Identifying the initial manifestations of pulmonary functional disorders associated with cystic fibrosis (CF) is essential for timely correction of the therapy and improvement of the prognosis.The aim of the study was to identify the age periods with the highest risk of a decrease in lung function in children with different CF genotypes.Methods. Lung function (LF) was analyzed using spirometry results in CF patients aged 6 to 18 years from the Registry of patients with cystic fibrosis in the Russian Federation 2018.Results. The forced expiratory volume in one second (FEV1) was statistically significantly lower in children aged 6 – 10 years with “severe” genotypes than in the children with “mild” genotypes. The lung function was reduced at 11 – 14 years of age in both “severe» and “mild” genotypes without any statistically significant difference. In general, the trend of a decrease in lung function in “severe” genotypes persists in the adolescent period from 15 to 18 years. The lung function is better in adolescents aged 15 – 18 with the “mild” variants of genotypes compared to the patients aged 11 – 14 years.Conclusion. The “severe” variants of CFTR negatively affect LF of CF patients in all age groups. The LF values in patients with “mild” genotypes at the age of 15 – 18 years were higher than in children aged 11 – 14 years with the same genotypes. There is a need for improved programs of medical care for adolescents with CF.

Background. Targeted therapy in patients with cystic fibrosis, which aims to restore the function of the cystic fibrosis transmembrane conductance regulator protein, is currently revolutionary in the treatment of the disease. The first drug available in Russia for the treatment of patients with this genetic disease is lumacaftor/ivacaftor (Orkambi®), which was registered on December 2, 2020.The aim. To study the efficacy of lumacaftor/ivacaftor during 12 weeks of administration in children in Astrakhan region.Materials and methods. This article presents the clinical experience of Orkambi medicine use in 3 children with F508del/F508del genotype and a severe course of cystic fibrosis for 12 weeks. According to the study design, such indices as body mass index, indexes of external respiratory function, character of respiratory tract microbiota, level of chloride in sweat fluid and pancreatic elastase in feces, dynamics of biochemical blood indexes were evaluated. The study was performed within the time periods specified in the study protocol, namely, before the start of therapy, 2, 4, and 12 weeks of treatment.Results. Two patients had a decrease in sweat test values by 11 and 19 mmol/l from the baseline, a significant increase in forced vital capacity of lungs. One patient had an adverse event in the form of hepatobiliary disorders manifested by increased liver transaminase activity, which was the reason for discontinuing the drug.Conclusions. The short-term experience of using pathogenetic therapy with lumacaftor/ ivacaftor in children in the Astrakhan region demonstrated both the expected effect on chlorine channel function and the possibility of side effects, including severe ones, that can lead to withdrawal of the drug.

Cystic fibrosis is an autosomal recessive disease caused by mutations in the CFTR gene. CFTR modulators are a complex of CFTR protein potenti­ator and correctors that improve chloride channel function. Currently, the most effective targeted therapy drug is the combination of elexacaftor/ tezacaftor/ivacaftor (ETI). However, data on the long-term efficacy and safety of triple combination therapy in real-world clinical practice in the Russian Federation are limited. The aim is to analyze the efficacy and safety of therapy with the three-component elexacaftor/tezacaftor/ivacaftor based on data from the registry of patients with cystic fibrosis of the Russian Federation for 36 months. Methods. A retrospective study was conduct­ed using data from the Russian Federation Cystic Fibrosis Patient Registry in the Targeted Therapy section for 2021 - 2024. The study included 900 patients over 6 years old with cystic fibrosis receiving triple targeted therapy with ETI. The following criteria were assessed for the effectiveness of therapy: sweat test, anthropometric data (weight, height, BMI), lung function parameters (FVC and FEV ₁ in absolute (L) and relative (% predict­ed) values), at the start of therapy and over 3 years. The following safety criteria were assessed in pairwise comparisons: ALT (U/L), AST (U/L), total bilirubin (^mol/L), systolic and diastolic blood pressure during 3 years of therapy. Results. Comparison of the sweat test results, FEV1 and FVC, BMI at the start of therapy, after one year, 2 years and 3 years showed a significant decrease in sweat test results, an improvement in anthropometric data (BMI), an increase in absolute and relative indicators of respiratory function (FVC, FEV ₁ ) during the first year of therapy, and stabilization of indicators on during the second and third years of therapy. The safety profile of ETI was characterized by stable median values of ALT, AST, and total bilirubin within the reference values at three-year follow-up. Adverse reactions were reported in 9.4% of cases at the start of therapy. After three years of therapy, the adverse reactions were rare and more related to the mental sphere. Conclusion. Patients with cystic fibrosis who received three-component ETI therapy showed significant improvement of basic health indicators compared to the initial ones they had while receiving only basic therapy. The long-term efficacy and safety of the elexacaftor/tezacaftor/ivacaftor combination has been demonstrated for three years.

In the Russian Federation, patients with cystic fibrosis (CF) under 19 years of age receive targeted therapy with two drugs: lumacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor. Currently, a large volume of information has accumulated regarding possible adverse drug reactions (ADRs) during long-term targeted therapy in children with CF.   The aim of the study was to investigate the ADR profile associated with long-term use of CFTR modulators in children with CF.   Methods. Data on the targeted therapy were taken from the Russian registry of CF patients (2021 – 2024). The data of 392 patients at the start of therapy with lumacaftor/ivacaftor, 196 patients after 1 year, and 36 patients after 2 years were analyzed. The data of 220 patients at the start of therapy with elexacaftor/tezacaftor/ivacaftor, 214 patients after 1 year, and 43 patients after 2 years were analyzed. Early adverse reactions were assessed within 30 days from the start of therapy. Change in the adverse reaction profile was assessed after 360 and 720 days.   Results. The number of adverse reactions in patients receiving lumacaftor/ivacaftor was 51.27 % for 1 month. It decreased more than 2-fold (20.4 %) by the end of the 1st year (p1–2 < 0.001) due to a decrease in the number of patients with cough, shortness of breath, elevated alanine aminotransferase (ALT) / aspartate aminotransferase (AST) levels, and diarrhea. After 2 years, the incidence of adverse reactions was 55.5 % (p2–3 < 0.001), the number of patients with subfebrile body temperature/fever increased (p2–3 < 0.001; p1–3 < 0.001), the rate of fatigue increased to 11.1 % (p2–3 = 0.029), and the rate of sleep disturbance increased (from 0.25% at the start to 11.1 % after 2 years of therapy; p1–3 < 0.001; p2–3 < 0.001). The average incidence of adverse reactions per patient was 2.27 ± 0.45 for lumacaftor/ivacaftor. The total incidence of ADRs with elexacaftor/tezacaftor/ivacaftor combination therapy was 48.2 % at the start, 19.6 % after 1 year (p1–2 < 0.001), and increased to 41.9 % after 2 years (p2–3 < 0.001) due to subfebrile body temperature/fever – from 1.9 to 6.9 % (p1–3 = 0.032), headache – from 2.3 to 11.6 % (p1–3 = 0.003), and fatigue – up to 13.9 % (p1–3 < 0.001; p2–3 = 0.002). The average incidence of ADRs per patient was 2.56 ± 0.71 with elexacaftor/tezacaftor/ivacaftor combination therapy. More ADRs were observed at the start of therapy with lumacaftor/ivacaftor compared to elexacaftor/tezacaftor/ivacaftor (p = 0.019). The frequency of elevated ALT/AST levels at the start of therapy with lumacaftor/ivacaftor was higher than for elexacaftor/tezacaftor/ivacaftor (p = 0.02). Rash was observed more often at the start of therapy with elexacaftor/tezacaftor/ivacaftor (p < 0.001), fatigue – at the start of lumacaftor/ivacaftor (p = 0.011). No difference in the ADR profile was found after 2 years of therapy.   Conclusion. A higher number of ADRs was associated with lumacaftor/ivacaftor compared to elexacaftor/tezacaftor/ivacaftor. Over time, the main adverse drug reactions associated with respiratory and gastrointestinal symptoms resolve, but the number of patients complaining of fatigue, sleep disturbances, headaches, subfebrile temperature and fever increases, requiring active follow-up and adjustment of the therapy if necessary.

Introduction. Cystic fibrosis is a severe systemic multiorgan exocrinopathy, the severity of the condition in 95% cases is caused by the depth of respiratory organ damage. Symptom management drugs that were developed over more than 50 years allowed to improve survival, but average life expectancy in cystic fibrosis (CF) remains well below the general population average. Targeted therapy is the most promising treatment, which restores the chloride channel function. Lumacaftor/ivacaftor is the first targeted therapy drug authorized in Russia.Aim. To evaluate the effect of lumacaftor/ivacaftor therapy on the respiratory function, microbiological profile, nutritional and oxygen status, as well as the rescue antibiotic therapy coverage in adult patients with CF.Materials and methods. 39 adult patients with CF received lumacaftor/ivacaftor for one year. The therapy effectiveness endpoints included the changes in indices of the pulmonary function tests: FEV₁, FVC, FEV₁/FVC, sweat test results, nutritional and oxygen status, antibiotic therapy coverage. The tolerability of the drug was assessed. The median age of patients was 28.9 (11.3) years. 6 patients (15.4%) discontinued therapy due to different adverse reactions.Results. The median increase in FVC was 2.9 (4.1)%, in FEV₁ – 3.1 (4.1)%, sweat chloride decreased by 21 (27) mmol/l during 1–1.5-month lumacaftor/ivacaftor therapy. After 12-month therapy, the median increase in FVC was 2.3 (3.6)%, in FEV₁ – 2.4 (3.8)%, BMI increased by 0.6 (0.6) kg/m² and the frequency of rescue antibiotic therapy decreased by half. The patients showed a significant increase in FVC and FEV¹ indices and a decrease in sweat chloride after 1-month therapy and an increase in FEV₁ indices, BMI vales as well as a reduced need for rescue antibiotic therapy after 12-month therapy.Conclusion. The first experience with a long-term pathogenetic therapy with lumacaftor/ivacaftor in adult patients with CF in Russia demonstrated the expected positive effect on the respiratory function and changes in nutritional status, a reduced need for rescue antibiotic therapy, and low rates of adverse reactions.