-2) infections in the northeast region of Brazil. The major clinical symptoms and signs reported were exanthema (60.9%), abdominal pain (56.3%), nausea and vomiting (46.9%), diarrhea (37.5%), and dyspnea (37.5%). Laboratory findings revealed that the levels of C-reactive protein (75.0%), hemoglobin (51.6%), D-dimer (48.4%), lymphocytes (43.8%), LDH (45.3%), AST (42.2%), ALT (51.6%), and ferritin (48.4%) were above the reference values for a given age and gender. The clinical findings were similar to those observed in Kawasaki disease, although it represents a separate entity, emphasizing the need for proactive surveillance and early treatment.

Since the emergence of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in China, in December 2019, the coronavirus disease 2019 (COVID-19) has affected more than 106 million people around the world 1 . Brazil was the most affected country in Latin America, with approximately 9.5 million cases and 230,000 SARS-CoV-2-associated deaths as of February 2021. 2 COVID-19 was declared a pandemic by the World Health Organization on March 11 2020, representing the most challenging public health crisis faced by this generation 2 .
A striking feature of the COVID-19 pandemic is that relatively lower number of cases have been reported in children and adolescents as compared to adults 3 . Although most children and adolescents infected with SARS-CoV-2 are asymptomatic or present mild symptoms, in rare cases, children can be affected, and clinical manifestations may differ from those of adults. A rare, potentially severe case of multisystem inflammatory syndrome in children (MIS-C) was initially reported in the UK and then globally to occur days to weeks following the acute SARS-CoV-2 infection. MIS-C represents a growing concern in the pediatric population 4 . The clinical characteristics of MIS-C share similar features with that of Kawasaki disease (KD), KD shock syndrome, macrophage activation syndrome (MAS), and toxic shock syndrome (TSS) 4,5 .
The state of Ceará in the northeast region was one of the most affected places in Brazil, with incidence rates of COVID-19 to be as high as 13,303/100,000 hab as of December 2020 6 .
To further understand the epidemiological and clinical patterns of this rare syndrome in low-and middle-income countries, we provide in-detail description of all cases of MIS-C temporally associated with COVID-19 reported between May 1 and December 31, 2020, in the State of Ceará. Figure 1 shows the number and We followed the case definition of MIS-C proposed by the Ministry of Health of Brazil, PAHO, and WHO, 7 following the RECORD guidelines.
Hospitalized or fatal cases with: (1) Fever and elevated inflammatory markers within 3 days or more; (2) at least two of the following symptoms: i) rash or bilateral non-purulent conjunctivitis or mucocutaneous inflammation signs (oral, hands, or feet); ii) hypotension or shock; iii) features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities (including echocardiogram findings or elevated troponin or N-terminal pro B-type natriuretic peptide); iv) evidence of coagulopathy (elevated prothrombin time, partial thromboplastin time, and elevated D-dimers); and v) acute gastrointestinal problems (diarrhea, vomiting, or abdominal pain); (3) Elevated inflammatory markers such as C-reactive protein (PCR), Erythrocyte Sedimentation Rate (ESR), Lactate Dehydrogenase (LDH), ferritin, and procalcitonin; (4) Excluded cases with other microbial cause of inflammation; and (5) Positive RT-PCR, antigen test, or serology; or any contact with patients with COVID-19 7 .
A total of 64 cases were included in the study, with 2 reported deaths (case-fatality rate of 3.1%). Most cases occurred in the month of July 2020 (n =31; 48.4%). About 48% of the patients were male. The median age was 7 years (range,0-16 years). The cases occurred in 17 different municipalities, predominantly in Fortaleza, the capital of Ceará (42; 65.6%). These cases were reported by five hospitals, particularly from the reference hospital in the State, Albert Sabin Hospital (N = 41; 64.1%). The majority of cases had positive testing, either real-time reverse transcription polymerase chain reaction (RT-PCR) and/or antigen testing, from nasopharyngeal specimens and less frequently serologic testing for SARS-CoV-2 ( Table 1).
Data regarding the treatment were available for a total of 30 patients (46.9%). Among them, 22 (73.3%) received corticosteroids, of which metiprednisolone (N=15; 68.2%) was the most common glucocorticoid prescribed. Another 23 (76.7%) patients received The first reported case of death was a 15-year-old female without any pre-existing chronic conditions, who succumbed to death due to sepsis after 9 days of hospitalization. The second was a 13-year-old female patient with a history of acute myeloid leukemia, declared dead after 7 days of hospitalization, without any data regarding the cause of death. Both patients were confirmed for SARS-CoV-2 using RT-PCR.   These cases occur predominantly in the month of July, a month after the transmission of COVID-19 peaked. The average age of these children was 7 years (20 days-16 years). Ceará state was one of the first to confirm sustained transmission, as well as the first to show an escalation in the number of cases and deaths 8 . However, the reported deaths due to COVID-19 was confirmed by a mobile death verification service that investigated the deaths which occurred at home 9,10 .

4/6
MIS-C appears to be a clinical syndrome that shares aspects with other inflammatory conditions, wherein large amounts of cytokines cause the dysfunction of several organs and systems.

5/6
Our findings were similar to other studies that reported presence of indecisive comorbidities, different from adult patients; however, it may contribute to severity and mortality 11 . This clinical picture represents a novel phenomenon that can affect previously asymptomatic children and young people with SARS-CoV-2 infection manifesting as a hyperinflammatory syndrome with multiorgan involvement. Clinical findings are very similar to those found in cases of Kawasaki disease, KD shock syndrome, MAS, and TSS, highlighting the need for proactive surveillance and creating awareness among health professionals regarding the symptoms and the importance of an early treatment. Some differences between MIS-C and KD may be noted, such as the predominance of gastrointestinal symptoms, left ventricular systolic dysfunction, shock, and markedly elevated inflammatory biomarkers. Our report described a high incidence of gastrointestinal symptoms (abdominal pain, nausea, vomiting, and diarrhea) and elevated inflammatory biomarkers, which are commonly present in most MIS-C series. Another essential difference between MIS-C and KD is the age of onset, with MIS-C being presented at an older age as compared to KD 4,5 .
This study had several limitations. This retrospective study was conducted based on secondary data analysis. Although it represents one of the largest samples of MIS-C temporally associated with COVID-19 in the medical literature, it is still a small sample. Another major limitation is the absence of data regarding cardiac complications (myocarditis, pericarditis, and cardiac dysfunction), neurological, and renal involvement. Despite these limitations, this study provides relevant data on the pandemic settings. During the study period, there were no data regarding variant circulation such as P1 (from Manaus) and P2 (Rio de Janeiro), although genetic studies have shown that the variant N9 was born in August 2020.
All these cases occurred when interactive classes were suspended in schools, indicating that school was not the source of infection. As the reopening of schools is being planned, there has been an ongoing debate around the possibility of the children's persisting schools being a super-disseminating site for SARS-CoV-2 infection 12 . The present study reinforces the capability of SARS-CoV-2 to develop severe catastrophic outcomes during the post-infectious phase. Further studies are required to fully understand the role of COVID-19 in transmission, epidemiology, clinical aspects, and severity of the disease in children.

ACKNOWLEDGMENTS
LPGC is recipient of the fellowship for research productivity granted by the Brazilian National Council for Scientific and Technological Development (CNPq/Brazil). EPISUS/MS team for field investigation.