Perfil genético de pacientes pediátricos com asma grave e refratária aos glicocorticóides

Abstract

Introduction: Severe asthma, although not very prevalent, is responsible for high morbidity and mortality among the pediatric age group. In addition to the multiple and complex factors that can explain the various mechanisms for the lack of control of symptoms, genetic predisposition is considered an important factor for the understanding of the various regulatory pathways of the inflammatory response. Alternative pathways to the classic TH2 response may explain the heterogeneity of severe asthma and may be related to IL-17A and IL-10 cytokines. Objectives: to evaluate associations between polymorphisms of IL-10 and IL-17 genes with susceptibility, asthma control, and bronchodilator responsiveness in a sample of patients with severe asthma Methods: This was an observational study, conducted between 2021 and 2022, involving children, adolescents and young adults aged 5-28 years with severe asthma (using doses greater than or equal to 800 μg budesonide equivalent in association or not with other controllers), with appropriate inhalation technique, medicated comorbidities and well-established functional diagnosis. The patients were divided into 2 groups according to the asthma clinical control: non-controlled (refractory) and controlled group. Healthy adults aged 20-57 years were also included for genetic controls. All patients were submitted to peripheral blood sampling for DNA extraction and genotyping. The single nucleotide variants (SNVs) genotyped were rs3024498 of IL-10 and rs2275913 and rs3819024 of IL17A. Results: 56 patients with severe asthma and 19 healthy controls were selected. In the severe asthma group, it was observed that only the variables ACT (Asthma Control Test), weight and height showed differences between the control and non-control groups, evidencing that the reduction in height can be associated with the high dose of inhaled corticosteroids and failure in asthma control. Regarding the chance of severe asthma, only the presence of the A allele of the rs2275913 variant (IL17A) showed a significant permutational p value. Lack of control of severe asthma was associated with the presence of at least one C allele of rs3024498 (IL10), (OR: 6.93, 95%CI: 1.00-47.9). Asthma patients with at least one G allele of rs3819024 (IL17A) showed a lower response to acute beta-2 adrenergic bronchodilator stimulation in the three models tested: allelic (OR: 3.89, 15 95% CI: 1.07-14.12), additive (OR: 4.72, 95% CI: 1.16-19.19) and dominant (OR: 5.20, 95% CI: 1.11-24.34). Conclusion: The IL17 and IL10 pathways and their genetic polymorphisms are involved in severe pediatric asthma. Due to the great interindividual variability of asthma, especially regarding the response to glucocorticoids, polymorphisms of the IL17 and IL10 pathways may play an important role in the pathophysiology of this condition and explain the refractoriness to treatment, to be used as alternatives for the therapeutic management of asthma, contributing to the reduction of the risks of continuous and progressive increase of the inhaled corticoid dose.