Biomarcadores (inflamatórios e imunológicos) de diagnóstico associados à mortalidade na síndrome inflamatória multissistêmica pediátrica temporalmente associada ao SARS-CoV-2: estudo de coorte da região amazônica
Data
2024-06-20
Autores
Farias, Emmerson Carlos Franco de 
Orientadores
Terreri, Maria Teresa de Sande e Lemos Ramos Ascensão
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Introdução: A síndrome inflamatória multissistêmica pediátrica (SIM-P) é caracterizada por inflamação sistêmica com evidência clínica associada à evidência epidemiológica ou microbiológica de exposição ao coronavírus 2 da síndrome respiratória aguda grave (SARS-CoV-2). Atualmente é considerada uma complicação pós-COVID-19 rara e grave, emergente, clinicamente com múltiplos fenótipos. As infecções virais respiratórias podem causar instabilidade genômica ao causar liberação excessiva de citocinas com aumento dos níveis de inflamação, o que causa instabilidade da resposta imunológica e níveis intracelulares elevados de espécies reativas de oxigénio (ERO) com danos aos lipídeos, proteínas e DNA, nomeado Estresse Oxidativo (EO). Objetivos: O objetivo deste estudo foi associar a mortalidade intra-hospitalar de pacientes com SIM-P hospitalizados na UTIP com biomarcadores (inflamatórios e imunológicos) no primeiro e terceiro dia da admissão hospitalar. Secundariamente, objetivamos associar a presença de choque cardiogênico e o tempo de permanência na UTIP com biomarcadores inflamatórios e avaliar a diferença entre os parâmetros laboratoriais no primeiro e no terceiro dia de seguimento. Métodos: Este estudo foi uma coorte prospectiva unicêntrica com amostra de conveniência composta por crianças e adolescentes com diagnóstico de SIM-P que necessitaram de internação em UTIP. Os dados clínicos e laboratoriais foram coletados dos prontuários eletrônicos da UTIP. As características demográficas e as de suporte intensivo também foram avaliadas sequencialmente até o final da internação. Amostras de sangue venoso foram coletadas de todos os pacientes no dia 1 e no dia 3 da admissão. Foram realizados exames laboratoriais inespecíficos e dosagens específicas de citocinas e marcadores de EO. As comparações entre os grupos (sobreviventes e não sobreviventes) foram feitas usando testes χ2 ou exato de Fisher para variáveis categóricas, e U de Mann-Whitney foi usado para testes contínuos. Para comparação entre o dia 1 e o dia 3 foi utilizado o teste de postos sinalizados de Wilcoxon. A taxa de sobrevivência foi calculada e as curvas de Kaplan-Meier foram realizadas. Os fatores de risco para a sobrevivência foram analisados por regressão de Cox univariada e multivariada (“tempo até o primeiro evento”). O modelo de regressão foi ajustado para risco de mortalidade utilizando idade menor de um ano e presença de comorbidade simultaneamente. A análise da curva ROC (Receiver Operating Characteristic) foi realizada para determinar o valor de corte de IL-17A associado a mortalidade. Resultados: Dos 41 pacientes incluídos, 33 (80,5%) eram do sexo masculino, 9 (22%) tinham até um ano de idade e 30 (73,2%) apresentavam condições crônicas complexas pediátricas. Formas críticas de SIM-P estiveram presentes em 21 (52,1%) pacientes e necessidade de ventilação mecânica invasiva em 22 (53,7%). Houve 16 (39%) não sobreviventes. Em relação às citocinas, os pacientes não sobreviventes apresentaram níveis mais elevados de IL-17A, IL-6 e IL-4 em comparação aos sobreviventes no dia 1 (p<0,001, p=0,001 e p=0,001) e no dia 3 (p<0,001, p=0,002 e p<0,001), respectivamente. Em relação aos biomarcadores oxidativos, os não sobreviventes apresentaram níveis mais elevados de nitrito plasmático em comparação aos sobreviventes, em ambos os dias (p<0,001 e p<0,001, respectivamente), e níveis mais baixos de glutationa redutase em comparação aos sobreviventes no dia 3 (p<0,001). O tempo médio de sobrevivência foi menor em pacientes com níveis mais elevados de IL-17A (≥ 19,71 pg/mL) no dia 1 (115 vs 323 dias, p = 0,004), níveis mais elevados de IL-4 (≥ 11,89 pg/mL) no dia 1 (123 vs 315 dias, p = 0,002), níveis mais elevados de IL-4 (≥14,96 pg/mL) no dia 3 (93 vs 283 dias, p = 0,001) e níveis mais elevados de NO (≥75,36 µM/ mg de proteína) no dia 1 (148 vs 322 dias, 0,009). Por outro lado, o tempo médio de sobrevida foi menor em pacientes com níveis mais baixos de GSH (< 0,036 µmol/mL) no dia 3 (32 vs 357 dias, p = 0,009). Após análise multivariada, o único fator associado ao maior tempo de sobrevida foi a IL-17A no dia 1, seja no modelo bruto (HR 1,03, IC95%1,004-1,057, p=0,022) ou ajustado (HR 1,043, IC95%1,013-1,075, p =0,012). Conclusões: Nosso estudo identificou níveis elevados de IL-17A em pacientes com SIM-P oriundos de uma região de baixo acesso aos serviços de saúde, especialmente naqueles com doença crítica e que evoluíram para o óbito. A análise da curva ROC mostrou que o valor de corte para o IL-17A foi de 14,32 pg/ml.
Introduction: MIS-C is characterized by systemic inflammation with clinical and epidemiological or microbiological evidence of exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is currently considered a rare and severe post-COVID-19 complication, emerging clinically with multiple phenotypes. Respiratory viral infections can cause genomic instability by causing excessive cytokine release with increased levels of inflammation, which causes immune response instability and elevated intracellular levels of Reactive Oxygen Species (ROS) that cause damage to lipids, proteins and DNA, named Oxidate Stress (OS). Objectives: The aim of this study was to associate the in-hospital mortality of MIS-C patients hospitalized in PICU with biomarkers (inflammatory and immunological) collected on the first day and third day of admission. Secondarily, we aimed to analyze the presence of cardiogenic shock and length of stay at PICU with inflammatory biomarkers and to evaluate the difference between the lab parameters on day one and three of follow-up. Methods: This study was a single center prospective cohort with convenience sample consisting of children and adolescents diagnosed with MIS-C and who required hospitalization in PICU. Clinical and laboratory data were collected from electronic records. Demographic data and intensive support characteristics were also assessed sequentially until the end of hospitalization. Blood samples were drawn on day 1 and 3 of hospital admission. Inespecific laboratorial parameters and specific measurements of cytokines and OE markers were performed. Comparisons between groups (survivors and non-survivors’ patients) were made using χ2 or Fisher exact tests for categorical variables, and Mann–Whitney U was used for continuous variables. For comparison between day 1 and day 3 we used the Wilcoxon signed-ranks test. Survival rate was calculated, and Kaplan-Meier curves were plotted. To determine risk factors for survival we performed a univariate and multivariate Cox regression “time - to first event” analysis. In the regression model we adjusted for a risk of mortality using age under one year old and presence of comorbidity simultaneously. The ROC (Receiver Operating Characteristic) curve analysis was performed. Results: Of the 41 patients included, 33 (80.5%) were male, 9 (22%) were up to one year old, and 30 (73.2%) presented pediatric complex chronic conditions. MIS-C critical forms were present in 21 (52.1%) patients, and requirement of invasive mechanical ventilation in 22 (53.7%). There were 16 (39%) non-survivors. Regarding cytokines, non-survivors patients presented higher levels of IL-17A, IL-6 and IL-4 compared to survivors on day 1 (p<0.001, p=0.001, and p=0.001) and day 3 (p<0.001, p=0.002 and p<0.001), respectively. Regarding oxidative biomarkers, non-survivors presented higher levels of plasma nitrite compared with survivors, in both days (p<0.001 and p<0.001, respectively), and lower levels of glutathione reductase compared with survivors in the day 3 (p<0.001). The mean survival time was shorter in patients with higher levels of IL-17A (≥ 19.71 pg/mL) on day 1 (115 vs 323 days, p = 0.004), higher levels of IL-4 (≥ 11.89 pg/mL) on day 1 (123 vs 315 days, p = 0.002), higher levels of IL-4 (≥14.96 pg/mL) on day 3 (93 vs 283 days, p = 0.001), and higher levels of NO (≥75.36 µM/mg protein) on day 1 (148 vs 322 days, 0.009). On the other hand, the mean survival time was shorter in patients with lower levels of GSH (< 0.036 µmol/mL) on day 3 (32 vs 357 days, p = 0.009). After multivariate analysis, the only factor associated with longer survival time was IL-17A on day 1 either in crude (HR 1.03, CI95%1.004-1.057, p=0.022) or adjusted model (HR 1.043, CI95%1.013-1.075, p=0.012). ROC analysys showed that the cutt-off value for the IL-17A was 14.32 pg/ml. Conclusions: Our study identified high levels of IL-17A in patients with MIS-C from a region with low access to health services, especially in those with critical illness who died.
Introduction: MIS-C is characterized by systemic inflammation with clinical and epidemiological or microbiological evidence of exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is currently considered a rare and severe post-COVID-19 complication, emerging clinically with multiple phenotypes. Respiratory viral infections can cause genomic instability by causing excessive cytokine release with increased levels of inflammation, which causes immune response instability and elevated intracellular levels of Reactive Oxygen Species (ROS) that cause damage to lipids, proteins and DNA, named Oxidate Stress (OS). Objectives: The aim of this study was to associate the in-hospital mortality of MIS-C patients hospitalized in PICU with biomarkers (inflammatory and immunological) collected on the first day and third day of admission. Secondarily, we aimed to analyze the presence of cardiogenic shock and length of stay at PICU with inflammatory biomarkers and to evaluate the difference between the lab parameters on day one and three of follow-up. Methods: This study was a single center prospective cohort with convenience sample consisting of children and adolescents diagnosed with MIS-C and who required hospitalization in PICU. Clinical and laboratory data were collected from electronic records. Demographic data and intensive support characteristics were also assessed sequentially until the end of hospitalization. Blood samples were drawn on day 1 and 3 of hospital admission. Inespecific laboratorial parameters and specific measurements of cytokines and OE markers were performed. Comparisons between groups (survivors and non-survivors’ patients) were made using χ2 or Fisher exact tests for categorical variables, and Mann–Whitney U was used for continuous variables. For comparison between day 1 and day 3 we used the Wilcoxon signed-ranks test. Survival rate was calculated, and Kaplan-Meier curves were plotted. To determine risk factors for survival we performed a univariate and multivariate Cox regression “time - to first event” analysis. In the regression model we adjusted for a risk of mortality using age under one year old and presence of comorbidity simultaneously. The ROC (Receiver Operating Characteristic) curve analysis was performed. Results: Of the 41 patients included, 33 (80.5%) were male, 9 (22%) were up to one year old, and 30 (73.2%) presented pediatric complex chronic conditions. MIS-C critical forms were present in 21 (52.1%) patients, and requirement of invasive mechanical ventilation in 22 (53.7%). There were 16 (39%) non-survivors. Regarding cytokines, non-survivors patients presented higher levels of IL-17A, IL-6 and IL-4 compared to survivors on day 1 (p<0.001, p=0.001, and p=0.001) and day 3 (p<0.001, p=0.002 and p<0.001), respectively. Regarding oxidative biomarkers, non-survivors presented higher levels of plasma nitrite compared with survivors, in both days (p<0.001 and p<0.001, respectively), and lower levels of glutathione reductase compared with survivors in the day 3 (p<0.001). The mean survival time was shorter in patients with higher levels of IL-17A (≥ 19.71 pg/mL) on day 1 (115 vs 323 days, p = 0.004), higher levels of IL-4 (≥ 11.89 pg/mL) on day 1 (123 vs 315 days, p = 0.002), higher levels of IL-4 (≥14.96 pg/mL) on day 3 (93 vs 283 days, p = 0.001), and higher levels of NO (≥75.36 µM/mg protein) on day 1 (148 vs 322 days, 0.009). On the other hand, the mean survival time was shorter in patients with lower levels of GSH (< 0.036 µmol/mL) on day 3 (32 vs 357 days, p = 0.009). After multivariate analysis, the only factor associated with longer survival time was IL-17A on day 1 either in crude (HR 1.03, CI95%1.004-1.057, p=0.022) or adjusted model (HR 1.043, CI95%1.013-1.075, p=0.012). ROC analysys showed that the cutt-off value for the IL-17A was 14.32 pg/ml. Conclusions: Our study identified high levels of IL-17A in patients with MIS-C from a region with low access to health services, especially in those with critical illness who died.
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Citação
FARIAS, Emmerson Carlos Franco de. Biomarcadores (inflamatórios e imunológicos) de diagnóstico associados à mortalidade na síndrome inflamatória multissistêmica pediátrica temporalmente associada ao SARS-CoV-2: estudo de coorte da região amazônica. 2024. 157 f. Tese (Doutorado em Pediatria e Ciências Aplicadas à Pediatria) - Escola Paulista de Medicina, Universidade Federal de Sâo Paulo (UNIFESP). São Paulo, 2024.