Characteristics of mukoviscisidosis in the southern regions of Russia

Introduction. Cystic fibrosis (CF) is a  hereditary disease with genetic heterogeneity and clinical polymorphism. Expanding the range of knowledge about the characteristics of the course of the disease in different regions is important to achieve the goal of improving the quality and life expectancy.Purpose. Comparative analysis of the features of the course of CF in the subjects of the Southern Federal District, Stavropol Territory.Methods. Data from the National Register of Patients of the RF MV 2016 were used. Results: there are clinical and genetic features between the regions of the Southern Federal District and the Stavropol Territory of the North Caucasus Federal District and in general with the Russian Federation. Analysis of the data showed differences in indicators: the proportion of patients aged ≥ 18 is the lowest in the Republic of Crimea (14.9%), in the Rostov region the lowest average age of patients (9.0 ± 6.3), and the lowest age of diagnosis 2.2 ± 3.1 years. Late terms of diagnosis were revealed in the Stavropol Territory (4.0 ± 8.0 years), but here there is one of the highest average age of CF patients (14.1 ± 11.5), the proportion of adult patients (23.3%) and the lowest allelic frequency of F508del, which is determined by the high number of patients with a “soft” genotype. There is a high proportion of patients with an undetermined genotype. A low proportion of two identified genetic variants of the CFTR gene is registered in patients of the Republic of Crimea. A low frequency of Burkholderia cepacia complex and Achromobacter spp was revealed, and a high infection with non-tuberculous mycobacteria was revealed in the Rostov region. FEV1 in children and adults was lower in Rostov Region and Stavropol Territory. In all regions, there is a discrepancy between the seeding of flora and azithromycin therapy and the severity of the genotype with the use of pancreatic enzymes.Conclusions. Analysis of the data of the registry, which allows substantiating the need to study the regional characteristics of the course of CF in order to differentiate the planning of measures to improve the quality of medical care for patients with CF

Изучение эффективности, безопасности и оценка удовлетворенности ингаляционной терапией препаратом Тобрамицин-Гобби при синегнойной инфекции у детей с муковисцидозом

Study of efficacy, safety, and patient satisfaction with inhaled tobramycin (Tobramycin-Gobbi) in children with cystic fibrosis and pseudomonas infectionAim 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.Антибактериальная терапия (АБТ) синегнойной инфекции при муковисцидозе (МВ) остается основным фактором, определяющим функцию легких и продолжительность жизни больных. Основным патогеном, который определяет степень тяжести течения МВ, продолжительность и качество жизни пациентов, является Pseudomonas aeruginosa.Целью исследования явилось изучение эффективности, безопасности и оценка удовлетворенности ингаляционной терапии препаратом Тобрамицин-Гобби при синегнойной инфекции у детей с МВ.Материалы и методы. В неинтервенционном проспективном когортном многоцентровом исследовании принимали участие дети (n = 35; возраст – 6–18 лет) с установленным диагнозом МВ, наличием синегнойной инфекции (первый высев, рецидивирующая и хроническая инфекция), наблюдавшиеся в 8 российских центрах МВ. В течение 6 мес. дети получали ингаляционную терапию указанным препаратом циклами по 28 дней ингаляций / 28 дней перерыв. Контролировались показатели респираторной функции, бактериальная флора дыхательных путей с оценкой степени обсемененности, показатели массы тела и роста, применяемая АБТ по поводу респиратор- ных эпизодов. Дети и их родители заполняли анкету пациента «Оценка удовлетворенности препаратом», при этом отмечалось самочувствие по визуальной аналоговой шкале до начала лечения и после каждого цикла приема препарата.Результаты. На фоне терапии в 6 (17,7 %) случаях (2 – с первичным высевом, 3 – с рецидивирующим, 1 – с хронической синегнойной инфекцией) выявлено отсутствие высева P. аeruginosa, уменьшение степени обсемененности, сокращение числа курсов АБТ, улучшение показателей объема форсированного выдоха за 1-ю секунду. Зарегистрированы нежелательные побочные реакции (n = 1).Заключение. Показана эффективность препарата Тобрамицин-Гобби при первичном высеве, интермиттирующей и хронической инфекции, вызванной P. аeruginosa, его безопасность и хорошая переносимость

Генетическая характеристика больных муковисцидозом в Российской Федерации по данным Национального регистра (2014)

The aim of this study was to investigate genetic features of patients with cystic fibrosis (CF) according to the National Register findings in Russia. Methods. The study involved 2,131 CF patients living in 74 regions of Russia who were included in the National Register of CF patients in 2014. Results. Genetic testing was performed in 89% of patients. The total mutant allele frequency was 81.2%. One hundred and twenty two mutations were found which comprised 173 genotypes; «mild» mutations took 23%. The most common mutant allele frequencies in the descending order were as follows: F508del, 51.53%; СFTRdele2,3, 5.93%; E92K, 2.62%; 3849+10kbC>T, 2.14%; 2184insA, 1.80%; W1282X, 1.80%; 2143delT, 1.69 %; N1303K, 1.43%; G542X, 1.16%; 1677delTA, 0.98%; L138ins, 0.95%; R334W, 0.85%; 394delTT, 0.85%; 3821delT, 0.42%; 2789+5G>A, 0.37%; S466X, 0.37%; S1196X, 0.37%; 3272-16T>A, 0.34%; W1282R, 0.29%; 3944delGT, 0.21%. Typical features of CFTR mutation distribution in Russian CF patients were lower frequency of mutations which are predominant worldwide, such as F508del, G542X, N1303K, and scarce G551D, 1717-1G>A, 2183AA>G mutations. On contrary, СFTRdele2,3, E92K, 2184insA, 2143delT, 1677delTA, L138ins mutations which are quite rare in Western Europe were encountered more often in Russia. «Mild» mutations were more common in Russian population of CF patients compared to European countries and have being increasing last years. Conclusion. Genetic features of Russian CF patients could be provided by Slavic, Turkic and Finno-Ugric genetic influence on Russian population.Генетическому разнообразию больных муковисцидозом (МВ) в России посвящены единичные работы на ограниченной выборке больных. Цель. Выявление особенностей генетического профиля больных МВ в России по данным Национального регистра (2014). Материалы и методы. Данные пациентов с МВ (n = 2 131) из 74 регионов России, включенные в Национальный регистр больных МВ (2014). Результаты. Генетическое обследование проведено у 89,0 % больных, суммарная аллельная частота выявленных мутаций составила 81,2 %. Выявлено 122 мутации, которые сформировали 173 различных генотипа, среди которых доля «мягких» генотипов составила 23,0 %. Аллельная частота самых распространенных мутаций представлена в порядке убывания: F508del – 51,53 %, СFTRdele2,3 – 5,93 %, E92K – 2,62 %, 3849+10kbC>T – 2,14 %, 2184insA – 1,80 %, W1282X – 1,80 %, 2143delT – 1,69 %, N1303K – 1,43 %, G542X – 1,16 %, 1677delTA – 0,98 %, L138ins – 0,95 %, R334W – 0,85 %, 394delTT – 0,85 %, 3821delT – 0,42 %, 2789+5G>A – 0,37 %, S466X – 0,37 %, S1196X – 0,37 %, 3272-16T>A – 0,34 %, W1282R – 0,29 %, 3944delGT – 0,21 %. Выявлено, что особенностями распределения мутаций. CFTRсреди российских больных МВ являются меньшая частота доминирующих в мире мутаций, таких как F508del, G542X, N1303K, единичная встречаемость мутаций G551D, 1717-1G>A, 2183AA>G и наоборот – более высокая частота мутаций, являющихся относительно редкими в западноевропейских странах: СFTRdele2,3, E92K, 2184insA, 2143delT, 1677delTA, L138ins. Другой особенностью является более высокая встречаемость «мягких» мутаций в России по сравнению со странами Европы. Выявлено, что доля «мягких» мутаций в популяции больных МВ на протяжении последних лет увеличивается. Заключение. При формировании населения России особенности генетического профиля российских больных МВ определяются славянскими, тюркскими и финно-угорскими влияниями

Late opening of occluded coronary artery in myocardial infarction patients: is it always advisable?

Aim. The study was aimed at verifying a hypothesis: in myocardial infarction (MI) patients with occluded MI‑related coronary artery (IMCA), routine percutaneous coronary intervention is more effective than conservative, pharmacological treatment, for reducing cumulative total mortality risk, risk of recurrent non‑fatal MI, or severe heart failure (HF). Material and methods. The study included 2166 MI patients, with stable clinical course and IMCA occlusion remaining at Day 3‑28, verified by coronary angiography. The participants were randomized into two groups: pharmaceutical treatment group (n=1084) and invasive treatment group (n=1082). Combined primary end‑point included death due to all causes; non‑fatal MI; severe HF with hospitalization. Secondary end‑points were separate components of primary end‑point. Results. By the end of follow‑up Year 4, primary end‑point rates were 17,2% and 15,6% in invasive and pharmaceutical treatment groups, respectively (р=0,2). No benefits for any strategy were observed in various subgroups by age, gender, ethnicity, coronary occlusion localization, left ventricular contractility, diabetes mellitus, severity and duration of the disease. Total mortality was identical in both groups. Recurrent MI rates were higher in invasive therapy group, compared to pharmaceutical therapy group. Conclusion. Therefore, late opening of occluded IMCA in stable patients did not reduce the risk of death, recurrent IM, or severe HF during four‑year follow‑up

THE INFLUENCE OF CARDIAC RESYNCHRONIZING THERAPY ON VEGETATIVE HEART RHYTHM REGULATION IN INDIVIDUALS WITH CONGESTIVE HEART FAILURE

Aim. To study the influence of cardiac resynchronizing therapy (CRT) on autonomous cardiac regulation during follow-up in patients (pts) with chronic heart failure (CHF).Material and methods. 22 pts (14 (63,6%) males, mean age 50±10,0 years) with implanted cardiac resynchronization devices were examined. 14 (63,6%) pts had ischemic cardiomyopathy, 12 pts (54,6%) were in NYHA class II, 6(27,3%) – III, 4(18,1%) – IV. Mean follow-up was 12,5 [9,3;13,3] months. Heart rate variability (HRV) analysis was performed on 5-minute ECG recordings made at rest and in active orthostatic test (AOT). Echocardiographic and electrocardiographic parameters were estimated. Pts with a decrease in left ventricular end-systolic volume ≥15% was classified as responders (n=11 – gr.I) and <15% – nonresponders (n=11 – gr. II).Results. At baseline in gr.II higher pulmonary artery systolic pressure (PASP) and right ventricle dimension were detected. At baseline in gr.I significant LF/HF increase, SDNN and TP decrease in AOT were observed. During prospective study in gr.I LF/HF increase in AOT was significant and LF and LF% were higher as compared with initial. At baseline and during follow-up in gr.II HRV parameters were unchanged.Conclusion. CRT exerts positive influence on autonomic cardiac regulation in CHF patients. Preservation of sympathetic reactivity in AOT probably can be used as a marker of a good CRT response

Prediction of 5-year survival in patients with heart failure and implanted cardiac resynchronization therapy devices

Aim. Based on clinical parameters and diagnostic investigations, to create a complex model of personalized selection of patients with heart failure (HF) for cardiac resynchronization therapy (CRT). To establish the diagnostic value of the created model in predicting 5-year survival.Material and methods. The study included 141 patients with HF (men, 77,3%; women, 22,7%). The mean age of patients at the time of implantation was 60,0 [53,0; 66,0] years. All patients had New York Heart Association (NYHA) class II-IV HF, left ventricular ejection fraction (LVEF) ≤35%, and QRS ≥130 ms. Patients were randomly divided into training (n=95) and test (n=36) samples, which were comparable in main clinical and functional characteristics.Results. The index included parameters that had a significant relationship with 5-year survival according to the Cox regression: male sex, prior myocardial infarction, hypertension, QRS <150 ms, no left bundle branch block, PR ≥200 ms with sinus rhythm/absence of radiofrequency ablation in atrial fibrillation, NYHA class III, IV HF, LVEF <30%, left ventricular end-diastolic volume ≥235,0 ml, NT-proBNP ≥2692,0 ng/ml. All variables were scored based on the в-coefficients. In the training sample, a value ≥45 points demonstrated a sensitivity of 82,4% and a specificity of 67,2% in predicting 5-year survival (AUC, 0,873; p<0,001). The index use on the test sample showed comparable results (AUC, 0,718; p=0,020; sensitivity — 71,4%, specificity — 62,5%). Also, in the training sample, the index ≥45 points was associated with1-year survival (sensitivity — 84,6%, specificity — 58,1%, AUC, 0,811; p<0,001).Conclusion. An index of personalized selection for CRT has been created, which makes it possible to accurately predict the 5-year survival rate, as well as the 1-year survival rate, regardless of the current selection criteria

SPECIFICS OF ACTIVE ORThOSTATIC TEST IN PATIENTS WITH CHRONIC HEART FAILURE

Aim. To reveal clinical and morphofunctional and biochemical differences among patients with chronic heart failure (CHF) with different response type on active orthostatic test (AOT).Material and methods. Totally 63 patients with CHF included with cardiomyopathy of ischemic and non-ischemic origin mostly of II-III functional class NYHA. All patients underwent echocardiography, heart rate variability analysis (HRV) resting and during DOT, plasma levels of NT-proBNP measured with C-reactive protein, tumor necrosis factor-α, interleukines (IL)-1β,6,10. According to the dynamics of HF% in AOT, all patients were divided into 2 groups: 1st group consisted of patients with decrease of HF% in AOT, 2nd group — with increase of HF% in AOT.Results. In patients from 2nd group we found larger heart chambers and volumes, as lower left ventricle ejection fraction comparing to the patients of the 1st group. Also in the 2nd group there were higher levels of NT-proBNP and IL-6. Resting patients of the both groups had very low values of all parameters of HRV. During AOT in the 1st group there was significant increase of HRV parameters, characterizing sympathetic and humoral systems activity. In the 2nd group the response on orthostasis was as a decrease of HRV values that characterize adreno-humoral influences, and sympathovagal index, characterizing sympathetic influence, was unchanged.Conclusion. Population of CHF patients is heterogenic according to neurohumoral activation. Decrease of sympatho-adrenal reactivity and relative increase of parasympathic influences in active orthostasis in CHF patients probably witnesses the exhaustion of sympatho-adrenal regulation and is a marker of CHF severity

Patchy villous atrophy of the duodenum in childhood celiac disease.

OBJECTIVES: Patchy villous atrophy of the duodenal mucosa has been described in adults with untreated celiac disease (CD) but not in children. The authors evaluated the presence and the distribution of villous atrophy in children with celiac disease to see whether this histologic pattern exists in children. METHODS: We studied 95 children at diagnosis (Group 1) and seven during gluten challenge (Group 2). We measured anti-endomysium antibodies (EMA) by immunofluorescence on monkey esophagus, antihuman-tissue transglutaminase autoantibodies (anti-tTG Abs) by radioimmunoprecipitation, and HLA-DQ2/DQ8 heterodimers by polymerase chain reaction using specific primers. During upper intestinal endoscopy, at least five duodenal biopsy samples were obtained, one from the duodenal bulb and four from the distal duodenum. RESULTS: Thirteen of 95 (13.7%) patients in Group 1 and in 3 of 7 (42.9%) in Group 2 had patchy villous atrophy of the duodenum. In all 16 patients, villous atrophy of the bulb was present. In four children from Group 1, villous atrophy was observed only in the bulb samples. EMA, anti-tTG Abs, and HLA-DQ2/DQ8 heterodimers were present in all patients. Fourteen of 16 had symptomatic CD, and two were silent, detected during screening in subjects at risk for CD. CONCLUSIONS: This is the first study demonstrating that children with CD may have patchy villous atrophy of the duodenum. The bulb mucosa may be the only duodenal area involved, both at diagnosis and after gluten challenge. Therefore, multiple endoscopic biopsies should always be performed, not only in the distal duodenum, but also in the bulb

Sanatorium rehabilitation effects on vegetative test dynamics in myocardial infarction patients

Aim. To study dynamics of vegetative reflex tests (VRT) during sanatorium rehabilitation in patients with noncomplicated myocardial infarction (MI).Material and methods. In total, 106 men (mean age 48,6±1,0 years) were examined 44,3±3,2 days after MI, beforeand after sanatorium6based rehabilitation. Heart rate variability (HRV) was assessed during 24-hour electrocardiography (ECG), ECG at rest, active orthostatic test (AOT) and controlled breath rate test (CBRT). Physical stress tolerability (PST) and echocardiography parameters were also assessed.Results. After rehabilitation course, low frequency HRV component was increased in rest ECG (by 19 % for absolute values (p=0,06), by 5 % for normalized values (p=0,08)) and during AOT (by 27,3 % (р=0,015) and 6,2 % (р=0,011), respectively). CBRT results remained the same. Veloergometry PST increased by 10,1 %, end-systolic and end-diastolic left ventricular (LV) volumes decreased by 8,7 % and 6,6 %, respectively, asynergic area reduced by 6,0 %, and LV ejection fraction increased by 6,1 %. Rehabilitation adequacy was also confirmed by some decrease in mean HR and ventricular extrasystole rate during 246hour ECG monitoring.Conclusion. The results obtained could facilitate HRV data use in physical rehabilitation effectiveness assessment,optimizing and individual tailoring of rehabilitation programs