Клинико-генетическая и микробиологическая характеристика больных муковисцидозом, проживающих в Московском регионе и Республике Беларусь

The aim of this study was a comparative analysis of course and treatment of cystic fibrosis (CF) in patients living at Moscow Region or at Republic of Belarus’. Methods. This was a comparative analysis of CF patients living at Moscow region (n = 197) or at Republic of Belarus’ (n = 110). The following clinical data were evaluated: sweat chloride test results if available, sputum microflora, nutritional status, complications of CF, and the current treatment. Results. The patient samples did not differ in gender, age, and lung function and had similar rates of F508del and CFTRdele2,3 mutations and Pseudomonas aeruginosa infection. Similar methods were used in both groups to confirm the diagnosis. The groups differed significantly in prevalence of Staphylococcus aureus, Burkholderia cepacia complex, and non-tuberculosis mycobacteria infections. Adult patients living at Moscow Region have lower forced expiratory volume for 1 sec compared to those living at Republic of Belarus’. CF patients younger 18 years of age who lived at Moscow Region had higher body mass index that those living at Republic of Belarus’. CF patients living at Republic of Belarus’ had hepatic cirrhosis and nasal polyps more often that those living at Moscow Region. Conclusion. CF patients living at Moscow Region and at Republic of Belarus’ had similar health status. Children and adolescents from those regions did not differ in key parameters predicting life expectancy and quality of life in CF. The groups differed in the prevalence of hepatic cirrhosis and nasal polyps. Modern ambulatory management using novel inhaled mucolytic and antibacterial agents, and regular follow-up every 3 months allow maintaining the lung functional status and P. aeruginosa infection rate close to that of the patients managed with regular in-hospital intravenous antibacterial and steroid therapy. Муковисцидоз (МВ) характеризуется поражением многих органов, но в большинстве случаев доминирует патология респираторного тракта. Общее число больных МВ в течение последнего десятилетия значительно увеличилось, возросли также доля взрослых пациентов и выживаемость, улучшилось качество жизни больных МВ. Целью исследования явился сравнительный анализ показателей течения МВ больных, проживающих в Московском регионе (МР) (Москва и Московская область) и Республике Беларусь (РБ) (Минск и регионы), а также объема медикаментозного лечения. Материалы и методы. Настоящая работа представляет собой сравнительный анализ данных пациентов с МВ, проживающих в МР (n = 197) и РБ (n = 110). Анамнестически оценивались следующие клинические данные: хлориды пота при проведении потового теста, микробный пейзаж, нутритивный статус, осложнения течения МВ, проводимая терапия. Результаты. Выборки обследованных больных МВ (n = 307), проживающих в МВ и РБ, практически не различались по частоте встречаемости мутации F508del и CFTRdele2,3, синегнойной инфекции в группах детей, показателям функции легких, полу и возрасту (до 18 лет). Применялись единые методы диагностики заболевания (потовые тесты, ДНК-диагностика). Различия отмечены по частоте Staphylococcus aureus, Burkholderia cepacia complex, нетуберкулезных микобактерий. Отмечены более низкие показатели функции легких по объему форсированного выдоха за 1-ю секунду среди взрослых, проживающих в МР. У детей моложе 18 лет, проживающих в МР, отмечено более высокое значение индекса массы тела. Цирроз и полипозный риносинусит чаще регистрировались среди жителей РБ. Заключение. У больных МВ, проживающих в МР и РБ, выявлены сходные характеристики здоровья. Различий по показателям, определяющим качество и продолжительность жизни при МВ, у детей и подростков обоих регионов не установлено. Зарегистрированы различия в отношении цирроза печени, полипоза и остеопороза. Применение амбулаторной тактики ведения больных, динамического наблюдения (1 раз в 3 мес.) с использованием современных ингаляционных муколитических и ингаляционных антибактериальных препаратов дает возможность поддерживать функцию легких и частоту Pseudomonas aeruginosa так же, как и при внутривенной антибактериальной и гормональной терапии в условиях стационара

Reproductive system status and the algorithm to solve fertility issues in men with cystic fibrosis

Rationale: Cystic fibrosis (CF) is a common hereditary disease related to the CFTR gene mutations and characterized by progression and multiple system involvement (primarily of the digestive tract and / or pulmonary system). Most men with CF are infertile. Due to new therapeutic options, the life expectancy of CF patients has increased, with reproductive issues becoming relevant.Aim: A multifaceted assessment of the reproductive system status and fertility in male patients with CF and improvement of the strategies to resolve their reproduction issues.Materials and methods: This cohort prospective study was performed 2006 to 2018 and included 81 unrelated Russian male patients with confirmed CF, aged from 15 to 69 years (mean age 25.6 ± 7.9 years). Forty two (42) patients had pancreatic sufficient and 39 pancreatic insufficient CF. The patients underwent clinical, andrological, laboratory and instrumental examination (scrotal ultrasonography, standard and biochemical semen examination and hormone levels).Results: Reproductive disorders and semen abnormalities found in CF patients varied from preserved fertility to infertility. The following andrological abnormalities were found: delayed puberty (48%), urological disorders (26%), uni- or bilateral testicular hypoplasia (42%), diffuse lesions and cysts of the epididymis (70%), diffuse lesions /calcifications of the prostate (50%), and decreased testosterone levels (24.2%). Azoospermia was diagnosed in 87.5% of the patients, “moderate” or “mild” pathozoospermia (oligo-/astheno-/teratozoospermia) in 11.1%, and normozoospermia in 1.4% of the patients. There were significant differences between the patients with pancreatic sufficient and pancreatic insufficient CF in the ejaculate volume (1.4 ± 1.5 ml vs. 0.6 ± 0.5 ml; р = 0.006), ejaculate pH (6.7 ± 0.7 vs. 6.1 ± 0.4; р < 0.0001), and sperm concentration (19.6 ± 56.0 Mio/mL vs. 0.001 ± 0.008 Mio/ mL; p = 0.011). Normal ejaculate volume was more frequent (21.1% vs 14.7%; p > 0.05) in patients under the age of 25. No bilateral obstruction of vas deferens was found in 71.4% patients with 3849+10kbC>T mutation. There was a significant difference (p < 0.00001) in the frequency of 3849+10kbC>T mutation between the patients with vas deferens obstruction (9.5%) and without it (93.8%). We developed an algorithm to resolve infertility issues (including assisted reproductive technologies) in male CF patients depending on their fertility / presence and type of pathozoospermia and some other factors that may influence the conception and CF risk in the offspring. We also suggested practical recommendations for the andrological assessment, maintenance of reproductive health, and planning of childbirth in these patients.Conclusion: Male CF patients require a multifaceted assessment of their reproductive system. The prognosis of their reproductive functions, the strategy to maintain their reproductive health and making a decision on childbirth depends on the CF type, the CFTR genotype, the results of semen analysis, and the patient’s age. Pancreatic sufficient CF type, 3849+10kbС>T mutation of the CFTR gene and younger age are favorable factors for potential maintenance of vas deferens patency and male fertility in CF patients

Characteristics of the mutation spectrum identified by comprehensive investigation of the <i>CFTR </i>gene in the Russian patients

Rationale: Cystic fibrosis (CF; OMIM 219700) is a  common hereditary disease caused by mutations in the CFTR gene (OMIM 602421). The distribution and frequencies of the CFTR gene mutations vary considerably between countries and ethnic groups. By now about 11%  alleles of the CFTR gene remain unidentified after testing for frequent mutations in the Russian patients. A full determination of the mutation spectrum in the CFTR gene is necessary to optimize medical and genetic assistance to the population and to implement the achievements of targeted therapy in the treatment of CF patients.Materials and methods: The sample included 121 Russian CF patients, in whom testing for 34 routinely analyzed mutations did not identify one (n = 107) or both (n = 14) mutant alleles. Assessment of the coding sequence of the CFTR gene, including the regions of exon-intron junctions, 5’- and 3’-untranslated regions was performed by the Sanger sequencing method; in addition, the search for large rearrangements was conducted by the multiplex ligation-dependent probe amplification (MLPA) method.Results: In addition to the previously identified, 88  more variants were determined, including 28  missense mutations, 15  nonsense mutations, 18 frameshift mutations (14 deletions, 4  insertions), 14  splicing mutations, 1  in-frame insertion, 1  in-frame deletion, 1  in/del mutation, and 10  large rearrangements (7  deletions, 3  duplications). Twenty three (23) novel variants were sequenced. Four (4) complex mutant alleles were found. Sixty (60) variants are found once each. One hundred and thirty four (134) of 135 tested mutant alleles were identified.Conclusion: Consequent use of the sequencing and MLPA methods has allowed for identification of a high proportion of the tested mutant alleles in CF patients from Russia (134/135, &gt; 99%), to detect a  significant diversity of the CFTR mutation spectrum (88  additional variants, 32  of them novel), a  number of repeated mutations (c.2353C&gt;T, c.1240_1244delCAAAA, c.1766+1G&gt;A and c.3929G&gt;A) encountered in 5 or more unrelated patients, which could be included in the panel of routinely analyzed variants in the Russian CF patients; and a high proportion of large rearrangements of the CFTR gene

The global impact of SARS-CoV-2 in 181 people with cystic fibrosis

With the growing SARS-CoV-2 pandemic, we need to better understand its impact in specific patient groups like those with Cystic Fibrosis (CF). We report on 181 people with CF (32 post-transplant) from 19 countries diagnosed with SARS-CoV-2 prior to 13 June 2020. Infection with SARS-CoV-2 appears to exhibit a similar spectrum of outcomes to that seen in the general population, with 11 people admitted to intensive care (7 post-transplant), and 7 deaths (3 post-transplant). A more severe clinical course may be associated with older age, CF-related diabetes, lower lung function in the year prior to infection, and having received an organ transplant. Whilst outcomes in this large cohort are better than initially feared overall, possibly due to a protective effect of the relatively younger age of the CF population compared to other chronic conditions, SARS-CoV-2 is not a benign disease for all people in this patient group