[The problem of viral hepatitis C in the Russian Federation].

The incidence of chronic viral hepatitides (CVH) has increased 2.2-fold in the Russian Federation over the past decade. This increase is mainly determined by an almost threefold rise in the incidence of chronic hepatitis C (CHC): from 12.9 in 1999 to 39.1 per 100,000 population in 2012. The calculated data of hepatitis C burden in the Russian Federation show that in 2010 the total medical and social losses and expenses associated with hepatitis C and its implications were 48.47 billion rubles or 0.108% of the gross domestic product, the direct medical costs were 17.1 billion (35.28%) rubles, GDP losses were 26.05 billion (53.75%) rubles, and the disability payments were 5.32 billion (10.97%) rubles. The patients (mean age 45 years) with liver cirrhosis (LC) were 15.2% in the structure of the CHC patients (mean age 37 years) admitted to Moscow infectious diseases hospitals in 2010. Analysis of the regional registers of the Russian Federation, the proportion of patients with LC among those with CHC was 18%. The existing forms for recording morbidity and mortality from poor CHC outcomes cannot significantly estimate the true disease stage distribution of patients and hepatitis C-associated disability and mortality rates. In this connection, it is necessary to introduce a federal register and to change recording forms for patients with viral hepatitides. Standard interferon, pegylated interferon alpha 2a and pegylated alpha 2b, and the HCV protease inhibitors telaprevir, boceprevir, and simeprevir have been registered for the treatment of hepatitis C in the Russian Federation.

[Some aspects of the treatment of adult patients with Epstein-Barr virus infection].

The review analyzes the basic aspects of treatment policy in patients with different forms of Epstein-Barr virus infection. Practical recommendations are given on the basis of the extensive literature data published in the past 20 years.

[Oral infections].

In the survey the basic aspects of the infectious pathology are analyzed, that are to be met in the work of stomatologist. There is in detail described the intra-hospital infection, caused by conditionally pathogenic flora. There is given the clinical characteristics of the oral manifestations of the basic of <> infectious diseases.

[Features of proliferative response of T-cells on hepatitis c virus antigens in healthy individuals contacting with this virus].

AIM: Evaluation of CD3+ and CD3-/CD56+ proliferative response on hepatitis C virus antigens in healthy medical workers. MATERIALS AND METHODS: The study included 15 medical workers with length of service of 2 and more years without common risk factors (blood and blood products transfusion, abdominal operations, invasive procedures, use of intravenous drugs). Control group consisted of 9 healthy individuals without risk factors. Peripheral mononuclears were isolated from blood and then incubated 72 hours in the presence of mitogen/PHA, Core+NS4 1b genotype HCV, NS4 HCV2a+3a genotypes or medium. Proliferative activity was registered by the presence of cell division marker ki67 by using FACS. RESULTS: The initial immunogram of medical workers differed from the control group by a significantly lower quantity of CD3+ lymphocytes, in particular CD3+/CD8+ population. Incubation with PHAresulted in a decrease of quantity of CD3+/ ki67+, CD4+/ki67+ and CD3-/CD56+/ki67+ in the medical workers group. Cultivation with HCV antigens resulted in a significant decrease of Treg (CD3+/CD25high/FoxP3+) and activated T-lymphocytes population in the case of stimulation by Core and NS4 1b genotype antigens. Analysis of cell response on virus antigens based on proliferative activity index detected significant differences only for CD8+/ki67+. Stimulation by Core and NS4 1b genotype antigens resulted in an increase of quantity of these cells whereas in the case of NS4 2a+3a genotypes their decrease was observed. CONCLUSION: The described changes may reflect exhaustion of cell reactivity due to extra antigen load in the group of medical workers, while differentiated immunologic shifts on hepatitis C viruses of various genotypes are noted.

[Immunogenetic factors of interaction of hepatitis C virus and human and possibilities of development of therapeutic tactic].

Various macroorganism factors influence spontaneous and therapy induced elimination of hepatitis C virus. Standard therapy is application of a combination of pegylated interfernos and ribavirin. However such tactics results in attainment of a resistant virological response in approximately half the cases during infection by genotype 1 virus. The future of viral hepatitis C therapy lies most probably in the sphere of application of specific antiviral preparations such as protease and/or polymerase inhibitors as an addition to standard therapy. The aim of this review was to describe mechanisms of resistance to therapy in light of reaction of innate and adaptive immune response as well as an attempt to determine factors capable of prognosing response to therapy

[Dengue fever in Russian tourists who have come from Thailand].

The review analyzes the major epidemiological and clinical aspects of Dengue fever, by providing the clinical examples of using its imported cases. It gives algorithms for examining patients who have come from tropical countries with the fever of unknown origin. Based on the extensive data available in the literature and international guidelines, the authors present treatment algorithms for out- and inpatients with Dengue fever. Promising studies of vaccination against Dengue fever are analyzed.

[The burden of viral hepatitis in the Russian Federation requires reducing its progression for the long term, including chronic hepatitis C)].

AIM: To evaluate the impact of using the innovative antiviral drugs in patients with chronic hepatitis C (CHC) on the disease burden in the long term. MATERIALS AND METHODS: A program was developed to increase the availability of innovative antiviral therapy (AVT) in patients with CHC covering the period from 2013 to 2020. To evaluate the impact of the program on the burden of hepatitis C (HC) in the Russian Federation, a Markov model of the disease progression was developed till 2030. Calculations were made in medical and social perspectives. RESULTS: The implementation of the program will allow to decrease the medical costs by RBL 2 billion and budget costs, including disability payments, by RBL 3.8 billion by 2030. During this period, in GDP losses will decrease by RBL 1.1 trillion and the total burden of HC taking into account the cost of the program by RBL 1 trillion. CONCLUSION: For the first time it was shown that the expanding coverage of CHC patients with innovative AVT will allow to reduce the costs of health and social services.

[Antagonistic activity of lactobacilli of the colon].

AIM: Study of antagonistic activity of lactobacilli of the colon against members of its autochthonous bacterial flora and agents of some acute infectious and chronic diseases of the gastrointestinal tract. MATERIALS AND METHODS: Antagonistic activity of 19 lactobacilli cultures against 28 cultures of bacteria belonging to various groups and fungi was evaluated within the framework of specially developed two-stage cultivation technique in the conditions of a combined system. The results of the study were evaluated according to a semi-quantitative scale that allows to put one or the other value of the zone of growth delay of the studied strain culture in compliance with the one or the other (low, moderate, high) level of antagonistic activity of the lactobacillus culture. RESULTS: Lactobacilli of the colon showed selective antagonistic activity against pathogenic enterobacteriae: pronounced against Salmonella enterica Serovar Enteritidis, Shigella flexneri 2b, Yersinia spp., and trace against Salmonella enterica Serovar Typhimurium. The level of antagonistic activity of lactobacilli against a wide range of members of autochthonous bacterial flora varied in a wide range, without revealing connection neither to its belonging to species, nor to its population level, nor to the belonging to group of the antagonistic effect objects. On the other hand a connection was traced with beloriging to a certain microbiota: being quite active against members of its own microbiota, lactobacilli often showed significantly lower level of antagonistic activity against cultures with the same species name isolated from other microbiota. CONCLUSION: In light of the results obtained, level of lactobacilli population may hardly be viewed as the only criteria of their full participation in the process of stabilizing microecological welfare of the colon, that allows to make a complete representation of the level of dysbiotic disorder in the mentioned biotope. With in the framework of rational bacteriological diagnostics of the level of dysbiotic disorders in the colon, evaluation of population level of lactobacilli should be evaluated along with the degree of their antagonistic activity against other components of the same microbiota.

[Proteomic technologies for identification of serum potential biomarkers of autoimmune demyelinating polyneuropathies].

Time-of-flight MALDI mass spectrometry (MALDI-TOF-MS) profiling of blood serum of patients with Guillain-Barré syndrome (GBS, 36 samples), chronic inflammatory demyelinating polyneuropathy (CIDP, 24 samples) and practically healthy donors (HD) (35 samples) was carried out in order to identify potential biomarkers of autoimmune demyelinating polyneuropathies (ADP). To simplify the peptide-protein mixture of serum prior to MALDI-TOF-MS analysis samples were pre-fractionated on magnetic microparticles with a weak cation-exchange (MB-WCX) surface. Comparative analysis of mass spectrometric data using the classification algorithms (genetic and neural network-controlled) revealed a characteristic set of peaks, agreed change area with a high specificity and sensitivity of the differentiated mass spectrometry profiles of the blood serum of patients with DPNP and healthy donors (for GBS values of these characteristics reached 100 and 100, and for CIDP 94.1 and 100% respectively). Comparative analysis of mass spectrometric profiles of serum samples obtained from patients with GBS and CIDP, allowed to build a classification model to differentiate these diseases from each other, with a specificity of 88.9 and a sensitivity of 80%.

[Immunological aspects of HCV/HIV coinfection].

AIM: To evaluate effects of HCV/HIV coinfection on blood lymphocyte phenotype including cells CD56+. MATERIAL AND METHODS: We studied standard immunogram, subpopulational composition and functional activity of blood cells CD56+ in 67 patients with verified diagnosis of HIV infection and virus hepatitis C. RESULTS: We discovered some pathogenetically sound indices of immune status in patients with HCV/HIV coinfection. Some of the immune shifts detected changed in response to intake of narcotic drugs, antiretroviral treatment, hepatic cirrhosis, pneumonia. CONCLUSION: Parameters of subpopulational composition and functional activity of cells CD56+ in the blood of patients with HCV/HIV coinfection elucidate some unknown features of the above infectious process which should be considered in this coinfection treatment and prophylaxis.

[Antiretrovirus drugs impair kidneys in HIV-infection].

Renal damage in HIV infection may result from direct action of HIV and from other causes including nephrotoxic action of medicines. HIV-infected patients receive a wide spectrum of medicines and can be placed in a risk group of drug-induced damage to the kidneys. Risk of nephrotoxicity should be considered in administration of antiretrovirus drugs in HIV patients. Strategy of preventive measures in relation to pharmacological harm to the kidneys consists in early detection of patients with high risk and correction of modifiable risk factors.

[Chronic Yersinia infections as a therapeutic problem].

Physicians of any specialty encounter the chronic course of yersiniasis, the clinical manifestations of which are polymorphic and similar to the symptoms of other diseases, including autoimmune ones. The long interval of an evolving pathological condition after the acute period of the disease leads to the fact that the clinical and laboratory manifestations of chronic yersiniasis are wrongly regarded as an independent nosological entities unassociated with the persistence of Yersinia. Dynamic blood tests for specific IgA to the Yersinia enterocolitica virulence factors that are an indirect sign of on-going pathogen persistence in the body are required to elaborate the tactics for the examination, treatment, and follow-up of patients.

[Outcomes of severe pandemic influenza A/H1N1/2009].

AIM: To study the outcomes of severe pandemic influenza A/H1N1/2009. SUBJECTS AND METHODS: The study enrolled 24 patients, including 8 males and 16 females (10 of whom were pregnant), aged 17 to 58 years, with a laboratorily verified diagnosis of pandemic influenza A/H1N1/2009, treated at the intensive care unit for the significant symptoms of acute respiratory failure (RF). Real-time RT-PCR was used to verify the diagnosis. Organs and tissues from deceased patients were histologically studied; chest computed tomography, body plethysmography, fibrobronchoscopy, breath test, and 6-minute walk test were performed in the late period. RESULTS: Within the first 30 days, a fatal outcome caused by therapy-resistant progressive RF was observed in 33% of the patients with pandemic influenza treated at the intensive care unit. Diffuse alveolar damage caused by influenza virus, which gives rise to hyaline membranes, underlies RF. Lung tissue fibrosis formed in recovered patients. CONCLUSION: The severity of pandemic influenza A/H1N1/2009 was determined by massive bilateral pneumonia, interstitial (alveolar) pulmonary edema, formation of diffuse bilateral lung fibrosis at the outcome of severe virus pneumonia (acute respiratory distress syndrome) with a decrease in vital and diffusing capacities, thereby generating a need to follow up this patient category and, possibly, to elaborate special rehabilitation programs.

[The course and treatment of chronic hepatitis B in HIV-infected patients].

The paper reviews the data available in the literature on patients with mixed hepatitis B virus (HBV) and HIV infection, its course and outcomes. The unity of the mechanisms of contamination with HBV and HIV increases the likelihood of these infections in patients. About 70% of HIV-infected patients are carriers of the markers, the presence of which is indicative of current or previous HBV infection. An average of 7.6% of HIV-infected patients were diagnosed as having chronic hepatitis B (CHB) in West Europe and North America. The notification rate of CHB in adult HIV-infected patients was 5-7% in the Russian Federation. Most specialists report that HIV-infected patients have a severer course of HBV. Mixed HBV and HIV infection, and low CD4+ lymphocyte count in particular, increase the risk for death from hepatic diseases and there is evident hepatotoxicity during antiretroviral therapy. The management of patients with mixed HBV and HIV infection is determined by indications for therapy for both HIV infection and CHV infection, by the availability of double-action antiviral drugs (that suppress either HIV or HBV replication), by the development of their resistance in one or both viruses. Indications and preferable variants of using various treatment regimens are given.

[Myonecrosis in users of injecting drugs (a clinical case)].

Myonecrosis remains one of the severest manifestations of skin and soft tissue infections. Clostridia (C. perfringens, C. novyi, C. septicum, C. sordellii, C. histolyticum) are dominant and Staphylococcus aureus, Streptococcus pyogenes, Bacillus cereus, and Bacteriodes fragilis are much less in the etiology of myonecrosis. Cases of gas gangrene have recently become more frequent among injection drug users all over the world. Russia has become the largest opiate market in Europe and consumption of these narcotic drugs is annually growing. In the Russian Federation, a larger number of injection drug users uniquely results in a rise of cases of Clostridium- and mixed flora-induced myonecrosis. Gas gangrene in HIV-positive drug abusers seems to rapidly progress to multiple organ failure and to show high death rates, rather than to develop a localized form. The analyzed case of mixed flora-induced gas gangrene is of interest to physicians of any specialties who can encounter this wound infection in HIV-positive patients.

[The etiological pattern of diseases in pregnant women with enhanced blood ALT and AST activities, admitted to the obstetric unit of infectious disease hospital].

AIM: to define a role of hepatotropic (HAV, HBV, HCV, and HDV) and opportunistic hepatotropic (HGV, CMV, EBV, HHV types 1, 2, and 6) viruses in the etiological pattern of diseases accompanied by enhanced blood AlAT and AsA T activities in pregnant women. SUBJECTS AND METHODS: Two hundred and eleven pregnant women, including 123 patients with chronic viral hepatitis, 74 with enhanced blood AlAT activity and no markers of viral hepatitis (EAlA T-NMVH), and 14 with acute viral hepatitis were examined. RESULTS: Most pregnant women with chronic HBV and HCV infections were found to have HBV DNA and HCV RNA in the blood in the presence of normal and enhanced activities of transaminases. In the EAlAT-NMVH group, there was none of the opportunistic hepatotropic viruses in more than 7% of cases. No genetic material of HAV, HBV, HCV, HDV, HGV, CMV, EBV, HHV types 1, 2, and 6 was found in the blood of all 10 patients with hepatitis of unspecified etiology. CONCLUSION: In the absence of serologic data supporting the presence of infectious pathology, blood testing using the polymerase chain reaction is of low informative value in detecting opportunistic hepatotropic viruses in pregnant women with hepatitis of unspecified etiology. However, by keeping in mind that the spectrum of opportunistic hepatotropic viruses is not confined to those included in this study, it is expedient to examine additionally pregnant women with enhanced blood AlAT and AsAT activity in order to identify TTV, B19V, HHV-8, SEN and NV-F in the blood.

[To the differential diagnosis of arthritis of pseudotuberculous and chlamydial etiology].

AIM: to define main differential diagnostic criteria for arthritides of chlamydial and pseudotuberculous etiology and to improve patient examination tactics. SUBJECTS AND METHODS: Forty-six patients with pseudotuberculosis and 41 patients with chronic urogenital chlamydial infection with articular involvement were examined. A bacteriological method of polymerase chain reaction (PCR), agglutination test, enzyme immunoassay (EIA) (IgA, IgG, IgM), indirect hemagglutination (IHA) test were used to diagnose pseudotuberculosis. Diagnostic techniques for chlamydiasis involved cultural, direct immunofluorescence (DIF), real-time PCR, and EIA (IgM, IgG, IgA). RESULTS: Patients with pseudotuberculosis developed polyarthritis and oligoarthritis in 56 and 39%, respectively. The development of arthritides was accompanied by fever in 89%, exanthema in 57%, gastrointestinal lesion in 56%, hepatomegalia in 78%. The pseudotuberculous etiology of the disease was confirmed by the agglutination test in 71% of the patients and by IHA in 7%. EIA revealed IgG in 78% of the patients, IgA in 11%, and IgM in 29%. PCR of synovial fluid (SF), synovial shell, and other biological substrates revealed Yersinia pseudotuberculosis DNA in 43%. Chlamydiasis and polyarthritis developed in 71 and 19%, respectively. The diagnosis of chlamydiasis was verified by EIA detection of IgG and IgA in 76 and 27% of cases, respectively. DIF, PCR, and culture studies of urethral scrapes found Chlamydia in 9, 32, and 29% of cases, respectively. Examination of SF and synovial shells revealed Chlamydia trachomatis in 24% of the patients and culture studies detected the pathogen in 21%. CONCLUSION: Asymmetrical polyarthritides mainly involving the knee joints are the most common arthritides of pseudotuberculous etiology. EIA detection of serum IgG and IgA and PCR study of SF are optimal diagnostic tools. Artritides of chlamydial etiology are asymmetrical oligoarthritides predominantly involving the knee and ankle joints. Examination of urethral and cervical canal scrapes, SF by culture and PCR studies and that of serum IgA and IgG by EIA are optimal diagnostic tests.

[Diagnostic value of a thiol-disulfide groups of the antioxidant system in brucellosis].

The functional state of a thiol disulfide link of the antioxidant system was evaluated in 322 patients with brucellosis (160 and 162 with its acute and chronic forms, respectively), including the patients with that involving the cardiovascular systems (120 and 92 with acute and chronic forms, respectively). Examination of the blood antioxidant system indicated that in brucellosis patients, cardiovascular involvement was accompanied by a reduction in SH groups and thiol disulfide coefficient and by an increase in the content of SS groups, which indicates the predominance of the oxidant system over antioxidant one. At the same time, the functional insufficiency of the blood antioxidant system was more evident in patients with acute brucellosis.

Hepatitis B virus genetic typing using mass-spectrometry.

Mini-sequencing with subsequent result registration using MALDI-ToF mass-spectrometry was employed for hepatitis B virus genetic typing in Russian population. This approach was employed for hepatitis B virus genetic typing in HBsAg-positive patients with chronic hepatitis B, hepatitis of combined etiology and hepatic cirrhosis and allowed to show the prevalence of D genotype (83.3%) in all groups of patients. Other hepatitis B virus genotypes: genotype A (5.9%), genotype C (3.6%), and mixed infection with D and C (7.2%) were also found in patients with chronic hepatitis B and hepatic cirrhosis. All genotypes were found in patients with chronic hepatitis B and hepatic cirrhosis. Chronic hepatitis of combined etiology was noted only in patients with genotype D. Possibility of detection of mixed infection with hepatitis B viruses of various genotypes is a distinct advantage of mini-sequencing approach over direct nucleotide sequence evaluation for hepatitis B virus genetic typing.

[HCV genome variability in acute and chronic viral hepatitis C].

AIM: To evaluate HCV genome variability in acute and chronic phases of viral hepatitis C. MATERIAL AND METHODS: The study of heterogeneity of HCV in acute hepatitis C has detected genetic heterogeneity and variability of individual HCV population circulating in the blood. Significant genetic heterogeneity of HCV was observed in 1b, 2a and 3a genotypes. Variability of HCV did not depend on virus load. Genetic HCV structure changed significantly both in patients with manifest ALT deviations and in normal ALT, mean number of HCV genetic variants in these groups being the same. No significant correlations were found between virus concentration in the patient's blood, its variability and ALT values. Genetic heterogeneity of interferon-sensitive region of gene NS5A subtype 1b HCV was studied in blood of 16 patients with chronic hepatitis C resistant to interferon therapy. RESULTS: It is shown that genetic heterogeneity and variability of an individual HCV population circulating in blood serum can not be a prognostic criterion in assessment of variants of acute hepatitis C course. No mutations in ISDR region were found in 25% of 16 patients studied. 75% cases had 1-3 replacements of amino acid sequences, most frequent mutation was replacements in position 2218 (histidin/arginin). The above results are close to those obtained in Japanese and European populations. Results of ISDR sequence-analysis conducted before treatment may predict efficacy of interferon-alpha2 treatment in an individual patient in future. Large-scale trials are necessary for detection of mutations responsible for resistance to interferon-alpha2 in patients living in Russia.