Vol 12, No 4 (2022)

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Lassa fever. Part 2. Laboratory diagnostics, treatment, development of medications

Kazachinskaia E.I., Aripov V.S., Ivanova A.V., Shestopalov A.M.


Globalization and high-speed means of transportation contribute to the spread of infections dangerous to humans. Airborne pathogens have pandemic potential as currently shown in case of the novel coronavirus SARS-CoV-2. Natural focal Lassa fever (LF) common in West African countries, in 35 cases was registered in non-endemic geographical areas because any person infected with Lassa virus (LASV) is a long-term source of infection (up to two months). Cases of person-to-person infection in endemic territories are described. In Germany, the facts of secondary virus transmission from patients to doctors have been recorded during the examination and blood collection from an apparently healthy person as well as during the autopsy of a deceased subjects due to severe LF course. Nonspecific malaise symptoms in LF are also characteristic of numerous other diseases common on the African continent, e.g., malaria and typhoid fever or viral infections such as yellow fever, Chikungunya, dengue and Zika, monkey pox and Ebola virus disease. In this regard, there may be similar dermatological manifestations. Timely detection of cases and differential diagnosis are crucial to ensure safe patient care and use of affordable antiviral therapy for LL provided by the drug Ribavirin. Research methods for studying LASV use polymerase chain reaction (PCR) for detecting viral RNA, electron microscopy, isolation of infectious virus cultured sensitive cells, indirect immunofluorescence reaction, enzyme immunoassay (ELISA) and immunochromatographic assays for the detection of antibodies and/or antigen as well as immunoblotting. Currently, test kits based on molecular and genetic methods are mainly used for LF laboratory diagnostics. Since the 1980s, ribavirin has been used to treat patients with LF. The serum accumulation of the drug in large quantities causes hemolysis, development of anemia and impaired renal function. In this regard, treatment options are being considered with decline in its concentration due to combined use with other antiviral drugs. A search for new therapeutic agents capable of inhibiting viral replication at disease early stage has been in progress due to lack of any approved vaccines.

Russian Journal of Infection and Immunity. 2022;12(4):609-623
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Rhino- and RS-viruses in the COVID-19 pandemic

Kiseleva I.V., Ksenafontov A.D.


Acute respiratory viral infections are distributed across the globe and are the most numerous human diseases caused by several hundreds of diverse viruses. Human rhinovirus is one of the most common respiratory pathogens worldwide, causing more than half of all acute respiratory viral infection cases. Seasonal human coronaviruses account for 10–15% of common cold cases; respiratory syncytial (RS) virus is the most common cause of respiratory hospitalization in infants; influenza viruses, adenoviruses, human parainfluenza virus, metapneumoviruses, and some other pathogens are also widespread. It is believed that viral common colds are mostly self-limited, causing mild infections that usually resolve within 8–10 days. However, the role of common seasonal respiratory viruses in total respiratory morbidity should not be underestimated. It turned out that during extraordinary conditions of pandemics, they behave differently. This was clearly demonstrated in the last 2009 influenza pandemic. Whereas some viruses lost relevance under the burden of a new aggressive pandemic strain, others, e.g., rhinovirus, continued to fight for existence and not only circulated along with the pandemic pathogen, but delayed its spread in some cases. For instance, the data from some European countries pointed out that the circulation of the H1N1pdm09 influenza A pandemic virus was interrupted by the annual rhinovirus outbreak. Ten years after the H1N1pdm09 influenza pandemic, a new virus outbreak emerged — the COVID-19 pandemic has begun. This pandemic, caused by the SARS-CoV-2 virus, has disrupted well-established pathogenetic and epidemiological relationships. The level of circulation of many respiratory pathogens has changed dramatically. For instance, global influenza activity has been at a much lower level than expected for the second year from now. In many regions of the world, the flu season has not been started yet. But what is interesting is that rhinoviruses together with RS-virus again showed their unique ability to compete with highly pathogenic and aggressive pathogens. Along with profoundly reduced circulation of many other seasonal respiratory viruses, rhinovirus, and RS-virus are the most frequently detected viruses. In this review, we have brought together the main biological characteristics of such genetically distinct viruses such as rhinovirus, influenza A virus, RS-virus, and SARS-CoV-2. We focused on their main similarities and discrepancies in the attempt to understand why they behave so differently in extreme pandemic conditions as well as what allows rhinoviruses and RS-viruses to coexist with SARS-CoV-2, which in turn almost fully replaced the influenza virus.

Russian Journal of Infection and Immunity. 2022;12(4):624-638
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Epidemiology and course of infectious diseases during the COVID-19 pandemic. Report 1. HIV infection, hepatitis c and tuberculosis

Belyakov N.A., Boeva E.V., Zagdyn Z.M., Esaulenko E.V., Lioznov D.A., Simakina O.E.


Pathological conditions of various natures are capable of mutual aggravation, significantly affecting the overall burden of the disease, its manifestations and severity. This analytical review is devoted to the interaction between pathogens of socially significant infections — human immunodeficiency viruses (HIV), hepatitis C, Mycobacterium tuberculosis and SARS-CoV-2. Foreign and own data covering the issues of syndemia and interference of pathogens are presented. The results of epidemiological analysis in the North-Western Federal District (NWFD) are presented, which demonstrated the absence of a significant impact of the pandemic caused by a new coronavirus infection (COVID-19) on the epidemic incidence of HIV, viral hepatitis C or tuberculosis at the population level, which may be due to various mechanisms of transmission of infections and the required infectious dose of the pathogen. The absence of a negative effect of COVID-19 on mortality rates in HIV infection, viral hepatitis C and tuberculosis in the territories of the NWFD was noted. Special attention is paid to the clinical picture of the combined course of HIV infection, tuberculosis and COVID-19. The data are demonstrated, which allow us to conclude that the worst prognosis and risk of death are patients in the progressive stage of the disease, which is characterized by the presence of opportunistic infections, especially AIDS-indicator conditions, with disseminated tuberculosis and in the cirrhotic stage of viral hepatitis. The significance of severe manifestations of infectious pathology in cases of deterioration of the prognosis of COVID-19 is shown. Based on the experience of two years of the pandemic, the problems contributing to the syndrome of new coronavirus infection and other conditions, as well as the causes of high mortality from COVID-19, which include: limited resources for non-infectious areas of medical care; insufficient funding for planned and high-tech care; a decrease in the volume of primary diagnosis and detection of infectious and non-infectious pathology; delayed and limited research in areas; distraction of specialists from preventive and dispensary work outside of infectious pathology; shortage of medicines and consumables; social instability and deterioration of the well-being of the population, characteristic of pandemics. The role of a personalized approach to patients with concomitant somatic and infectious diseases as a preventive measure for the severe course and complications of COVID-19 is determined.

Russian Journal of Infection and Immunity. 2022;12(4):639-650
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Opportunities for correction of immunosuppression in patients with COVID-19

Kiselevskiy M.V., Treshalina H.M., Mikhailova I.N., Martirosyan D.V., Manina I.V., Reshetnikova V.V., Kozlov I.G.


Here, we review thematic publications in available literature sources of the databases PubMed, Scopus, Web of Science, eLibrary, 49 of which were dated of the years 1997–2022. Analysis of such reports is aimed at assessing features of cytokine storm-induced hyperinflammatory reaction with signs of immunosuppression accompanied by pronounced lymphopenia and lowered count of CD4+T helpers during severe COVID-19. The prognostic factor for unfavorable prognosis was based on the marker of systemic inflammatory reaction correlating with the disease severity — the soluble IL-2 receptor as well as the neutrophil-to-lymphocyte ratio and the lymphocyte subset imbalance. An immunosuppressive therapy of severe forms of COVID-19, aimed at weakening the inflammatory response, exacerbates immune dysfunction by suppressing the T cell function, mainly due to Th1 lymphocytes involved in recognizing and eliminating intracellular pathogens particularly viruses. Upon that, cell-mediated immunity becomes compromised that relies on cytotoxic T-lymphocytes, natural killer cells and macrophages. Timely and targeted immunocorrection is required to prevent or reduce the immunosuppression that accompanies a severe disease course and leads to serious and prolonged complications, as well as to association of secondary infections. In fight against the cytokine storm, it is important not to miss a time point of developing immunosuppressive condition that transitions into immunoparalysis as follows from recent publications covering the tactics of treating immune-mediated complications of coronavirus infection. The review discusses opportunities for immunosuppressive therapy along with glucocorticosteroids and monoclonal antibodies blocking IL-6 or cognate receptors. Studies using mesenchymal stem cells (MSCs) to reduce systemic inflammatory response at COVID-19 are outlined in the review. The use of antigen-specific Treg and their combinations with antagonists of tumor necrosis factor-α (TNFα), interferon-γ (IFNγ) as well as low-dose IL-2 in patients with SARS-CoV-2 infection were analyzed. The prognostic perspectives for CAR-T cells and CAR-NK cells technology have been considered as novel therapeutic approaches aimed at “training” effector cells to recognize the surface SARS-CoV-2 virus spike-like (S) protein. The feasibility of a therapeutic approach is also emphasized by comparatively analyzed of efficacy of using IL-7 or IL-15 during lymphopenia in patients with COVID-19. Here, side effects complicating immunocorrection come to the fore. Critical evaluation of corrected immunosuppressive conditions in patients with COVID-19 in the post-COVID-19 period by using low-dose IL-2 therapy revealed its ability to repair cellular immune response. As a result, a low-dose IL-2 therapy is recommended as a cytokine replacement therapy in such patients with COVID-19 during hyper-to-hypo-inflammatory phase transition in immune response.

Russian Journal of Infection and Immunity. 2022;12(4):651-658
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Physicochemical and antigenic properties of the urea-extracted surface structures of Yersinia pseudotuberculosis O:1b

Kryukova A.V., Markov E.Y., Nikolaev V.B., Popova Y.O., Klimov V.T., Igumnova S.V., Andreevskaya N.M., Ulanskaya A.V., Zagoskina T.Y., Chesnokova M.V.


Immuno-serological diagnostic tools particularly identifying pathogen antigens are the most important methods of pseudotuberculosis studies. The main immunodominant and species-specific antigens located in the surface structures of the bacterial cell are of practical interest. Thereby the aim of the work was to isolate and characterize biologically active surface structures of the pseudotuberculosis microbe. Here, the living cells of Y. pseudotuberculosis 3704 (O:1b) were lysed by using 9 M urea solution to extract antigens localized in the microbial surface structures. The subcellular fractions obtained such as outer membranes (OM), urea extract (UE) and isolated protein-lipopolysaccharide complex (PLPSC) are characterized by physical and chemical parameters. The protein content in the preparations ranged from 42% to 53%. The polypeptide band of the OM preparation, UE polypeptide and PLPSC for pseudotuberculosis microbe was presented by 14, 16 and 9 major polypeptides with molecular weight ranging from 13.9 kDa to 131.5 kDa, 13.5 kDa to 101.6 kDa, and 20.7 kDa to 66.6 kDa, respectively. Proteolytically active proteins and polypeptides were detected in isolated subcellular fractions (OM and UE) by using the radial enzyme diffusion test and substrate-gel electrophoresis found to be presented by 4 and 7 polypeptides with molecular weight ranging from 28.0 kDa to 118.0 kDa and 29.2 kDa to 97.7 kDa in the OM and UE preparation, respectively. The subcellular fractions obtained are capable to exhibit immunogenic activity after inoculation to experimental animals and antigenic activity while interacting with specific antibodies in the radial immunodiffusion (RID) assay and antibodies labeled with colloidal silver nanoparticles in dot immunoassay (DIA). OM and PLPSC preparations in DIA with immunoglobulins isolated from experimental antisera and labeled with colloidal silver nanoparticles were detected at a concentration of ≥ 0.12 μg/ml (dry weight), cells of strain Y. pseudotuberculosis 3704 at a concentration of ≥ 3, 9 × 106 m.c./ml, which is similar to the results of DIA with immunoglobulins isolated from commercial pseudotuberculosis antiserum (St. Petersburg) and labeled with nanoparticles of colloidal silver. Thus, the subcellular fractions of pseudotuberculosis microbe isolated by using urea as a lysing and decontaminating agent retain their antigenic and immunogenic properties and enzymatic activity suggesting about their potential benefits for use to improve early diagnostics of pseudotuberculosis.

Russian Journal of Infection and Immunity. 2022;12(4):659-667
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Диагностика синдрома активации макрофагов в зависимости от исходного уровня IL-6 у пациентов с новой коронавирусной инфекцией, вызванной вирусом SARS-CoV-2

Popov A.F., Markelova E.V., Komarova I.A., Kostiushko A.V., Shchelkanov M.Y.


An effect of the antiviral drug Kagocel on the levels of metalloproteinases MMP-8 and MMP-9 and their tissue inhibitors TIMP-1 and TIMP-2 in induced sputum during treatment of community-acquired viral-bacterial pneumonia was analyzed. 60 adult patients with verified community-acquired pneumonia of viral-bacterial etiology were included in the follow-up monitoring.

Materials and methods. All patients were randomly stratified into 2 groups: group 1 (comparison group) consisted of 30 patients receiving Ceftriaxone monotherapy; group 2 (main group) — 30 subjects who were prescribed Ceftriaxone and the antiviral drug Kagocel as etiotropic treatment. Both groups were comparable in gender, age and time of admission to the hospital.

Results. During hospitalization, patients in both groups had elevated levels of MMP-8, MMP-9, TIMP-1 and TIMP-2 in induced sputum compared to the reference values. By 7 days of inpatient treatment, the level of MMP-8 was still significantly higher than the reference values in both groups, being in patients from group 2 it decreased compared to baseline values, whereas in patients from group 1, on the contrary, it was markedly elevated. The activity of MMP-9 during hospitalization was also high in patients from both groups compared with its level in healthy subjects. By day 7 of therapy, changes in various parameters were recorded. The level of MMP-9 in patients from group 1 increased, whereas in group 2 — on the contrary — decreased. The level of TIMP-1 decreased in patients of the 1st group below the control value, and in patients of the 2nd group — reached the reference values. The level of TIMP-2 decreased in both groups and reached that of in control group.

Conclusion. Antiviral drug Kagocel being included in the standard antibacterial regimen of community-acquired viral-bacterial pneumonia reduces the level of MMR-9 and intensity in imbalance between MMP and TIMP parameters by 7 days of therapy, which leads to accelerated clinical recovery.

Russian Journal of Infection and Immunity. 2022;12(4):668-676
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Formation of anti-infectious and post-vaccination anti-SARS-CoV-2 humoral immunity in medical workers of the perinatal center

Chistyakova G.N., Malgina G.B., Ustyuzhanin A.V., Remizova I.I.


In the context of the global spread of the new coronavirus infection, studies aimed at investigating formation of anti-infectious and post-vaccination immunity are of special importance, which is necessary to prevent and reduce morbidity and mortality due to SARS-CoV-2 infection. Purpose: to assess anti-infectious immunity against SARS-CoV-2 in various forms of the disease and development of post-vaccination humoral reactions in medical workers of the perinatal center.

Materials and methods. A study of blood serum was carried out to assess SARS-CoV-2-specific IgM and IgG antibodies in 119 medical workers recovered after COVID-19, divided into groups based on the disease severity (mild, moderate and asymptomatic), as well as in 62 vaccinated employees, divided into groups according to age. Semi-quantitative measurement of virus-specific antibodies was carried out by ELISA with test systems “SARS-CoV-2-IgG-ELISA-BEST” and “SARS-CoV-2-IgM-ELISA-BEST”. Statistical processing of the research results was carried out using Microsoft Excel 2010 and Statistica 6. Quantitative characteristics were presented as median (ME), lower and upper quartiles (LQ1-UQ3); qualitative parameters — as absolute value and relative number (%). Difference between groups was analyzed by using the χ2 test (qualitative) and the Mann–Whitney U-test (quantitative).

Results. The results of the study showed that the majority of employees with a moderate-severe form of SARS-CoV-2 had a high level of IgG (PR — a positivity rate of more than 9.0 arbitrary units) 9 months after the disease compared to those who suffered from mild or asymptomatic (83.3% versus 25.8% and 13.3%, p < 0.017) infection. The duration of IgG circulation after former illness had no relation to its severity and patient age. The effectiveness of the primary vaccination “Sputnik V” and revaccination with “Sputnik Light” and “KoviVak” was 100% after inoculating the vaccine second component. The lowest level of antibodies after the first vaccination is recorded in persons over 60 years old (1.48 (1.12–3.25 versus PR = 8.48 (5.78–10.11) and 9.27 (5.84–10.31) arbitrary units, p < 0.017)), in comparison with young and middle-age subjects. The speed SARS-CoV-2 elimination of IgG at 6, 9 or more months after vaccination depends on relevant initial peak antibody concentration. Subjects who were initially vaccinated with the KoviVac vaccine, IgG was not detected 2 months after vaccination. The protective effect of “Sputnik V”, “Sputnik Light”, “KoviVac” after re-infection with SARS-CoV-2 averages 71.2%.

Conclusion. Thus, the results obtained on assessing anti-infectious and post-vaccination immunity against SARS-CoV-2 emphasize the need for further studies on a larger patient cohort, especially in those with asymptomatic infection as well as the elderly subjects.

Russian Journal of Infection and Immunity. 2022;12(4):688-700
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Diagnostics of macrophage activation syndrome, depending on IL-6 initial level in patients with a novel coronavirus infection

Perepelitsa S.A.


Introduction. The novel coronavirus infection caused by the SARS-CoV-2 remains the main problem, which is being studied by all the efforts of the global scientific community. Large clinical recourse has been accumulated that allows to conduct more effective treatment of patients, but there are still unresolved issues on the pathogenesis for development and course of the disease.

Materials and methods. The study included 163 patients admitted to the infectious diseases hospital diagnosed with “Novel coronavirus infection caused by the SARS-CoV-2”. Upon admission, all patient serum samples were quantified for IL-6 level that allowed to stratify patients into three groups: A — 55 patients with IL-6 below 5.0 pg/ml. The mean age in the group was 57.3±14.9 years, body mass index (BMI) was 28.2±5.6 kg/m2; C — 52 patients whose serum IL-6 level was in the range of 5–49 pg/ml. The average age in the group was 60.8±11.8 years, BMI — 29.6±5.5 kg/m2; C — 56 patients in whom the level of IL-6 in the blood serum ranged within 50–300 pg/ml. The average age in the group was 62.5±15.6 years, BMI — 28.8±5.6 kg/m2. Patients at admission were analysed for serum level of IL-6, IL-8, and C-reactive protein (CRP), ferritin, lactate dehydrogenase (LDH) were also determined on day 3 and 7.

Results. The minimum production of IL-6 within the range of 0.1–5 pg/ml, corresponds to the minimum changes in IL-8, CRP, and ferritin as well as LDH that was within the range of physiological values. Moderate cytokinemia, IL-6 is within the range of 5–49 pg/ml was associated with elevated ferritin and LDH not tending to decline by the end of treatment. Significant cytokinemia, the level of IL-6 within the range of 50–300 pg/ml was associated with hyperferritinemia and increased LDH. The course of COVID-19 in such patients is characterized by increased ferritin by day 3 of treatment, consistently high level of LDH, without a significant trend towards a decline in the studied markers by the end of treatment.

Conclusion. The risk of developing macrophage activation syndrome is not observed of the serum IL-6 level was below 5 pg/ml, whereas ferritin and LDH were within the range of physiological values, with no/degree I ARF. Moderate macrophage activation syndrome is characterized by increased serum IL-6 level within the range 5–49 pg/ml, a moderate increase in LDH and ferritin, as well as signs of ARF I–II degree. Severe signs are diagnosed in case of serum IL-6 level exceeded 50 pg/ml, along with significant increase in LDH and ferritin, as well as signs of II–III degree ARF.

Russian Journal of Infection and Immunity. 2022;12(4):677-687
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Intra-laboratory validated “TigraTest® SARS-CoV-2” — test assessing release of interferon gamma in vitro to identify peripheral blood T-lymphocytes specifically responding against SARS-CoV-2 virus antigens

Lyagoskin I.V., Kargopolova P.E., Obyedkov D.A., Egorova I.Y., Shukurov R.R.


SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2), also known as 2019-nCoV (2019-Novel Coronavirus) is a strain of coronavirus from the genus Betacoronavirus, discovered in China at the end of 2019 in patients with pneumonia. “Coronavirus infection COVID-19” (COrona VIrus Disease 2019) caused by coronavirus 2019 (COVID-19) has spread around the world at a very fast pace, with death toll exceeding more than 5.2 million people worldwide. Limited success in developing new drugs as well as use of existing drugs for the treatment of COVID-19 resulted in situation when the main prevention measures for a long time were based on testing and isolation of sick subjects, which started to reverse due to vaccination. Monitoring the formation of humoral and T-cell population immunity against the SARS-CoV-2 virus during the COVID-19 pandemic is a necessary element for epidemiological surveillance. ELISA-based methods are widely used to assess humoral immunity, and various test systems including ELISPOT (Enzyme-Linked ImmunoSpot) are used to analyze cellular immunity. The ELISPOT assay is a highly sensitive and specific method for quantifying individual cytokine-secreting T cells after being stimulated with a specific antigen. “TigraTest® SARS-CoV-2” Test assessing release of interferon gamma in vitro to detect peripheral blood T-lymphocytes that specifically respond to the SARS-CoV-2 virus antigens manufactured by GENERIUM JSC, is created on the ELISPOT platform. This study describes the procedure for laboratory validation of this test system to analyze the following parameters: specificity of antibody pair, effect of interfering substances, sensitivity and specificity, precision, stability of blood samples till isolation of target cells. The developed test system showed high diagnostic sensitivity and specificity. The specificity of TigraTest® SARS-CoV-2 was 100%, the sensitivity for subjects immunized with the Gam-COVID-Vac vaccine (Sputnik V) was 91.67%, and the sensitivity in convalescent COVID-19 patients was 95.45%. At the same time, the data variability both during within and between series comparison did not exceed 25%, whereas 24-hour storage of peripheral blood samples at (18–25)°С after blood collection followed by isolation of target cells did not affect the test results.

Russian Journal of Infection and Immunity. 2022;12(4):701-713
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Characteristics of respiratory tract bacterial microflora detected in patients suffering from community-acquired pneumonia during continuing spread of the new coronavirus infection in Khabarovsk city (december 2020 — march 2021)

Trotsenko O.E., Bondarenko A.P., Shmylenko V.A., Bazykina E.A., Pshenichnaya N.Y., Zaitseva T.A., Tkacheva N.K., Ogienko O.N.


Objective of the research — to specify respiratory tract bacterial microflora in patients suffering from community-acquired pneumonia (CAP) during initial and repeat examination. To determine local factors affecting microflora in the cohort examined.

Materials and methods. Surveillance subject — 241 patients with CAP differed by their status and age who stayed in two healthcare facilities of the Khabarovsk city. Examination of respiratory smears was performed. Results. Indices of Gram-negative enterobacteria (30.8% [22.6–39.7%]) and Gram-negative nonfermentable bacteria (14.5% [8.6–21.7%]), isolated from patients hospitalized in healthcare institution No. 1 and mostly comprised of the elderly (aged over 61 years — 82.0%; 74.3–88.6%) with more severe disease state including patients at the ICU, were higher compared to data obtained from healthcare institution No. 2 (19.8% (13.4–27.0); 6.1% (2.7–10.8) respectively). Prevalent pathogen was Klebsiella pneumoniae — 13.6% (7.8–20.6) and 10.7% (6.0–16.5). Identification of Acinetobacter baumannii complex — 6.4% (2.6–11.7) and 3.1% (0.8–6.7) — should be also noted. A high percentage of drug-resistant bacterial variants was observed and for Klebsiella pneumoniae totaled 66.7% (41.8–87.4) and 57.1% (32.2–80.2) at the healthcare institutions No. 1 and No. 2, respectively. A. baumannii complex drug resistant variants were found in 85.7% (52.7–99.97) at healthcare institution No. 1. All isolates of A. baumannii complex at the healthcare institution No. 2 were drug resistant. High prevalence of Candida spp. was revealed in both healthcare institutions reaching 54.5% (45.2–63.7) and 58.0% (49.5–66.3), respectively, with minimal detection rate of classic pathogens such as S. pneumoniae — 5.4% (2.0–10.4) and 5.3% (2.1–9.8) and H. influenzae — 3.6% (0.9–7.9) and 3.8% (1.2–7.7), respectively. Repeat examination of 122 patients conducted 7–10 days later showed diverse changes in microflora spectrum regardless of the healthcare institution that was manifested as loss or emergence of drug-resistant variants as well as simultaneous presence of different variants of the same pathogen.

Conclusion. The results obtained evidence about complexity and variety of mechanisms underlying microorganism community formation during the course of infectious process in patients. Local factors influencing microflora characteristics of patients at the two healthcare institutions were revealed.

Russian Journal of Infection and Immunity. 2022;12(4):713-725
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The clinical effectiveness of probiotics and autoprobiotics in treatment of Helicobacter pylori-associated dyspepsia

Ermolenko E.I., Molostova A.S., Baryshnikova N.V., Svarval A.V., Gladyshev N.S., Kashchenko V.A., Suvorov A.N.


The aim of our study was to evaluate the clinical performance of a monotherapy by Enterococcus faecium-based probiotics and indigenous autoprobiotics against H. pylori associated dyspepsia.

Materials and methods. There were examined 95 patients with dyspepsia. The entire patient cohort underwent clinical evaluation including filling out the questionnaire to assess dyspepsia symptoms before and after treatment, gastric endoscopy as well as gastric multi-focal biopsy (gastric body and gastric antrum) and verification of H. pylori infection with the three clinical laboratory methods (biochemical, bacteriological and molecular detection). An antagonistic in vitro activity of probiotics against H. pylori was detected by drop plate method for probiotic strains Enterococcus faecium SF68 and Bifidobacterium bifidum (Bifiform), Enterococcus faecium L3 (Laminolact), and autoprobiotic strains combined with indigenous Enterococcus faecium. To examine an antagonistic activity of probiotics and autoprobiotics in clinical trials, we used a starter culture based on the Enterococcus faecium L3 strain and an autoprobiotic based on indigenous Enterococcus faecium. The probiotic or autoprobiotic were administered orally to patients with gastritis twice a day at dose of 50 ml (8.0 lgCFU/ml) for 20 days. H. pylori eradication was assessed by stool antigen test 1.5–2 months after the end of treatment.

Results. Initially the H. pylori infection was confirmed with 49.4% of patients. The sensitivity of H. pylori to the probiotics was detected in 81% of individuals for indigenous Enterococci (the autoprobiotic), 76% — for Laminolact, and in 62% — for Bifiform. 22 patients with previous history of allergic reactions to antibiotics used in routine H. pylori eradication regimens were divided in two cohorts. One cohort (10 patients) received the autoprobiotic only, another cohort (12 patients) received only probiotic. Monotherapy with autoprobiotic resulted in 100% H. pylori eradication, single-agent therapy with probiotic led to 60% eradication of H. pylori. Dyspepsia symptoms were completely resolved in both groups of patients.

Conclusion. Our research demonstrated the sensitivity of examined H. pylori strains to be similar for traditional eradication treatment agents (antibiotics) and the proposed intervention agents (probiotics and autoprobiotics). An autoprobiotic monotherapy with indigenous enterococci led to higher levels of H. pylori eradication than with E. faecium L3-based probiotic agent. Our work demonstrated advantage for application of probiotics in patients with antibiotic allergies or other obstacles for the standard eradication therapy. Nonetheless, further investigation to better understand underlying mechanisms of action, as well as larger observational and randomized studies, are necessary to determine the scope of therapeutic application for probiotics and autoprobitics to eradicate H. pylori infection.

Russian Journal of Infection and Immunity. 2022;12(4):726-734
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Detection of human papillomavirus, viral load and risk factors in patients with precancerous diseases and malignant neoplasms in St. Petersburg

Kholopov D.V., Vyazovaya A.A., Topuzov E.E., Alekseeva D.A., Molchanov S.V., Lyalina L.V.


Molecular genetic studies have revealed the involvement of different genotypes of human papillomavirus (HPV) in the carcinogenesis of cervical cancer and malignant lesions of other localizations. It is reported that patients with HPV-positive cancer have a better prognosis of the disease and survival than patients with unconfirmed HPV infection or with a low viral load. The objective was to identify the detectability, viral load, genotypes of human papillomavirus in HPV-associated precancerous and malignant neoplasia of various localization and to determine risk factors for their occurrence in the metropolis of St. Petersburg at the present time.

Materials and methods. A total of 80 samples taken from morphologically confirmed tissues of oropharyngeal and anal cancer, malignant tumors of vulva, vagina, cervix and cervical intraepithelial neoplasia were studied in St. Petersburg Clinical Oncologic Center. Detection, quantification and genotyping of HPV DNA were carried out by real-time PCR at the St. Petersburg Pasteur Institute.

Results. HPV was detected in 89.7% (61/68) of patients with malignant tumors and 83.3% (10/12) — with severe cervical dysplasia. The vast majority (85.9%) of HPV-positive patients were infected with HPV genotype 16; papillomavirus mixed infection (genotypes 16, 18, 31, 33, 35, 39, 45) was detected in anal cancer, cancer and severe cervical dysplasia. The average viral load in stages III–IV of anal cancer, cervical cancer and severe cervical dysplasia exceeded 5.7 lg HPV DNA/105 cells. Among patients with oropharyngeal cancer, men predominated (85.7%); anal cancer was detected in women (90.0%). No statistically significant risk factors (smoking and alcohol consumption) for the occurrence of HPV-associated malignancies were identified.

Conclusions. The detection of HPV, mainly of genotype 16, varied depending on the location of the neoplasia: anal cancer — 100%, cancer of the female genitalia — 94% (in case of cancer of the vagina and cervix — 100.0%), head and neck cancer — 76.2%. The highest HPV DNA load in the tumor tissue was found in III–IV stages of the cervical and anal cancer.

Russian Journal of Infection and Immunity. 2022;12(4):735-744
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Development of quantitative criteria for assessing epidemic potential of the natural-focal viral infections

Safonova M.V., Simonova E.G., Lopatin A.A., Dolgova A.S., Dedkov V.G.


Notonly directly detected new infection, but also determining prerequisites for associated epidemiological complications becomes relevant with growing importance of “new and recurring infections”. As a result, a need to assess a degree of their epidemiological threat, or epidemic potential, i.e. determining the significance of related properties that determine a potential to cause an epidemic process and complications of the epidemiological situation is emphasized. Purpose. Develop methodology for quantitative assessment of the epidemic potential universal for natural-foci viral infections.

Materials and methods. А multifaceted assessment of the virological and epidemiological characteristics of causative agents for natural-focal viral infections was carried out to develop criteria for determining the epidemic potential. The developed methodology for determining the epidemic potential is based on connection between the epidemic potential and the concept of epidemiological hazard, which forms an epidemic risk, and consists of the hazards for source of infection, the mechanism of transmission and host susceptibility.

Results and discussion. The platformfor quantitative assessment of the epidemic potential of natural-foci viral infections was developed. Within each link of the epidemic process, factors were identified, ranked in accordance with their significance for enabling epidemiological risk and score assigned. The epidemic virus potential is determined by the sum of points in three categories, the ratio of points between them allowing to evaluate a lead factor of epidemiological risk. To assess an epidemic virus potential in accordance with the developed criteria, it is necessary to summarize and analyze the known data on the three considered groups of factors involved in formation of epidemiological threat. To test the assessment methodology, the epidemic potential of a number of diversepathogens of natural-foci viral was determined. The values obtained on the epidemic potential for such infections is based on the degree of relevant epidemiological hazard. Thus, the evaluation system allows to quantify anepidemic potential of the pathogen, compare parameters of various pathogens with assessment of the lead epidemiological risk factor. The platform can serve as an additional tool in assessment of epidemiological threat in case of epidemiological emergencies. Meanwhile, assessment of epidemic potential fornew infections is closely associated with the need to investigate their basics. The epidemic potential is a dynamic parameter that can change with the advent of new data on ecological and genetic foundations of pathogen existence as well as mechanisms for related variability.

Russian Journal of Infection and Immunity. 2022;12(4):745-754
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Antimicrobial activity of aqueous dispersions of silver nanoparticles against pathogens of purulent-inflammatory diseases

Nechaeva O.V., Shulgina T.A., Zubova K.V., Glinskaya E.V., Bespalova N.V., Darin N.I., Tichomirova E.I., Afinogenova A.G.


Currently, metal nanostructures are widely used in medical, microbiological, and veterinary practice. Silver nanoparticles are especially promising as antimicrobial agents, becauseno published data regarding antimicrobial resistance are available. Whiledeveloping preparations based on metal nanoparticles, an important remainingissue is the choice of a stabilizer, introduction of which during the synthesis ensures the preservation of structures at the nanoscale range, and, consequently, relevant main characteristics, including biocidal properties. The object of the study was to investigate silver nanoparticle aqueous dispersions stabilized by natural and synthetic polymeric compounds. Routine strains of Gram-positive and Gram-negative bacteria were used as experimental models: S. aureus 209 P, Escherichia coli ATCC 25922, Proteus mirabilis ATCC 3177 (O-form), Klebsiella pneumoniae ATCC 31488, obtained from the Scientific Centre for Expert Evaluation of Medicinal Products. The antimicrobial activity of diverse variants of silver nanoparticle aqueous dispersions was assessed by serial dilution platingon dense nutrient medium. In this work, we examined no effect of silver nanoparticles without stabilizers, because their absence led to rapid agglomeration of nanostructures and loss of nanoscale characteristics. The highest sensitivity of Gram-positive and Gram-negative bacteria was foundto the action of ansilver nanoparticle aqueous dispersions stabilized by polyazolidinammoniumand modified with iodine hydrate ions. Drug working concentrations ranging from 0.5 to 3% had a bactericidal effect against pathogens of purulent-inflammatory diseases, and the minimum working concentration of 0.125% led to decreased colony-forming units by 20–57% for diverse bacterial strains. Silver nanoparticles stabilized with sodium dodecyl sulfate showed high efficiency against the studied test strainsprobably due to the high toxicity of the stabilizer used as was previously established during a comprehensive safety assessment using biotest objects and cell cultures. In this regard, its use as a component of antimicrobial preparations is not preferred. The results of the studies showed that among the variants of silver nanoparticle aqueous dispersions, preparations stabilized with polyvinyl alcohol and polyazolidinammonium modified with iodine hydrate ions are the most promising for use in biomedical practice, because they demonstrate a high level of antibacterial activity against both Gram-positive and Gram-negative bacteria as causative agents of purulent-inflammatory diseases and a low toxicity level. This allows us to recommend them as safe and effective antimicrobial components indisinfectants, as well as antiseptic preparations for prevention and treatment of skin and soft tissue infectious diseases.

Russian Journal of Infection and Immunity. 2022;12(4):755-764
pages 755-764 views


Type of cercaria in freshwater snails at Tunggu Pampang Reservoir, Makassar City, Indonesia

Jabal A.R., Mutiasari D., Akbar H., Arfah M., Marhani M., Rini R., Sobak N.A., Pisu A.J., Toemon A.I., Ratnasari A.


The Tunggu Pampang Reservoir is one of the reservoirs located in the city of Makassar. The functions of the reservoir area was tourist attractions and fish farming locations so that the local community uses them for swimming, fishing, selling, and gardening. The existence of various types of freshwater snails in the reservoir has the potential to act as intermediate hosts for trematodes in animals and humans. This study aimed to analyze the type of cercariae in freshwater snails. This research is a descriptive survey to determine the distribution of trematode larvae. The stages of this research began with the snails were collected from Tunggu Pampang Reservoir, Makassar City. Freshwater snails were collected at several points in the reservoir. Freswater snail collection using hand collecting method. The snails were put into a plastic bag with different types of snails and site of collection. The collected samples and cercariae were examined in the Tropical Disease Laboratory of the Study Program of DIII Medical Laboratory Technology, Megarezky University, South Sulawesi, Indonesia. Freshwater snails are placed on a petri dish and their shells were gently crushed with a stamper. Dropped with aquadest on the crushed snail shell. The next step was observed using a microscope to determine the presence of cercariae. Cercariae found then identified according to morphological classification as previously study. A total number of 500 freshwater snail were collected in Tunggu Pampang Reservoir. The results showed that overall snails infected with cercariae was 33,4%. The highest prevalence of cercariae in Indoplanorbis exustus was 94.3%. Total of Echinostoma cercariae found (n = 224) compared to furcocercous cercariae (n = 5). Cercariae of Echinostoma sp., Fasciola gigantica, Fasciolopsis buski living in Tungu Pampang Reservoir can cause diseases in humans and animals. Larval trematodes can be controlled in snails using reducing parasite contamination, monitoring surveillance, information dissemination, and preventive education.

Russian Journal of Infection and Immunity. 2022;12(4):765-770
pages 765-770 views

Characterizing A “N-CoV-2-IgG PS” diagnostic kit to quantify SARS-CoV-2 nucleocapsid protein-specific human IgG antibodies

Zueva E.V., Belyaev N.N., Verbov V.N., Likhachev I.V., Bachinin I.A., Khamitova I.V., Korobova Z.R., Arsentieva N.A., Totolian A. .


Confirming detected SARS-CoV-2-specific antibodies is necessary to reveal immune response in COVID-19 convalescent subjects as well as to conduct population studies by screening for specific antibodies to assess rate of COVID-19 prevalence. With this purpose St. Petersburg Pasteur Institute was the first in Russia to develop the ELISA kit for the quantitative determination of human IgG to the SARS-CoV-2 nucleocapsid (N-CoV-2-IgG PS). Arbitrary units (AU/ml) were used to assess the level of antibodies. The data shown in AU/ml were recalculated later to the international units (BAU/ml) in accordance with established the First WHO International Standard for anti-SARS-CoV-2 human Immunoglobulin. Comparing the data of the N-CoV-2-IgG PS calibration curve with those of the First WHO International Standard for anti-SARS-CoV-2 human Immunoglobulin revealed a complete inter-assay association (r = 0.999, R2 = 0.997) allowing to find that 1BAU/ml = 5.97 AU/ml. The aim of the study was to characterize the “SARS-CoV-2 protein N Human IgG Quantitative ELISA Kit” (N-CoV-2-IgG PS), compare quantitative and qualitative data of ELISA kits, assess a correlation between the binding antibodies to SARS-CoV-2 N proteins and the neutralizing antibodies against SARS-CoV-2. The data of correlation analysis of the 83 COVID-19 convalescent blood plasma samples a significant relationship between the antibodies quantitative values and titers SARS-CoV-2-specific antibody (r = 0.8436, R2 = 0.7802) as well as a moderate relationship between antibody concentration and positivity index (r = 0.6648, R2 = 0.3307), assessed by Chaddock scale. Comparing concentration of N-protein binding antibodies with neutralizing antibody titers level uncovered data consistency obtained by quantitative and virus microneutralization assays (r = 0.7310, R2 = 0.6527) used in parallel to analyze 80 blood plasma samples obtained from COVID-19 patients and convalescents. AUC under the ROC curve comprised 0.701 (P < 0.0001) evidencing about a satisfactory informative value for “N-CoV-2-IgG PS” compared with microneutralization assay. In addition, the efficacy of the “N-CoV-2-IgG PS” was 95%, while the positive and negative prognostic value was 97% and 87%, respectively. The data obtained confirmed a correlation between N-protein binding antibody level and neutralizing antibody titer. Checking inter-assay agreement evidenced about acceptance for informativeness and efficacy of using “N-CoV-2-IgG PS”, thereby confirming an opportunity to apply the Kit to screen for SARS-CoV-2 N protein-specific IgG antibody level and assess seroprevalence in diverse population cohorts.

Russian Journal of Infection and Immunity. 2022;12(4):771-778
pages 771-778 views

A case of abscessed pneumonia due to COVID-19 infection in a young patient

Vorobeva O.V., Romanova L.P.


Viral infections are the first ranked conditions among infectious diseases causing 5–15% of all community-acquired pneumonia. The aim of the study was to describe a case of COVID-19 infection, proceeding with acquired bacterial infection and developing abscess pneumonia in a young patient.

Material and methods. The accompanying medical documentation was examined, clinical and morphological analysis was carried out for assessing macro- and micropreparations.

Results. Patient A.E., 31 years old, within 5 hours 10 minutes was at in-hospital treatment with a diagnosis of Coronavirus infection, severe course. Community-acquired bilateral polysegmental pneumonia. The patient admitted with complaints of respiratory difficulty, shortness of breath, weakness, fever up to febrile level, severe pain in the right groin area, both lower extremities, swelling in hands and feet. However, despite initiated treatment, the patient’s condition worsened and biological death was verified. The postmortem examination revealed signs of total bilateral hemorrhagic pneumonia. Histological examination showed areas of necrosis in the alveolar epithelium and signs of marked edema with a hemorrhagic component; hemolyzed erythrocytes were found in alveolar lumen. Focal hemorrhages were visualized in the pulmonary parenchyma, sometimes merging along with lung tissue with forming microabscesses. a well-defined shaft consisting of granular leukocytes and congested vessels with erythrocyte sludge was noted on the periphery of necrosis area. In the alveoli located closer to the abscesses, fibrinous and serous exudate was detected. Signs of edema were observed in the brain; histological examination revealed perivascular, pericellular optical voids with vascular congestion, erythrocyte sludge and minor hemorrhages. SARS-CoV-2-caused pneumonia and acquired bacterial infection, in this case due to staphylococcus, led to abscess pneumonia and severe respiratory failure with developing acute distress syndrome. Obviously, the high frequency of destructive processes in staphylococcal pneumonia is due to the pathogenic staphylococci characterized by production of high-level proteolytic enzymes destroying body tissues. Thus, the current case of COVID-19 infection in a young patient is of particular importance and relevance, because it demonstrates an unfavorable disease outcome despite patient young age and lack of concomitant pathology.

Russian Journal of Infection and Immunity. 2022;12(4):779-783
pages 779-783 views

Assessing SARS-CoV-2-related mortality rate in Russian regions, based on the econometric model

Stepanov V.S.


The objects of the study were the daily data on the population morbidity and mortality due to coronavirus disease 2019 (COVID-19) in Russian regions, as well as regional medical, demographic and environmental data recorded in recent years. COVID-19 is a contagious disease caused by the novel coronavirus (SARS-CoV-2). The mathematical methods consist of correlation and regression analysis, methods of testing statistical hypotheses. First, a multiple Variable Structure Regression should be specified. The intercept in the model differs from region to region, depending on the combination of values for dummy variables. The role of the dependent variable Y t was chosen as the cumulative mortality published by the operational headquarters for the regions that has been linked to day t, so that COVID-19 was considered the main cause of death. The complex of explanatory variables included two factorial variables that changed daily, and had a lag relative to t value. Also, this complex included a number of variables that did not change with the growth of t: the explanatory variable with the region’s availability with doctors of certain specialties; and four dummy variables. One of them coded the region’s belonging to the two southern Russian Federal Districts. Three other variables characterized the increased air pollution in settlements recorded in recent years, as well as the level of radiation pollution of the region’s territory and the population health estimated for 10 classes of diseases (for the circulatory system, endocrine system, etc.). The values of such dummy variables were obtained from open data from the Federal State Statistics Service (Rosstat) etc. The model parameters were estimated by the least squares method using the training table, which included 40 Russia’s regions, the t parameter for variable Y t was assessed starting from November, 1, 2021. As a result, a statistical model was built with an approximation error equal to 3%. For ¾ regions of the regions examined this error was 1.94 (±1.5)% for the value Y t that has been fixed on the 1st Nov. The plots show daily prediction for mortality rate due to COVID-19 in the first half of November for seven Russian regions compared with actual data. The model can be useful in development of medical and demographic policy in geographic regions, as well as generating adjusted compartment models that based on systems of differential equations (SEIRF, SIRD, etc.).

Russian Journal of Infection and Immunity. 2022;12(4):783-789
pages 783-789 views


Clinical case of rhino-orbital mucormycosis in a convalescent COVID-19 patient: diagnostic and treatment tactics

Popova A.Y., Demina Y.V., Zaytseva N.N., Kucherenko N.S., Denisenko A.N., Tochilina A.G., Belova I.V., Belozerov G.A., Polyanina A.V., Sadykova N.A., Soloveva I.V.


According to current data, SARS-CoV-2 virus has the ability to cause multi-organ pathology, leading to acute damage of various organs and systems and long-term consequences characterized by polymorphic symptoms. Recently, a high incidence of invasive mycoses, particularly mucormycosis — COVID-M, has been noted among the COVID-19 complications. The predisposing factor for the development of this pathology is diabetes mellitus, immunodeficiency states, and prolonged use of high doses of glucocorticosteroids. Mucormycosis is characterized by severe clinical manifestations and high lethality, and timely diagnostics of this pathology often represents a difficult problem. The aim of this study was to analyze a clinical case of rhino-orbital mucormycosis in convalescent COVID-19 patient. In the study, there was used mucopurulent nasal discharge from the patient previously hospitalized with a severe novel coronavirus infection. Here, we describe the methodology allowing to isolate and identify a pure mold fungus culture from the biomaterial using methods of routine bacteriology and MALDI-ToF mass spectrometry. Direct microscopy examination of nasal cavity discharge revealed branched non-septic hyphae with a characteristic branching angle, allowing to preliminarily diagnose invasive mucormycosis. Growth of mycelial fungus colony was observed by using Sabouraud’s medium with potassium tellurite. Microscopy of the pure culture revealed branching mycelium without septa, broad, with irregular thickness, unsegregated hyphae, and sporangia with a typical column specific to mucormycetes. Analysis of the obtained mass spectra allowed to establish the microbial species identity as Lichtheimia corymbifera. The latter along with other members of the order Mucorales, are known to cause mucormycosis. As a result of antifungal treatment (Amphotericin B) and timely surgical intervention, the patient was discharged from the hospital with prominent clinical improvement and no complaints during further outpatient follow-up period. The analysis of this clinical case showed the lack of alertness in some clinical diagnostic laboratories to detect pathogens of invasive mycoses. To avoid errors, while making a diagnosis, attention should be paid not only to detection of fungal spores in clinical material, but also take into account the structure of mycelium underlying major difference between yeast-like fungi, higher and lower molds. The isolation and identification of a pure pathogen culture allows to confidently verify the diagnosis, timely correct the treatment tactics and monitor circulation of mycotic agents to prevent occurrence of mycoses in most vulnerable patients cohorts.

Russian Journal of Infection and Immunity. 2022;12(4):790-797
pages 790-797 views

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