Análise de variantes genéticas patogênicas na Síndrome Inflamatória Multissistêmica Pediátrica / Analysis of pathogenic genetic variants in Pediatric Multisystem Inflammatory Syndrome

Introdução. Alguns meses após o início da pandemia de COVID-19, houve o surgimento de uma nova síndrome que acomete crianças e adolescentes. Suas manifestações clínicas são potencialmente graves e se assemelham à doença de Kawasaki, sendo caracterizadas por resposta inflamatória exacerbada e acometimento de múltiplos órgãos. Esse fenótipo recebeu o nome de síndrome inflamatória multissistêmica pediátrica (SIM-P). Apesar do grande número de publicações sobre a resposta imune de pacientes com SIM-P nos meses que se seguiram, permanecem obscuros os fatores determinantes na evolução destes pacientes. Estas respostas podem residir, pelo menos em parte, na genética. Especula-se que pelo menos uma parte dos pacientes com SIM-P possa ter um algum Erro Inato da Imunidade (EII) subjacente, seja de origem monogênica, digênica ou mesmo oligogênica. Objetivo. Identificar pacientes que apresentem o fenótipo da SIM-P, descrever suas manifestações clínicas, exames laboratoriais e evolução, além de buscar variantes genéticas patogênicas e provavelmente patogênicas que possam estar relacionadas ao fenótipo através do sequenciamento de exoma completo. Metodologia. Estudo observacional, descritivo, do tipo série de casos, longitudinal (retrospectivo e prospectivo) e multicêntrico. Foi realizada revisão de prontuário médico, além de exames laboratoriais e de imagem. Foram coletadas amostras de sangue dos pacientes participantes para realização de sequenciamento de exoma. Durante a análise das variantes genéticas encontradas, foram consideradas a frequência alélica, preditores para avaliação da patogenicidade das variantes e a relevância clínica das mesmas. Resultados. Um total de 29 pacientes foram incluídos, a mediana de idade foi de 6 anos, a maioria dos pacientes eram do sexo feminino (62%) e apenas 10% apresentavam comorbidades, sendo a asma a mais comum (7%). Os pacientes apresentaram uma mediana de 6 dias de febre e o fenótipo clínico mais frequente foi disfunção cardíaca aguda (48,1%) seguido de pacientes com manifestações Kawasaki-like (33,3%). Foram identificados 16 pacientes com variantes patogênicas ou provavelmente patogênicas. Nesses casos, um total de 22 variantes foram identificadas em 11 genes diferentes: BLK, CFB, ERAP1, FCN3, INFA21, IFIH1, MASP2, MPO, PRF1, TNFRSF13B e ZFHX3. Conclusão. Dentre os genes identificados, há uma predominância de genes relacionados ao sistema complemento, a resposta à infecção viral e a função das células B, todas vias importantes na infecção pelo SARS-CoV-2. Para melhor compreender quais são os fatores determinantes desta doença, são necessárias outras estratégias de busca de variantes, coortes maiores, estudos com controles saudáveis e outras formas de investigação como análise de HLA, proteômica e RNAseq.

Introduction. A few months after the beginning of the COVID-19 pandemic, there was the emergence of a new syndrome that affects children and adolescents. Its clinical manifestations are potentially severe and resemble Kawasaki's disease, being characterized by an exacerbated inflammatory response and involvement of multiple organs. This phenotype was named multisystem inflammatory syndrome in children (MIS-C). Despite the large number of publications on MIS C patients' immune response in the months that followed, the determining factors in the evolution of these patients remain elusive. Answers may lie, at least in part, in genetics. It is speculated that at least a part of MIS-C patients may have some underlying innate error of immunity (IEI), whether of monogenic, digenic or even oligogenic origin. Goal. Identify patients who present the clinical phenotype of SIM-P, describe their clinical manifestations, laboratory tests and evolution, in addition to search for pathogenic and likely pathogenic genetic variants that may be related to the phenotype through whole exome sequencing. Methodology. Observational, descriptive, case series, longitudinal (retrospective and prospective) and multicenter study. A review of medical records was performed, in addition to laboratory and imaging tests. Blood samples were collected from participating patients for exome sequencing. During the analysis of the genetic variants found, the allele frequency, predictors for evaluating the pathogenicity of the variants and their clinical relevance were considered. Results. A total of 29 patients were included, the median age was 6 years, most patients were female (62%) and only 10% had comorbidities, with asthma being the most common (7%). Patients had a median of 6 days of fever and the most frequent clinical phenotype was acute cardiac dysfunction (48%) followed by patients with Kawasaki-like manifestations (33%). Sixteen patients with pathogenic or likely pathogenic variants were identified. In these cases, a total of 22 variants were identified in 11 different genes: BLK, CFB, ERAP1, FCN3, INFA21, IFIH1, MASP2, MPO, PRF1, TNFRSF13B e ZFHX3. Conclusion. Among the genes identified, there is a predominance of genes related to the complement system, response to viral infection and the B cell function, all important pathways in SARS-CoV-2 infection. To better understand what are the determining factors of this disease, other strategies are needed to search for variants, larger cohorts, studies with healthy controls and other forms of investigation such as analysis of HLA, proteomics and RNAseq.

Multisystem inflammatory syndrome in children (MIS-C) during SARS-CoV-2 pandemic in Brazil: a multicenter, prospective cohort study

Abstract Objective To describe the clinical, laboratory, and radiological characteristics, as well as the outcomes of children with MIS-C. Method Multicenter, prospective cohort study, conducted in 17 pediatric intensive care units in five states in Brazil, from March to July 2020. Patients from 1 month to 19 years who met the MIS-C diagnostic criteria were included consecutively. Results Fifty-six patients were included, with the following conditions: Kawasaki-like disease (n = 26), incomplete Kawasaki disease (n = 16), acute cardiac dysfunction (n = 10), toxic shock syndrome (n = 3), and macrophage activation syndrome (n = 1). Median age was 6.2 years (IQR 2.4−10.3), 70% were boys, 59% were non-whites, 20% had comorbidities, 48% reported a contact with COVID-19 cases, and 55% had a recent SARS-CoV-2 infection confirmed by RT-PCR and/or serology. Gastrointestinal symptoms were present in 71%, shock symptoms in 59%, and severe respiratory symptoms in less than 20%. -Dimer was increased in 80% and cardiac dysfunction markers in more than 75%. Treatment included immunoglobulin (89%); corticosteroids, antibiotics, and enoxaparin in about 50%; and oseltamivir and antifungal therapy in less than 10%. Only 11% needed invasive mechanical ventilation, with a median duration of five days (IQR 5-6.5). The median length of PICU stay was six days (IQR 5-11), and one death occurred (1.8%). Conclusions Most characteristics of the present MIS-C patients were similar to that of other cohorts. The present results may contribute to a broader understanding of SARS-CoV-2 infection in children and its short-term consequences. Long-term multidisciplinary follow-up is needed, since it is not known whether these patients will have chronic cardiac impairment or other sequelae.