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PULMONOLOGIYA

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Vol 31, No 2 (2021)
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EDITORIAL

135-146 3833
Abstract

The aim of the experts who provide health care for patients with cystic fibrosis (CF) has been to develop clinical guidelines on cystic fibrosis for children and adults.

Methods. The 2020 Clinical Guidelines were based on the European consensus documents on cystic fibrosis and the national consensus “Cystic fibrosis: definition, diagnostic criteria, therapy” (2016, 2019). When creating clinical guidelines, the experts were guided by Article 2 of the Federal Law No.323-FL “On the basics of health care in the Russian Federation” as of November 21st, 2011, and the regulatory legal documents governing the development and approval of clinical guidelines (https://rosmedex.ru/kr/).

Results. The clinical guidelines were approved by the Federal State Budgetary Institution “Centre for Expertise and Quality Control of Medical Care” of the Russian Ministry of Health in August 2020. Standards of medical care for children and adults with cystic fibrosis were prepared based on these guidelines. The diagnostic algorithms have been expanded with a three-stage DNA diagnostic strategy, functional assays of CFTR channel, laboratory and instrumental diagnostic tools for assessing disorders of respiratory and other systems, diagnosis of the microbial inflammatory process, microbiological monitoring, and therapeutic approaches. The antibiotic therapy with dosages and courses is described in detail. The updated document should describe a unified tactic for the management of Russian CF patients.

Conclusion. Unified clinical guidelines for children and adults should develop unified tactics for the diagnosis, therapy, and follow-up of CF patients in the Russian Federation and ensure continuity between health care services for children and adults.

ORIGINAL STUDIES

148-158 784
Abstract

The variety of clinical manifestations of cystic fibrosis is driven by the diversity of the CFTR gene nucleotide sequence. Descriptions of the clinical manifestations in patients with the newly identified genetic variants are of particular interest.

The aim of this study was to describe clinical manifestations of the disease with the newly identified genetic variants.

Methods. Data from Registry of patients with cystic fibrosis in the Russian Federation (2018) were used. The data review included three steps — the search for frequent mutations, Sanger sequencing, and the search for extensive rearrangements by MLPA. 38 pathogenic variants were identified that were not previously described in the international CFTR2 database. We selected and analyzed full case histories of 15 patients with 10 of those 38 pathogenic variants: p.Tyr84*, G1047S, 3321delG, c.583delC, CFTRdele13,14del18, CFTRdele19-22, c.2619+1G>A, c.743+2T>A, p.Glu1433Gly, and CFTRdel4-8del10-11.

Results. A nonsense variant p.Tyr84* was found in 5 patients (0.08 %). Two missense variants c.3139G>A were found in 2 siblings (0.03 %). The c.4298A>G was found in 1 patient. Other variants were detected in a single patient (0.02 %) each. They included two variants of a deletion with a shift of the reading frame 3321delG and c.583delC, two splicing disorders c.2619+1G>A and c.743+2T>A, three extended rearrangements CFTRdele19-22, CFTRdele13,14del18, and CFTRdel4-8del10-11. The last two variants include 2 rearrangements on one allele, which cause the severe course in two young children. 8 of the 10 variants are accompanied by pancreatic insufficiency (PI). Among patients with p.Tyr84*, one had ABPA, one had liver transplantation, and all had Pseudomonas aeruginosa infection. Nasal polyps were diagnosed in 2 patients with p.Tyr84*, 1 with G1047S, 1 with CFTRdel4-8del10-11, and 1 patient with 3321delG, who also had osteoporosis and cystic fibrosis-related diabetes (CFRD). 2 patients with PI with 3321delG and CFTRdel4-8del10-11 genetic variants, and 1 with PI with p.Glu1433Gly genetic variant had severe protein-energy malnutrition (PEM).

Conclusion. Clinical manifestations of previously undescribed CFTR genetic variants were described. 5/10 genetic variants should be attributed to class I, 3/10 – to class 7 of the function classification of pathogenic CFTR gene variants associated with transcription and translation disruptions. Class of the identified missense variants c.3139G>A and c.4298A>G has not been established and requires further functional, cultural, and molecular genetic studies.

159-166 685
Abstract

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.

167-177 1104
Abstract

Intestinal current measurement (ICM) and forskolin-induced swelling (FIS) assay in human intestinal organoids from rectal biopsies of cystic fibrosis (CF) patients are the new functional tests for assessment of CFTR channel activity that are widely used in the leading laboratories worldwide for scientific and clinical studies.

The aim of the study was to assess the use of the new functional tests in adult CF patients with identified N1303K and R334W CFTR gene variants.

Methods. Rectal suction biopsies were obtained from the two CF patients aged 36 and 27 years with N1303K/3821delT and R334W/F508del CFTR mutations, respectively. Results of the ICM and FIS assay in intestinal organoids were compared to the clinical data.

Results. ICM has demonstrated that R334W is a ‘mild’ genetic variant with high residual CFTR channel activity. At the same time, N1303K is a ‘severe’ genetic variant and leads to a severe loss of CFTR channel function. These findings correlate with the clinical data. CFTR modulators compensate for the reduced activity of the R334W CFTR variant, as shown by the FIS assay. But there was a limited response of the forskolin-stimulated organoids to VX-770 potentiator and VX-809 corrector in the cells with N1303K genetic variant.

Conclusion. ICM and FIS assay in human intestinal organoids are reliable methods for quantification of CFTR channel activity. They can also predict the efficacy of the targeted therapy in CF patients in vivo.

178-188 1233
Abstract

Cystic fibrosis (CF) is a systemic hereditary disease caused by a mutation of the CFTR gene and characterized by damage to the glands of external secretion and severe dysfunctions of the respiratory system. The “severe” genotypes are associated with more pronounced and early clinical manifestations. The “mild” genotypes are associated with a delayed onset of clinical manifestations.

Methods. An analysis of the medical history of patients with asymptomatic CF from the Russian CF centers was carried out. Rectal biopsy specimens were used for intestinal current measurement (ICM) and forskolin-induced swelling assay in intestinal organoids. DNA for sequencing was isolated from the venous blood leukocytes.

Results. 2 CF patients with genotypes F508del/c.1584+18672A>G (patient 1, 12 years old) and F508del/G509D-E217G (patient 2, 3 years old) were examined. The diagnosis was based on neonatal screening. The ICM assay showed a reduced function of the CFTR channel: ΔISC for forskolin was 12.33 ± 2.35 μA/cm2 in patient 1 and 25 ± 3.37 μA/cm2 in patient 2. The negative response to carbachol and histamine reflects the entry of potassium ions into the cells, which is typical for CF. The assay in intestinal organoids showed that the amount of functional protein on the apical membrane of the intestinal epithelium increases both under the action of the potentiator and the corrector in both patients. The greatest effect is observed when the VX-770 and VX-809 are used together.

Conclusion. The ICM functional assay and the forskolin-induced swelling assay in intestinal organoids are sensitive enough to determine the residual functional activity of the CFTR channel and clarify the diagnosis in difficult cases. The studied genetic variants c.1584+18672A>G and G509D-E217G belong to class IV – VI mutations. The clinical picture corresponds to the manifestations of “mild” mutations. The studied patients still attend the Russian cystic fibrosis centers.

189-196 597
Abstract

March 11, 2020 WHO has declared the COVID-19 coronavirus pandemic. The European Society for Cystic Fibrosis (ECFS) has developed the ECFSCOVID- 19 surveillance program to collect information on the characteristics of COVID-19 in patients with cystic fibrosis (CF). CF centers in the Russian Federation also joined the ECFS study. The ECFS collected information only through national Registers. In our country, the national register of CF patients has existed since 2011, its data is included in the European Register. Тo analyze the prevalence and course of COVID-19 in adult CF patients in Saint-Petersburg and the Leningrad region.

Methods. From 11.03.20 to 24.12.20, 10 cases of adult CF patients (4 women, 6 men) with COVID-19 were analyzed in Saint-Petersburg and the Leningrad region. At the beginning of the study, 56 adult CF patients lived in Saint-Petersburg and Leningrad Region. All patients were monitored remotely by telephone, in case of ARVI symptoms, disease exacerbation, a PCR smear was performed on SARS-CoV-2, therapy was prescribed remotely, and inpatient treatment was prescribed if indicated.

Results. COVID-19 was diagnosed in 10 adult CF patients aged 21 to 43 years. Two patients (32-year-old male and 31-year-old female with severe mixed cystic fibrosis form) were hospitalized with polysegmental pneumonia. 8 people were treated on an outpatient basis. Only 1 outpatient patient aged 43 years had pronounced clinical manifestations of COVID-19, the condition was regarded as moderate, the remaining outpatient patients suffered from a mild ARI disease. All patients were treated with positive dynamics. During the period of this follow – up, 3 CF patients (2 men, 1 woman) died, the death cause was the respiratory failure progression. Clinical and radiological, repeated laboratory data for COVID-19 were not obtained. At the point of December 24, 2020 53 adult CF patients are alive.

Conclusion. According to our data, the incidence of COVID-19 among adult CF patients in Saint-Petersburg and the Leningrad Region was 17.85%, which is a lower indicator than in the general population. The disease was rarely severe, and effective treatment was noted in outpatient settings. There were no deaths from COVID-19.

197-206 844
Abstract

Study of efficacy, safety, and patient satisfaction with inhaled tobramycin (Tobramycin-Gobbi) in children with cystic fibrosis and pseudomonas infection

Aim of the study was to assess efficacy and safety of Tobramycin-Gobbi in CF, as well as the patients’ satisfaction with the treatment.

Methods. 35 children from 6 to 18 years with CF were enrolled in this non-interventional prospective cohort multicenter study. All children had P. aeruginosa in the respiratory tract (newly diagnosed, recurrent, or chronic infection). The children received inhalation treatment with Tobramycin-Gobbi in the following cycles: 28-day treatment/28-day break, for 6 months. The studied parameters included respiratory function, bacterial cultures of the respiratory tract with a bacterial count, growth and body weight, antibiotic therapy for the respiratory episodes. The children and parents filled in a questionnaire “Treatment satisfaction assessment” and assessed their state of health on the visual-analog scale before and after each treatment cycle.

Results. P. aeruginosa was eradicated in 17.7% of cases (6 patients, including 2 newly diagnosed, 3 recurrent infections, and 1 chronic infection), reduced bacterial count, decreased number of courses of antibiotic therapy, improvement of FEV1. Adverse reactions were reported by one patient.

Conclusion. The efficacy, safety, and tolerability of Tobramicine Gobbi were confirmed in the patients with newly diagnosed, recurrent, and chronic infection caused by P. aeruginosa.

207-215 837
Abstract

Chronic rhinosinusitis (CRS), including chronic rhinosinusitis with nasal polyps (CRSwNP), is one of the manifestations of cystic fibrosis (CF). The paranasal sinuses (PNS) are considered as a reservoir of pathogenic microflora and a source of descending infection of the entire respiratory tract. Nevertheless, paranasal sinuses pathology is usually assessed in isolation from both the lower respiratory tract and the entire spectrum of multiple organ damage in CF.

Aim. To determine the prevalence of CRSwNP and its correlation with other characteristics of CF in children in Russia.

Methods. The study included data of 2216 children from 0 to 18 years old from 81 regions of the Russian Federation from the Registry of patients with cystic fibrosis in the Russian Federation for 2018. Children with an established diagnosis of CRSwNP (n = 599) were compared to those without this condition (n = 1 617). The prevalence was assessed in the subgroups by age, sex, respiratory function, nutritional status, microbiological status, complications, the need for various therapies, and the average duration of inpatient treatment during the year. The statistical analysis included parametric and nonparametric tests.

Results. According to the Registry, the average prevalence of CRSwNP among children with CF was 27.03% and tended to increase with age. Children with CRSwNP had statistically significant higher incidence of homozygous F508del mutation, more common intermittent and chronic infection with P. aeruginosa, S. aureus (MSSA and MRSA), cystic fibrosis-associated diabetes mellitus with daily use of insulin, liver damage (as with or without cirrhosis), osteoporosis, a more frequent need for systemic antibacterial and inhalation (except for bronchodilators) therapy, as well as a relatively high need for hospital stay. Unexpectedly, the respiratory function indicators (FEV1, %, FVC, %) and body mass index turned out to be higher in the group of patients with nasal polyposis. A likely explanation is that the study included only children, and the lung function was not analyzed in the children and adolescents.

Conclusion. The results suggest that CRSwNP is a predictor of adverse course of CF and requires attention from CF specialists and otorhinolaryngologists, as well as interdisciplinary collaborations.

216-224 939
Abstract

Today, achieving clinical control in patients with chronic obstructive pulmonary disease (COPD) remains relevant. Thus, the results of a large multicenter study of clinical efficacy of dual bronchodilatory therapy in real practice conducted in Eastern Europe, including the Russian Federation, are of great interest.

Aim. Assessment of changes in the clinical control in patients with COPD receiving treatment with LABA/LAMA combination (tiotropium/olodaterol 5/5 μg via the Respimat® inhaler) in real clinical practice.

Methods. The study included patients (n = 1 476) with COPD older than 40 years who were prescribed tiotropium/olodaterol 5/5 μg via the Respimat® inhaler according to the current Russian and foreign clinical guidelines. The observation period was 6 weeks. The clinical control of COPD was assessed by the CCQ questionnaire, the patient’s general condition, the severity of dyspnea according to the mMRC scale, the incidence of using short-acting bronchodilators to relieve symptoms. The criterion for therapeutic success was a 0.4 point decrease in the CCQ score, the minimal clinically important difference

Results. The treatment with tiotropium/olodaterol 5/5 μg was successful, i.e., led to a decrease in the number of CCQ points by more than 0.4 points, in 89.84% of patients (95% CI 88.2 – 91.3 %; p < 0.0001). On average, the overall CCQ score between the first and second visit decreased by 1.31 ± 0.97 points, the severity of symptoms – by 1.39 ± 1.03 points, the functional state – by 1.2 ± 1.1 points, the mental condition – by 1.38 ± 1.31 CCQ points. Achievement of clinical control did not depend on comorbid pathology, disease severity, patient age, and the previous therapy.

Conclusion. The results obtained on a wide sample of patients from real practice confirmed the high clinical efficacy of tiotropium/olodaterol 5/5 μg in achieving clinical control of COPD.

REVIEW

226-236 4789
Abstract

The basic therapy of cystic fibrosis is currently aimed at slowing down the pathological processes associated with a decrease in the CFTR protein activity (cystic fibrosis transmembrane conductance regulator) in the gastrointestinal tract and the respiratory system. The pancreatic insufficiency is well compensated by replacement therapy with microsphere enzyme preparations and a high-calorie diet rich in proteins and fat. Chronic treatment of cystic fibrosis-related lung disease aims to improve the clearance of the bronchial tree, suppressing chronic bacterial infection and local chronic inflammation. However, no therapy was available to correct the defect in the gene or its product until 2012.

The aim was to analyze literature on CFTR modulators, including their efficacy and safety, and assess the potential for developing new modulators to treat cystic fibrosis.

Materials. The review included literature data (45 publications) on the use of CFTR modulators and international websites’ data.

Results. Since the discovery of the CFTR gene in 1989, more than 2000 mutations or variants of the CFTR gene (hereinafter referred to as genetic variants) have been described. They interfere with the synthesis of the CFTR protein, its transport to the apical membrane of the cell, or disrupt its function as a channel for chloride anions. Although it is currently not possible to completely replace the mutant gene with a normal copy, small molecules have been identified that can modify the mutant CFTR protein and amend its function. The potential therapeutic measures are determined by class of the mutation. In clinical practice, pharmacological modeling of ion transport is currently possible only with the use of CFTR modulators: correctors and potentiators. The review defines these groups of drugs and describes 4 licensed CFTR modulators, including molecules of ivacaftor, lumacaftor, tezacaftor, elexacaftor. The data on the promising emerging next generation modulators and the prospects for the personalized selection of drugs using the assays on intestinal organoids are presented.

HEALTHCARE MANAGEMENT

238-249 669
Abstract

Despite the low prevalence of cystic fibrosis (CF), the costs of treating this disease are significant for the healthcare system. The aim of this economic study was to assess the total cost of drugs per year for children with CF, depending on age and course of the disease.

Methods. For this pharmacoeconomic analysis, groups of “hypothetical” patients were formed according to the characteristics of the course of CF, taking into account the required volume of basic CF therapy, antibiotic therapy, and complications.

Results. The cost of basic treatment for CF patients of different ages and disease progression in the hypothetical patient models can vary greatly. The cost of CF therapy increases significantly with age and Pseudomonas aeruginosa respiratory infection, especially in the patients with chronic infection, concomitant polyposis sinusitis, and low nutritional status.

Conclusion. Patients with CF require regular follow-up with control of the microflora of the respiratory tract and effective eradication therapy for P. aeruginosa and other pathogenic microorganisms. Reducing infection rates and the severity of the disease can lead to significant cost savings.

OBITUARY



ISSN 0869-0189 (Print)
ISSN 2541-9617 (Online)