Vol 87, No 3 (2015)


Protracted pneumonia

Chuchalin A.G.


The paper discusses the current characteristics of the etiology and clinical presentation of protracted pneumonia (PP), gives approaches to its differential diagnosis in detail, and considers risk factors for PP and approaches to treating patients with this pathology.
Terapevticheskii arkhiv. 2015;87(3):4-9
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Clinical and laboratory parameters in assessing the risk of exacerbations in chronic obstructive pulmonary disease

Kadushkin A.G., Shman Т.V., Goncharik А.V., Germenchuk I.А., Коlb А.V., Taganovich А.D.


Aim. To estimate the significance of measuring the concentrations of cytokines and immunoglobulins and the relative counts of lymphocyte subpopulations in peripheral blood, as well as clinical parameters in patients with chronic obstructive pulmonary disease (COPD) in order to assess the risk of exacerbations. Subjects and methods. Thirty-seven patients with COPD were examined. A study group consisted of 31 patients. Patients with rare exacerbations were assigned to those who had no or one case; patients with frequent exacerbations were those who had two or more cases a year after examination. A prognostic model was created using the binary logistic regression analysis. Results. A significant statistical model was developed as a regression equation involving 4 indicators (vascular endothelial growth factor, C-reactive protein, CAT scores, and number of exacerbations in the previous year). This mathematical model can predict frequent exacerbations in next year with a sensitivity of 94.1% and a specificity of 80%. Conclusion. The mathematical model created to estimate the risk of frequent exacerbations may be used to elaborate adequate individual treatment regimens for both smoking and non-smoking patients with COPD.
Terapevticheskii arkhiv. 2015;87(3):10-16
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New ideas on the therapeutic effect of a combination of vaccines against pneumococcal, Haemophilus influenzae type b infection, and influenza in patients with chronic obstructive pulmonary disease

Kostinov M.P., Zhestkov A.V., Protasov A.D., Magarshak O.O., Kostinova T.A.


Aim. To estimate the indicators of the therapeutic effect of combination vaccination against pneumococcal, Haemophilus influenzae type b infection, and influenza in patients with chronic obstructive pulmonary disease (COPD). Subjects and methods. Clinical, bacteriological, and immunological studies, by determining the quality of life (QL), were conducted in COPD patients during a year after combination vaccination against pneumococcal, Haemophilus influenza type b infection, and influenza. Results. One year after the vaccination, there were reductions in the number of COPD exacerbations by 3.7 times, in that of antibiotic therapy cycles by 3.4 times, in the levels of inflammatory mediators of interleukins 2 and 8 and interferon-γ, and in the synthesis of IgG antibodies to Streptococcus pneumoniae, Haemophilus influenzae type b, and influenza virus strains as compared to the baseline values. Conclusion. Combination vaccination against bacterial and viral infections substantially improves the major clinical parameters of COPD, positively affecting LQ indicators that generally characterize the therapeutic effect of immunization.
Terapevticheskii arkhiv. 2015;87(3):17-22
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The concept of risk factors in assessing the impact of smoking on an exacerbation of chronic obstructive pulmonary disease

Zhukova O.V., Konyshkina T.M., Kononova S.V.


Aim. By using the risk concept, to determine a quantitative relationship between smoking in patients with chronic obstructive pulmonary disease (COPD) and the development of an exacerbation. Subjects and methods. Case history data were studied in 166 patients admitted for a COPD exacerbation in 2009 to 2012. There were 2 exacerbations for a year or longer. The patients were divided into 2 groups: smokers (n=110) and nonsmokers (n=56). The concept for estimating the risks was based on the calculation of absolute risk in the exposed and unexposed groups, attributable risk, relative risk, and population attributable risk and on the determination of standard errors for each type of risk and confidence interval. Results. The methodological aspects of determining the quantitative relationship between smoking in patients with COPD and the development of its exacerbations (twice or more per year) were considered on the basis of the statistical concept of risk factors. A risk factor concept- based analysis has shown that the impact of smoking is directly related to the worsening of COPD. The frequency of exacerbations is 71.8% in the group of smoking patients and 32.1% in that of nonsmoking patients; the risk factor increases the likelihood of this event by 39.7%. Conclusion. Smoking leads to a 2.2-fold increase in the frequency of COPD exacerbations. The potential hazard index was 2.5.
Terapevticheskii arkhiv. 2015;87(3):23-26
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Impact of tobacco smoking on the clinical and functional indicators and markers of systemic inflammation in patients with severe asthma

Solovyeva I.A., Sobko E.A., Ishchenko O.P., Kraposhina A.Y., Demko I.V., Eidemiller N.S.


Aim. To study cytokine status and to reveal a possible relationship of clinical and functional indicators and systemic inflammation in patients with severe asthma to tobacco smoking. Subjects and methods. Examinations were made in 139 patients with severe asthma during its exacerbation and without the latter after 12 months. Groups 1 and 2 included 98 nonsmoking and 41 smoking patients with severe asthma, respectively. A control group consisted of 40 apparently healthy volunteers. External respiratory function, plasma TNF-α, IFN-γ, IL-2, IL-4, IL-6, IL-8, IL-10, C-reactive protein, and neutrophil elastase levels, and integral cytokine index were studied. Results. Systemic inflammation that was more marked on a disease exacerbation and mediated by elevated TNF-α, IL-2, and C-reactive protein levels was detected in severe asthma in both groups. The smoking patient group showed a statistically significant increase in IL-8 and neutrophil elastase levels, which may be indirectly indicative of the active participation of neutrophils in the development of chronic persistent inflammation. Conclusion. Tobacco smoking is a clinically significant risk factor that aggravates both the course of asthma and the magnitude of inflammation during a disease exacerbation.
Terapevticheskii arkhiv. 2015;87(3):27-33
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An immune response and an alveolar macrophage phenotype in asthma, gastroesophageal reflux disease and their concurrence

Maev I.V., Lyamina S.V., Мalysheva E.V., Yurenev G.L., Malyshev I.Y.


Aim. To test the hypothesis that an impaired pulmonary immune response in asthma, gastroesophageal reflux disease (GERD) and their concurrence of these diseases is largely determined by disordered alveolar macrophage (AM) reprogramming and to assess the pulmonary immune response and an AM phenotype in patients with asthma, GERD and their concurrence. Subjects and methods. The levels of proinflammatory M1 cytokines, such as IL-1β, IL-8, IL-12p70, IFN-γ, TNF-α, and TNF-β, anti-inflammatory М2 cytokines, such as IL-4, IL-5, and IL-10, and bivalent М1/М2 cytokines, such as IL-2 and IL-6, were determined in bronchoalveolar lavage fluid (BALF) and AM culture medium. Results. Serious deformations in the pulmonary immune response were first detected in patients with mixed pathology towards to an anti-inflammatory M2 phenotype. The change in the pulmonary immune response phenotype in GERD towards M1 and in comorbidity towards M2 was coincident with that of the AM phenotype. In asthma, the change in the pulmonary immune response phenotype occurred towards to M2 and that in the intrinsic AM phenotype did towards M1. This phenotype is likely to form a proinflammatory component and to cause an asthma exacerbation. Conclusion. Analysis of the spectrum of cytokines in BALF and produced by macrophages in asthma, GERD and their concurrence validated the hypothesis that impaired pulmonary immune responses in these diseases are associated with disordered AM reprogramming. The findings also suggest that therapy for the inflammatory component in these diseases should be performed by taking into account the specificity of the cytokine structure of an immune response and the phenotypic heterogeneity of immune cells.
Terapevticheskii arkhiv. 2015;87(3):34-41
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Clinical value of surfactant protein D as a biomarker of pulmonary fibrosis in patients with scleroderma systematica in relation to the presence of gastroesophageal reflux

Sosnovskaya A.V., Fomin V.V., Popova E.N., Lebedeva M.V., Moiseev S.V., Svistunov A.A., Mukhin N.A.


Aim. To study the role of serum surfactant protein D (SP-D) as a biomarker of lung injury in scleroderma systematica (SDS) in relation to the presence of gastroesophageal reflux (GER). Subjects and methods. Fifty-six patients (mean age 46±14 years) with diffuse and circumscribed SDS were examined and underwent pulmonary functional tests, X-ray and, if lung injury was present, high-resolution computed tomography of the lung, echocardiography, gastroduodenoscopy, and barium X-ray of the esophagus; an enzyme-linked immunosorbent assay was used to determine serum SP-D levels. Results. SP-D concentrations significantly correlate with the presence of lung injury in SDS and are significantly higher in the presence of pulmonary fibrosis and the signs of frosted glass and honeycomb lung patterns. SP-D levels were higher in the patients with lung injury and SDS in the group of those with pulmonary fibrosis and GER than in the group of pulmonary fibrosis patients without the latter. Conclusion. Serum SP-D may be considered in a number of biomarkers for the severity of lung injury in SDS, including GER-associated lung injury.
Terapevticheskii arkhiv. 2015;87(3):42-47
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X-ray, laboratory, and functional parallels in intrathoracic sarcoidosis

Vizel I.Y., Vizel A.A., Shaimuratov R.I.


Aim: to compare respiratory function and laboratory data with the radiographic stages of intrathoracic sarcoidosis. Subjects and methods. Three hundred and eleven patients (70.4% for women and 29.6% for men; mean age, 44.7±0.6 years) with histologically verified sarcoidosis underwent X-ray computed tomography, spirography, estimation of carbon monoxide diffusing capacity (DLCO), oxygen saturation, blood count and serum total calcium blood test. The patients were assigned according to sarcoidosis stages as follows: 3.9% with stage 0; 16.4% with stage I; 65.3% with stage II; 13.2% with stage III; 1.3% with stage IV, and 12.9% with Löfgren’s syndrome. Results. DLCO decreased together with an increasing sarcoidosis stage (<80% of the due χ2=8.69 for DLCO; p=0.057); the difference was significant between stages I (84.2±2.8%) and III (76.1±2.9%, p=0.05). According to the radiographic changes, there were decreases in forced vital capacity (FVC) from 99.0±2.5% in stage I to 76.1±3.5% in Stage IV and in forced instantaneous expiratory flow rate at 75% of lung volume (FEF75) from 64.4±3.1 to 44.0±5.9%, respectively. DLCO correlated with FVC, peak expiratory flow, and FEF75 (p<0.01) and arterial oxygen saturation (SaO2) did only with FVC. There was a strong association between the decrease in DLCO and FVC below 80% of the due values (χ2=28.23; d.f.=1; p<0.001). Löfgren’s syndrome failed to affect functional data. In the patients with Löfgren’s syndrome, the serum level of calcium was significantly lower (2.09±0.10 versus 2.35±0.02 mmol/l (p=0.023); however, this indicator did not significantly differ between the radiological stages of intrathoracic sarcoidosis. Conclusion. In sarcoidosis, the changes in DLCO and FVC vary with radiological stages. Decreased SaO2 was observed in Stage IV. The total level of total blood calcium is an indicator independent of the radiological stages of sarcoidosis.
Terapevticheskii arkhiv. 2015;87(3):48-52
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Pulmonary paecilomycosis: Diagnosis and treatment

Strelyaeva A.V., Svistunov A.A., Dzhomaa R.A., Sapozhnikov S.A., Chebyshev N.V., Ashurov A.A., Maksimov M.L., Lazareva N.B., Gabchenko A.K., Sadykov V.M.


Aim. To represent the advances of Russia and Uzbekistan in studying the problem of paecilomycosis. The goal of the investigation was to develop the diagnosis and treatment of pulmonary paecilomycosis (PP). Subjects and methods. Two hundred and twenty-five people, including 200 patients with bronchopulmonary infection with fungi of the Paecilomyces genus and 25 clinically healthy individuals (a control group), were examined. Clinico-anamnestic, laboratory diagnostic, mycological, and immunological studies were conducted; a lymphocyte antigen-binding test was used for differential diagnosis. Paecilomyces infection was diagnosed by microscopically examining the morphology of the fungi in the pathological material (blood, sputum) and by isolating the cultured fungi in the media (Sabouraud’s and Czapek’s ones). The severe complication of PP — atypical paecilomycosis-associated myocarditis (APAM) — was studied in 112 patients with helminthiasis-complicated paecilomycosis. These patients underwent using the conventional echocardiography. Results. Bronchopulmonary paecilomycosis resulting from primary and secondary infection with fungi of the Paecilomyces genus was clinically manifested as chronic obstructive bronchitis (11.5%), recurrent pneumonia (13.5%), exogenous allergic alveolitis (37%), and asthma (26%) complicated by helminthiasis (12%). Iodine deficiency promotes the prevalence of paecilomycosis and echinococcosis favors Paecilomycosis infection; moreover, the helminth capsule itself serves as a nutrient medium for the development of the mycelial form of the fungus. APAM is a severe complication of PP. Almost 50% of the patients with PP presented with carditis. The patients with APAM occasionally experienced fear and the most severe intermittent pain. The latter first occurred in the chest and irradiated to the axilla, left hand, and its fingertips, paralyzing the arm. In some patients, the pain manifested itself in both arms with abdominal irradiation, by being accompanied by faints. Current analgesics (meloxicam, tizanidine, nimesulide, morphine, promedole) in combination with fluconazole provided a temporary positive effect. Conclusion. Further investigations that must also include neurologists and anesthetists are required to work out effective pain relief regimens for APAM in patients with PP.
Terapevticheskii arkhiv. 2015;87(3):53-58
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Positive effect of low-activity thromboxane A synthase 1 gene on prognosis in coronary heart disease

Kopylov F.Y., Mesitskaya D.F., Nikitina Y.M., Aksenova M.G., Dobrovolsky A.V., Lomakin O.V., Chernyi O.V.


Aim. To analyze the influence of pharmacogenetic factors on the risk of clopidogrel resistance and cardiovascular events during 18-months follow-up. Subjects and methods. Two hundred and fifty patients taking clopidogrel were examined. Platelet function was determined by optical aggregometry. Thromboxane A synthase 1 (TBS1) gene polymorphism was investigated in all the patients. The impact of TBS1 gene polymorphism on the risk of clopidogrel resistance and cardiovascular events was analyzed during 18 months of follow-up. Results. The carriage of TBS1 gene polymorphism AA was shown to affect the risk of clopidogrel resistance. Cardiovascular complications significantly less frequently occurred in TBS1 gene polymorphism AA carriers during 18 months. Conclusion. The carriage of a slow AA allele of the TBS1 gene is suggested to be a clinically significant protective factor in the secondary prevention of coronary heart disease
Terapevticheskii arkhiv. 2015;87(3):59-65
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Optimization of treatment in hypertensive patients in real clinical practice: Role of a fixed-dose perindopril A and amlodipine combination (Results of the Russian observational CONSTANTA trial)

Kobalava Z.D., Kotovskaya Y.V., Khodorovich N.A.


Aim. To provide a detailed analysis of the efficacy and tolerability of Prestance (perindopril A/amlodipine) in a subgroup of 1936 people participating in the Russian observational CONSTANTA program, most cases of whom were given the drug as a substitute for earlier ineffective monotherapy and combination therapy, without using other antihypertensive agents. Subjects and methods. The analysis included 1936 patients (aged 58.2±7.5 years; 35% men) with uncontrolled hypertension who received angiotensin-converting enzyme (ACE) inhibitors or angiotensin II (AT II) receptor antagonists alone or in conjunction with free or fixed-dose combinations of two-three antihypertensive agents and who were given Prestance to correct antihypertensive therapy, as decided by their doctors. The goal blood pressure (BP) was <140/<90 mm Hg for all the patients. Their treatment lasted three months. Results. At the end of trial, the patients received Prestance (perindopril A/amlodipine) in the following doses: 5/5 mg (15% of the patients), 10/5 mg (39.9%), 5/10 mg (9.8%), 10/10 mg (36.6%). In the analyzed group, the baseline BP was 163.4±13.7/94.6±10,1 mm Hg; heart rate (HR), 74.0±10.9 beats/min; 3 months later, there were decreases in BP to 130.8±10.2/78.5±7.2 mm Hg (as compared to the baseline values; p<0.001) and in HR to 67.9±5.4 beats/min (p<0.01). The mean BP reduction was 32.6±10.8/16.1±7.2 mm Hg. A total of 1607 (83.0%) patients achieved the goal BP while 1520 (78.5%) patients did this without having another antihypertensive therapy. Conclusion. To switch hypertensive patients receiving ineffective monotherapy or dual therapy using ACE inhibitors or AT II receptor blockers to fixed-dose perindopril A and amlodipine combination (Prestance) is a rational way of optimizing a therapy regimen in these patients with a wide range of baseline BP levels; moreover, four out of five patients did not need any additional antihypertensive drug.
Terapevticheskii arkhiv. 2015;87(3):66-70
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Workplace stress and its impact on the 16-year risk of myocardial infarction and stroke in an open female population aged 25—64 years in Russia/Siberia (WHO MONICA-psychosocial program)

Gafarov V.V., Panov D.O., Gromova E.A., Gagulin I.V., Gafarova A.V.


Aim. To determine the impact of workplace stress on the hazard ratio (HR) of myocardial infarction (MI) and stroke in an open female population aged 25—64 years in Russia/Siberia (Novosibirsk) for 16 years. Subjects and methods. A random representative sample of 25-64-year-old women (n=870) residing in a Novosibirsk district was surveyed within the framework of the WHO «MONICA-psychological» program. Workplace stress was investigated using the Karasek scale; an attitude towards work and health prophylactic examinations was studied applying the Health Awareness and Attitude questionnaire of the WHO «MONICA-psychological» program. For 16 years (1994 to 2010), a cohort of all new cases of MI and stroke was examined employing the WHO «Acute MI Registry» program and all possible medical records. The Cox regression model was used to determine HR for MI and stroke in the open female population aged 25—64 years for 16 years. Results. The prevalence of high-level stress in the open female population aged 25—64 years was 31.6%. The high level of job stress was associated with a high responsibility, impossibility to have a rest at the end of a working day, frequent professional dissatisfaction, and a reduced work capacity. During 16 years, the women having high-level job stress showed a 3.22- and 1.96-fold increases in the HR of MI (p<0.05) and stroke (p<0.05), respectively. The incidence of MI and stroke was higher in married women expressing job stress as managers or manual laborers and having high and low educational attainment. Conclusion. The prevalence of high-level workplace stress was substantial in the open population of 25—64-year-old women in Russia/Siberia (Novosibirsk). The stress-related HR of MI and stroke was 3—2 times higher than in those without high-level stress. The HR of MI and stroke is affected by a social gradient.
Terapevticheskii arkhiv. 2015;87(3):71-76
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Efficiency and safety of different etoricoxib regimens in patients with axial spondyloarthritis, including ankylosing spondylitis

Gaydukova I.Z., Rebrov A.P.


Aim. To study the clinical and laboratory efficiency and safety of different etoricoxib (ET) regimens in patients with axial spondyloarthritis (axSpA), including ankylosing spondylitis. Subjects and methods. Forty patients with high axSpA activity (Bath Ankylosing Disease Activity Index (BASDAI ≥4) were examined and randomized to 2 groups: 1) 30 patients who received ET 90 mg continuously every day; 2) 10 patients who took the drug in the same dose intermittently 1—3 times weekly. The activity of axSpA (BASDAI, Ankylosing Spondylitis Disease Activity Score (ASDAS), erythrocyte sedimentation rate (ESR), and high-sensitivity C-reactive protein (hs-CRP)) was evaluated at baseline, 2 and 12 weeks; adverse events were recorded at baseline, 2, 6, and 12 weeks. The number of patients who had achieved an ASAS40 response at 2 and 12 weeks were taken into consideration. Results. At 12 weeks, the continuous administration group displayed decreases in BASDAI from 8 to 4, in ASDAS from 3.8 to 2.6, and in hs-CRP levels from 9.5 to 3.9 mg/l; the intermittent administration group exhibited decreases in BASDAI from 7.6 to 6.0, in ASDAS from 3.5 to 3.1, and hs-CRP from 8.8 to 4.5 mg/l (p<0.05). At this time, an AS40 response was achieved by 22 (73.3%) and 2 (20%) patients in Groups 1 and 2, respectively (p<0.05 for all). No serious adverse events were recorded. Conclusion. The efficacy of ET given in a daily dose of 90 mg was much higher than that of the drug used thrice or less weekly in the patients with axSpA.
Terapevticheskii arkhiv. 2015;87(3):77-82
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Familial partial lipodystrophy (Dunnigan syndrome) due to LMNA gene mutation: The first description of its clinical case in Russia

Sorkina E.L., Kalashnikova M.F., Melnichenko G.A., Tyulpakov A.N.


Hereditary lipodystrophies (HLD) are a heterogeneous group of rare diseases characterized by a complete or partial loss of subcutaneous fat and by the development of metabolic disturbances: diabetes mellitus with obvious insulin resistance and acanthosis nigricans, dyslipidemia, hepatic steatosis, hypertension, and polycystic ovary syndrome. The laminopathy variant familial partial lipodystrophy type 2 or Dunnigan syndrome (FPLD2) is the most common cause of partial LD. The paper describes a family (3 clinical cases) with FPLD2 caused by heterozygous R482W missense mutations in the gene encoding the protein lamin A/C (LMNA; 150330). This observation demonstrates that specialists should be more aware of this disease and make a timely diagnose in cases of concurrent severe metabolic disturbances at a young age, which contributes to more effective treatment of patients and to medical genetic counseling of their families.
Terapevticheskii arkhiv. 2015;87(3):83-87
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Multicentric carpotarsal osteolysis in a rheumatologist’s practice

Dolgikh V.V., Pogodina A.V., Knyazeva T.S., Rychkova L.V., Lutsenko L.A.


Multicentric carpotarsal osteolysis (MCTO) syndrome is a rare skeletal dysplasia associated with missense mutation in the MAFB gene, usually manifesting in young childhood, and showing variative phenotypic signs and course. The clinical manifestations of the syndrome include aggressive osteolysis predominantly of carpal and tarsal bones, progressive nephropathy, and mild craniofacial anomalies. The similarity between the initial clinical manifestations of MCTO and the symptoms of childhood inflammatory joint diseases makes a diagnosis very difficult, in the early stages of the disease in particular, and frequently leads to the ungrounded use of long-term immunosuppressive therapy. The paper describes a familial case of MCTO without affecting the kidneys in the mother and daughter.
Terapevticheskii arkhiv. 2015;87(3):88-91
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Choice of basic therapy for asthma in real clinical practice

Leshchenko I.V., Baranova I.I.


According to the Global Initiative for Asthma, the treatment of asthma should be mainly based on its control that encompasses symptom control and exacerbation risk reduction. Control-based treatment contributes to decreases in the frequency of exacerbations, the incidence of drug side effects, the needs of asthmatic patients for emergency care, and the number of their visits to a doctor and hospitalizations, resulting in a reduction of direct health care costs of asthma. Drugs for the basic therapy of asthma are chosen on the basis of evidence for their efficacy and safety and the view of availability and cost of treatment. In case of poor asthma control it is important to reveal its causes and to change basic therapy according to the individual needs of the patient. A major role in the achievement of asthma control is assigned to a combination of inhaled glucocorticosteroids (ICS) and long-acting β2-agonists. Combined medications are prescribed to asthma patients in accordance with the daily ICS dose required to achieve asthma control.
Terapevticheskii arkhiv. 2015;87(3):92-97
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Impact of respiratory viruses on the course of chronic obstructive pulmonary disease: Towards optimizing treatment

Kalyuzhin O.V., Chelenkova I.N., Ponezheva Z.B.


The paper analyzes the currently available data on the impact of respiratory viruses (RVs) on the exacerbations and clinical phenotype of chronic obstructive pulmonary disease (COPD), as well as on the molecular mechanisms of this impact. It emphasizes the role of acute respiratory viral infections (ARVI), primarily rhinovirus infections (RVI) as the most important triggers of COPD exacerbations and the causes of their severe and long-term course. Particular attention is given to ARVI-induced secondary bacterial infections that worsen COPD exacerbations. The mechanisms of how RVs potentiate chronic inflammation and remodeling of the airway, which are caused by tobacco smoke, are depicted. There are arguments that there is a much greater correlation of the acute episodes showing the more severe respiratory symptoms of COPD with ARVI than can be found by molecular methods for RV verification. The body’s genetic and/or acquired excessive response to viral invasion does not reflect the efficacy of antiviral defense and is an endogenous damaging factor in this situation. The role of RVs in the formation of the clinical phenotypes of COPD with frequent exacerbations remains debatable. The need for a search and more active practical introduction of means to prevent virus-induced COPD exacerbations appears obvious. In this regard, the authors identify chemical and mechanical polyvalent bacterial lysates for oral and sublingual administration. In addition to nonspecific stimulation of antiviral defense, these medicines induce antigen-specific mucosal and systemic reactions against bacterial pathogens. The role of ARVI pathogens in COPD exacerbations deserves a greater practical attention focused towards optimizing the treatment of this social disease.
Terapevticheskii arkhiv. 2015;87(3):98-104
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