Pathogenetic therapy in children with cystic fibrosis: practical experience

Cystic fibrosis (CF) is a severe inherited disease caused by mutations in the cystic fibrosis CFTR gene, resulting in systemic damage to the respiratory, digestive, and other body systems. Before the advent of pathogenetic therapy, the prognosis in CF remained unfavorable, but with the introduction of CFTR modulators, such as the combination of ivacaftor, tezacaftor, and elexacaftor, the course of the disease has been brought under control. Despite significant progress, there are still questions related to the variability of response to therapy depending on genotype, long-term effects of treatment and optimal approaches to its correction, especially in patients with rare mutations in the CFTR gene. Objective. To evaluate the clinical efficacy of elexacaftor/tezacaftor/ivacaftor therapy in children with cystic fibrosis depending on their genetic profile. Patients and methods. A retrospective single-center study included 75 patients aged 6 to 17 years with a verified diagnosis of CF who received therapy from 2019 to 2024. Depending on the genotype, patients were divided into 3 groups: heterozygotes for the F508del mutation (n = 40), homozygotes for F508del (n = 17), and carriers of other mutations (n = 18). The efficacy evaluation included analysis of anthropometric parameters (SDS of growth and body mass index (BMI) according to the World Health Organization criteria), lung function parameters (forced expiratory volume in 1 s (FEV1), forced vital capacity of lungs (FVCL)), dynamics of sweat chloride concentration and registration of adverse events. Results. On the background of therapy in patients with heterozygous carrier of F508del there was a significant improvement of nutritional status (ΔSDS BMI +0.46, p < 0.001) and lung function (12.5%D increase in FEV1, p < 0.05). In the F508del homozygote group, there was a significant increase in spirometry parameters (FEV1 +10.2%D, p < 0.03; FVC +14.8%D, p < 0.001), no significant dynamics of SDS growth and BMI were observed (p > 0.05). Rare mutation carriers also showed improved lung function (FEV1 +9.1%D, p < 0.01) and weight gain (ΔSDS BMI = +0.48, p < 0.001). All groups showed a decrease in sweat chloride concentration (mean 22–28 mmol/L from baseline, p < 0.05), indicating restoration of sodium-chloride channel function. Side effects were rare (1 case of transient cytolysis; 1 case of cataract onset). Conclusion. Triple pathogenetic therapy demonstrated high efficacy in improving lung function and nutritional status in children with CF, regardless of their genotype. The greatest improvement was observed in F508del heterozygotes and rare mutation carriers. In F508del homozygotes the dynamics of anthropometric parameters was less pronounced. The obtained data confirm the importance of personalized approach to CF treatment taking into account the genetic features of the patient.