Polymorphism in cytolytic pathway genes in patients with pediatric inflammatory multisystemic syndrome temporally associated with SARS-CoV-2 / Polimorfismos em genes da via citolítica em pacientes com síndrome inflamatória multissistêmica pediátrica temporariamente associada ao SARS-CoV-2

Introduction: Pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) is a systemic hyperinflammatory disease that occurs in a small number of children after being infected with SARS-CoV-2. Macrophage activation syndrome, an aggressive condition characterized by the excessive inflammation and activation of well-differentiated macrophages, has been shown to occur in patients infected by SARS-CoV-2. Considering the clinical and pathophysiological similarities between these diseases, our main objective was to determine whether gene polymorphisms associated with macrophage activation syndrome were also present in patients with PIMS-TS. Methods: DNA from 10 pediatric patients with PIMS-TS (case group) and ten COVID-19 patients without PIMS-TS (control group) were genotyped by Real-time PCR analysis (TaqMan®) for single nucleotide polymorphisms (SNP) in four genes associated with macrophage activation syndrome: perforin 1 (PRF1), granzyme B (GZMB), syntaxin 11 (STX11), and syntaxin binding protein 2 (STXBP2). The SNP analysis was performed using the additive, dominant, and recessive models. Results: A significantly higher frequency of an SNP (C wild allele in rs6573910) in the GZMB gene was observed in both the additive and dominant models in the PIMS-TS group than controls. A borderline significant difference was also observed for the G allele in rs7764017 of the STX11 gene in the PIMS-TS group in the additive model. Conclusions: This study indicated the presence of two polymorphisms in genes associated with macrophage activation syndrome (GZMB and STX11) in patients who developed PIMS-TS. If the presence of these SNPs is validated in a larger number of PIMS-TS cases, they can be used as potential biomarkers for early identification of pediatric patients with a higher probability of developing PIMS-TS associated with SARS-CoV-2 infection.

Introdução: A síndrome multissistêmica inflamatória pediátrica temporariamente associada ao SARS-CoV-2 (SIMP-TS) é uma doença hiperinflamatória sistêmica que ocorre em um pequeno número de crianças após serem infectadas pelo SARS-CoV-2. A síndrome de ativação de macrófagos (SAM), uma condição agressiva caracterizada pela inflamação excessiva e ativação de macrófagos bem diferenciados, demonstrou ocorrer em pacientes infectados por SARS-CoV-2. Considerando as semelhanças clínicas e fisiopatológicas entre essas doenças, neste estudo o nosso principal objetivo foi determinar se polimorfismos gênicos associados à SAM também estavam presentes em pacientes com SIMP-TS. Métodos: DNA de dez pacientes pediátricos com SIMP (grupo caso) e dez pacientes COVID-19 sem SIMP (grupo controle) foram genotipados por análise de PCR em tempo real (tecnologia TaqMan®) para polimorfismos de nucleotídeo único (SNPs) em quatro genes selecionados associados com SAM: perforina 1 (PRF1), granzima B (GZMB), sintaxina 11 (STX11) e proteína de ligação de sintaxina 2 (STXBP2). A análise dos SNPs foi realizada utilizando o modelo aditivo, dominante e recessivo. Resultados: Uma frequência significativamente maior de um SNP (alelo selvagem C em rs6573910) no gene GZMB foi observada pelos modelos aditivo e dominante no grupo SIMP quando comparado aos controles. Além disso, uma significância limítrofe foi observada para o alelo G em rs7764017 do gene STX11 no grupo SIMP pelo modelo aditivo. Conclusões: Nosso estudo indicou a presença de dois polimorfismos em genes associados à SAM (GZMB e STX11) em pacientes que desenvolveram SIMP-TS. Uma vez validada a presença desses SNPs em um número maior de casos de SIMP-TS, eles podem ser usados como potenciais biomarcadores para a identificação precoce de pacientes pediátricos com maior probabilidade de desenvolver SIMP-TS associado à infecção por SARS-CoV-2.

COVID-19: Immunohistochemical Analysis of TGF-ß Signaling Pathways in Pulmonary Fibrosis.

Acute respiratory distress syndrome (ARDS) followed by repair with lung remodeling is observed in COVID-19. These findings can lead to pulmonary terminal fibrosis, a form of irreversible sequelae. There is evidence that TGF-ß is intimately involved in the fibrogenic process. When activated, TGF-ß promotes the differentiation of fibroblasts into myofibroblasts and regulates the remodeling of the extracellular matrix (ECM). In this sense, the present study evaluated the histopathological features and immunohistochemical biomarkers (ACE-2, AKT-1, Caveolin-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-ß1 tissue expression) involved in the TGF-ß1 signaling pathways and pulmonary fibrosis. The study consisted of 24 paraffin lung samples from patients who died of COVID-19 (COVID-19 group), compared to 10 lung samples from patients who died of H1N1pdm09 (H1N1 group) and 11 lung samples from patients who died of different causes, with no lung injury (CONTROL group). In addition to the presence of alveolar septal fibrosis, diffuse alveolar damage (DAD) was found to be significantly increased in the COVID-19 group, associated with a higher density of Collagen I (mature) and III (immature). There was also a significant increase observed in the immunoexpression of tissue biomarkers ACE-2, AKT-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-ß1 in the COVID-19 group. A significantly lower expression of Caveolin-1 was also found in this group. The results suggest the participation of TGF-ß pathways in the development process of pulmonary fibrosis. Thus, it would be plausible to consider therapy with TGF-ß inhibitors in those patients recovered from COVID-19 to mitigate a possible development of pulmonary fibrosis and its consequences for post-COVID-19 life quality.

Perinatal brain lesions and epilepsy: prematurity and cerebral hypoxia evolving with west syndrome / Lesões cerebrais perinatais e epilepsia: prematuridade e hipóxia cerebral evoluindo com Síndrome de West / Lesiones cerebrales perinatales y epilepsia: prematuridad e hipoxia cerebral evolucionando con Síndrome de West

Introduction: West syndrome (WS) is the most frequent epileptic encephalopathy in the first year of life and is strongly correlated with prenatal and perinatal brain injury. Objective: To analyze the relationship between prematurity and birth asphyxia (cerebral hypoxia) with WS. Methods: This is an observational and cross-sectional study. All the patients with WS treated at Pediatric Neurology Service of Pequeno Príncipe Children?s Hospital from January 2010 to January 2015 were analyzed. The patients underwent magnetic resonance imaging (MRI) of the brain and electroen- cephalogram (EEG). Results: Thirty-eight patients with WS, 23 (60.53%) females; ages ranging from 9 to 27 months (±16.6 months). Twenty (52.63%) patients had a history of hypoxia/anoxia perinatal, 8 (21.05%) were premature, 8 (21.05%) had brain malformations, 4 (10.53%) had Down syndrome, 4 (10.53%) had tuberous sclerosis, and 2 (5.26%) had no comorbidities. MRI showed: 9 (23.68%) multi-cystic encephalomalacia, 4 (10.53%) periventricular leukomalacia, 4 (10.53%) periventricular leukomalacia with cerebral atrophy, 4 (10.53%) periventricular nodules, 3 (7.89%) brain atrophy, 2 (5.26%) pachygyria associated with agenesis of corpus callosum, one (2.63%) agenesis of the corpus callosum, one (2.63%) right frontal dysplasia, one (2.63%) left frontal dysplasia, one (2.63%) right frontoparietal dysplasia, one (2.63%) left frontoparietal dysplasia, and one (2.63%) pachygyria. Conclusion: The history of hypoxia/anoxia perinatal and prematurity is very frequent in WS. Improved care during pregnancy and childbirth is very important to reduce perinatal brain injury, premature birth, and neurological morbidity.

Introdução: A síndrome de West (SW) é a mais frequente encefalopatia epiléptica do primeiro ano de vida e está fortemente relacionada com lesões cerebrais pré-natais e perinatais. Objetivo: Analisar a relação entre prematuridade e asfixia perinatal (hipóxia cerebral) e SW. Métodos: Este é um estudo observacional e transversal. Todos os pacientes com SW tratados no Serviço de Neurologia Pediátrica do Hospital Infantil Pequeno Príncipe entre janeiro de 2010 e janeiro de 2015 foram analisados. Os pacientes foram submetidos a ressonância magnética (RM) do encéfalo e eletroencefalograma (EEG). Resultados: Trinta e oito pacientes com SW, 23 (60,53%) do sexo feminino; idade entre 9 a 27 meses (±16,6 meses). Vinte (52,63%) pacientes tinham história de hipóxia/anóxia perinatal, 8 (21,05%) eram prematuros, 8 (21,05%) tinham malformações cerebrais, 4 (10,53%) tinham síndrome de Down, 4 (10,53%) tinham esclerose tuberosa e 2 (5,26%) não apresentavam nenhuma comorbidade. A RM mostrou: 9 (23,68%) casos de encefalomalácia multicística, 4 (10,53%) leucomalácia periventricular, 4 (10,53%) leucomalácia periventricular com atrofia cerebral, 4 (10,53%) nódulos periventriculares, 3 (7,89%) atrofia cerebral, 2 (5,26%) paquigiria associada à atrofia de corpo caloso, um (2,63%) agenesia de corpo caloso, um (2,63%) displasia frontal direita, um (2,63%) displasia frontal esquerda, um (2,63%) displasia frontoparietal direita, um (2,63%) displasia frontoparietal esquerda e um (2,63%) paquigiria. Conclusão: A história de hipóxia/anóxia perinatal e prematuridade é muito frequente na SW. A melhora dos cuidados durante a gestação e o parto é muito importante para reduzir lesões cerebrais perinatais, nascimentos prematuros e consequentemente, a morbidade neurológica.

Introducción: El síndrome de West (SW) es la más frecuente encefalopatía epiléptica del primer año de vida y está fuertemente relacionado con lesiones cerebrales prenatales y perinatales. Objetivo: Analizar la relación entre prematuridad y asfixia perinatal (hipoxia cerebral) y SW. Métodos: Este es un estudio observacional y transversal. Fueron analizados todos los pacientes con SW tratados en el Servicio de Neurología Pediátrica del Hospital Infantil Pequeno Príncipe entre enero de 2010 y enero de 2015. Los pacientes fueron sometidos a resonancia magnética (RM) del encéfalo y electroence- falograma (EEG). Resultados: Treinta y ocho pacientes con SW, 23 (60,53%) del sexo femenino; edad entre 9 a 27 meses (±16,6 meses). Veinte (52,63%) pacientes tenían historia de hipoxia/anoxia perinatal, 8 (21,05%) eran prematuros, 8 (21,05%) tenían malformaciones cerebrales, 4 (10,53%) tenían síndrome de Down, 4 (10,53%) tenían esclerosis tuberosa y 2 (5,26%) no presentaban ninguna comorbilidad. La RM mostró: 9 (23,68%) casos de encefalomalacia multiquística, 4 (10,53%) con leucomalacia periventricular, 4 (10,53%) con leucomalacia periventricular con atrofia cerebral, 4 (10,53%) con nódulos periventriculares, 3 (7,89%) con atrofia cerebral, 2 (5,26%) con paquigiria asociada a la atrofia de cuerpo calloso, uno (2,63%) con agenesia de cuerpo calloso, uno (2,63%) con displasia frontal derecha, uno (2,63%) con displasia frontal izquierda, uno (2,63%) con displasia frontoparietal derecha, uno (2,63%) con displasia frontoparietal izquierda y uno (2,63%) con paquigiria. Conclusión: La historia de hipoxia/anoxia perinatal y prematuridad es muy frecuente en SW. La mejora de los cuidados durante la gestación y el parto es muy importante para reducir lesiones cerebrales perinatales, nacimientos prematuros y consiguientemente, la morbilidad neurológica.