Vol 10, No 3 (2020)

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Russian Journal of Infection and Immunity. 2020;10(3):409
pages 409 views


Lessons to learn: COVID-19 epidemic in Italy

Semenov A.V., Pshenichnaya N.Y.


Here we provide the assessment of COVID-19 epidemic in Italy, which scale has led to serious challenges both for society and national health care system. Despite timely information regarding the pandemic spread of the novel coronavirus infection, the country’s health care was not prepared to dramatically increased rate of patients with viral pneumonia at the first stage of the epidemic, infection control measures were not fully implemented that also led to spread of infection among health care workers. Socially vulnerable population groups did not seek timely medical care due to the lack of hospital facilities as well as well-trained medical personnel. At the second stage of developing epidemic, were also delayed and executed at varying timepoints in neighbor regions, with sustained insufficient management after implementing them that was reflected as ongoing rise of epidemic curve over long time. Delayed execution of anti-epidemic restrictive measures aimed at fighting against ongoing epidemic resulted in substantially increased morbidity and mortality among vulnerable population groups and retarded rate of decreasing COVID-19 epidemic curve. Analyzing response measures taken in Italy against COVID-19 epidemic should be appreciated by other countries while dealing with the current pandemic and preparing to react to novel biological threats in the future.

Russian Journal of Infection and Immunity. 2020;10(3):410-420
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COVID-19: etiology, clinical picture, treatment

Shchelkanov M.Y., Kolobukhina L.V., Burgasova O.A., Kruzhkova I.S., Maleev V.V.


Whereas the XX century marked the history of acute respiratory disease investigation as a period for generating in-depth system of combating influenza viruses (Articulavirales: Orthomyxoviridae, Alpha-/Betainfluenzavirus) (based on environmental and virological monitoring of influenza A virus in its natural reservoir — aquatic and semi-aquatic birds — to supervising epidemic influenza), a similar system is necessary to build up in the XXI century with regard to especially dangerous betacoronaviruses (Nidovirales: Coronaviridae, Betacoronavirus): Severe acute respiratory syndrome-related coronavirus (SARS-CoV) (subgenus Sarbecovirus), Severe acute respiratory syndrome-related coronavirus 2 (SARSCoV-2) (Sarbecovirus), Middle East respiratory syndrome-related coronavirus (MERS-CoV) (Merbecovirus). This became particularly evident after pandemic potential has been revealed in 2020 by the SARS-CoV-2. This review provides an insight into the historic timeline of discovering this virus, its current taxonomy, ecology, virion morphology, life cycle, molecular biology, pathogenesis and clinical picture of the etiologically related COVID-19 (Coronavirus disease 2019) as well as data available in the scientific literature on the anti-SARS-CoV-2-effectiveness of passive immunotherapy and most debated drugs used to treat COVID-19: Chloroquine, Hydroxychloroquine, Nitazoxanide, Ivermectin, Lopinavir and Ritonavir, Camostat mesilate, Remdesivir, Ribavirin, Tocilizumab, Anakinra, corticosteroids, and type I interferons. The pathogenesis of SARS-CoV-2 infection implicates decreased efficacy of artificial respiration, which, in this case might be replaced by more efficient extracorporeal membrane blood oxygenation supplemented with nitrogen oxide and/or Heliox inhalations.

Russian Journal of Infection and Immunity. 2020;10(3):421-445
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Some opportunities for immunotherapy in coronavirus infection

Smirnov V.S., Totolian A.A.


Here we review means of immunomodulatory therapy for coronavirus infection caused by SARS-CoV-2 (COVID-19). It has been appreciated that highly limited arsenal of relatively effective means and methods of prevention and treatment of the COVID-19 pandemic is available. The goal of our study was to analyze some therapeutic approaches based on available publications for COVID-19 treatment viewed from acting via innate immunity system. Convalescent plasma serotherapy represents one of the means with verified therapeutic efficacy that was accompanied with decreased viral load and relief of the disease symptoms. The drawback of serotherapy results from limited number of potential plasma donors and profound variety in amount of SARS-CoV-2-specific antibodies found in donor plasma. Another approach to COVID-19 therapy is based on using monoclonal antibodies engineered to target specific virus antigenic determinants, most often surface spike antigen. Antibodies blocking such antigen are able to prevent virus entrance into target cells and development of overt infection. On the other hand, there are monoclonal antibodies abrogating production or binding of excessive amounts of pro-inflammatory cytokines, such as IL-6, TNFα, etc., some of which (tocilizumab) have been already tested in COVID-19 therapy, whereas the remaining preparations are being currently investigated and tested. A certain breakthrough in COVID-19 therapy was provided by the well-known drugs chloroquine and dihydrochloroquine, which have proven to be effective as antiviral, anti-inflammatory and immunomodulatory means. Finally, a new multicomponent immunomodulatory preparation Cytovir-3 has been proposed already passed clinical trials and recommended for use in prevention and treatment of influenza and SARS and might have found its own niche in preventing COVID-19, as SARS-CoV-2 also belongs to the group of acute respiratory viruses. Thus, the arsenal of means for COVID-19 prevention and treatment contains the drugs for immunomodulatory therapy and prevention of immune-related disorders developing in response to invasion pathogenic viruses and lowering a risk of possible damage. Hence, correct and scientifically justified use of such remedies will increase overall effectiveness of fight against the coronavirus pandemic.

Russian Journal of Infection and Immunity. 2020;10(3):446-458
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COVID-19 and BCG vaccine: is there a link?

Lyadova I.V., Starikov A.A.


The spread of the novel coronavirus infection (COVID-19) makes the search for new approaches to prevent the infection of great importance. As one of the relevant approaches, the vaccination of risk groups with BCG vaccine has recently been suggested. BCG (Mycobacterium bovis, Bacillus Calmette–Guérin) is a live vaccine for tuberculosis, which is used in many countries with a high tuberculosis prevalence and helps preventing childhood tuberculosis, primarily, military disease and tuberculosis meningitis. Whether BCG may be used to increase the protection against COVID-19 is currently a question of debates. The review considers scientific background underlying possible impact of BCG in increased protection against COVID-19. BCG is able of inducing the heterologous and trained immunity, and its capacity to stimulate antiviral immune response has been demonstrated in experimental animals and humans. Our comparison of the dynamics of COVID-19 morbidity and mortality in countries with different BCG vaccination policies has demonstrated a milder course of COVID-19 (i.e., a slower increase in disease cases and mortality) in countries where BCG vaccination is mandatory for all children. However, an association between BCG vaccination and a milder COVID-19 course is not obligatory direct. Other factors that may affect the association, such as the level of virus testing, the rigidity and the speed of quarantine implementation and others are discussed. An important argument against a role of BCG in the protection against COVID-19 is that BCG is given in childhood and may hardly induce long-lasting immunity. Because mandatory BCG vaccination is implemented in countries with high TB burden and because in these countries latent tuberculosis infection is widely spread, we suggest a hypothesis that latent tuberculosis infection may contribute to the maintenance of heterologous/trained antiviral immunity in countries with mandatory BCG vaccination. Four countries have recently initiated clinical trials to investigate whether BCG vaccination can increase the level of protection against COVID-19 in risk groups. The results of these studies, as well as COVID-19 epidemiological modeling will help understanding the impact of BCG in the level of the protection against COVID-19. Performing analogous clinical trials in Russia seems appropriate and scientifically sound.

Russian Journal of Infection and Immunity. 2020;10(3):459-468
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A role of peptidoglycan recognition proteins in regulating innate immune response

Slonova D.A., Posvyatenko A.V., Kibardin A.V., Georgiev G.P., Gnuchev N.V., Larin S.S.


By now, a whole number of pathogenic antibiotic-resistant or tolerant microorganisms has been progressively increased. Hence, efficient fight against them requires to change the class of antibiotics, increase their dose, or develop new antimicrobial drugs. On the contrary, another option could rely on augmenting innate immunity. During coevolution, eukaryotes have developed several ways for their protection against microorganisms. Innate immunity conserved in all multicellular organisms. The essential principles of innate immunity include recognition of a foreign structures and their subsequent destruction. A set of specific receptors recognize conserved pathogen-derived structures. Elimination occurs due to phagocytosis and cleavage, e.g. via oxidative burst in phagocytic cells, compliment system or antimicrobial peptides. Recognition system in innate immunity is based on the pattern recognition receptors. Due to the pathogen diversity, multiple conserved structures typical to pathogens (e.g. lipopolysaccharide, peptidoglycan, flagellin etc.) are sensed by numerous receptors. The family of peptidoglycan recognition proteins is among such receptors, which were first isolated in 1996 from the silkworm Bombyx mori and mice. Later, it was demonstrated that this family is conserved and its members are found in insects, fish and mammals. Here, functions of insect peptidoglycan recognition proteins in Drosophila melanogaster as well as mammals are discussed. Such proteins are expressed mainly in liver cells (insects — in adipose tissue cells as analogue of mammalian liver), intestinal cells, and epidermis. Numerous studies demonstrate that peptidoglycan-recognition proteins moderate immune response, and may act as antimicrobial proteins, or to regulate microbiota as well as prevent enterocyte activation and restrict inflammatory response. Due to evolutionary conservatism observed for such proteins and inability for bacteria to evade their protective effects, it seems promising to use peptidoglycan recognition proteins in a combination therapeutic approach against antibiotic-resistant and antibiotic-tolerant forms of microorganisms.

Russian Journal of Infection and Immunity. 2020;10(3):469-476
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Rickettsialpox — a rare but not extinct disease: review of the literature and new directions

Eremeeva M.E., Muniz-Rodriguez K.


Rickettsialpox is an urban zoonosis caused by Rickettsia akari. To date R. akari is the only well-characterized mite-borne member of the spotted fever group. It is transmitted by the mouse mite, Liponyssoides sanguineus, commonly found on peridomestic rodents. While the disease was first discovered in New York City in 1946, a few years later a similar outbreak occurred in the Ukraine SSR. Numerous serosurveys and diagnosis of sporadic cases of rickettsialpox suggest its global distribution; however, the actual contemporary geography of rickettsialpox and its incidence are unknown. Rickettsialpox is characterized by the classic clinical triad found in rickettsioses of a black eschar, high fever, and rash but the latter is atypical as it is papulovesicular. Dermatological manifestations and the progression of rickettsialpox may mimic other infectious and noninfectious syndromes, including sexually transmitted diseases. The purpose of this review is to increase awareness of this unique disease through reanalysis of classic and contemporary clinical descriptions of rickettsialpox, evaluation of its worldwide distribution, and updates on the public health importance of the disease as well as the ecology and vector associations of R. akari. Our review data suggests that only limited genetic diversity exists among the available isolates of R. akari associated with previous outbreaks; additional effort is still required to define specific genetic markers permitting direct surveillance, accurate and reliable diagnosis, tracking and studying of the vector and host associations of contemporary isolates. The potential of R. akari to cross into other vector species emphasizes the necessity for detection of outbreaks of the disease in new regions of the world and in novel ecological settings. We describe existing gaps and limitations in our current understanding of the pathogenesis of rickettsialpox, the epidemiology of this disease and the genetic diversity of R. akari. We propose research priorities for what is needed to improve our understanding of this neglected rickettsial disease and its etiologic agent.

Russian Journal of Infection and Immunity. 2020;10(3):477-485
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Current status of healthcare-associated enteroviral (non-polio) infections

Alimov A.V., Igonina E.P., Feldblyum I.V., Chalapa V.I., Zakharova Y.A.


Here we present the data on foreign research publications describing healthcare-associated enteroviral (nonpolio) infections (HAI) sought in the Worldwide Database for Nosocomial Outbreaks (Institut für Hygiene und Umweltmedizin, Universitȁtmedizincomplex “Charite”, Germany) as well as PubMed search engine (The United States National Library), covering 1936–2017 timeframe. The publications retrieved contained the data on 28 nosocomial outbreaks caused by Enterovirus A (EV-A71), В (Echoviruses 11, 17, 18, 30, 31, 33, Coxsackie viruses А9, В2, В5) and D (EV-D68). It was discovered that the majority of the nosocomial enteroviral (non-polio) outbreaks occurred in obstetric hospitals and neonatal units so that children were mainly maternally infected. In addition, a case associated with intrauterine infection was described. It was shown that outbreaks might be started by an infected child at the incubation period. Single publications reported nosocomial outbreaks in geriatric hospitals. Generally, nosocomial enteroviral (non-polio) outbreaks were characterized by polymorphic clinical picture caused by any certain pathogen serotype and within a single site of the infection. Few lethal outcomes were recorded. Enterovirus B species dominated among identified etiological agents. Violated hospital hygiene and infection control contributing to spread of infection were among those found in neonatal units: putting used diapers out on baby bed prior disposal, sharing bathtub, toys and household objects as well as poor hand hygiene in medical workers. One of the measures recommended to improve diagnostics of enteroviral (non-polio) infections was virology screening of children with suspected sepsis in case of unidentified etiology. It was established that etiological decoding of nosocomial outbreaks was impossible without applying pathogen-specific diagnostic tools, mainly nested RT-PCR and direct sequencing of followed by subsequent phylogenetic analysis.

Russian Journal of Infection and Immunity. 2020;10(3):486-496
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Molecular typing of Rickettsia akari

Eremeeva M.E., Sturgeon M.M., Willard J.K., Karpathy S.E., Madan A., Dasch G.A.


Rickettsia akari, an obligately intracellular bacterium, is the causative agent of the cosmopolitan urban disease rickettsialpox. R. akari is an atypical representative of spotted fever group rickettsiae (SFG) as it is associated with rodent mites rather than ticks or fleas; however, only limited information is available about the degree of genetic variability found among isolates of R. akari. We examined 13 isolates of R. akari from humans, rodents and mites in the USA, the former Soviet Union, and the former Yugoslavia made between 1946 and 2003 for diversity in their tandem repeat regions (TR) and intergenic regions (IGR). The 1.23 Mb genome of R. akari strain Hartford CWPP was analyzed using Tandem Repeat Finder software (http://tandem.bu.edu) and 374 different TRs were identified, with size variation from 1 to 483 bp and with TR copy numbers ranging between 21 and 1.9, respectively. No size polymorphisms were detected among the 11 TR regions examined from 5 open reading frames and 6 IGR. Eighteen non-TR IGR’s were amplified and sequenced for the same isolates comprising a total of 5.995 bp (0.49%) of the Hartford CWPP strain chromosome. Three single nucleotide polymorphism (SNP) sites were detected in two IGR’s which permitted separation of the five R. akari isolates from Ukraine SSR from the other eight isolates. In conclusion, this is the first study reporting genetic heterogeneity among R. akari isolates of different geographic origins. Further exploration of this genetic diversity is needed to understand better the geographic distribution of R. akari and the epidemiology of rickettsialpox. The potential of mites as hosts for other rickettsial agents also needs further investigation.

Russian Journal of Infection and Immunity. 2020;10(3):497-505
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Lung memory T-cell response in mice following intranasal immunization with influenza vector expressing mycobacterial proteins

Shurygina A.S., Zabolotnykh N.V., Vinogradova T.I., Vasilyev K.A., Buzitskaya Z.V., Stukova M.A.


Improving specific prevention of tuberculosis continues to be a top priority in phthisiology. “Prime-boost” vaccination schemes aim to maintain adequate levels of specific immunity while forming long-term protection. They are based on sequential use of BCG vaccine and new vaccine candidates expressing protective mycobacterial proteins. The development of new tuberculosis prevention approaches requires an understanding of how the anti-tuberculosis immune response forms and which mechanisms provide TB protection. Since tuberculosis is an airborne infection, vaccine effectiveness largely depends on mucosal immunity based on the formation of long-lived, functionally-active memory T-lymphocytes in the respiratory tract. We have previously shown that the influenza vector expressing ESAT-6 and Ag85A mycobacterial proteins (Flu/ESAT-6_Ag85A) in vaccination scheme of intranasal boost immunization resulted in significant increase of BCG's protective effect according to key indicators aggregate data in experimental tuberculosis infection. The aim of this work was to study the effect of intranasal immunization with the Flu/ESAT-6_Ag85A influenza vector on the formation of antigen-specific central and effector memory T cells and the cytokine-producing activity of effector T cells (TEM) in BCG standard and “BCG prime — influenza vector boost” vaccination schemes in mice. Intranasal immunization with the influenza vector has been shown to increase the proportion of antigen-specific CD4+ central memory T cells (TCM) in the pool of activated lymphocytes of lung and spleen reaching significant differences from the BCG group in the percentage of spleen CD4+ TCM (p < 0.01). In contrast to BCG, vaccination with the studied vaccine candidate was accompanied by accumulation of highly differentiated CD8 effector cells in lung, the target organ during tuberculosis infection. Comparative evaluation of the cell-mediated, post-vaccine immune response after immunization with influenzavector-based vaccine candidate (intranasal/mucosal) or BCG vaccine (subcutaneous) showed advantages in the mucosal group: in formation of functionally active subpopulations of effector CD4 and CD8 T lymphocytes (CD44highCD62Llow) in lungs secreting IL-2 as well as polyfunctional cells capable of coproducing two cytokines (IFNγ/TNFα or IFNγ/IL-2) or three cytokines (IFNγ/TNFα/IL-2). Due to their more pronounced effector function, polyfunctional T-lymphocytes can be considered to be potential immunological markers of protective immunity in tuberculosis.

Russian Journal of Infection and Immunity. 2020;10(3):506-514
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Metabolic changes in peripheral blood lymphocytes from children with recurrent respiratory infections

Kurtasova L.M., Shakina N.A., Lubnina T.V.


Objective: to examine activity and correlative relations for peripheral blood lymphocyte NAD (P)-dependent dehydrogenases in young children with recurrent respiratory infections with hypertrophy of the pharyngeal tonsils and bronchial obstructive syndrome.  Methods. 89 children, aged 1–3 years, with recurrent respiratory infections were examined, including 35 children with hypertrophy of pharyngeal tonsils (HPT) and 54 children — with bronchial obstructive syndrome (BOS). Control group contained 20 age-matched healthy children. Activity and relations for peripheral blood lymphocyte for NAD(P)-dependent dehydrogenases were assessed by using bioluminescent method proposed by А.А. Savchenko and L.N. Suntsova (1989).  Results. It was found that children with recurrent respiratory infections displayed altered enzyme status in peripheral blood lymphocytes. In particular, activity ribose-5-phosphate- and NAD(P)-dependent metabolic events as well as substrate flux via the tricarboxylic acid cycle were elevated that was paralleled with decreased lactate dehydrogenase anaerobic reaction, thereby implicating a role for malate-aspartate shunt in the energy turnover, substrate efflux from the tricarboxylic acid cycle into amino acid metabolic pathways as well as activity of glutathione reductase. Moreover, features of altered enzymatic profile in peripheral blood lymphocytes were uncovered, which depended on type of complication related to respiratory infection. In addition, children with hypertrophy of pharyngeal tonsils were featured with increased influx of lipid catabolism products into glycolysis, elevated level of malic enzyme activity and decreased pyruvate production. However, children with bronchial obstructive syndrome were found to have decreased glycerol-3-phosphate dehydrogenase activity resulting in lowered shunting activity of slow reactions in Krebs cycle and increased influx of amino acid metabolism intermediates into the tricarboxylic acid cycle. Reshaping of enzymatic profile in peripheral blood lymphocytes depended on type of complications coupled to respiratory infections (ENT-pathology or BOS syndrome). A correlation analysis revealed features of relationship between parameters of NAD(P)-dependent dehydrogenase activity in peripheral blood lymphocytes found in children with hypertrophy of pharyngeal tonsils and bronchial obstructive syndrome marked by quantity, modality and power of correlative links.  Conclusion. Children with the recurrent respiratory infections require metabolic therapy aimed at restoring intracellular pathology-driven metabolic processes in immune cells.

Russian Journal of Infection and Immunity. 2020;10(3):515-523
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Effect of vitamin D and interferon α-2b on cytokine profile in pregnant women with vaginal infections

Kostinov M.P., Ignatieva M.A., Novikova S.V., Shmitko A.D., Polischuk V.B., Akhmatova N.K., Savisko A.A., Kostinov A.M.


A study was conducted to evaluate effectiveness of vitamin D and interferon α-2b preparations on cytokine profile in pregnant women with vaginal infections. It was shown that pregnant women with vs. without bacterial vaginosis were featured with low vitamin D level in 53.8–60.5% cases. Administration of vitamin D and interferon α-2b preparations in combination with antibacterial therapy in pregnant women with bacterial vaginosis conferred anti-inflammatory effect resulting in normalized IL-8 level corresponding to that one in healthy subjects. Use of vitamin D altered interferon status and augmented antimicrobial activity in pregnant women confirmed by reduced rate of ARI episodes.

Russian Journal of Infection and Immunity. 2020;10(3):524-532
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Ecological and epidemiological characteristics of tick-borne encephalitis in St. Petersburg

Siuziumova E.A., Telnova N.V., Shapar A.O., Aslanov B.I., Stoyanova N.A., Tokarevich N.K.


Here, we provide an analysis on 1996–2016 St. Petersburg tick-borne encephalitis (TBE) epidemiological and ecological data. In particular, two main TBE transmission vectors were observed in St. Petersburg: Ixodes persulcatus Ixodes ricinus. TBE tick contamination was 0.61% as shown by ELISA and polymerase chain reaction data. It is found that number of subjects seeking for medical aid due to tick bites rises, whereas TBE incidence declines. In particular, a mean 1996–2002 vs. 2010–2016 tick-bite incidence rate increased from 141.9 up to 288.9, respectively. Despite that the Leningrad region is a major area for TBE spread, however, a risk of exposure to tick bites as well as TBE infection exists even in the city of St. Petersburg. In connection with this, around 1,000 subjects undergo tick bites within the city limits. Moreover, whereas a 1996–2002 mean TBE incidence rate was 1.66, it decreased in 2010–2016 down to 1.17. A peak TBE incidence was documented in St. Petersburg Kurortny, Pushkinsky and Primorsky districts. In addition, males vs. females suffered from TBE at higher frequency in Russian Federation, with its peak incidence rate being reported in children under 14 that differs St. Petersburg from the most of other regions in the Russian Federation. A seasonal distribution of TBE cases in St. Petersburg does not differ from that one for the remainder of Russian regions, which displays a spring-summer seasonality lasting from April to September. Of note, 1996–2016 St. Petersburg TBE mortality was 1.37%. A coverage of TBE vaccinated population tends to rise but still remains at low level (0.25–0.58%). Lack of reported TBE cases in occupationally threatened human cohorts evidences about efficient preventive measures. Detection of TBE virus-specific serum antibodies in 5.0% apparently healthy and unvaccinated residents in St. Petersburg significantly complements the official TBE recording data and provides a more accurate understanding of its actual spread.

Russian Journal of Infection and Immunity. 2020;10(3):533-542
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Features of the endoscopic picture in paediatric gastroduodenal diseases caused by Helicobacter pylori

Turdieva S.T., Shamansurova E.A.


The aim of the study was to examine the features of the endoscopic picture in the upper digestive tract mucosa in paediatric chronic gastroduodenal pathology (CGDP) associated with Helicobacter pylori. Materials and methods. There were examined 286 patients, aged 6–15 years. Diagnostic criteria for chronic gastroduodenal pathology were anamnestic as well as instrumental and functional studies data: gastric fractional intubation, esophagogastroduodenoscopy (EPGDS) with endoscopic pH-metry without biopsy, and ultrasound examination of abdominal organs. H. pylori testing was carried out by two unrelated methods such as respiratory test and a immunochromatographic fecal test. Results. Detection of H. pylori in children with CGDP peaked in patients with peptic gastric and duodenal ulcer (up to 87.5%, p < 0.05). The main endoscopic signs were edema, hyperaemia and contact bleeding, as well as local haemorrhage were the major endoscopic signs of inflammation in the stomach and duodenum mucosa. Atrophic mucosal lesions were characterized by thinning, pale colour together with transilluminated submucosal vessels. Non-atrophic antral gastritis was featured with delayed gastric emptying, antral stasis and pyloric spasm. In contrast, hypotension of the gastric wall, duodenogastric reflux and decreased motility were more typical to chronic atrophic gastritis. Major endoscopic feature in patients with H. pylori infection was presented by dominant atrophic changes combined with gastroduodenal reflux (77.6%, p < 0.05) compared to patients without H. pylori infection. Conclusion. Detection of HP infection was peaked in children with CGDP coupled to peptic ulcer disease compared to patients with inflammatory diseases (p < 0.05). Endoscopic examination in HP-positive patients showed that atrophic changes were found by 4-fold more frequently together with gastroduodenal reflux compared to patients without HP infection (p < 0.05).

Russian Journal of Infection and Immunity. 2020;10(3):543-550
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Phagocytic activity of blood monocytes in response to methicillin-resistant strains of Staphylococcus aureus

Kolenchukova O.A., Sarmatova N.I., Moshev A.V.


Current study performed to estimate the phagocytic activity of blood monocytes of varying phenotypes exposed to MRSA and MSSA strains.  Objects: Blood monocytes were collected from 25 healthy adults (age: 25–45 years). Live suspensions of MRSA/MSSA strains were used at concentration of 106 colony-forming units (CFU)/mL.  Metods. Phagocytic functions were estimated by using fluorescein isothiocyanate (FITC)-labelled MRSA and MSSA strains followed by running flow cytometry on FC 500 series flow cytometer (Beckman Coulter, USA). Whole peripheral blood cells were directly labelled with immunofluorescently tagged monoclonal CD14-PE/CD45-ECD/HLA-DR-PC5/CD16-PC7 antibodies (Beckman Coulter, USA). Respiratory burst intensity was evaluated in monocytes by measuring activity of lucigeninand luminol-dependent spontaneous and induced chemiluminescence. Monocytes were induced by using live suspension of MRSA/MSSA strains at a concentration of 106 CFU/mL. Results and discussion. While studying luminol-dependent monocyte activities after exposure to MRSA vs. MSSA, it was observed a 3.5-fold decreased curve square, whereas lucigenin-dependent chemiluminescence was increased by 6-fold. Compared to MSSA exposure, index of activation (IA) was decreased by 1.1-fold in response to MRSA exposure that was confirmed by lowered release of reactive oxygen species (ROS) from monocytes in response to MRSA exposure. Moreover, IRSS increased by 1.3-fold upon MRSA exposure. Examining monocyte oxygen-independent phagocytosis against MRSA vs. MSSA revealed significantly increased phagocytic number and concomitantly decreased phagocytic index. An evaluation of the activities of various monocyte subsets in response to MRSA vs. MSSA revealed increased phagocytic index by 1.5-fold for CD14lowCD16+ and CD14+CD16+ monocyte subsets as well as 3-fold for CD14+CD16 monocytes. Counts for all phagocytic subsets were decreased (1.4-, 1.5- and 4-fold for CD14lowCD16+, CD14+CD16+ and CD14+CD16– monocytes, respectively). To summarize, intensity of the respiratory burst was lowered upon MRSA exposure and percentage of monocyte subsets. Overall deficiency of superoxide anion production was observed in response to MRSA. In contrast, oxygen-independent event revealed phenotypic changes in frequency of peripheral blood monocytes upon MRSA exposure. We observed that CD14+CD16 classical monocytes were more rapidly activated. Conclusion. Thus, we concluded that CD14+CD16 monocytes became more rapidly activated but exhibited less effective phagocytosis, whereas CD14+CD16+ and CD14lowCD16+ monocytes were more slowly activated and demonstrated stronger phagocytic activity.

Russian Journal of Infection and Immunity. 2020;10(3):551-557
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Advancing diagnostics of chronic paradontitis in children

Agarkov N.M., Makaryan A.S., Gontareva I.S.


Chronic periodontitis in children and adolescents holds a lead place in morbidity pattern of dental pathology. Development of chronic periodontitis is accompanied by emergence of various complications in the maxillofacial region, leading to bite disturbance being of high relevance for pediatric patients. These and other complications are related to immune system immaturity in children and adolescents as well as virulence of microorganisms. However, the immunological changes developing in children with chronic periodontitis remain poorly studied. The aim of the work was to improve diagnostics of chronic periodontitis in children and adolescents based on informative parameters of systemic immunity and discriminative models taking into account such changes. We examined systemic immunity in 127 children and adolescents with chronic periodontitis, aged 12 to 16 years, by using flow cytometry and enzyme immunoassay. In control group, age-matched 108 patients lacking overt somatic and dental pathology were enrolled. Generation of mathematical models was carried out by using a discriminative approach, whereas informativeness was assessed in accordance with generally accepted formula. Relative and absolute count of peripheral blood CD13+ cells exert the peak informativeness holding the first and second ranking places with marked dominance of informativeness value for assessing relative amount of CD13+ cells are among immunological parameters in children with chronic periodontitis. High informativeness value evidencing about pronounced intensity of developed pathological changes and diagnostic significance for chronic periodontitis in children is intrinsic to the relative percentage of peripheral blood CD8+ cells being slightly lower than that one in absolute count of CD13+ cells. On the other hand, humoral immune-parameters were of lowest informative value among all analyzed immunological parameters in patients with chronic periodontitis serum referring to all antibody classes. Generated discriminative models for the most valuable immunological parameters ensure adequate medical diagnostics for chronic periodontitis in childhood. Diagnostic sensitivity for created mathematical models was high and reached 0.94, whereas diagnostic specificity — 0.92. Immunological examination of patients improves diagnostics of chronic periodontitis. It was found that patients with chronic periodontitis had lowered immune status peaking in decreased absolute and relative count of peripheral blood CD3+ lymphocytes. Finally, parameters of humoral immunity in children with chronic periodontitis were also reduced.

Russian Journal of Infection and Immunity. 2020;10(3):558-564
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Detection of international high-risk clones of food-borne pathogens Salmonella and Escherichia coli in the Russian Federation

Kaftyreva L.A., Egorova S.A., Makarova M.A.


The use of whole genome sequencing, standard analyze methods and international databases allows to detect international high-risk clones of food-borne pathogens, to assess their evolution and geographical distribution due to international trade of animal food products and farm animals. In Saint-Petersburg, Russian Federation, Salmonella Newport, Salmonella Kentucky and Escherichia coli O26:H11 of well-known international high-risk clones were first identified from patients with diarrhea. Two S. Kentucky strains isolated in 2015 and 2019 were identical to the international clone ST198 widely distributed in European countries: had multidrug resistance, high-level fluoroquinolone resistance (MIC of ciprofloxacin  >  32,0 mg/l) due to three single-nucleotide substitutions in the gyrA (Ser83Phe and Asp87Asn) and parC (Ser80Ile). In 2008, a multidrug resistant S. Newport strain resistant to extended-spectrum cephalosporins due to AmpC-cephalosporinase CMY-2 was isolated, belonging to the international clone of S. Newport MDR-AmpC/CMY-2  which caused sporadic cases and outbreaks in the USA and Europe in the 2000s. The plasmid containing the blaCMY-2 had a PstI-restriction profile, one of the most prevalent in the international clone. E. coli O26:H11 strains, isolated in Saint-Petersburg,  produced the shiga-like toxin STX1 (stx1a), had additional virulence genes: ehxA (enterohemolysin), katP (catalase peroxidase), espP (serine protease), as well as cba (colicin B), gad (glutamate decarboxylase), cif (type III secreted effector), iss (increased serum survival), belonged to the phylogenetic group B1 and the international high-risk clone  E. coli O26:H11 ST21 widely distributed in Europe and the USA. 25% of the strains had multidrug resistance and produced CTX-M extended spectrum beta-lactamases. In the Russian Federation E. coli O26 is consider as the pathogen of diarrheal diseases and registered as Enteropathogenic E. coli in routine bacteriological laboratories without detecting of H-antigen and shiga-like toxins.
Russian Journal of Infection and Immunity. 2020;10(3):565-569
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Detection of measles cases in the Republic of Guinea in 2017–2018

Lavrentieva I.N., Bichurina M.A., Antipova A.Y., Camara J., Magassouba N.


In 2017, WHO reported 596 confirmed measles cases in Guinea Republic connected to the 2016–2017 epidemic outbreak that was stopped after additional immunization (SIA) against measles in two provinces of the country. Improving the effectiveness of SIA is associated with the identification of epidemiologically significant groups of the population. The aim of the study was to analyze 2017–2018 measles cases and assess population immunity to measles virus in the Republic of Guinea. Materials and methods. A total of 810 blood serum samples collected from patients with maculo-papular rash and clinical diagnosis “measles?” were tested for measles virus-specific IgM-and IgG antibody level. 445 sera of conditionally healthy individuals aged 7 months to 67 years were examined for anti-measles virus IgG antibody level. Immunoglobulins of classes M and G were detected by ELISA with test systems «Anti-Measles Virus ELISA (IgM)» (Euro immun, Germany) and «Anti-Measles Virus ELISA (IgG)» (Euroimmun, Germany). Results and discussion.In 2017–2018, the epidemic process of the measles in the Republic of Guinea proceeded very intensively, being markedly prevalent in children among age groups. In 2018, more than half of the cases (61.6%) were identified in children aged 1 to 5 years old; the second most abundant age group was children under one year (18.6%), probably due to violated measles vaccination, which in GR are subject to children of nine months of age. It was found that 16.4% of patients (60 out of 366) had documented data on measles vaccination. Potentially, high proportion of measles cases among pre-vaccinated subjects was due to insufficient immune response to a single immunization in children of 9 months of age. Moreover, lowered vaccine-related properties might also be violated “cold chain” during vaccine transportation occurring in tropical climate. Analyzing 445 subjects revealed that total number of measles virus seronegative subjects was 8.3%. However, the vast majority of them were children and young adults aged 7 months to 22 years, where 52.4% of seronegative subjects were identified. Thus, the data obtained indicate that intensive measles virus circulation in human population was continued that necessitate interventions for improving epidemiological surveillance, extend routine measles vaccination coverage and conduct SIAs against measles in GR.

Russian Journal of Infection and Immunity. 2020;10(3):570-574
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Features of the course of contemporary intestinal amebiasis

Cherenova L.p., Arakelyan R.S., Mikhailovskaya T.M.


Acute intestinal infections, including intestinal amebiasis, remain a pressing public health problem. Amebiasis still represents an important and partially solved problem to health care. In the Astrakhan region, intestinal amebiasis is being continuously recorded. We analyzed the clinical picture of acute intestinal amebiasis in 150 adult patients dominated by female patients comprising 60.7%, aged 18 to 79 years old, and treated within 2010–2016 at the Regional Infectious Clinical Hospital. All patients were mostly of young and middle age (up to 50 years) — 108 patients. More than 50% of patients were admitted to the hospital within the first three days of the disease. However, in 35 cases (23.3%), late hospitalization was carried out (5 days after the onset). Proper diagnosis was made to 44 patients (29.3%), most commonly diagnosing preliminarily with acute gastroenteritis and acute dysentery. All cases of intestinal amebiasis were confirmed by detecting in the feces of patients with a vegetative form of entamoeba histolytica. The disease was featured with sporadic course, being mostly recorded during the summer-autumn period (78.0%). In 142 patients (94.7%), the moderate severity was observed. Cardiovascular disorders were mainly found in severe amebiasis as well as patients comorbid with cardiovascular diseases. A coprological method was used to confirm the diagnosis. Microscopic examination of feces was carried out immediately after defecation (warm type). A combination therapy was applied to patients with intestinal amebiasis. A great attention was paid to patient nutrition: high-protein sparing diet, grated food. Patients with ulcerative colitis received individualized diet (restricted carbohydrates, exclusion of milk and fiber). Etiotropic therapy was carried out with using 5-nitroimidazole preparations: metronidazole (Trichopol, Flagin, Tiberal), MacGioror, Tinidazole (Phasycin) combined with tetracycline. The treatment included group B vitamin cocktail, methyluracil (suppository), enzymes (creon, mezim, pancreatin), enterosorbents (smecta, polyphepan, enterosgel), antispasmodics (no-spa, drotaverin). Patients were administered with therapeutic microenemas containing furacilin solution, rosehip oil, and sea buckthorn oil. Infusion therapy consisting of polyionic solutions was applied by assessing blood electrolyte level. Fresh frozen plasma and albumin were transfused upon decline of serum protein and albumin level. Packed erythrocytes Erythrocyte mass and hemostatic drugs were injected in case of severe intestinal amebiasis if indicated: dicynone, cryoprecipitate, and calcium preparations. Finally, anemia cases were treated as well. In all cases, the disease outcome was favorable, without any mortality. Complications were noted in the form of intestinal bleeding observed in 6 patients (4.0%), wherein amebiasis proceeded together with ulcerative colitis. Acute intestinal amebiasis is currently featured with typical clinical picture that proceeds with less severe symptoms. Intestinal bleeding was observed in patients with intestinal amoebiasis in combination with ulcerative colitis. Chronization of intestinal amebiasis occurs in single cases (3.9%).

Russian Journal of Infection and Immunity. 2020;10(3):575-580
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Clinical characteristics of foodborne botulism in the southern region of the Kyrgyz Republic

Salieva S.T., Zholdoshev S.T.


The main factors of botulism transmission are identified as home-canned products (vegetable salads, fruit compotes, seaberry jam), pickled cucumbers and tomatoes. Botulism proceeds clinically as moderate-to-severe disease. High prevalence of type A and untypeable C. botulinum toxins along with type B species in the southern region accounts for its severe course. In our study, clinical manifestations of botulism were presented by moderate and severe clinical picture in 72.3% (47 patients) and 27.7% (18 patients) cases. No mild forms of the disease were diagnosed. Length of incubation period in examined patients on average was 13.6 hours. Upon that, a short incubation period was observed after consumption of canned fruit compote and sea buckthorn jam, cucumbers and tomatoes (16 subjects) or canned vegetables (38 subjects) on average ranging from 4 to 8 hours, 8 hours to 1 day, or 15 hours to 1.5 days, respectively. All subjects were featured with acute onset manifested as general intoxication and gastrointestinal syndromes. The former was characterized by headache, dizziness, and severe general weakness. Subfebrile temperature (37.1–37.5°C) was noted in patients with a short incubation period. Such syndrome in case of moderate disease course was also characterized by moderate severity in 70.2±6.7% cases, with acute appearance in 29.8±6.9% cases; in severe course it was featured with extremely severe course (100%), and in one case it resulted in lethal outcome. Intensity and persistence of neurological disorders clearly correlated with the disease severity, which pointed at its progression. Upon admission to the hospital, patients noted moderate and marked dry mouth in 63.1±5.9% and 36.9±5.9% cases, respectively. Ophthalmoplegic syndrome was characterized by: doubling of object contours, diplopia, limited eye movement, mydriasis, lethargy or lack of pupillary reaction to light, anisocoria, and ptosis. Phagonazoglossoneurological syndrome was early manifested by swallowing problem. Next, tongue deviation, amimia, flattened nasolabial fold, and soft palate paresis were added up. Phonolaryngology syndrome was evident depending on disease severity in a form of varying intensity of dysphonia and dysarthria. Syndrome of general myoneuroplegia was characterized by lowered strength in hands and feet.

Russian Journal of Infection and Immunity. 2020;10(3):581-586
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Organ-specific pathomorphological changes during COVID-19

Vorobeva O.V., Lastochkin A.V.


COVID-19 is an acute respiratory infection caused by SARS-CoV-2 coronavirus causing pneumonia, lesions in the cardiovascular system and other organs, high mortality risk, especially in geriatric patients. Due to the great relevance, this study was aimed at describing the case of severe COVID-19 with development of multiple organ failure. Materials and methods. Available accompanying medical documentation (outpatient charts, medical history) was analyzed. Clinical and morphological analysis was carried out by providing description of macro- and micropreparations; histological methods (hematoxylin and eosin staining, Lee reaction) were used. Results. Female patient K.G., 69 years old, was hospitalized to the therapeutic department diagnosed with coronary heart disease. Acute coronary syndrome with ST segment elevation was made on 04/20/2020. A competing diagnosis: severe community-acquired bilateral multi-segmental pneumonia. The patient’s condition was aggravated wile applying therapy followed by biological death occurred. An autopsy revealed bilateral subtotal hemorrhagic pneumonia. Macroscopic lung examination demonstrated “lungs filled with red fluid”. In the brain — perivascular and pericellular edema, hyalinosis, blood stasis and sludge, marked dystrophic and necrotic neuronal changes. Cardiomyocyte fragmentation, areas of perivascular sclerosis with inflammatory infiltrates as well as erythrocytic sludge are found in the heart and blood vessels, respectively. A weak positive reaction according to Lee method was observed. Such clinical and morphological case demonstrates along with lung damage involvement of the heart resulting in acute coronary syndrome (morphologically manifested by ischemic myocardial dystrophy) and the brain. Thus, premorbid background in elderly patients results in developing acute pulmonary heart failure, pulmonary and cerebral edema.

Russian Journal of Infection and Immunity. 2020;10(3):587-590
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Selective synthetic growth medium “Acinetobacter phenylalanine agar” for isolation and identification of Acinetobacter calcoaceticus — Acinetobacter baumannii complex species

Sivolodskii E.P., Gorelova G.V., Bogoslovskaya S.P., Zueva E.V.


The aim of the study was to carry out clinical and microbiological testing of selective growth medium Acinetobacter phenylalanine agar to isolate and identify bacterial species belonging to the Acinetobacter calcoaceticus — Acinetobacter baumannii complex (ACB complex). For this, 400 samples of clinical material (wound discharge, blood, urine, bronchoalveolar lavage) were examined in 2018 in the Clinical and Bacteriological Laboratory of the Military Medical Academy by using routine assays (seeding on blood agar growth medium, pure culture isolation and identification by using biochemical assays as well as VITEK 2 microbial identification system, bioMerieux) and plating together with growth medium Acinetobacter phenylalanine agar selective to Acinetobacter spp. owing to L-phenylalanine as a sole nitrogen and carbon source additional selected with trimethoprim. ACB complex Acinetobacters were identified 18–24 hours later after incubation at 37°C by emergence of typical colonies on selective medium. Control tests for cytochrome oxidase as well as oxidative/fermentation (OF)-glucose test by using peroxide-hydrogen microvolume method (for 1 h) allowed to rapidly distinguish ACB complex Acinetobacters from other bacteria as well as from Acinetobacter spp. unable to glucose oxidation. Next, species identity for all isolated Acinetobacter strains was established by using matrix-activated laser desorption/ionization with time-of-flight mass spectrometry (MALDI-TOF MS). It was found that by using novel vs. routine assay Acinetobacter spps. were isolated in 26 (18 samples — in monoculture, 8 — in association with Pseudomonas aeruginosa or Klebsiella pneumoniae subsp. pneumoniae with tiny associate colonies) vs. 20 (7 — in monoculture, 13 — in association with Pseudomonas aeruginosa, Klebsiella, Escherichia, Citrobacter, Providencia, Staphylococcus, Enterococcus, C. albicans). Using MALDI-TOF MS method revealed that 25 out of 26 Acinetobacter strains isolated on selective growth medium belonged to the ACB complex (A. baumannii — 23, A. pittii — 2), whereas one strain (A. baylyi) did not belong to ACB complex. Hence, the diagnostic specificity of the Acinetobacter phenylalanine agar synthetic growth medium for isolation and identification of the A. calcoaceticus — A. baumannii complex species comprised 96.2%, with diagnostic sensitivity exceeding that one for routine assay by 25%. Use of selective growth medium accelerates research by allowing to isolate and identify ACB complex Acinetobacter spp. 18–24 h later after plating clinical material. Selectivity of growth medium was potentially stable, as its major trophic selection factor did not depend on acquired bacterial antibiotic resistance, which is also suitable as a synthetic growth medium for standardized studies.

Russian Journal of Infection and Immunity. 2020;10(3):591-596
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