[Assessment of inhalation technique in patients with bronchial asthma and chronic obstructive pulmonary disease].

AIM: Investigate inhalation techniques using different inhalers types and their effect on the course of disease. MATERIALS AND METHODS: This cross-sectional study included 110 patients with asthma, chronic obstructive pulmonary disease using the inhaler at least one month. Inhaler errors performed during demonstration were evaluated for each patient and entered in the check-lists. We also collected information about co-morbidities, education, mMRC dyspnea score, rate of exacerbations, and performed spirometry. RESULTS: 80.9% of patients used metered-dose inhaler, 20.9% - single-dose and 21.8% - multiple-dose dry powder inhaler, 22.7% - soft-mist inhaler. Inhaler errors were made by 80.9% patients. The mean number of mistakes in metered-dose inhaler use was 2±1.6, single-dose powder inhaler -1.5±1.3, multiple-dose dry powder inhaler - 1.25±1.4, soft-mist inhaler - 0.68±0.7 (р=0.003). Age, diagnosis, duration of disease, education level, inhalers usage by relatives have no influence on the inhalation technique. A number of errors was related to female gender (р=0.007) and usage of more than 2 inhalers (r=0.3, p=0.002), previous instruction about inhalation technique (r=0.3, p=0.001). On the other hand, there were correlations between the number of errors and degree of bronchial obstruction, asthma control, severity of dyspnea by mMRC score, exacerbation rate. CONCLUSION: Patients with bronchoobstructive diseases perform many inhaler errors, that substantially influences the severity and course of asthma and chronic obstructive pulmonary disease.

[Triple combination therapy with macitentan, riociguat, and selexipag in a patient with idiopathic pulmonary arterial hypertension (functional class III)].

The article presents a clinical case of successful triple combination therapy in a female patient with functional class III idiopathic pulmonary arterial hypertension. Supplementing the previous macitentan and riociguat treatment with selexipag reduced the severity of clinical manifestations of pulmonary hypertension. Also, the treatment efficacy was demonstrated by improvement of laboratory and instrumental indexes. Time-related changes were evaluated at 3 months after initiation of the selexipag treatment.

[Exacerbation of idiopathic pulmonary fibrosis].

Idiopathic pulmonary fibrosis (IPF) is usually characterized by a chronic and slowly progressive course. According to several studies, a small number of patients with IPF (about 515%) develops an acute deterioration of deasese exacerbation of IPF. Exacerbations of IPF can occur at any time of the disease and sometimes becomes the first manifestation of IPF. Pulmonary hypertension in IPF is a fairly frequent complication, which leads to severe violations of gas exchange and reduced tolerance to physical stress. Currently, proven effective treatments for exacerbations of IPF do not exist, the management of this condition is based on supportive therapy (oxygen, respiratory support) and interventions with inadequate evidences (corticosteroids, immunosuppressant). During exacerbation of IPF a careful search of all the possible triggers is justified. In the presented clinical case of exacerbation of IPF there was demonstrated the efficacy of complex therapy including antifibrotic therapy, PAH-specific medicines and enhanced oxygen therapy.

[Risk factors for the early development of septic shock in patients with severe COVID-19].

AIM: In a retrospective study, we evaluated factors associated with the early development of septic shock in patients with severe COVID-19. MATERIALS AND METHODS: We collected medical records of the intensive care unit patients submitted by the local COVID-19 hospitals across Russia to the Federal Center for the Critical Care at the Sechenov First Moscow State Medical University (Sechenov University). Septic shock in crticially ill patients requiring mechanical ventilation was defined as a need in vasopressors to maintain blood pressure. RESULTS: We studied 1078 patients with severe COVID-19 who were admitted to the intensive care units for respiratory support. There were 611 males and 467 females. The mean age was 61.013.7 years. Five hundred twenty five medical records (48.7%) were received from the Moscow hospitals, 159 (14.7%) from the Moscow region, and 394 (36.5%) from the hospitals located in 58 regions of the Russian Federation. In 613 (56.9%) patients, diagnosis of SARS-CoV-2 infection was confirmed by PCR, and in the other cases it was established on the basis of the clinical picture and the results of the chest CT scan. Septic shock developed in 214 (19.9%) of 1078 patients. In the logistic regression model, the risk of septic shock in patients older than 50 years was higher than in patients of a younger age (OR 2.34; 95% CI 1.533.67; p0.0001). In patients with more severe SARS-CoV-2 infection, there was an increase in the prevalence of cardiovascular diseases, including coronary heart disease and atrial fibrillation, type 2 diabetes and malignant tumors. The risk of septic shock in patients with three or more concomitant diseases was higher than in patients without any concomitant chronic diseases (OR 1.76; 95% CI 1.762.70). CONCLUSION: The risk of septic shock in patients with acute respiratory distress syndrome induced by SARS-CoV-2 is higher in patients older than 50 years with concomitant diseases, although a severe course of the disease is also possible in younger patients without any concomitant disorders.

[Risk stratification methods and their significance in pulmonary arterial hypertension].

Despite significant advances in therapy, pulmonary arterial hypertension (PAH) remains a progressive disease with a poor prognosis. Immediately after establishing the diagnosis of PAH, urgent treatment with PAH-specific therapy is required. Due to the progressive nature of the disease, all patients should be closely monitored and their treatment regimen should be promptly changed according to clinical need. Risk stratification is an important method for informing the clinician and the patient about the prognosis of disease and the choice of therapy methods. The REVEAL scale and the ESC/ERS 2015 risk assessment table are important multifactorial tools for making decisions about the prescription and correction of PAH therapy, as well as for assessment of patients' response to therapy. Current guidelines for PAH indicate that the most important task of treatment of PAH is to achieve the low - risk status.

New Tactics for the Treatment of Pulmonary Hypertension: Switching to a More Effective Therapy.

The article deals with the modern tactics of pulmonary hypertension therapy, used in case of unsatisfactory clinical response to previous therapy. All classes of pathogenetic therapy of pulmonary hypertension are presented, as well as modern views on the risk stratification of annual mortality of patients. Switching to a more effective drug both within one group of pathogenetic PAH-therapy, and to drugs of other classes is discussed. The latest classification of pulmonary hypertension (Nice, 2018) is presented.

[Natriuretic peptides as markers of development and prognosis of pulmonary hypertension severity in patients with chronic obstructive disease.]

Studied the diagnostic and prognostic significance of N-terminal precursor of natriuretic peptide С-type (NT-proCNP) and brain natriuretic peptide (NT-proBNP) in patients with COPD with pulmonary hypertension (PH). The study included 47 patients with COPD (II - IV degrees of severity, 2016 GOLD, men - 44, women -3, mean age 59,3±9.12 years, disease duration of 13.7±5.93 years, the index of Smoking at 23.1±10,93 pack-years, BMI of 27.2±12,06 m/kg2.). Criteria of pulmonary hypertension on the basis of the doppler-echocardiography was an increase of pulmonary artery systolic pressure (PASP) > 40 mmHg alone. Depending on the presence and degree of enhancement PASP patients were divided into three groups: 1 - without pulmonary hypertension (PASP < 40 mmHg, n=168), 2 - moderate pulmonary hypertension (PASP 40 - 55 mmHg, n=101), 3-group with severe pulmonary hypertension (PASP > 55 mmHg, n=19). There was a statistically significant intergroup differences (p1-2 0,001, p 2-3 0,001, p1-3 < 0,001) values of NT-proCNP and NT-proBNP. There was a significant correlation relationship SDLA with the concentration of NT-proCNP (r=0,53, p<0,05) and NT-proBNP (r=0,67; p=0,05). A high diagnostic value of determination of NT-proCNP and NT-proBNP to predict the development and severity of PH in patients with COPD. Cox regression analysis showed that elevated levels of NT-proCNP and NT-proBNP in COPD patients of PH c are the predictors of hospital mortality.

Combination therapy is a new standard for treatment of pulmonary arterial hypertension.

At present, compelling evidence has been obtained that combined therapy of pulmonary arterial hypertension (PAH) with specific drugs can significantly slow progression of PAH. Therefore, in current guidelines combination therapy is already considered as standard treatment for a significant proportion of patients with moderately severe and severe forms of PAH. However, the quality of life and long-term prognosis of patients receiving combination therapy, should be the object of further research. The future research is absolutely necessary to identify the most optimal strategy of treatment of patients with PAH, such as initial combination therapy or rapid sequential combination therapy, double or triple combinations as well as exploring new signaling pathways PAH, which can become targets for new specific drugs PAH.

[A patient with severe idiopathic pulmonary arterial hypertension: Is there a way out?] / Patsient s tiazhelym techeniem idiopaticheskoi legochnoi arterial'noi gipertenzii: est' li vykhod?

The paper considers a clinical example of current therapy for idiopathic pulmonary arterial hypertension in a female patient with its clinical deterioration. It shows the tactics of switching from one drug (bosentan) to others (macitentan) within in the same pathogenetic therapy group (endothelin receptor antagonists). The latest pulmonary hypertension classification (Nice, 2013) is presented. The current strategies of pathogenetic therapy for pulmonary hypertension are discussed.

[Clinical guidelines for the diagnosis and treatment of pulmonary hypertension].

Pulmonary hypertension (PH) is a group of diseases characterized by progressive increases in pulmonary vascular resistance and pulmonary artery pressure, which results in right ventricular heart failure and sudden death. Based on the current version of the guidelines for PH diagnosis and treatment, adopted by the experts of the European Society of Cardiology and the European Respiratory Society in 2009, and on the data of Russian and foreign clinical trials, the Russian experts elaborated clinical guidelines for PH in 2013. The latter consider the current classifications of PH, the specific features of its pathogenesis, and its diagnostic algorithm. The section dealing with drugs for maintenance therapy discusses data on the use of oral anticoagulants, diuretics, cardiac glycosides, and oxygen therapy. PH-specific therapy includes calcium antagonists, prostanoids, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors. Surgical procedures for PH involve atrial septostomy, thromboendartectomy, and lung or heart-lung transplantation. A treatment algorithm is proposed for PH patients. The current medicinal approaches using specific therapy agents and their combinations offer new promises for the effective treatment of patients with PH and improve its prognosis.

[First clinical experience with endothelin receptor antagonist bosentan used in patients with pulmonary hypertension: results of a one-year study].

AIM: To evaluate the efficiency and safety of long-term (12-month) treatment with the endothelin receptor antagonist bosentan (tracleer (Actelion, Switzerland)) in patients with pulmonary hypertension (PH). SUBJECTS AND METHODS: The prospective observational study enrolled 10 patients (8 with idiopathic PH and 2 with PH and systemic scleroderma). The patients' mean age was 50.0 +/- 6.9 years; mean pulmonary artery pressure (mPAP) 65 +/- 12 mm Hg; cardiac output (CO) 3.4 +/- 0.8 l/min; 6-minute walk test (6'WT) distance, 318 +/- 94 m. Before and 3, 6, and 12 months after the treatment, the patients underwent Doppler echocardiography, arterial blood gas analysis, external respiratory function test, and dyspnea evaluation using the MRC scale and 6'WT. The initial dose of bosentan was 62.5 mg b.i.d., then 125 mg b.i.d. following 4 weeks. RESULTS: Bosentan treatment resulted in a reduction in pulmonary artery systolic pressure and mPAP (at 12 months: 76.8 +/- 11.5 and 58.8 +/- 11.4 mm Hg, respectively; p < 0.01) and an increase in CO (at 12 months: 4.2 +/- 1.2 l/min; p = 0.002). Six patients were observed to have a lower WHO classification functional class (FC). Lung diffusing capacity tended to improve (at 12 months, the increment was more than 6% of the reference value; p = 0.059). In the patients, dyspnea was relieved as shown by MRS scores from 3.1 +/- 0.7 (at baseline) to 2.1 +/- 0.6 (at 12 months); p = 0.002. The 6'WT distance increased up to 342 +/- 67 m (at 12 months); p = 0.005. The drug was well tolerated; only one patient had a transient increase in the activity of liver enzymes. CONCLUSION: The long-term bosentan treatment in patients with PH leads to improvements in pulmonary hemodynamics, WHO classification functional class, a reduction in dyspnea, and a rise in exercise tolerance.

[Role of the endothelin receptor antagonist bosentan in the treatment of patients with pulmonary hypertension].

The paper reviews current views of the problem of pulmonary hypertension. It shows the classification of pulmonary hypertension and considers the general issues of its pathogenesis, morphological changes, clinical picture, and main approaches to treating patients with pathology. Particular emphasis is placed on the review of clinical trials of the class of endothelin receptor antagonists.

[Idiopathic and secondary pulmonary hypertension].

In the available literature, there are single papers on the association of the values of external respiratory function and the EchoCG sings of pulmonary hypertension with the morphological parameters of pulmonary arterial branches in idiopathic pulmonary hypertension (IPH) and secondary pulmonary hypertension (SPH). The present investigation comprised a comprehensive study of life-time functional changes in the cardiopulmonary system and postmortem morphometric changes in the heart and pulmonary vessels in idiopathic pulmonary fibrosis (IPF)-induced SPH and IPH. The investigation has indicated that PPH and SPH are characterized by the same-type rearrangement of pulmonary arterial branches as intimal hyperplasia and medial hypertrophy; however, IPH, as compared with SPH, induces a more significant cor pulmonale. The magnitude of right and left ventricular dysfunction corresponds to the degree of pulmonary hypertension (PH) and cor pulmonale. In IPF, the decreases in tidal volumes and pulmonary diffusion capacity favor PH progression.

Rapid evolution of translational control mechanisms in RNA genomes.

We have introduced 13 base substitutions into the coat protein gene of RNA bacteriophage MS2. The mutations, which are clustered ahead of the overlapping lysis cistron, do not change the amino acid sequence of the coat protein, but they disrupt a local hairpin, which is needed to control translation of the lysis gene. The mutations decreased the phage titer by four orders of magnitude but, upon passaging, the virus accumulated suppressor mutations that raised the fitness to almost wild-type level. Analysis of the pseudorevertants showed that the disruption of the local hairpin, controlling expression of the lysis gene, had apparently been so complete that its restoration by chance mutations could not be achieved. Instead, alternative foldings initiated by the starting mutations were further stabilized and optimized. Strikingly, in the pseudorevertants analyzed, translational control of the lysis gene had been restored. This feat was accomplished by, on average, four suppressor mutations that generally occurred at codon wobble positions. We also introduced 11 mutations in a hairpin more upstream in the coat protein gene and not implicated in lysis control. Here the titer dropped by three logs, but pseudorevertants with a fitness close to wild-type were soon generated. These pseudorevertants again were the result of the optimization of alternative foldings induced by the mutations. The transition of the secondary structure from wild-type to pseudorevertant could be visualized by structure probing. Our study shows that the folding of the RNA is an important phenotypic property of RNA viruses. However, its distortion can easily be overcome by optimizing alternative base-pairings. These new structures are not qualitatively equivalent to the original one, since they do not successfully compete with the wild-type.