Vol 11, No 1 (2021)

Cover Page

Full Issue

REVIEW ARTICLES

To the question regarding accuracy of COVID-2019 laboratory diagnostics

Kulichenko A.N., Sarkisyan N.S.

Abstract

Issues of accuracy (sensitivity and specificity) of PCR-analysis depending on features of performing preanalytical and analytical stages of laboratory diagnostics of COVID-19, as well as comparing PCR and lung computed tomography (CT) results have been analyzed in the study. Currently, a molecular genetic test based on polymerase chain reaction (PCR) is used for diagnostics of a new coronavirus infection (COVID-19). As of November 1, 2020, more than 750 million PCR tests have been conducted globally. Evidence accumulated by now allows to estimate diagnostic sensitivity and specificity of the SARS-CoV-2-specific PCR as high as 82—91% and 99—100%, respectively. In addition, increased PCR sensitivity may be noted upon performing repeated testing of the upper respiratory tract samples comprising 82.2% during the primary analysis that was further elevated up to 90.6% after two consecutive tests. A whole set of factors affect the PCR accuracy. In particular, false negative data might result from insufficient amount of virus-coupled genetic material in the sample, timeframe and mistakes made upon selecting biological samples. It was found that SARS-CoV-2 virus RNA was detected at the maximum diagnostic sensitivity in the upper respiratory tract 1—3 days before the onset of symptoms and sustained within the 5—6 days after disease onset. Such period of time is associated with the peak risk of SARS-CoV-2 transmission. On week 2 after disease onset, there have been noted elevated rate of detecting viral RNA in bronchopulmonary samples. The duration of detecting virus-related markers (including those found in the absence of viable virus forms) correlates with disease severity and may last for as long as 1—2 months. Another real-world issue related to PCR analysis is posed by an opportunity of obtaining false positive data, which solution requires high level organized laboratory research, especially in case large-scale studies. Upon that, it is worth noting that positive PCR results may account for detecting solely certain RNA-related fragments present in any sample, rather than a viable virus. It was noted that PCR in comparison to CT analysis demonstrates higher specificity, but does not allow to distinguish pneumonia caused by SARS-CoV-2 from pneumonia caused by other etiological agents (up to 25% false positive results). However, the diagnostic CT sensitivity was 97.2% that exceeds such parameter for PCR by 10—15%. It was concluded that the approach combining use of both PCR and CT by taking into account their own features as well as factors affecting the accuracy of the data obtained, allows us to correctly interpret the diagnostical results.

Russian Journal of Infection and Immunity. 2021;11(1):9-16
pages 9-16 views

Second ethical comments towards COVID-19 (one year later)

Kubar O.I., Bichurina M.A., Romanenkova N.I.

Abstract

At the beginning of COVID-19 development, when social vulnerability in the face of the global infectious threat became obvious, we presented target information on a key civilizational issue — the role of ethics in epidemic emergencies. The compliance of RF legislation and the world ethical standards analyzed on based on the study of the humanitarian heritage of pandemic management and a review of existing international documents. Today, one year later, it is time to practically evaluate the effectiveness of the ideology of ethical commitment and objectively comprehend the conflicts that have arisen, their causes and consequences. It should be emphasized that this work is not a so-called “moral lesson learned from COVID-19”, but representation of a real picture of how the centuries-old experience of former epidemics and pandemics was taken into account and the unique truth of the ethical content of management decisions and actions was accepted. It is particularly important to have a possibility to present this article as a continuation of our research topic on the bioethics of pandemics, on the pages of such an authoritative, specialized journal, which fully allows us to preserve the integrity of ideas about the humanitarian essence of anti-epidemic measures. This humanitarian parallel starts from the moment of managing a particular patient with infectious pathology until large-scale measures for eradication vaccine-preventable diseases. A comprehensive and dynamic look at the need to find ways and the nature of overcoming ethical conflicts during the ongoing pandemic of the new coronavirus infection could determine the ethical approach of longterm recommendations in the field of public health protection and ensure the stability of social trust in the future.

Russian Journal of Infection and Immunity. 2021;11(1):17-24
pages 17-24 views

Neutrophil granulocytes: participation in homeostatic and reparative processes. Part II

Dolgushin I.I., Mezentseva E.A.

Abstract

A supportive homeostatic function of neutrophilic granulocytes is accomplished in the physiology of diverse tissues and body systems. Neutrophils are found along the entire female reproductive tract (FRT), gradually declining in numbers from the upper parts towards the vagina. At the same time, both quantity and activity of FRT mucosal neutrophils are controlled by hormonal changes at different phases of menstrual cycle. Tissue neutrophils serve as an important source of broad-spectrum proteolytic enzymes such as matrix metalloproteinases and elastase necessary for extracellular matrix remodeling as well as vascular endothelial growth factor (VEGF) required for physiological FRT angiogenesis. During pregnancy, decidual neutrophils play a prominent role in vascular remodeling in pregnant uterus as well as development of maternal-fetal immune tolerance. The influx of neutrophils into the intestinal mucosa due to its trauma or infection not only ensures defense against pathogens, but also leads to increased proliferation of intestinal epithelial cells. Neutrophilic granulocytes elicit signals and events protective for the epithelium by marking them with a “hypoxic signature” to trigger transcription of the gene set responsible for production of mucins, mucin-modifying peptides, antimicrobial proteins, в-defensins, ultimately contributing to lesion healing and recovery of epithelial barrier function. “Inflammatory hypoxia” initiated by neutrophils and subsequent stabilization of the transcription factor hypoxia-induced factor (HIF) in intestinal epithelial cells trigger mechanisms of self-limited and resolved inflammation, which prevent excessive accumulation of neutrophils in the intestinal lumen and development of chronic inflammatory process. Neutrophilic granulocytes dominate in the oral cavity mucosa and comprise more than 95% of total leukocyte population recruited into the gingival sulcus and gingival fluid. Neutrophils maintain physiological amount and stability of symbiotic microflora composition in dental and gingival biofilms, counteracting pathogenic bacteria via phagocytosis, degranulation and extracellular trap formation, thereby ensuring healthy state in periodontal structures. Finally, similar to some other congenital disorders affecting neutrophil quantity and functions it was shown that in case of leukocyte adhesion deficiency type 1 (LAD-1) pathogenesis of periodontitis may not only be associated with a defect in their protective effector activity, but also with altered immunoregulatory function of tissue neutrophils.

Russian Journal of Infection and Immunity. 2021;11(1):25-41
pages 25-41 views

The use of statistical phylogenetics in virology

Vakulenko Y.A., Lukashev A.N., Deviatkin A.A.

Abstract

Molecular phylogenetics, particularly statistical phylogenetics, is widely used to solve the fundamental and applied problems in virology. Bayesian, or statistical, phylogenetic methods, which came into practice 10—15 years ago, markedly expanded the range of questions that can be answered based on analyzing nucleotide and amino acid sequences. An opportunity of using various evolution models allows inferring the chronology, geography and dynamics of the infection spreading. For example, analysis of globally distributed HIV group M by Bayesian methods demonstrated with a probability of 99% that the most recent common ancestor of these viruses existed in the surroundings of the city of Kinshasa (Democratic Republic of the Congo) in the early 1920s. Another study showed that H9N2 influenza virus most likely passed on to humans from wild ducks in Hong Kong in the late 1960s. In addition, using of the Bayesian analysis allows to evaluating the effect of measures taken on the development of the epidemic process. For example, it was shown retrospectively that the rate of hepatitis C virus infection cases in Egypt increased by several orders of magnitude in the mid-20th century. A sharp rise in new case rate is associated with the treatment for schistosomiasis by using non-sterile repeatedly used syringes. A set of Bayesian analysis methods has been applied in tens of thousands of researches describing various aspects of the occurrence and spread of infectious diseases in humans and animals. This was facilitated by the development and accessibility of software that implements these methods. The complexity of Bayesian phylogenetic methods imposes strict requirements on the data being analyzed. The correctness of the phylogenetic analysis data depends on various factors. For example, it is necessary to choose an evolutionary model that most adequately describes the studied objects. A mandatory step in formulating the results is the justification of the selected model. For viruses, the acquisition of genetic elements from other organisms is typical, therefore, the genomes even from closely related viruses may have non-homologous regions unsuitable for phylogenetic analysis. Another aspect is the creation of a representative dataset. Sometimes, all stages of the analysis are not indicated in publications, so that the data obtained can be interpreted ambiguously. The correct use of statistical phylogenetics methods in virology is possible only upon understanding their principles, proper methods of data preparation and evolutionary model selection criteria.

Russian Journal of Infection and Immunity. 2021;11(1):42-56
pages 42-56 views

Development of antiviral therapeutics combating coxsackievirus type B3 infection

Volobueva A.S., Zarubaev V.V., Lantseva K.S.

Abstract

Enteroviruses comprise highly diverse group of single-stranded positive RNA viruses belonging to Enterovirus genus, Picornaviridae family. They are the most prevalent viruses worldwide highlighted by high resistance to environmental cues. Enteroviruses normally cause seasonal self-limiting infections, but also known as causative infectious agents of encephalitis, myocarditis, poliomyelitis, acute heart failure and sepsis. Enterovirus genetic plasticity contributes to widespread epidemics and sporadic outbreaks (e. g., outbreaks of Enterovirus D68 and Enterovirus 71). Type B Coxsackieviruses of Enterovirus B species is one of commonly identified infectious agents associated predominantly with mild upper respiratory and gastrointestinal illnesses. Nevertheless, Coxsackieviruses B3 infection can result in severe myocarditis leading ultimately to heart failure. The pathogenesis of Coxsackievirus B3-induced myocarditis is well known being mediated by both direct damage due to viral proteases and indirectly via secondary host immune responses. Despite success in preventive vaccination of some enterovirus infections that allowed to control some of them direct antiviral agents for treatment of enteroviral infection particularly Coxsackieviruses B3 myocardial infection are still in demand. In addition, no ongoing clinical trials for therapy or prevention of Coxsackieviruses B3 infection are available. Current treatment strategies are mainly aimed to stabilize patient condition and relieve discomfort condition. It seems that relatively small market for anti-enteroviral drugs prevents pharma industry from developing new drugs. The Coxsackieviruses B3 lifecycle have been extensively studied and potential targets for drug design have been identified. The aim of our review was to describe current state in the field of antiviral drug design combating Coxsackieviruses B3 infection emphasizing direct-acting antivirals, albeit paying some attention to host factor-targeting inhibitors (including compounds from medicinal plant extracts) as well. The following categories of direct Coxsackieviruses B3 inhibitors are discussed in detail: capsid binders (pleconaril and its derivatives), viral 3C protease inhibitors (rupintrivir and its analogs), drugs targeting viral replication (both nucleoside analogs and non-nucleoside inhibitors). Results of drug repurposing screens for amiloride, benzerazide, dibucaine and fluoxetine are also discussed.

Russian Journal of Infection and Immunity. 2021;11(1):57-67
pages 57-67 views

Helicobacter pylori infection and inflammatory bowel diseases

Uspenskiy Y.P., Baryshnikova N.V., Suvorov A.N., Svarval A.V.

Abstract

Helicobacter pylori is detected in the human intestine on average in 35% of clinical cases, but the question about its etiopathogenetic role in intestinal diseases has not been fully investigated. Many scientists study a relationship between the H. pylori persistence and development of various bowel diseases. Diverse viewpoints have been proposed regarding a potential link between H. pylori and inflammatory bowel diseases (IBD). Here we review the data from domestic and foreign studies aimed at examining potential role of H. pylori both as a trigger and protector resulting in the pathogenetic alterations leading to developing Crohn‘s disease and ulcerative colitis. The former is favored by the hypothesis wherein H. pylori may trigger IBD due to potential connection between extragastric infection and its direct damaging action as well as indirect effects contributing to the initiation of oxidative stress, autoimmune aggression and development of intestinal dysbiosis. In addition, the effects of enterohepatic Helicobacter spp. promoting IBD pathogenesis are discussed. The mechanisms underlying the protective role of H. pylori infection may be driven via differentially expressed acute and/or chronic local inflammatory mucosal response able to downmodulate systemic immune responses and suppress autoimmune reactions, as well as skewing host immune response from a pro-inflammatory Th1/Th17 cell-mediated towards regulatory T-cell response. Moreover, it was found that H. pylori may induce production of antibacterial peptides counteracting potentially pathogenic bacteria involved in IBD pathogenesis. In particular, it was found that IBD patients are dominated with moderate active antral gastritis coupled to atrophy, with the peak intensity observed in patients under 30 years of age. Intensity of intestinal metaplasia in the gastric mucosa of IBD patients accounted for by the duration of the disease course. Basal IBD therapy with 5-aminosalicylic acid lowers severity and activity of gastritis, degree of atrophy as well as magnitude H. pylori invasion in the gastric mucosa. There is evidence that 5-aminosalicylic acid-containing drugs may result in a so-called “spontaneous eradication” of H. pylori infection. Extended investigations are required to examine a role of H. pylori in IBD pathogenesis.

Russian Journal of Infection and Immunity. 2021;11(1):68-78
pages 68-78 views

Treatment of human papillomavirus infection in HIV-infected patients

Smirnov V.S., Kudryavtseva T.A.

Abstract

The first reports about HIV (human immunodeficiency virus) were appeared to the 1980s. By 2017 more than 37 million people were living with HIV. Human papilloma virus (HPV) is universally spread, with some estimates showing that about 1% of the sexually active population having genital warts. Human papilloma virus (HPV)-induced infection frequently accompanies the clinical course of HIV and can manifest itself in a full spectrum of clinical-pathologic forms ranging from common warts to malignant neoplasia. Due to the widespread use of antiretroviral therapy, the number of patients with a combined infection (HIV+HPV) is steadily increasing. Here we review current clinical treatment options for HPV manifestations. High-dose antiretroviral therapy does not impede HPV treatment, and can even improve its efficacy in some cases. The topical administration of imiquimod, an immune response modifier, is an effective conservative treatment in HIV-infected patients with HPV. The immunomodulation therapy of imiquimod can serve as an effective alternative of aggressive chemical and mechanical procedures. Maximum efficacy with the lowest replaces rates may be expected from combined use of mechanical ablation methods with a subsequent follow up treatment with imiqui-mod. The best therapeutic result is expected in HIV-positive patients who are received high-dose antiretroviral treatment. The advantages of Vartocid, the modified Russian equivalent of the generic imiquimod.

Russian Journal of Infection and Immunity. 2021;11(1):79-84
pages 79-84 views

ORIGINAL ARTICLES

Effects of experimental protein-containing pneumococcal preparations on maturation of murine dendritic cells

Akhmatova N.K., Gruber I.M., Kukina O.M., Akhmatova E.N., Makarenkova I.D., Stolpnikova V.A., Kalinichenko E.O., Bisheva I.A., Skhodova S.A.

Abstract

Dendritic cells as the most active and highly specialized antigen presenting cells, play a key role in initiating immune responses. Currently, generation of medications activating dendritic cells for development of anti-infective and anticancer vaccines is of highly relevance. Preparations of microbial origin are promising to augment activity of dendritic cells, because they carry innate immune ligands for Toll-like receptors. Such preparations include experimental protein-containing pneumococcal preparations, obtained from acetone-inactivated microbial mass of the deposited S. pneumoniae 6B vaccine strain No. 296, followed by aqueous extraction and separation of 30—100 kDa fraction. Dendritic cells were obtained from bone marrow cells of CBA mice (n = 15), and cultured in complete growth medium RPMI-1640 added with recombinant GM-CSF and IL-4 (Biosource, USA). On day 6, experimental protein-containing pneumococcal preparations (50 pl/ml) were administered to the cultured immature dendritic cells. Commercial TNFa (20 ng/ml, Biosource, USA) was used as a standard maturation inducer (positive control). Immunophenotyping of dendritic cells was conducted by using flow cytometry with FITC- and PE-labeled monoclonal antibodies against cell surface receptors: CD34, CD38, CD83, CD86, CD80, CD11c, MHC II, CD14, CD282 (TLR2), CD284 (TLR4), (eBioscience, USA). Studying an effect of preparations on maturation of dendritic cells revealed that morphological characteristics of dendritic cells generated by using experimental protein-containing preparations did not differ significantly between each other as well as those induced by TNFα. The cells were characterized by large sizes, oval or irregular shape, veiled cytoplasm, eccentrically located nucleus and numerous long thin protrusions. Experimental proteincontaining preparations induced in cultured dendritic cells decrease in count of CD34+ immature and TLR2/TLR4+ cells, increased count of cells expressing markers of adhesion (CD38+), activation (MHC II+), costimulation (CD80/ CD86+) and terminal differentiation (CD83+), which may evidence about events of differentiation upon dendritic cell maturation. The 30—100 kDa fraction increased count of cells expressing adhesion molecules to a greater extent than aqueous extract that more pronouncedly stimulated rise in count of dendritic cells bearing costimulatory molecules (p < 0.05). The activity of the examined proteins regarding their effect on CD83+ cells was comparable. Experimental protein-containing antigens derived from pneumococcal vaccine strain were shown to induce maturation of dendritic cells from bone marrow precursors, induce a decrease in the count of TLR2 and TLR4-expressing cells accounting for activating effect on innate immune effectors.

Russian Journal of Infection and Immunity. 2021;11(1):85-92
pages 85-92 views

Morphometric characteristics of effects induced by Ensifer meliloti lipopolysaccharide fractions on parenchymatous organs in laboratory rats with secondary immunodeficiency

Mavzyutov А.R., Glazutdinova L.R., San'chokov D.V., Shchekin V.S., Garafutdinov R.R., Chizhova A.V., Gabdrahmanova A.R.

Abstract

Introduction. Gram-negative bacteria-derived lipopolysaccharides (LPS) are better known as bacterial endotoxins. However, an increasing body of evidence has been accumulated regarding a whole range of LPS-bound physiological effects also observed in normal settings. In particular, LPS derived from some bacterial species was shown to exhibit an immunomodulating activity.

Study objective — to characterize physiological effects of Ensifer meliloti lipopolysaccharides in modelled rat induced immunodeficiency.

Materials and methods. Biological activity of intraperitoneally administered E. meliloti LPS fractions was studied for 21 days in 60 outbred male rats after induction of a minimal immunodeficiency state 24 hours later after inoculating cytostatic agent cyclophosphamide (CF). Animals were euthanized on day 22 followed by conducting an autopsy and morphometric study of internal organs. Later, paraffin-embedded sections of parenchymal organs were stained with hematoxylin-eosin and examined histologically by light microscopy.

Results. It was found that at the end of the experiment cyclophosphamide applied to laboratory animals insignificantly decreased weight of liver and kidney, but not that of heart and spleen (compared to intact animals). In contrast, lung weight was solely significantly increased in immunodeficient rats compared to control. Intraperitoneally administered LPS fractions during secondary immunodeficiency affected weight parameters in the liver and kidney as the most intensively blood supplied organs suggesting its systemic effects. Quantity of follicles with large germinal centers as well as secondary follicles and lymphatic sheath formation in splenic stroma was increased that features activated immune response. Moreover, hepatic lymphoid infiltration in the portal tracts and reversal to normal vascular pattern were found as well. In contrast, LPS and Licopid administered to rats resulted in marked lung hyperplasia of lymphoid tissue containing large germinal centers.

Conclusion. The data obtained indicate that E. meliloti-derived LPS fractions administered to rats with secondary immunodeficiency positively affected immunoreactivity.

Russian Journal of Infection and Immunity. 2021;11(1):93-100
pages 93-100 views

Phenotype remodeling in neutrophilic granulocyte subsets CD64-CD32+CD16+CD11B+NG, CD64+CD32+CD16+CD11B+NG in de novo experimental model of viral-bacterial infection in vitro

Nesterova I.V., Chudilova G.A., Rusinova T.V., Pavlenko V.N., Yutskevich Y.A., Barova N.K., Tarakanov V.A.

Abstract

A search for new targeted therapeutic strategies based on examining immunopathogenetic mechanisms for emerging co-infections is relevant and may further contribute not only to optimizing choice of immunotropic drugs, but also to achieving positive clinical and immunological remission for abnormal infectious processes. Previously, our studies found that recurrent viral-bacterial respiratory infections are associated with dysfunction of neutrophilic granulocytes (NG) with varying degree of intensity in altered effector properties. NG dysfunctions are often associated with diverse phenotypic profiles characterized by varying density for expression level of functionally significant trigger receptors. The aim of the study was to pinpoint phenotype transformation in CD64-CD32+CD16+CD11b+, CD64+CD32+CD16+CD11b+ neutrophilic granulocytes in experimental model of viral-bacterial infection in vitro. We examined 52 peripheral blood samples collected from 13 healthy adult volunteers. Viral, bacterial and virus-bacterial infection was modelled in vitro by incubating blood-derived cell samples with formyl-methionyl-leucyl-phenylalanine (fMLP), double-stranded RNA (dsRNA) or in combination followed by assessing changes in immunophenotyping of CD64-CD32+CD16+CD11b+NG, CD64+CD32+CD16+CD11b+NG by using using MAbs CD16-ECD, CD64-FITC, CD32-PE, CD11b-PC5 conjugates (Beckman Coulter International SA, France). It was demonstrated that NGs from healthy adult volunteers were dominated by CD64-CD32+CD16+CD11b+NG as well as minor subset СD64+CD32+CD16+CD11b+ NG varying in expression density of membrane molecules. Percentage of the minor subset СD64+CD16+CD32+CD11b+ NG was significantly increased after exposure with dsRNA, fMLP and dsRNA+fMLP compared to untreated samples. Comparative analysis revealed that various immunotropic agents differed in affecting expression of surface receptor molecules CD16, CD32 and unidirectional effects, but of varying magnitude altering CD11b marker both in major and minor subsets. Preincubation with dsRNA followed by adding fMLP allowed to find that they co-stimulated expression of surface receptors in both NG subsets. We generated an experimental model of viral-bacterial co-infection in vitro by using fMLP and dsRNA and observed types of phenotype transformation in CD64-CD32+CD16+CD11b+ NG and CD64+CD32+CD16+CD11b+ NG subsets. This model can be used to evaluate transformation of other NG subset phenotypes, NG functional activity, features of NET formation as well as impact of various immunotropic agents on NG.

Russian Journal of Infection and Immunity. 2021;11(1):101-110
pages 101-110 views

Major and minor lymphocytes subpopulations in peripheral blood and cerebrospinal fluid of children with meningitis

Zhirkov A.A., Alekseeva L.A., Zheleznikova G.F., Sckripchenko N.V., Monakhova N.E., Bessonova T.V.

Abstract

Introduction. The analysis of current publications indicates at our insufficient understanding of subpopulation composition of lymphocytes in peripheral blood and cerebrospinal fluid (CSF) during pediatric neuroinfectious diseases. It has been found that the main lymphocyte populations are divided into many small (minor) subpopulations.

The purpose of this research was to assess percentage of major and minor blood and CSF lymphocyte subsets in children with aseptic viral meningitis (AM) or bacterial purulent meningitis (BM).

Materials and methods. Phenotyping of blood and CSF lymphocytes of children aged from 4 months to 17 years diagnosed with AM (n = 86) and BM (n = 39) was carried out by using flow cytometry. As a comparison group, we analyzed peripheral blood and CSF samples collected from children with acute respiratory viral infections (ARVIs) associated with syndrome of meningism (n = 27). There was evaluated percentage of the major cell subpopulations (CD3+ T-lymphocytes, T-helpers — CD3+CD4+ Th, cytotoxic T-lymphocytes — CD3+CD8+ CTL, natural killer cells — CD3-CD16+CD56+ NK, B-cells — CD3-CD19+), as well as minor lymphocyte subsets (double positive (DP) (CD3+CD4+CD8+), double negative (DN) (CD3+CD4-CD8-) T-cells, NKT (CD3+CD16+CD56+), CD3-CD8+ NK, CD3+CD8dim and CD3+CD8 8bright).

Results. It was found that the acute period of BM and AM vs. the comparison group (ARVI) was characterized by significant differences in the blood and CSF composition of major and minor lymphocyte subsets. In particular, blood T-cells, Th, CTL, NK, NKT, DN, CD3-CD8+ NK, CD3+CD8bright and CD3+CD8dim dominated in parallel with significantly lowered B-cell frequency in AM vs. BM. In the CSF of children with AM, T-cells and Th prevailed, whereas count of B-cells and CD3-CD8+ NK was lower compared to those in BM. In addition, further differences were revealed in CSF and blood cell subset composition depending on nosological entity, while maintaining differences in some major and minor lymphocyte subpopulations lacked in the comparison group. Calculating the CSF/blood ratio for the major and minor lymphocyte subsets uncovered the prevalence for the majority of cell subpopulations (the coefficients ranged from 1.2 to 16.4) in the CSF of the comparison group (ARVI), except B-cells, NK and CD3-CD8+ NK (coefficients ranged from 0.07 to 0.31). AM and BM were featured with various changes in the CSF/blood ratio found for most of the studied subpopulations in the acute period as well as the recovery phase highlighted with characteristic traits for each nosological form.

Conclusion. The data obtained indicate about finding specific features in the activation of systemic and intrathecal immune response during viral and bacterial meningitis in children, which may be used as an additional differential diagnostic criterion.

Russian Journal of Infection and Immunity. 2021;11(1):111-122
pages 111-122 views

Humoral immunity, vaccination period and demographic characteristics of first immunized smallpox vaccine recipients

Ermilova O.S., Gin’ko Z.I., Belyavskaya V.A.

Abstract

General vaccination of population with vaccinia virus leaded to the eradication of smallpox, then it was finished because of the danger of adverse events. The recurrence of research interest in smallpox vaccine is due to the research of using the virus as a weapon of bioterrorism and the increased frequency of orthopoxvirus infections whereas the population immunity decline. The vaccinia virus is also used as a vector for creating recombinant vaccines. Understanding the pathway and predicting the immune response it will be able to avoid possible adverse events and excessive immunization. The aim of the study was to assess the correlations between humoral immunity, clinical signs during a vaccination period, sex and age characteristics of adults who had received several doses of vaccinia virus. We studied a vaccination clinical data of 135 subjects revaccinated with a smallpox vaccine from twice to 10 times. A total of 95% and 5% vaccine recipients experienced mild or moderate vaccination period, respectively. Inoculation skin lesions was noted at 127 subjects (94.1%). Among them more than 22% vaccine recipients experienced local or systemic adverse events. Compared to mild group moderate group had larger hyperemia (p = 0.04), scab (p = 0.01), healing time (p = 0.001). The age subjects with a moderate vaccination period is less than mild (p = 0.03), the chance of lymphadenopathy development is higher within moderate vaccination period (p < 0.001). Vaccinia neutralizing antibody titers were determined for 54 subjects using plaque reduction neutralization tests. There was a noted tendency of higher protective antibody values at women compared with men. Negative correlation between the antibody titers and the hyperemia size was revealed. Frequently axillary adenopathy is assotiated with higher protective antibody values. Vaccinia neutralizing antibody titers value are not associated with the presence and size of the lesion, the scab falling time, age and the number of previous vaccinations. The clinical variability and the immune response using the same vaccine and the same pattern vaccination would be explained by individual genetic differences that should be further explored.

Russian Journal of Infection and Immunity. 2021;11(1):123-130
pages 123-130 views

Pertussis immunity in pregnant women and factors associated with seronegative status

Krieger E.A., Samodova O.V., Titova L.V.

Abstract

Despite high level of vaccination coverage, pertussis remains a serious problem of modern medicine. Pertussis cases are registered among infants, adolescents, and adults. Infants younger than three months of age have the highest rate of serious clinical pertussis course. Transplacental transfer of pertussis-specific antibodies induce protection against infection. The available data regarding anti-pertussis antibody level in pregnant women in Russia remain sparce. To evaluate the humoral immunity to Bordetella pertussis in pregnant women and factors associated with seronegative status, we performed a cross-sectional study with 388 participants. SeroPertussis IgG (Israel) ELISA kit was used to quantitate antibodies against pertussis toxin/hemagglutinin. Binary logistic regression analysis was performed to assess factors associated with seronegative status. The median age of the subjects was 30 years old, more than half of which (51.3%) provided no verified pertussis vaccination data so that their children will not receive transplacental anti-infectious immunity. Gestational age was significantly associated with seronegative status. Compared to women tested during the first trimester, participants in the third trimester of pregnancy were more likely to be seronegative against pertussis. The odds of being susceptible rose with increased gestational period (p < 0.01 for linear trend). Age, number of pregnancies and vaccination status revealed no impact on significant differences between seropositive and seronegative subjects. Pertussis booster vaccinations for preschool children, adolescents and healthcare workers dealing with pregnant women and neonates as well as cocoon vaccination strategy and vaccination during pregnancy were necessary to be implemented to protect infants against pertussis.

Russian Journal of Infection and Immunity. 2021;11(1):131-136
pages 131-136 views

Detection of influenza virus and pathogens of acute respiratory viral infections in population of Kazakhstan during 2018-2019 epidemic season

Klivleyeva N.G., Ongarbayeva N.S., Baimukhametova A.M., Saktaganov N.T., Lukmanova G.V., Glebova T.I., Sayatov M.K., Berezin V.E., Nusupbaeva G.E., Aikimbayev A.M.

Abstract

Influenza and other acute respiratory viral infections are the most common infectious diseases of our time, causing a significant harm to human health as well as great economic damage. At least five groups of viruses, including more than 300 subtypes, are currently related to ARVI pathogens. Such infectious agents are characterized by a high degree of variability resulting in replaced virus antigenic characteristics augmenting their contagiousness, immunoevasion, and resistance to chemotherapeutic drugs. Of relevance, influenza and other ARVIs also pose a threat due to subsequent rapid formation of bacterially-associated respiratory diseases as well as their continuous variability and emergence of new pathogenic species. In recent years, subtype A (H1N1) and A (H3N2) with predominance of pandemic strain, as well as type B influenza viruses have been simultaneously found in circulation. Most common among the causative agents of noninfluenza ARVIs, are respiratory syncytial virus, rhino- and adenoviruses, as well as I/III parainfluenza viruses. Here we present the results of virological and serological studies of clinical samples collected during the 2018—2019 epidemic season in the territory of the Republic of Kazakhstan after analyzing 2794 clinical samples (2530 nasopharyngeal swabs and 264 blood serum samples) of patients diagnosed with ARVI, ARI, bronchitis, and pneumonia. Examining nasopharyngeal swabs by using RT-PCR showed that the mixed etiology influenza viruses with predominant A/H1N1pdm virus circulated in Kazakhstan. In particular, influenza virus genetic material was found in 511 swabs (20.20% of total examined samples), so that influenza A virus RNA was detected in 508 biological samples such as A/H1N1 — in 289, A/H3N2 — 209, unverified virus subtype — 10 samples. Type B influenza virus was detected in 3 samples. Analyzing 264 blood serum samples by the HAI assay and ELISA showed the presence of antibodies specific to influenza A/H1N1, A/H3N2, and B viruses in the population of various regions of Kazakhstan, thereby indirectly confirming their co-circulation. 42 influenza virus strains were isolated in chicken embryos, of which 28 were assigned to A/H1N1pdm virus, 13 — A/H3N2 virus, and one isolate was identified as influenza B virus. The laboratory diagnostics of clinical samples for ARVIs revealed that respiratory syncytial virus prevailed among identified non-influenza agents, whereas rhino- and adenoviruses were less common. Metapneumoviruses, bocaviruses, coronaviruses, and type I parainfluenza viruses were detected in few cases. Comparison of our study data with the data on 2017—2018 circulation of influenza pathogens showed that in Kazakhstan influenza A and B viruses continued to circulate, with the dominance of A/H1N1pdm virus as it was in the previous epidemic season. Identification of non-influenza viruses, the causative agents of 2018—2019 respiratory infections, showed the predominance of respiratory syncytial virus that correlated with the aforementioned results.

Russian Journal of Infection and Immunity. 2021;11(1):137-147
pages 137-147 views

Genetic diversity of hepatitis C virus in Nanaian region, Khabarovsk territory

Kotova V.O., Balakhontseva L.A., Bazykina E.A., Trotsenko O.E., Beldy V.N., Kirdyashova S.E.

Abstract

Examining hepatitis C virus (HCV) genetic diversity is of great practical value in molecular-epidemiological research, development of specific prevention tools and outlining therapeutic strategy.

Aim of study is to conduct analysis assessing HCV genetic diversity circulating in the Nanaisky Region population of the Khabarovsk Krai.

Materials and methods. Molecular and genetic analysis of 124 blood plasma samples collected from patients with chronic hepatitis C and residing in the Nanaisky Region was conducted.

Results. HCV RNA was detected in 84 (67.7±4.2%) plasma samples. HCV genotyping was performed by using AmpliSens — 1/2/3 kit (Central Research Institute of Epidemiology, Moscow, Russian Federation) showing that genotype 3 dominated reaching up to 47.6±5.4% (n = 40). Genotype 1 was detected in 30 patients (35.7±5.2%). In thirteen cases (15.5±3.9%) genotype 2 was identified, whereas in one case (1.2±1.2%) virus genotype was unidentified. Phylogenetic analysis of the nucleotide sequences in HCV NS5B region was performed for 60 HCV RNA-positive samples showing subtype ratio as follows: 1a — 2 (3.3±2.3%), 1b — 23 (38.3±6.3%), 2а — 6 (10.0±3.9%), 2с — 2 (3.3±2.3%), 3а — 27 (45.0±6.4%). Three samples of RF2k/1b recombinant virus were found. A full NS2 gene nucleotide sequence was cloned in order to confirm the recombination event. The results of the study evidence about a need to conduct multi-layered examination of patients with chronic hepatitis C by using current molecular and biologic methods for assigning proper therapy coupled to characteristics of the isolated strains. The data regarding hepatitis C virus molecular and genetic parameters circulating in the Far Eastern Federal District, Russia, are rather limited. Hence, our study would contribute to current understanding of HCV genovariants circulating in territories of the Russian Federation.

Russian Journal of Infection and Immunity. 2021;11(1):148-156
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SHORT COMMUNICATIONS

Altered interferon defense in children with dynamically changed infectious mononucleosis

Kukushkina E.A., Koteleva S.I., Blyakher M.S., Fedorova I.M., Ramazanova Z.K., Zvereva N.N., Novosad E.V., Samkov A.A., Bazarova M.V.

Abstract

The state of the interferon system in 38 children with acute infectious mononucleosis (IM) caused by the Epstein—Barr virus was analyzed. Interferon status was examined in accordance with F.I. Ershov method based on assessing related biological activity by measuring interferon level in the blood serum or produced by blood cells. The aim of the study was to gain scientifically justified data for use of interferon preparations or interferonogens in IM combination therapy. For this, interferon status in children with acute IM was compared with that one not only in control group (30 healthy children, aged 3—6 and 20 children, aged 7—14 years, examined earlier to create an intra-laboratory interferon normal range), but also in children with lacunar angina or acute respiratory viral infection, hospitalized in the same department of the clinic and comparable with the main group in severity of the condition. In addition, we assessed changes in IFN-status in IM patients receiving no interferon preparations, one month after the disease onset. The study showed that patients with moderate acute IM were featured with decreased potential of blood leukocytes to virus-induced IFNa and mitogen-induced IFNy production observed with almost similar or some lower rate as in the control group of children hospitalized with angina or acute respiratory viral infection. Peripheral blood cells from moderate acute IM patients in the 3-6-year age group were found to produce virtually unaltered interferon level, whereas almost sole IFN-alpha production was affected in 7-14-year-old patients. Moreover, in 7-14-year old patients the level 1 and level 2 of IFNa deficiency was observed in 38% and 6% of cases, respectively. It is likely it was just this patient group requiring administration of any IFNa replacement therapy. As few as 12 children were re-examined after discharge from the clinic. Initially, prevalence and severity level of impaired interferon production in this subgroup did not differ from that one for total patient sample, whereas 1 month later a host potential to produce both IFNa and IFNy even without therapy acting on interferon system was noted to be moderately augmented.

Russian Journal of Infection and Immunity. 2021;11(1):157-164
pages 157-164 views

New data on the level of immune stratum against Q fever agent in population of the of Republic of Guinea

Naydenova E.V., Kalivogui S., Kartashov M.Y., Boyko A.V., Boumbaly S., Safronov V.A., Zakharov K.S., Nassour A.A., Drame F., Konstantinov O.K., Magassouba N.F., Boiro M.A., Scherbakova S.А., Kutyrev V.

Abstract

which is bacteria of the species Coxiella burnetii. One of the factors showing the possibility of pathogen circulation in a certain territory is assessed by the presence of an immune stratum in the inhabitants of the region. In the 1980s, the study of the immune structure of the population of the Republic of Guinea in relation to coxiellosis has begun. The present study, carried out in 2015—2019, has been aimed to obtain new information about the immune stratum of the population of the Republic of Guinea against the causative agent of Q fever and to compare it with previous studies. Specific IgG antibodies in the blood of the Guinea residents were detected by using enzyme-linked immunosorbent assay (ELISA) with a set of reagents manufactured at the St. Petersburg Pasteur Institute (St. Petersburg, Russian Federation). The serum samples were tested in at 1:100 dilution. Antibodies against C. burnetii were detected in 124/2346 (5.3% [CI 4.5-6.3]) samples. This study confirms the previously obtained data on the circulation of the causative agent of coxiellosis in all landscape and geographical zones of the Republic of Guinea. The natural and climatic conditions of the region, the variety of ixodic tick species currently inhabiting this territory being a reservoir and vector of infection, as well as a large amount of livestock are the factors for active circulation of the Q fever pathogen and the emergence of related disease outbreaks. The data obtained necessitate continuing further studies on distribution of C. burnetii in the territory of the Republic of Guinea. Taking into consideration the epidemiological significance of Q fever, a pressing task is to study a proportion of this infectious disease in the overall structure of diseases registered in the territory of the Republic of Guinea. It is also necessary to conduct regular epizootological monitoring in order to clarify the types of carriers and vectors of C. burnetii in different landscape and geographical zones of the Republic of Guinea as well as to assess the immune stratum against the pathogen in large and small cattle being the main sources of infection for humans. The data obtained will allow us to determine presence of a natural focus of this infection as well as its borders and develop a set of preventive (anti-epidemic) measures.

Russian Journal of Infection and Immunity. 2021;11(1):165-170
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A herd immunity to measles and rubella viruses in the population of the Republic of Serbia

Bichurina M.A., Filipovic-Vignjevic S., Antipova A.Y., Bancevic M., Lavrentieva I.N.

Abstract

According to the WHO Strategic Plan, measles should be eradicated in 2020 in the five WHO Regions including European Region. However, large measles outbreaks are being periodically registered in diverse European countries. In the Republic of Serbia (SRB), 5,076 measles cases were detected in 2018, among which 15 cases were fatal.

Aim of the study was to examine herd immunity to measles and rubella viruses in the population of the Republic of Serbia.

Materials and methods. Blood serum samples obtained in 2018 and 2019 from conditionally healthy residents of the Republic of Serbia were tested for the presence of IgG antibodies to measles and rubella viruses in five age groups: I — children from 2 to 6 years old, II — children from 8 to 14 years old, III — 15 to 24 years old, IV — 25 to 49 years old and V — over 50 years old. A total of 1000 samples were obtained, 200 sera in each group. Enzygnost® Anti-Measles virus/IgG and Enzygnost® Anti-Rubella virus/IgG ELISA test systems (Siemens Healthcare Diagnostics Products GmbH, Germany) were used according to the manufacturer's instructions.

Results. Overall, around 23.0% and 33.7% of the surveyed persons had no or low level of anti-measles IgG antibody (≥ 275.0 — ≤ 1000.0 IU/1). In age group I, 60% children contained no or “low” anti-measles antibodies titer (29.5% and 30.5%, respectively). In addition, low antibody titer level was mainly detected in individuals from age group II and III (p < 0.05). A third of children under 8—14 contained high IgG-antibodies titer against measles (> 3000.0 IU/l) that might serve as an evidence that such subjects recently recovered after measles. Similar results were obtained for IgG antibodies to rubella in the same age groups.

Discussion. The study results evidence about altered routine immunization against measles and rubella in children aged 12—15 months (first vaccination) and those at age of 6—7 years (revaccination) with MMR vaccine. The data obtained correlate with official data on coverage with measles and rubella vaccines in the Republic of Serbia.

Russian Journal of Infection and Immunity. 2021;11(1):171-176
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Immune system parameters in chronic opisthorchiasis patients related to genes polymorphisms associated with developing ischemic heart disease

Grigoryeva S.A., Kosyreva A.N., Stepanova T.F., Stepanova K.B., Bakshtanovskaya I.V., Kalgina G.A., Kurlaeva L.V.

Abstract

The aim of the study was to identify a relationship between gene polymorphisms associated with developing coronary heart disease and pathogenetic features of opisthorchiasis invasion. There were compared laboratory parameters assessing the immune system functioning (lymphocyte immunophenotyping evaluated by flow cytometry, serum immunoglobulin and cytokine concentrations, non-specific resistance indices) in patients with chronic opisthorchiasis (caused by Opisthorchis felineus) of various genotypes with/without mutations in loci associated with predisposition to developing coronary heart disease. It was found that opisthorchiasis invasion leads to altered immune response in patients bearing mutations in genes encoding adenosine monophosphate deaminase 1, hypoxia induced factor 1 alpha, and apolipoprotein E affecting relevant protein functions compared to those without minor alleles. Upon that, patients carrying mutation in the adenosine monophosphate deaminase 1 gene, turned out to have lowered cellular (decreased count of cytotoxic lymphocytes) and humoral immunity (decreased immunoglobulin A level). Patients with opisthorchiasis bearing a rare allele in the hypoxia-induced factor 1 alpha gene were featured with activated adaptive immunity and reduced activation of innate immunity. Moreover, mutated apolipoprotein E gene was coupled to decreased activity of cellular immune response, which exacerbates the course of opisthorchiasis invasion, whereas minor allele of the rs1333049 polymorphism in the cyclin-dependent kinase inhibitor gene results in no significantly altered immune response. Thus, gene-related dysfunction of certain proteins may allow opisthorchiasis invasion to elicit multidirectional changes in immune response, so that approaching the normal range of diverse immune-related parameters during chronic parasitic invasion may not necessarily be interpreted as a “protective” effect exerted by any of gene polymorphisms. The most prominent changes in immune response of patients with chronic opisthorchiasis were detected in case of polymorphism in the factor-induced hypoxia-1 alpha gene. The data obtained suggest that the aforementioned genetic polymorphisms may predispose to manifestation of certain opisthorchiasis clinical forms.

Russian Journal of Infection and Immunity. 2021;11(1):177-183
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Clinical and microbiological aspects of Enterococcus faecalis -associated urinary tract infection

Zaitseva E.A., Luchaninova V.N., Melnikova E.A., Komenkova T.S., Krukovich E.V.

Abstract

Urinary tract infections (UTIs) pose a topical problem in current pediatrics, pediatric nephrology and urology. UTI-related clinical picture in childhood is polymorphic, sometimes being rather subtle and undergoing age-related alterations. Often, typical UTI symptoms in infants and early children occur subclinically. Microbe-related properties colonizing renal tissues dominate among multiple factors involved in developing UTI. In recent years, etiological importance of Enterococcus faecalis in development of such pathology has been increased. Our study was aimed to determine E. faecalis-associated UTI clinical signs in children and unveil their biological characteristics to assess related clinical significance.

Materials and methods. A nine-year pediatric UTI etiological pattern was analyzed at the multi-field pediatric clinical hospital. The data of clinical and laboratory examination of 181 UTI children aged 3 days — 17 years as well as microbiological study of 60 E. faecalis strains isolated from patient urine were obtained.

Results. Clinical and laboratory characteristics of E. faecalis-associated UTIs, age-related symptom variability were presented. Intoxication syndrome and fever dominated in the clinical picture. A key sign of UTIs was gastrointestinal dysfunction (in neonates and one-year old children) and pain in the lumbar region (in older children). The identified clinical symptoms may be associated with the upper urinary tract damage, concomitant diseases, and the pathogenic properties of E. faecalis. Other symptoms were less common, consistent with the age of the patients, although abdominalgia was equally common for children in all age groups. Data of laboratory examination also depended on patient age. It was noted that leukocytosis and thrombocytosis were more prominent in neonates, whereas leukocyturia and proteinuria — in children above one year of age, although clinical symptoms in this group were less overt. Specific features and clinical significance of E. faecalis-related biological properties, their heterogeneity related to patient age were noted. An inter-connected relationship between pathogenic properties and certain clinical symptoms was revealed.

Conclusion. The dominant clinical symptoms (intoxication, hyperthermia), indicative of damaged upper urinary system is related, among other things, to the set of E. faecalis biological properties exerting tissue-damaging and cytolytic effects.

Russian Journal of Infection and Immunity. 2021;11(1):184-190
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Clinical and laboratory characteristics of influenza infection in hospitalized adult patients during the 2018-2019 epidemic season

Voloshchuk L.V., Go A.A., Pisareva M.M., Guzhov D.A., Bichurina M.A., Petrova P.A.

Abstract

Despite the success in prevention and therapy, influenza remains a mass disease with mortality rate up to 0.01—0.2% worldwide.

Purpose. Conducting clinical and laboratory analysis of influenza infection cases and evaluating their etiological significance in adult hospitalized patients during 2018—2019 epidemic season.

Materials and methods. There were analyzed 569 case histories of patients hospitalized at the Clinical Infectious Diseases Hospital named after S.P. Botkin. Patients were examined by PCR that resulted in verified influenza virus in 260 cases. Nasopharyngeal swabs collected from 36 patients were examined by virological method on MDCK cell culture. 24 influenza virus strains were isolated and identified.

Results. The study allowed to identify a viral landscape represented by influenza viruses A and B found in 98.5% and 1.5% cases, respectively. Influenza viruses isolated on cell culture in 50% of cases were identified. Among the influenza viruses isolated on cell culture there were identified serotype A influenza viruses (H1N1) closely related to the pandemic influenza A (H1N1)pdm09. Some isolates (41.7%) belonged to serotype A (H3N2), which were related to strain A/Singapore/16-0019/16. Influenza B virus strain of the Victoria lineage isolated from a hospitalized patient possessed a triple deletion in hemagglutinin gene, which antigenic properties substantially differed from those of the influenza virus strain being included into current influenza vaccines. Upon admission, the condition of most patients was estimated as moderate (males — 48.7%, females — 51.3%). The median patient age was 35 years old, with comorbidities being registered in 50% cases. The clinical picture for 2018—2019 seasonal influenza displayed no distinctive features as compared to previous epidemic seasons. The duration of intoxication and catarrhal syndrome was 4.3±0.13 and 6.9±0.29 days, respectively, with median body temperature ranging within 39.2±0.06°С. All patients received standard pathogenetic therapy. Complications were noted in 86.7% cases such as pneumonia — 11.1%, sinusitis — 6.9%, bronchitis — 56.9%. The bed day length was 5.93±0.29, no lethal outcomes were recorded.

Conclusion. It was found that influenza A viruses were dominant in patients observed comprising up to 98.5% cases, whereas influenza viruses B were found in as few as 1.5% patients. The clinical picture was characterized by severe intoxication and catarrhal syndrome, being frequently associated with complications.

Russian Journal of Infection and Immunity. 2021;11(1):191-196
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