Vol 12, No 3 (2022)

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Full Issue


T helper cell subsets and related target cells in acute COVID-19

Kudryavtsev I.V., Golovkin A.S., Totolian A.A.


Current review presents a brief overview of the immune system dysregulation during acute COVID-19 and illustrates the main alterations in peripheral blood CD4+ T-cell (Th) subsets as well as related target cells. Effects of dendritic cell dysfunction induced by SARS-CoV-2 exhibited decreased expression of cell-surface HLA-DR, CCR7 as well as co-stimulatory molecules CD80 and CD86, suggesting reduced antigen presentation, migratory and activation capacities of peripheral blood dendritic cells. SARS-CoV-2-specific Th cells could be detected as early as days 2–4 post-symptom onset, whereas the prolonged lack of SARS-CoV-2-specific Th cells was associated with severe and/or poor COVID-19 outcome. Firstly, in acute COVID-19 the frequency of Th1 cell was comparable with control levels, but several studies have reported about upregulated inhibitory immune checkpoint receptors and exhaustion-associated molecules (TIM3, PD-1, BTLA, TIGIT etc.) on circulating CD8+ T-cells and NK-cells, whereas the macrophage count was increased in bronchoalveolar lavage (BAL) samples. Next, type 2 immune responses are mediated mainly by Th2 cells, and several studies have revealed a skewing towards dominance of Th2 cell subset in peripheral blood samples from patients with acute COVID-19. Furthermore, the decrease of circulating main Th2 target cells — basophiles and eosinophils — were associated with severe COVID-19, whereas the lung tissue was enriched with mast cells and relevant mediators released during degranulation. Moreover, the frequency of peripheral blood Th17 cells was closely linked to COVID-19 severity, so that low level of Th17 cells was observed in patients with severe COVID-19, but in BAL the relative number of Th17 cells as well as the concentrations of relevant effector cytokines were dramatically increased. It was shown that severe COVID-19 patients vs. healthy control had higher relative numbers of neutrophils if compared, and the majority of patients with COVID-19 had increased frequency and absolute number of immature neutrophils with altered ROS production. Finally, the frequency of Tfh cells was decreased during acute COVID-19 infection. Elevated count of activated Tfh were found as well as the alterations in Tfh cell subsets characterized by decreased “regulatory” Tfh1 cell and increased “pro-inflammatory” Tfh2 as well as Tfh17 cell subsets were revealed. Descriptions of peripheral blood B cells during an acute SARS-CoV-2 infection werev reported as relative B cell lymphopenia with decreased frequency of “naïve” and memory B cell subsets, as well as increased level of CD27hiCD38hiCD24 plasma cell precursors and atypical CD21low B cells. Thus, the emerging evidence suggests that functional alterations occur in all Th cell subsets being linked with loss-of-functions of main Th cell subsets target cells. Furthermore, recovered individuals could suffer from long-term immune dysregulation and other persistent symptoms lasting for many months even after SARS-CoV-2 elimination, a condition referred to as post-acute COVID-19 syndrome.

Russian Journal of Infection and Immunity. 2022;12(3):409-426
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Lassa fever. Part 1. Etiology, epidemiology and clinical manifestations

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


Lassa fever is a natural focal disease dangerous for humans. In the larger part of sub-Saharan West Africa 37.7 million people in 14 countries live in areas where living conditions are suitable for zoonotic transmission of the virus from secretions of infected rodents of the species Mastomys natalensis. Routes of transmission can be via alimentary, airborne dust or airborne droplet pathways in case of accidental human contact with secretions of infected rodents. Mastomys natalensis penetrates into residence and place of storage of food and drinking water. In addition, the residents use such animals for food, so infection is also possible upon butchering carcasses. The etiological agent of this disease is the Lassa virus being one of the members of the Arenaviridae family. Unlike other arenavirus infections (e.g., Argentine and Bolivian fevers caused by Junin viruses and Machupo, respectively), human infection with Lassa virus can also occur from person to person. Cases of nosocomial infection among patients in conditions of poor hygiene and through contaminated medical equipment are described. Medical workers become infected during surgical operations or through contact with patients, because the pathogen can be transmitted via blood, saliva, vomiting, stool or urine. In endemic territories, Lassa fever is associated with significant morbidity, because 500 thousand clinical cases and due to 5 to 10 thousand fatal outcomes of this disease are registered annually (i.e. 1–2% mortality). The likelihood that this disease will become a more widespread threat worldwide may be associated with increased globalization as well as climate change leading to the expansion of the Lassa fever endemic zone into regions suitable for the settlement of M. natalensis and other rodent species capable of lifelong pathogen carriage. Among hospitalized persons with severe hemorrhagic symptoms, the mortality rate can be very high — ranging from 14 to 89.5%. But in the majority of cases, the disease proceeds asymptomatically, and due to its long-term incubation period all ill subjects may be a source of infection, especially travelling at long distance by plane or train. Clinically evident disease occurs in the form of various nonspecific symptoms — from malaise, fever, sore throat and chest, cough, myalgia and gastrointestinal disorders to signs of central nervous system disorders. The diagnosis of Lassa fever is often difficult due to the similarity of its course with other viral diseases common in Africa or malaria or typhoid fever. More specific symptoms for Lassa fever are revealed as conjunctivitis, hepatitis, pharyngitis, tonsillitis as well as developing oropharyngeal ulcers. Severe disease is complicated by abnormal bleeding, generalized edema, respiratory failure, hypotension, proteinuria, transaminitis, encephalopathy. Deafness develops in about 20% of cases. Multiple organ failure and open bleeding lead to death. The review is devoted to analyzing publications on the etiology, epidemiology and clinical picture of Lassa fever due to a threat of its importation with sick subjects to the territory of the Russian Federation.

Russian Journal of Infection and Immunity. 2022;12(3):427-438
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ESAT-6 and CFP-10 antigens as a biotechnology molecule substrate. Applications in medicine

Kudlai D.A., Doktorova N.P.


Recombinant technologies have been long widely used in medicine. This article presents a review on the application of medical technologies based on ESAT-6 and CFP-10 proteins in diagnostics and prevention of tuberculosis. ESAT-6 and CFP-10 are specific proteins whose genes are encoded in the RD-1 zone (region of difference) of M. tuberculosis. M. bovis BCG and in most nontuberculous mycobacteria lack the RD-1 genome fragment. The discovery of ESAT-6 and CFP-10 antigens allowed to make the first and so far, the only breakthrough in improving the diagnostics of latent tuberculosis infection after the first tuberculin skin test (TST) was implemented. The article describes the principle of action and the experience with diagnostic tools based on ESAT-6 and CFP-10 such as in vitro interferon-gamma release assays (IGRA) and in vivo recombinant tuberculosis allergen (RTA, Diaskintest). RTA is inoculated intradermally similar to TST followed by developing delayed-type immune reaction detected in the area closest to M. tuberculosis. Combined use of ESAT-6 and CFP-10 for early detection of tuberculosis infection allowed to ameliorate for many drawbacks related to TST. High sensitivity and specificity was confirmed for ESAT-6- and CFP-10-based tests, so that former BCG vaccination had no more effect on test results and lowered frequency of false positive results due to reaction to non-tuberculous mycobacteria. The results of a large-scale meta-analysis on studies with patients at high risk demonstrated that the risk of developing tuberculosis in subjects with positive vs. negative IGRA was increased by 9.35-fold (95% confidence interval (CI [6.48–13.49]), whereas for TST — by 4.24-fold (95% CI [3.3–5.46]). 95.1%, (95% CI [95.06–95.1]). Analyzing available publications demonstrated sufficient evidence base regarding efficacy of using ESAT-6–CFP-10-based tests in tuberculosis diagnostics. Finally, there are also reviewed the diagnostic tests and vaccines based on using such proteins currently being under development.

Russian Journal of Infection and Immunity. 2022;12(3):439-449
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Convergence of multiple resistance and hypervirulence in Klebsiella pneumoniae

Ageevets V.A., Ageevets I.V., Sidorenko S.V.


Since 2018, Klebsiella pneumoniae isolates have been described in Russia, demonstrating the convergence of hypervirulent properties and multiple antibiotic resistance. The problem of the Klebsiella hypervirulent pathotype has been actualized relatively recently that was progressively described in the 1980s in the Pacific region. These Klebsiella spp. can cause serious community-acquired infections in healthy people, which fundamentally differs from the classic Klebsiella pathotype initially preserving sensitivity to most antibacterial drugs. In 2018–2020, there were reported detection of hypervirulent K. pneumoniae isolates in the Russian Federation. Like multiple resistance, hypervirulence is associated with the acquiring additional genetic material and formation of genetic lineages that effectively support such acquired determinants. For a long time, it was believed that the convergence of multiple resistance and hypervirulence is unlikely due to a large genetic burden as well as different ecological strategies in same species. The spread of hypervirulent strains, primarily in the Asian region, is associated with the conserved plasmids of the pLVPK “group”. The conservatism of both the originally discovered virulence plasmids (such as pLVPK and pK2044) and the genetic lineages associated with them (mainly CG23) is probably determined by the absence of a gene cluster responsible for conjugation in these plasmids. The driver of the spread of non-conjugative plasmids with determinants of hypervirulence is clonal spread, not horizontal gene transfer. Nevertheless, after a sufficiently long period of circulation of plasmids bearing markers of hypervirulence (described since 1986) in Klebsiella, a relatively limited number of genetic lineages, there were events of mobilization of the determinants of hypervirulence and, as a consequence, the inclusion in horizontal gene transfer in the population (described cases in 2016 ), which led to a sharp increase in the number of genetic lineages and variants of genetic platforms carrying hypervirulence genes. In Russia, first cases of hv-MDR-Kpn were described in 2018 in Moscow based on analyzing collection of Klebsiella isolated in 2012–2016. In 2020 and 2021, similar cases were described in St. Petersburg. In case of repeated pessimistic scenario observed over the last decade due to spread of carbapenemases, effectiveness of health care will be more than substantially harmed.

Russian Journal of Infection and Immunity. 2022;12(3):450-460
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Methodological approaches to differential detection of EBV1/EBV2 and HHV6A/HHV6B in saliva

Popkova M.I., Utkin O.V., Bryzgalova D.A., Senatskaia A.O., Soboleva E.A., Sakharnov N.A., Filatova E.N., Kulova E.A.


Epstein–Barr virus (EBV) and human herpesviruses 6A and 6B (HHV6A and HHV6B) are ubiquitous, infecting representatives of all social groups, starting from early childhood. Currently, information on the genetic heterogeneity of EBV, even at the level of the main types (EBV1 and EBV2), as well as HHV6A and HHV6B, their prevalence and clinical significance are limited mainly by foreign data. In Russia, there are not so many publications devoted to this issue. In this case, the objects of study are mainly plasma and leukocytes of peripheral blood, scrapings or swabs from the oropharynx are used much less often. Saliva is the main factor in the transmission and spread of EBV and HHV6A/B infections. Saliva testing is an affordable, inexpensive, and non-invasive method for detecting viral DNA. The purpose of this work is to improve the methodological base for differential detection of HHV6A/HHV6B and the main types of EBV in saliva. The material for the study was unstimulated mixed saliva of children aged 1–17 years with acute infectious mononucleosis (n = 22) and no clinical symptoms of this disease (n = 26), as well as conditionally healthy adults (n = 9). Samples were collected once and dynamically (daily for 14 days). The detection and quantification of EBV DNA and HHV6A/B DNA was performed using real-time PCR. For the differential determination of EBV1/EBV2 and HHV6A/HHV6B, an optimized one-round PCR variant with electrophoretic detection of amplification products in an agarose gel was used. Statistical data processing was carried out using the R programming language and the RStudio environment. According to the results of our own research, the frequency of detection of EBV, HHV6A/B and EBV+HHV6A/B DNA in acute infectious mononucleosis was 95, 91 and 86%, and among conventionally healthy children — 69, 85 and 61.5%, respectively. It was found that among the examined children of the Nizhny Novgorod Region, EBV1 and HHV6B prevail in the viral population, which is consistent with existing ideas about their geographical distribution in the adjacent territories. EBV2 and HHV6A were not detected in any of the examined saliva samples. According to the results of 14-day dynamic monitoring of saliva virus secretion in healthy virus carriers (adults and children), it was shown that a single EBV DNA study does not allow to reliably assess the infection of individuals or the intensity of EBV secretion. In this case, HHV6A/B is characterized by a more constant and uniform release. The methodological approach optimized in this work makes it possible to separately detect EBV1/EBV2 and HHV6A/HHV6B according to a single laboratory protocol, and in combination with an additional stage of saliva sample preparation increases the diagnostic sensitivity of PCR analysis, minimizes the proportion of discordant and false negative results. Such an integrated approach can be applied for diagnostic, epidemiological and research purposes.

Russian Journal of Infection and Immunity. 2022;12(3):461-474
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Topical issues of clinical symptoms and diagnostics of septic shock

Leplina O.Y., Tikhonova M.A., Meledina I.V., Zheltova O.I., Shevela E.Y., Ostanin A.A., Chernykh E.R.


Viral hepatitis remains the most common cause of liver cirrhosis (LC). Monocytes, capable of migrating to the liver and participating in inflammation and fibrogenesis, play an important role in the LC pathogenesis as confirmed by the association of certain monocyte subsets with the disease severity and mortality in alcoholic and biliary LC. However, the clinical and prognostic relevance of monocytes in viral LC remains poorly investigated. This study was aimed to investigate the disturbances in circulating monocytes including classical (CD14++CD16, cMo), intermediate (CD14++CD16+, iMo) and non-classical monocytes (CD14+CD16++, nMo) in patients with viral LC, as well as their correlation with viral characteristics, LC severity and progression of the disease 12 months after combination therapy. A significant increase in iMo and nMo, cMo level tended to decrease, and a two-fold decline in cMo/iMo ratio was revealed in patients with viral LC vs. healthy donors. These changes in monocyte pattern did not depend on the type of virus (HCV vs HBV/HDV) or its replication (replication vs the integrative phase), but were associated with the LC severity. The iMo level was positively correlated with laboratory indicators of liver damage, Child–Pugh (rS = 0.57; P = 0.001) and MELD score (rS = 0.41; P = 0.033). ROC analysis showed that the cMo/iMo ratio at < 9.5 allowed to predict the risk of LC progression with a sensitivity of 83.3% and a specificity of 76.2%. Of note, in comparison groups patients with alcoholic or biliary/autoimmune LC also demonstrated increased frequencies in iMo and nMo and decreased cMo/iMo ratio. However, in this case, the LC severity was negatively correlated with CD16+monocytes, particularly with the iMo and nMo subset, respectively, in alcoholic and biliary LC, evidencing the protective role of such cell subsets. Thus in viral LC the changes in circulating monocyte profile to increased iMO and nMo as well as decreased cMo are not associated with the virus type and replication; in contrast to the alcoholic and biliary/autoimmune LC, the level of iMo directly correlates with the indicators of liver damage and LC severity; cMo/iMo ratio is a biomarker of therapy response/disease progression.

Russian Journal of Infection and Immunity. 2022;12(3):475-485
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The circulating immune complexes as a biomarker of the endogenous intoxication in pulmonary tuberculosis

Lesnic E.V., Ghinda S.S.


The aim of the study was to establish the concentration of the circulating immune complexes (CICs) with high (CIC 2,5%), medium (CIC 4,2%) and low (CIC 8.0%) molecular weights in patients with pulmonary tuberculosis (TB) as biomarkers of the endogenous intoxication and the degree of severity. We investigated 56 patients diagnosed with pulmonary TB and 36 healthy persons (control group). The patients were assigned to 2 groups: the study group 1 (I SG) included 29 patients in which the test established the drug susceptible TB and in the study group 2 (II SG) that included 27 patients with multidrug-resistant TB (MDR-TB). The inclusion criteria were: primary detected pulmonary TB, age older than 18 years, confirmed drug susceptibility (I SG) and confirmed MDR-TB (II SG). The exclusion criteria were: anti-TB treatment in anamnesis, extrapulmonary TB, age below 18 years, HIV infection, severe somatic diseases. The method of CIC quantification consisted in placing 50 μl serum into 3 tubes followed by adding 100 μl borate buffer and solution of 2.5%, 4.2% and 8.0% polyethylene glycol. The tubes were incubated 15 minutes at 25°C and the optical density was assessed at the wavelength 340 nm. The results were compared with the general blood count and leucocital intoxication index Kalf-Kalif (LIIKK) as an alternative method to identify endogenous intoxication. As the results of the research we established that the peak level was observed for CICs with high and medium molecular weight, wrereas less pronounced it was for CICs with low molecular weight. The high severity of the endogenous intoxication predominated in the I SG and middle degree in the IISG, without achieving the statistical significance. LIIKK was lower in study groups comparing with the control healthy subjects due to increased count of eosinophils.

Russian Journal of Infection and Immunity. 2022;12(3):486-494
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Comparison of the humoral and cellular immunity in COVID-19 convalescents

Toptygina A.P., Semikina E.L., Zakirov R.S., Afridonova Z.E.


The SARS-CoV-2 virus caused the COVID-19 pandemic is related to the SARS-CoV-1 and MERS coronaviruses, which were resulted in 2003 and 2012 epidemics. Antibodies in patients with COVID-19 emerge 7–14 days after the onset of symptoms and gradually increase. Because the COVID-19 pandemic is still in progress, it is hard to say how long the immunological memory to the SARS-CoV-2 virus may be retained. The aim of this study was to study a ratio between humoral and cellular immunity against the SARS-CoV-2 S protein in COVID-19 convalescents. There were enrolled 60 adults with mild to moderate COVID-19 2 to 12 months prior to the examination. The control group consisted of 15 adults without COVID-19 or unvaccinated. Specific antibodies to the SARS-CoV-2 virus were determined by ELISA with the SARS-CoV-2-IgG-ELISA-BEST kit. To determine the specific IgG and IgA subclasses, the anti-IgG conjugate from the kit was replaced with a conjugate against the IgG subclasses and IgA. Additional incubation with or without denaturing urea solution was used to determine the avidity of antibodies. Peripheral blood mononuclear cells were isolated by gradient centrifugation, incubated with or without coronavirus S antigen for 20 hours, stained by fluorescently labeled antibodies, and the percentage of CD8highCD107a cells was assessed on flow cytometer BD FACSCanto II. In the control group, neither humoral nor cellular immunity against the SARS-CoV-2 S protein was found. In the group of convalescents, the level of IgG antibodies against the SARS-CoV-2 S protein varies greatly not being strictly associated with the disease duration, with 57% and 43% of COVID-19 patients having high vs. low level of humoral response, respectively. A correlation between level of specific IgG and IgA was r = 0.43. The avidity of antibodies increased over time in convalescents comprising 49.9% at 6–12 months afterwards. No virus-specific IgG2 and IgG4 subclasses were detected, and the percentage of IgG1 increased over time comprising 100% 6–12 months after recovery. 50% of the subjects examined had high cellular immunity, no correlations with the level of humoral immunity were found. We identified 4 combinations of humoral and cellular immunity against the SARS-CoV-2 S protein: high humoral and cellular, low humoral and cellular, high humoral and low cellular, and vice versa, low humoral and high cellular immunity.

Russian Journal of Infection and Immunity. 2022;12(3):495-504
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Quantitative and qualitative composition of lymphocyte populations and subpopulations in patients with varying severity of a new coronavirus infection

Ivanova I.A., Trufanova A.A., Filippenko A.V., Omelchenko N.D., Noskov A.K., Chemisova O.S.


SARS-CoV-2 can cause a decrease in the number of lymphocytes and their functional activity. In patients with COVID-19, especially with a severe course of the disease, a decrease in the quantitative composition of the main populations of lymphocytes is recorded. These indicators do not recover for a long time after recovery. However, it is still not known how long the quantitative and qualitative changes in the composition of lymphocytes will last and whether the severity of the infection affects this process. The aim of our study was to assess the quantitative and qualitative composition of the main populations and subpopulations of lymphocytes in patients with a new coronavirus infection of varying severity. 65 patients with a new coronavirus infection were examined. The average age of the subjects was 47.3±14.5 years. The volunteers were divided into three groups according to the severity of the infection: asymptomatic (n = 21); moderate (n = 32); severe (n = 12). The relative and absolute number of T-lymphocytes (CD3+), T-helper cells (CD3+CD4+), cytotoxic lymphocytes (CD3+CD8+), natural killers (CD3CD16+CD56+), TNK-lymphocytes (CD3+CD16CD56+) and B-lymphocytes (CD45+CD19+) were determined. To calculate the percentage of lymphocytes, whole blood was lysed with OPTILYSE C solution (Beckman Coulter, USA) and stained with monoclonal antibodies CD3+-FITC/CD8+-ECD/CD4+-PC5/CD16+CD56+PE and CD45+-Pacific Blue/CD19+-PC5 (Beckman Coulter, USA). Cytofluorometry was performed on a flow cytofluorometer “Navios™” (Beckman Coulter, USA). The results of our studies showed that there were no statistically significant changes in the relative and absolute number of immunocompetent cells in asymptomatic patients with a new coronavirus infection, compared with the control group. With an average severity of the disease, a decrease in the relative and absolute content of CD3+ and CD8+ lymphocytes was revealed, these indicators were restored to control values six months after recovery. In patients with severe infection, there was a decrease in the relative and absolute number of T cells and cytotoxic lymphocytes. These values remained significantly below normal for six months and returned to normal only seven to eight months after recovery. Also, the volunteers of this group were found to have a decrease in the number of natural killers and TNK cells. Thus, the data obtained by us indicate that pathological changes concerning the relative and absolute number of the main populations and subpopulations of lymphocytes in patients with COVID-19 depend on the severity of the disease. The number of T-lymphocytes, cytotoxic lymphocytes, natural killer cells, that is, populations of cells that play a crucial role in effective antiviral protection, has been reduced in those who have undergone a new coronavirus infection in moderate and severe form. This information can be useful for expanding methodological approaches to the diagnosis, treatment of a new coronavirus infection, as well as measures for the rehabilitation of those who have suffered it.

Russian Journal of Infection and Immunity. 2022;12(3):505-510
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Evaluation of serum levels of IL-6 and adiponectin in COVID-19 patients and their relationship with disease severity

Norouzian M., Sharifi-Sarasiabi K., Najafi-Asl M., Hassani Azad M., Estabraghnia Babaki H.


Background. The SARS-CoV-2 pandemic has prompted researchers around the world to identify risk factors associated with disease severity and mortality. Results suggest that COVID-19 mortality might be due to a ‘cytokine storm’ involving IL-6, and that obesity can be considered a risk factor for COVID-19 prevalence, severity, and mortality. The current study aimed to evaluate the serum levels of IL-6 and adiponectin in patients and their relationship with disease progression. Materials and methods. ELISA was used to assess the levels of IL-6 and adiponectin in serum samples from a control group and from patients with COVID-19 at the time of admission to ICU or non-ICU wards. The results were analyzed using the Mann–Whitney and Spearman tests. Results. Mean serum levels of adiponectin in patients admitted to ICU (10.18±15.4 ng/ml) were significantly higher than patients admitted to non-ICU wards (3.14±3 ng/ml, p = 0.001). Mean serum IL-6 levels showed a similar pattern, however the difference was not statistically significant (p = 0.18). In addition, a significant direct correlation was observed between adiponectin expression and IL-6 (R = 0.2, p = 0.03). Conclusion. The results of this study show that serum levels of adiponectin in COVID-19 patients with severe lung involvement were significantly higher than those with less lung involvement. This finding is of high importance mainly due to the critical role of the lungs in adiponectin signaling, and as a result, adiponectin disorders may be associated with pulmonary complications in COVID-19 patients.

Russian Journal of Infection and Immunity. 2022;12(3):511-518
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An impact of lactoferrin, serum albumin and secretory immunoglobulin A in actimicrobial activity of breast milk whey

Arzumanian V.G., Kolyganova T.I., Svitich O.A., Samoylikov P.V., Konanykhina S.Y., Zaytseva T.A., Zverev V.V.


The contribution of the antimicrobial activity of sIgA, lactoferrin, α-lactalbumin, serum albumin, and lysozyme to the total antimicrobial activity of whey was evaluated. 66 breast milk samples from healthy women aged from 23 to 45 years collected at different periods of lactation were studied. It was found that along with proceeding the lactation period, not only the total antimicrobial activity (r = –0.944) decreased, but also the activity of the low molecular weight fraction containing the sum of antimicrobial peptides (r = –0.950). The median lactoferrin level varied from 3.46 mg/ml in colostrum down to 0.94 mg/ml one year after the onset of lactation that correlated with whey activity (r = 0.616). The concentration of sIgA was peaked in the whey of colostrum (5.01 mg/ml) and significantly reduced in mature milk, remaining approximately at the same level in subsequent periods of lactation (1.0 mg/ml). Serum albumin concentration significantly decreased while proceeding through lactation period (from 5.52 to 4.68 mg/ml) and correlated with whey activity (r = 0.589). Evaluating effects of the purified α-lactalbumin on C. albicans cells within the range of 5–20 mg/ml by spectrophotometry and microscopy showed the absence of fungicidal activity. At the same time, purified lactoferrin, IgA, lysozyme, and serum albumin demonstrated a direct fungicidal effect. The activity of the IgA preparation at a concentration relevant to the sIgA content in the whey of the first day colostrum was 50.0%, and in the whey after 12 months — 31.0%; lactoferrin — 26.7% and 3.4%; serum albumin — 15.0% and 17.7%; lysozyme — 0.1% and 1.8%. Thus, the sum of the activities of these polypeptides at concentrations typical for the first-day colostrum was 91.7%, which is comparable to the total activity of this whey — 82.4%. The sum of the activities of these polypeptides, typical for 12 months of lactation, was 53.9%, and the total whey activity relevant to this period was 64.5%. Therefore, IgA and lactoferrin contribute the most significant antimicrobial activity in the whey of colostrum, whereas after 12 month-breastfeeding IgA and serum albumin become most significant.

Russian Journal of Infection and Immunity. 2022;12(3):519-526
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Urine excreted antibodies significance in the hemorrhagic fever with renal syndrome specific diagnosis

Dzagurova T.K., Murzabaeva R.T., Kutluguzhina F.G., Morozov V.G., Volnyh E.V., Kurashova S.S., Balovneva M.V., Tkachenko P.E., Ishmukhametov A.A., Belyakova A.V., Tkachenko E.A.


Relevance. Hemorrhagic fever with renal syndrome (HFRS) is an acute viral zoonosis. Being widespread in Eurasia, it holds a leading place in Russia among natural focal human diseases. The vast majority of HFRS cases in Russia, about 98%, are associated with Puumala virus. The disease is characterized by a wide range of clinical manifestations. Early specific diagnostics appears to be of a great importance for starting timely pathogenic therapy. The aim of the study was to clarify the diagnostic value of detecting hantavirus antibodies in the HFRS suspected patient urine. Materials and methods. Blood sera and urine samples from 68 patients at the Infectious Diseases Hospital in the city of Ufa, obtained with a 2-day interval, as well as urine and blood serum samples from 15 convalescents 1, 2, 3 and 6 months after disease onset were examined for hantavirus antibodies. 53 blood sera and urine samples from patients residing in Moscow, Moscow and Samara regions collected at different time points during the disease course were investigated in parallel. Antibodies were detected by the indirect immunofluorescence method. Results. On day 3, 4, 5 and 6 of disease, while specific antibodies were detected in the blood serum, antibodies in the urine were found in 85.7%, 89.4%, 93.1% and 100% of patients, respectively. The peak quantity of antibodies was excreted in the urine from days 5 to 11, which corresponds to the oliguric stage of the disease. In the convalescent period, antibodies were still detected in urine 1, 2 and 3 months afterwards in 86.7%, 46% and 20% of cases, respectively, but not detected 6 months later, which probably reflects the process of long-term restoration of the kidneys function. A moderate positive correlation between specific antibodies in serum and urine was observed only in the oliguric period of the disease. Conclusions. Detection of hantavirus antibodies simultaneously in blood serum and urine of febrile patients instead of paired blood sera allows to conduct HFRS diagnostics within the very first days of hospitalization and prevent severe complications due to timely pathogenic therapy.

Russian Journal of Infection and Immunity. 2022;12(3):527-534
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Evaluation of the two in-patient hospitals on potential environmental hazard during the period of new coronavirus infection in the Khabarovsk city (december 2020 — march 2021)

Trotsenko O.E., Bondarenko A.P., Pshenichnaya N.Y., Zaitseva T.A., Garbuz Y.A., Chishagorova I.V., Shmylenko V.A., Bazykina E.A., Ogienko O.N.


Microbiological monitoring after infectious diseases in the system of epidemiological surveillance implies simultaneous pathogen identification both among patients and in hospital environment. Our aim is to assess potential hospital environmental hazard for the two in-patient infectious disease hospitals of the Khabarovsk city by using bacteriological and epidemiological analysis during new coronavirus disease pandemic. Materials and methods. Bacteriological assessment of nasopharyngeal microflora in 241 patients suffering from community-acquired pneumonia that were hospitalized in the two prevention and treatment facilities of the Khabarovsk city was performed. Sanitary-bacteriological control of hospital environment (428 hospital environment samples and 91 air samples) was carried out in parallel. Bacteriological assessment was performed with classical methods. Identification of isolated bacteriological pathogens and evaluation of drug-resistant strains were carried out by utilizing bacteriological analyzer Vitek 2 Compact. Results. Nine different pathogens (Pseudomonas aeruginosa, Pseudomonas stutzeri, Acinetobacter baumannii, Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter cloacae, Pantoea, Enterococcus faecium, Staphylococcus haemolyticus) were isolated in 20 out of 428 samples — 4.7% [2.7–6.7]. Half of isolated agents — 2.3% [0.9–3.8] — were represented by drug-resistant isolates (10 out of 20 isolates) including 5 carbapenem-resistant isolates (Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae) and 5 isolates with multiple drug resistance (Enterobacter cloacae, Pantoea, Enterococcus faecium, Staphylococcus haemolyticus). Air samples contained pathogenic biological agents found in 6 out of 91 samples — 6.6% [1.5–11.7], and half of them — 3.3% [0.6–7.9] — were identified as drug-resistant variants, including S. aureus и S. haemolyticus. One of the surveyed hospitals was recognized as more hazardous due to microflora isolated from intensive care unit (A. baumannii and P. aeruginosa were resistant to 3rd–4th generation cephalosporins and carbapenems). Conclusion. Revealed circulation of wide range of microorganisms isolated from environment of two in-patient hospitals indicates high risk of healthcare-associated infections formation. Intensive care units can serve as a reservoir of healthcare-associated infections due to high percentage of patients with severe disease cases (“main reservoir” of drug-resistant strains).

Russian Journal of Infection and Immunity. 2022;12(3):535-542
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Gene polymorphism of mannose-binding lectin-associated serine protease (MASP2) in indigenous populations of the Russian Arctic Territories

Smolnikova M.V., Malinchik M.A., Tereschenko S.Y.


Mannose-binding lectin-associated serine proteases (MASP) are among of the key components in the lectin pathway (LP) of the complement activation. MASP-2 is the most studied agent among specific enzymes activating both mannose-binding lectin (MBL) and ficolins, pattern-recognition proteins involved in the elimination of pathogenic microorganisms through LP complement activation. There are some mutations in MASP2, with the most significant identified as rs72550870 (p.D120G). The homozygous GG rs72550870 is associated with congenital MASP-2 deficiency and characterized by a total lack of serum protease activity, which leads to impaired binding to lectins. This, in turn, results in severe course of infectious diseases with a high risk of adverse outcome. There seem to be some marked populational differences in the genotype and haplotype prevalence in MASP2 gene polymorphisms. To date, no data are available on the genotype distribution for the MASP2 gene in the indigenous populations of the Russian Arctic regions. The aim of the work was to study the prevalence and ethnic specificity in the distribution of allelic variants of MASP2 rs72550870 in the populations of the Taymyr Dolgan-Nenets District of the Krasnoyarsk Territory (Nenets, Dolgans, Nganasans) as well as the city of Krasnoyarsk (Russians). MASP2 genotyping was performed by using real-time PCR. The frequencies of the AG genotype associated with low MASP-2 level was 6.6% for ethnic Russian newborns in the Eastern Siberia. The prevalence of the AG genotype was significantly lower in newborns of the Arctic populations than in the Russians, being 0.3% and 0.9% for the Nenets and the Dolgan-Nganasans, respectively, which is close to the prevalence values identified for Asian and African populations (0%). No homozygous GG rs72550870 associated with congenital MASP-2 deficiency in newborns of the indigenous populations of the Taymyr Dolgan-Nenets region of Krasnoyarsk Territory (Nenets and Dolgan-Nganasans) and ethnic Caucasian subjects of the Krasnoyarsk city was detected. The frequency of the rare allelic variant G rs72550870 in ethnic Russian subjects was 3.3%, being close to the frequencies in the European populations of the world (4.0%), whereas it was 0.5% in the indigenous inhabitants of the Arctic Region. We have suggested that isolated Arctic populations encounter some intracellular infections historically later and, as contrasted with Caucasoid populations, retained a high activity in the lectin pathway of the complement activation established at the early stage of human evolution.

Russian Journal of Infection and Immunity. 2022;12(3):543-550
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Sputum smear positivity grade and chest X-ray findings in tuberculosis: a cross-sectional study

Behzadmehr R., Nejadkehkha E.


Despite many advances in the diagnosis, screening, and rapid treatment of tuberculosis, it is still a public health concern in the world. Due to the importance of this issue in diagnosis and reduction of transmission of infection and treatment of the disease especially where this study was conducted due to the high prevalence of tuberculosis, the aim of our study was to determine the relationship between sputum smear positivity grade and chest X-ray findings in pulmonary tuberculosis patients in a hospital in southeast of Iran. This cross-sectional study was performed on all patients with pulmonary TB referencing the health centers in the Zabol city from January 1, 2015 to December 30, 2020. Sputum smear and radiographic findings of the chest X-ray were evaluated. Data was collected using a form of information and finally analyzed by SPSS 22. Out of 101 patients examined in the present study, 71 were women and 30 were men. The mean age of the patients was 62.68±13.61 years. The frequency of opacity in patients with grades 1, 2, and 3 was 71.4, 78.5, and 76.5%, respectively. Frequency of cavitation in patients with grade 1, 2 and 3 was 11.5%, 28.5% and 52.9% respectively (P value 0.001). The frequency of reticulonodular presentations in patients with grade 1, 2, and 3 was 24.2, 7.1, and 0%, respectively. In general, the results of this study showed that, with increasing grading of smears (1+, 2+, and 3+), the frequency of cavitation presentation increased significantly and the frequency of reticulonodular presentations decreased significantly. The findings of the present study can help physicians to improve TB diagnostics.

Russian Journal of Infection and Immunity. 2022;12(3):551-555
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Comparison of vitamin D levels between mothers and infants with and without prolonged membrane rupture

Boskabadi H., Rakhshanizadeh F., Zakerihamidi M.


Background. Premature membrane rupture is a known causes of preterm labor and accounts for approximately one-third of cases. Vitamin D deficiency may play a role in preterm labor as well. Objective. The present study aimed to compare vitamin D levels in mothers and infants with and without prolonged rupture of membranes (PROM). Materials and methods. This cross-sectional study was conducted with 241 babies, with and without a history of membrane rupture, in mothers in the neonatal ward of Ghaem Hospital, Mashhad, from 2019 to 2021 with available sampling methods. After confirmation of prolonged membrane rupture (more than 18 hours before birth) based on history and examination with a speculum, we completed a data collection tool, a checklist including laboratory evaluation and neonatal and maternal characteristics. The conditions of neonates with and without prolonged membrane rupture were compared. Data were analyzed by T-test and Chi-square. Results. We examined a total of 241 neonates including 148 (61.4%) without prolonged rupture of the membranes in mothers and 93 (38.6%) with PROM. There were statistically significant differences between the two groups regarding: maternal vitamin D level (p = 0.001); neonatal vitamin D level (p = 0.001); and fifth minute Apgar score (p = 0.003). These variables were lower in the group of neonates with PROM. Conclusion. Vitamin D deficiency in mothers was significantly associated with prolonged membrane rupture. With increasing severity of vitamin D deficiency, the probability of PROM increases and, therefore, the likelihood of preterm labor and its complications rises.

Russian Journal of Infection and Immunity. 2022;12(3):556-562
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Resistance factors of klebsiella pneumoniae bacteria during COVID-19 pandemic

Kolotova O.N., Kataeva L.V., Bakshtanovskaya I.V., Stepanova T.F., Stepanova K.B.


Multidrug-resistant K. pneumoniae bacterial strains producing extended range of beta-lactamases or carbapenemases are of serious clinical concern. The aim of the study was to determine the resistance factors of K. pneumoniae strains isolated from the lower respiratory tract of patients diagnosed with community-acquired pneumonia during the COVID-19 pandemic. Materials and methods. The study of resistance to antimicrobial drugs included 138 strains of K. pneumoniae isolated from the sputum of patients treated in infectious diseases monohospitals in the city of Tyumen and the Tyumen region within the period from May 2020 to June 2021. Among the strains examined, 51.4% of them were isolated from SARS-CoV-2 positive patients. The presence of resistance genes was determined by PCR in 71 strains of K. pneumoniae (34 strains from COVID-19-positive and 37 strains from COVID-19-negative patients). Identification of isolated bacterial strains was carried out according to the protein spectra by using a desktop time-of-flight mass spectrometer with matrix laser desorption MALDI-TOF MS (Bruker, Germany). The belonging of the strains to the hypermucoid phenotype was determined using the string test. Sensitivity to antimicrobial drugs was assessed in the disk diffusion method on Muller–Hinton medium. The sensitivity of culture strains to bacteriophage preparations was determined by the drop method (spot-test). In the study, we used “Polyvalent Sextaphage Pyobacteriophage” and “Purified Polyvalent Klebsiella Bacteriophage” (JSC NPO Microgen, Russia). Detection of resistance genes to beta-lactam antibiotics by real-time PCR was carried out using the BakRezista kit (OOO DNA-technology, Russia). Results. The results of the study evidence that K. pneumoniae bacteria isolated from COVID-19-positive and COVID-19-negative patients diagnosed with community-acquired pneumonia displayed a high resistance to antimicrobial drugs and commercial phage-containing drugs. Resistance of K. pneumoniae strains was recorded from 50% (to aminoglycosides and carbapenems) to 90% (to inhibitor-protected penicillins). Sensitivity to bacteriophages was noted on average in no more than 20% of strains. It is important to emphasize that strains isolated from COVID-19-positive patients more often showed a hypermucoid phenotype, suggesting a high bacterial virulence, and also showed greater resistance to all groups of antibacterial drugs examined in the study, which is confirmed by the presence of resistance genes of the ESBL group and carbapenemase. The results of the study suggest that the high level of resistance of K. pneumoniae strains isolated from COVID-19-positive patients is associated with immunosuppression provoked by the SARS-CoV-2 virus, which contributes to their colonization by more virulent strains.

Russian Journal of Infection and Immunity. 2022;12(3):563-568
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Features of the new coronavirus COVID-19 infection in identical twins

Yudina S.M., Kiseleva V.V., Rusanova T.S., Ivanova I.A.


The problem of the clinical course and principles of treatment for the new coronavirus infection COVID-19 remains the most debated issue. At the same time, reliable prognostic criteria that determine characteristics of the disease course and outcome have not been established. Taking it into consideration, we present clinical cases of COVID-19 in identical twins. Patients A. and S., 39 years old, were admitted to the Regional Clinical Infectious Diseases Hospital. The patients were clinically diagnosed with COVID-19 coronavirus infection, verified, moderate form; bilateral polysegmental pneumonia of moderate severity, 1st degree respiratory failure. The course of COVID-19 coronavirus infection in identical twins markedly differed. Patient A. had peripheral blood lymphocytosis, slightly increased ESR, CRP, ferritin, IL-6, and D-dimer level. A paired twin brother (patient S.) had lymphopenia, ESR accelerated up to 20 mm/h, CRP pronouncedly increased up to 10 mg/ml, IL-6 — up to 9,5 pg/ml, and D-dimer — up to 750 ng/ml. Condition of the patient A. remained stable, on day 13th of treatment, the patient was discharged from the hospital. The condition of the patient S. on day 3rd of hospitalization deteriorated sharply. Considering the decrease in SpO2 level down to 88%, the damage of the lung parenchyma was more than 70%, resulting in the use of antibacterial drugs, anti-IL-6 monoclonal antibodies as well as selective reversible inhibitor of Janus-kinases 1 and 2. On day 16th of treatment, subjectively, the patient showed an improvement in general condition. During the next two days, the patient’s condition revealed marked positive dynamics on day 19th of hospital stay, the patient was discharged for rehabilitation. Thus, significant differences in the severity of the course of the new coronavirus infection in identical twins with similar medical history and lack of confounding comorbidities are most likely due to the initial dose of the viral load which was an important factor determining the development and course of infection.

Russian Journal of Infection and Immunity. 2022;12(3):569-574
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Enhanced hydroxyl radical generation by human leukocytes exposed to bacterial diamines highlighting immunomodulatory effect of microbial metabolites

Godovalov A.P., Karpunina T.I., Morozov I.A.


Recently, there have been increasing an interest to study a role of polyamines in intercellular interactions, especially in the focus of inflammation, where accumulation of such polycations is observed. In this regard, products of microbial origin — cadaverine and putrescine — are of particular attention. The role of polyamines as «scavengers» of free radicals has been described, but no data of their effect on the leukocyte radical-producing activity have been obtained so far. The aim of the investigation was to study features of hydroxyl radical generation by human leukocytes exposed to microbe-derived polyamines. Materials and methods. Peripheral venous blood samples were obtained from 20 healthy donors. To assess radical production, a luminol-dependent chemiluminescence reaction was carried out with blood leukocytes pre-incubated with cadaverine (0.01 M) and putrescine (0.01 M), measured on a Luminoskan Ascent® Thermo Labsystems luminometer (USA) for 180 min. For statistical analysis, an integral chemiluminescence index was used for the entire measurement period (RLU). Results and discussion. It was shown that cadaverine has a stimulating effect on the leukocyte potential to produce radicals (averaged area under the curve is 6.7±0.7 r.u., p < 0.05). Putrescine had little effect on the radical-producing activity of human cells (2.8±0.4 r.u., p < 0.05). This might be due to the direct influence of polycations on the mechanisms of radical generation, as well as increased activity of leukocyte diamine oxidase catalyzing the conversion of diamines into aminoaldehyde, which is accompanied by the release of hydrogen peroxide reacting with luminol. In addition, the enzyme inactivates other compounds, such as histamine leading to formation of a less pronounced clinical picture. Polyamines, particularly cadaverine and putrescine, can be referred to the factors remodeling the metabolic activity of the host leukocytes, which is aimed at maintaining the viability and increasing the number of microorganisms. Conclusion. Thus, cadaverine and putrescine produced by microorganisms, depending on the conditions of the microenvironment, might be evidently considered as mediators of the mild or asymptomatic course of inflammatory diseases, which contributes to underlying persistent potential of bacteria.

Russian Journal of Infection and Immunity. 2022;12(3):575-579
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Estimating allergic sensitization to some mold fungi

Metelskaya V.А., Matveevskaya N.S., Grechishnikova O.G., Safronova A.V.


The assessment of allergic sensitization of 894 patients (478 and 416 of them examined in 2018 and 2019, respectively) who were examined at the consultative and Diagnostic center of G.N. Gabrichevsky Scientific Research Institute for Epidemiology and Microbiology, Moscow, for some mold fungi was carried out by measuring serum specific IgE antibody level by using a highly specific and highly sensitive immunoblot method (RIDA AllergyScreen test systems, R-Biopharm AG, Germany). The prevalence of patients with elevated levels of specific IgE antibodies to mold fungi Alternaria alternata, Aspergillus fumigatus, Cladosporium herbarum and Penicillium notatum was found. All the examined patients at each time point was divided into two age groups: group 1 — children aged 1 to 17 years, 548 children within the two-year period (303 of them girls and 245 boys), group 2 — adults aged at least 18 years old, 346 subjects within the same period (231 of them women and 115 men). Results. In 2018, out of 478 serum samples, atopic sensitization to mold fungi was detected in 25.3% (n = 121) of the examined subjects, of which 17.9% (n = 86) and 7.4% (n = 35) was found in group 1 and group 2, respectively. In 2019, out of 416 serum samples, atopic sensitization to mold fungi was detected in 20.7% (n = 86) of the examined subjects, of which 13.5% (n = 56) and 7.2% (n = 30) was found in group 1 and group 2, respectively. In 2018, out of 121 positive samples, specific IgE antibodies to various mold fungi were slightly more often detected in females — 53.7% (n = 65), of which 75.3% (n = 49) and 24.7% (n = 16) were girls and women, respectively. In contrast, in 2019, out of 86 positive samples, specific IgE antibodies to various mold fungi were slightly more often detected in males reaching 51.2% (n = 44), of which 79.5% (n = 35) and 20.5% (n = 9) were boys and men, respectively. Atopic sensitization to the mold fungus Alternaria alternata was most often detected: during the study period, out of 207 positive samples, it was found in 186 samples (89.9%). Serum IgE antibodies to mold fungi are more often detected in children under 17, in sex-independent manner.

Russian Journal of Infection and Immunity. 2022;12(3):580-584
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The clinical case: COVID-19 in a child with chronic kidney disease

Ermolaeva Y.A., Samoilova Y.G., Oleynik O.A., Kudlay D.A.


Since the spread of the novel coronavirus infection, most researchers have noted a low proportion of sick children in general pediatric cohort compared to adults, who had a mild disease course and rare complications. The most frequent clinical manifestations of the disease are respiratory and, some less frequently diarrheal syndromes. The disease has predominantly mild or asymptomatic course. The risk of adverse outcomes in children, similar to adults, clearly correlate with the presence of background chronic pathology. The need for respiratory support prevails in children with a severe premorbid burden. Here, a clinical case of ongoing novel coronavirus infection in adolescent patient comorbid with chronic kidney pathology is described. In adolescence, the patient was diagnosed with mesangioproliferative glomerulonephritis (IgA-nephropathy), and further registered at the dispensary receiving a combination therapy with angiotensin converting enzyme inhibitors and disaggregation drugs. The epidemiological history contained no established contacts with infectious patients. The clinical manifestations of COVID-19 in the patient are represented by catarrhal and diarrheal syndromes, transient renal dysfunction in the acute period of the disease. The onset of coronavirus infection was clinically characterized by symptoms of damaged gastrointestinal tract and was considered as acute gastroenteritis of infectious etiology. Empirically prescribed antibacterial therapy in combination with antiplatelet agents and symptomatic drugs had no effect. The diagnosis of the novel coronavirus infection was verified only on day 4 of hospitalization, clinical and laboratory signs of lung damage emerged. The inflammatory process developed in the patient lungs was secondary to the main pathology. The severity of the patient’s condition was determined by the presence of respiratory and renal insufficiency. Lung damage with minimal severity complaints and clinical data had a bimodal pattern and required respiratory support. A comprehensive approach to treatment, including respiratory, antiviral, enterosorption, anticoagulation, anti-inflammatory, antihypertensive, hepatoprotective, symptomatic therapy with change in antibacterial drugs allowed to achieve positive dynamics. On day 12 of the illness, the patient required no respiratory support. The presence of symptoms of gastrointestinal tract damage in COVID-19 necessitates the mandatory inclusion of PCR assay for SARS-CoV-2 into diagnostic protocol in patients with diarrheal syndrome to perform etiological disease interpretation.

Russian Journal of Infection and Immunity. 2022;12(3):585-590
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Local and systemic adverse reactions following COVID-19 vaccine

Zherebtsova N.Y., Kajdanek T.V.


The mass vaccination against novel coronavirus infection (COVID-19) requires to dynamically evaluate risks of adverse events following immunization to prevent them and develop vaccination tactics for various population groups. We describe a clinical case of reaction following administration of the second dose of the heterologous recombinant adenovirus based COVID-19 vaccine Gam-COVID-Vac (Sputnik V) in 48-year-old female healthcare worker. No adverse events after administration of the first dose were recorded. After vaccination, the patient complained of weakness, malaise, headache, loss of appetite, and nausea that lasted for a single day. Reaction at the injection site appeared 10 hours after vaccination manifested as pruritic erythema, induration area up to 1.5 cm size, sharp pain, which resolved within 24 hours. On the second day post-vaccination, an inflammation area up to 1.5 cm size within the Bacillus Calmette–Guérin (BCG) scar site was noted and manifested as erythema, induration, painful to palpate, pruritus located 2 cm away from the injection site. BCG scar reaction with dull pain and severe pruritus lasted for three weeks. Erythema and induration at the BCG scar site resolved two months after the onset, which were resolved by using antihistaminic agent. The patient was vaccinated according to the Russian Federation Immunization Program, not associated with any adverse events following immunization. The patient had comorbidities such as vasomotor rhinitis, urolithiasis, stomach, duodenal ulcer, type 2 diabetes, arterial hypertension, and her body mass index of 35.2. The patient permanently receives antihypertensive and antihyperglycemic drugs, and has allergic reaction in the form of urticaria to Berodual. The patient has menopause during two years, but a five-day postmenopausal bleeding three days after vaccination with the second dose was noted. Thus, a high-quality surveillance of any local and systemic reactions associated with vaccination is needed to reveal adverse events to the vaccines against COVID-19 and elaborate a safe immunization program for preventing COVID-19.

Russian Journal of Infection and Immunity. 2022;12(3):591-594
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For the anniversary of Vitalii V. Zverev

Russian Journal of Infection and Immunity. 2022;12(3):595-596
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