Vol 93, No 11 (2021)

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Peculiarities of blood coagulation disorders in patients with COVID-19

Evtugina N.G., Sannikova S.S., Peshkova A.D., Safiullina S.I., Andrianova I.A., Tarasova G.R., Khabirova A.I., Rumyantsev A.G., Ataullakhanov F.I., Litvinov R.I.


Aim. To study the relationship of hemostatic disorders with inflammation and estimate their role in the course and outcomes of COVID-19.

Materials and methods. We examined 215 consecutive patients with moderate and severe forms of acute COVID-19. The patients were on anticoagulants and immunosuppressive drugs. Hemostasis was assessed using the thrombodynamics assay, thromboelastography, fibrinogen and D-dimer levels, prothrombin time, and soluble fibrin-monomer complexes (ethanol gelation test). The hemostatic parameters were correlated with hematological and biochemical tests, including markers of inflammation (C-reactive protein, interleukins 6 and 8), as well as with the disease severity and outcomes.

Results. Laboratory signs of coagulopathy were revealed in the vast majority of the cases. Despite the use of low-molecular-weight heparins in the prophylactic and therapeutic doses, coagulopathy in COVID-19 manifested predominantly as hypercoagulability that correlated directly with the systemic inflammation and metabolic changes due to liver and kidney dysfunction. A direct relationship was found between the grade of coagulopathy and the severity of COVID-19, including comorbidities and the mortality. The chronometric hypocoagulability observed in about 1/4 cases was associated with a high level of C-reactive protein, which may decelerate coagulation in vitro and thereby mask the true inflammatory thrombophilia. Persistent hyperfibrinogenemia and high D-dimer in the absence of consumption coagulopathy suggest the predominance of local and/or regional microthrombosis over disseminated intravascular coagulation.

Conclusion. The results obtained substantiate the need for laboratory monitoring of hemostasis and active prophylaxis and treatment of thrombotic complications in COVID-19.

Terapevticheskii arkhiv. 2021;93(11):1255-1263
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Original articles

Herpesviruses in patients after renal transplantation

Dzhumabaeva B.T., Tikhomirov D.S., Biryukova L.S., Tupoleva T.A., Nesterenko I.V., Purlo N.V., Chebotarev D.I.


Aim. To estimate graft function after kidney transplantation during active herpesviruses or superinfection

Materials and methods. The study included 32 patients (men – 21, women – 11) with end-stage chronic kidney disease. The median age was 43 years. Cytomegalovirus (CMV), Epstein–Barr virus (EBV) and human herpes virus 6 (HHV-6) DNAs were screened by RT-PCR in the donor's transplant biopsy, and recipients’ peripheral blood and urine after kidney transplantation (KT) on 0, 1, 2, 4, 6, 12 months. Antiviral antibodies (IgM and IgG) were also screened by Enzyme-linked immunoassay analysis (ELISA) along with PCR. The 500 or less copies of viral DNA per 105 nuclear cells or 1 ml of urine was considered as low, more than 1000 copies – high.

Results. On the first month after KT CMV DNA was detected in 50% of pts., EBV DNA – in 40% and HHV-6 DNA – in 33%. During first year after KT two or three viruses simultaneously were found in 12 recipients: CMV, EBV, and HHV-6 were detected in 5 recipients; CMV and EBV – in 4 patients; CMV and HHV-6 – in 2 pts; EBV and HHV-6 – in 1 pt. Graft dysfunction was observed in 9 patients with a high concentration of viral DNA of one, two or three viruses simultaneously. An upraise of the concentration of virus DNA (CMV, EBV and HHV – 6) was detected primarily in the urine, while in the blood its concentration was less than 500 cop or undetectable. Renal dysfunction was not observed on the background of low concentrations of viral DNA in urine and blood. However, with an increase of DNA concentration, an impaired graft function in 8 of 12 patients appeared. Low viral DNA level proved to be a background for another virus activation or bacterial/fungal superinfection.

Conclusion. Graft dysfunction occurs at high viral DNA levels detection during mono-or superinfection. Low viral load can serve as a background for another virus activation and/or bacterial/fungal superinfection.

Terapevticheskii arkhiv. 2021;93(11):1264-1270
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Functional activity of blood neutrophilic granulocytes in patients with opisthorchiasis, depending on the severity of liver fibrosis

Tsukanov V.V., Gorchilova E.G., Kolenchukova O.A., Gvozdev I.I., Savchenko A.A., Kasparov E.V., Vasyutin A.V., Tonkikh J.L., Borisov A.G., Rzhavicheva O.S.


Aim. To study the activity of neutrophilic granulocytes in patients with opisthorchiasis, depending on the severity of liver fibrosis.

Materials and methods. A total of 74 patients with chronic opisthorchiasis (39 men and 35 women, average age 42.3 years) and 32 practically healthy patients (17 men and 15 women, average age 41.5 years) aged 24 to 60 years were examined. Diagnosis of opisthorchiasis was carried out by two methods: coprooscopy and identification of eggs or bodies of adult parasites in duodenal content. Liver fibrosis was determined by the method of elastometry according to the METAVIR scale in all 74 patients with opisthorchiasis. The study of the functional activity of neutrophils in the blood was performed to all 74 patients with opisthorchiasis and 32 healthy individuals from the control group by chemiluminescent analysis with measurement of the reactive oxygen species (ROS) production intensity in a spontaneous and zymosan-induced reaction in lucigenin and luminol-dependent processes.

Results. Liver fibrosis F2 by METAVIR was registered in 20.3% of the examined individuals, liver fibrosis F3–F4 by METAVIR was detected in 17.6% of patients with opisthorchiasis. In patients with opisthorchiasis with liver fibrosis F3–F4 by METAVIR, a significant decrease in the functional activity of neutrophilic granulocytes was registered in comparison with individuals with liver fibrosis F0–F1 by METAVIR, as evidenced by a significant decrease in the maximum intensity of ROS production (Imax) and the area under the curve (S) chemiluminescence in lucigenin and luminol-dependent processes both in the spontaneous and zymosan-induced reaction.

Conclusion. These results provide new information to explain the mechanisms of liver fibrosis in patients opisthorchiasis and create opportunities for the development of diagnostics and preventive technologies.

Terapevticheskii arkhiv. 2021;93(11):1271-1277
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Unspecified encephalitis in HIV-infected patients: clinical and postmortem evaluation

Voznesenskiy S.L., Shakhgildyan V.I., Petrova E.V., Kozhevnikova G.M., Ermak T.N., Tichkevich O.A., Samotolkina E.S., Soboleva Z.A., Emerole K.C.


Background. The search for an aetiology of central nervous system (CNS) lesions In HIV patients can be extremely challenging.

Aim. To establish the nature and character of CNS lesion according to the data of pathological examination of deceased HIV-patients who had an antemortem clinical diagnosis of unspecified encephalitis.

Materials and methods. We analysed clinical and laboratory data of 225 HIV-patients admitted to the ICU at the Infectious Clinical Hospital №2 (Moscow, 2018). The principal diagnosis was unspecified encephalitis characterized by cerebral oedema. Had died 183 (67.9%) patients. We conducted pathological examination in 43 (23.5%).

Results. CNS lesions occurred in 331 patients (58.8% of 563 ICU). The antemortem diagnosis established were as follows: 12.1% – toxoplasmosis; 6.6% – HIV-encephalitis; 5.1% – CNS lymphoma; 3.6% – cryptococcal meningoencephalitis; 3.0% – cytomegaloviral diseases; 2.1% – progressive multifocal leukoencephalopathy. The cause of the pathology remained unidentified in 225 patients (68% with CNS lesions). Majority of patients were ART-naive. Post-mortem verification was conducted in 29 (67.4%) deceased patients, of which HIV-encephalitis – 34.5%, toxoplasmosis – 10.3%, progressive multifocal leukoencephalopathy – 3.4%. The nature of brain damage in the remaining 20.7% cases was not established even after post-mortem investigation. Productive lepto-meningitis – 8 (27.6%), indicating a prolonged duration of the inflammatory process. In the brain 48.1% patients with subacute and productive changes, had a pre-hospital time of more than 30 days, in contrast to 11.1% of patients who had acute pathological processes in the CNS (p<0.05). Autopsy didn’t reveal any inflammatory changes in the brain in 14 (32.6%) patients, though cerebral oedema – 93.3%, haemorrhagic syndrome – 60% cases.

Conclusion. Accurate retrospective identification of the aetiology of CNS lesions combined with assessing in vivo characterisation of the pathological process plays an essential role in subsequent formation of diagnostic approaches in pathologies of the CNS in HIV-patients.

Terapevticheskii arkhiv. 2021;93(11):1278-1282
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Clinical portrait of a patient with COVID-19. The experience of a multidisciplinary clinic

Baimakanova G.E., Khatkov I.E., Dudina G.A., Chegodar A.S., Rumyantsev K.A., Sviridov F.S., Osipova A.V., Danishevich A.M., Noskova K.K., Pinashina E.S., Orlova N.V., Slezinger V.M., Chernova M.E., Tovstyko K.A., Bodunova N.A.


Aim. Evaluation of the clinical characteristics in patients with COVID-19.

Materials and methods. The article presents clinical and instrumental data of 1169 patients included in a single-center mixed study. Patients were tested for COVID-19 using polymerase chain reaction, computed tomography (CT), and antibody screening. Clinical history data were collected.

Results. In patients with confirmed COVID-19, lung damage and a positive test for antibodies were observed in 75.5 and 45.2% of cases, respectively. The most common symptoms of COVID-19 were: fever (73.2%), weakness, (72.7%) dry cough (62.8%) and shortness of breath (55.4%). Patients with CT-visualized lung lesions were more likely to have clinical symptoms and elevated levels of antibodies. Patients with chronic diseases of the endocrine system, circulatory system, and respiratory system had a more severe course of the disease (CT-1–4: 91.2–96.3%) than patients without chronic diseases (CT-1–4: 85,1%).

Conclusion. We have compiled a clinical profile of patients with COVID-19 and highlighted the most significant clinical characteristics corresponding to a more severe course of the disease. Our data showed that patients with chronic diseases require a personalized approach and the development of specific criteria for the diagnosis and treatment of COVID-19.

Terapevticheskii arkhiv. 2021;93(11):1283-1289
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Efficacy and safety of bulevirtide in patients with chronic hepatitis D and compensated cirrhosis

Bogomolov P.O., Ivashkin V.T., Bueverov A.O., Maev I.V., Sagalova O.I., Sleptsova S.S., Yushuk N.D., Gusev D.A., Zhdanov K.V., Chulanov V.P.


Aim. To study the efficacy and safety of bulevirtide, the HBV and HDV entry inhibitor.

Materials and methods. Analysis of the results of using bulevirtide in randomized controlled open-label comparative studies MYR202 and MYR203 in 56 patients with chronic hepatitis D and compensated cirrhosis, in monotherapy and combination with pegylated interferon alpha-2a (PEG-IFN).

Results. Monotherapy with bulevirtide for 24 weeks in the MYR202 study in 46 patients with compensated liver cirrhosis demonstrated: 1) a high rate of virological (100%) and biochemical response (alanine aminotransferase normalization rate – 45.7%), 2) superiority of bulevirtide in efficacy over the control group (tenofovir), 3) comparability of treatment efficacy in patients with and without cirrhosis, 4) no progression of liver fibrosis with elastometry in most patients.

Treatment with bulevirtide in monotherapy and combination with PEG-IFN for 48 weeks in 10 patients with compensated liver cirrhosis in the MYR203 study was accompanied by a high rate of virological response (80%) and normalization of alanine aminotransferase (70%).

Bulevirtide was well tolerated, there was no deterioration in tolerability compared with patients without cirrhosis, there were no serious adverse events and cases of treatment cancellation due to adverse events.

Conclusion. Bulevirtide is recommended as the first line of treatment for chronic hepatitis D in patients with compensated cirrhosis in monotherapy and combination with PEG-IFN.

Terapevticheskii arkhiv. 2021;93(11):1290-1299
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Results of immunoprophylaxis of HIV-infected patients with 13-valent conjugated pneumococcal vaccine

Zhestkov A.V., Zolotov M.O., Lyamin A.V., Borisova O.V., Chernova O.E., Zheleznova E.A., Ismatullin D.D.


Aim. To assess changes in the composition of the microflora of the upper respiratory tract and indicators of cellular immunity 1 year after the administration of 13-valent conjugated pneumococcal vaccine (PCV13) in adult HIV-infected patients.

Materials and methods. Were recruited 100 participants of both sexes (50% male and 50% female). All patients underwent microbiological and immunological (determination of the level of CD3+, CD3+CD4+, CD3+CD8+, CD19+, CD45RO+ peripheral blood lymphocytes) examinations before vaccine administration and after 12 months.

Results. Immunization with PCV13 leads to a statistically significant decrease in the carriage of Streptococcus pneumoniae 1 year after vaccination (p=0.012). After 1 year after the administration of PCV13, the patients showed a statistically significant increase in the total number of T-lymphocytes, T-helpers, and cytotoxic T-lymphocytes in comparison with pre-vaccination levels. A statistically significant increase in the level of CD45RO+ lymphocytes was found 1 year after the administration of PCV13 (p<0.0001). S. pneumoniae was found on the mucous membrane of the posterior pharyngeal wall in 16% of the participants, indicating its high prevalence in HIV-infected patients. Also, representatives of enterobacteria and Candida spp. were found in smears. (22 and 15% of participants, respectively). One year after the vaccine administration, pneumococcus was isolated from 5 participants, which is statistically significantly lower than before immunization (p=0.012). After the introduction of PCV13, there is a statistically significant increase in the total number of T-lymphocytes, T-helpers and cytotoxic T-lymphocytes 1 year after immunization. However, there is no statistically significant increase in the B-lymphocyte population. In addition, PCV13 leads to the formation of immunological memory cells in HIV-infected patients.

Conclusion. Thus, immunoprophylaxis with PCV13 in adult HIV-infected patients leads to a decrease in the carriage of S. pneumoniae, and also promotes the stimulation of the T-cell link of the immune system and stimulates the formation of immunological memory cells.

Terapevticheskii arkhiv. 2021;93(11):1300-1305
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Pharmacoepidemiological research of COVID-19 in the Russian Federation EGIDA-2020

Pshenichnaya N.Y., Kareva E.N., Leneva I.A., Bulgakova V.A., Kravchenko I.E., Nikolaeva I.V., Grekova A.I., Ivanova A.P., Puzyreva L.V., Khasanova G.M., Orlova S.N., Tikhonova E.P., Petrov V.A., Malinin O.V., Kolaeva N.V., Volchkova E.V., Kanshina N.N., Chulanov V.P.


Aim. An analysis of coronavirus infection in Russia and evaluation of different AVT regimens effectiveness.

Materials and methods. The study involved a retrospective analysis of 1082 patient records with laboratory-confirmed COVID-19 in 17 regions of Russia. The number of men and women was equal, mean age – 48.7±18.1 (median – 50). Patients with moderate COVID-19 (85%) versus mild COVID-19 (15%) were characterized by higher age (median – 54 vs 21 years; p<0.001), higher body mass index (27.8 vs 23.4; p<0.001), prevalence of chronic diseases (75.3% vs 8.5%; p<0.001), including circulatory system diseases (37.8%). Moderate COVID-19 characterized higher intoxication (10.8±6.1 vs 4.2±2.7 days; p<0.001) and catarrhal symptoms duration (10.2±5.4 vs 6.1±4.1 days; p<0.001).

Results. During hospitalization 92% of the patients received AVT, 77% – antibiotics, and 16% – corticosteroids. Umifenovir therapy resulted in a significant reduction of intoxication (8.7±5.5 vs 11.7±5.5 days; p<0.001) and catarrhal symptoms duration (8.8±5.1 vs 12.0±4.9 days; p<0.001) compared to the group without AVT. The usage of INF reduced intoxication symptoms compared with the group without AVT (8.9±7.5 vs 11.7±5.5; p<0.05). Therapy with hydroxychloroquine, imidazolylethanamide pentandioic acid, and lopinavir + ritonavir combination did not affect the course of COVID-19. Most of adverse reactions were related to antibiotics.

Conclusion. Umifenovir therapy and inclusion of interferon in AVT regimens was associated improvement in the clinical manifestation of the disease among patients.

Terapevticheskii arkhiv. 2021;93(11):1306-1315
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Criteria for the optimal use of interleukin-6 receptor blockers in patients with COVID-19

Kruglova T.S., Fomina D.S., Poteshkina N.G., Frolova N.F., Beloglazova I.P., Mutovina Z.Y., Samsonova I.V., Kovalevskaja E.A., Zagrebneva A.I., Serdotetckova S.A., Chernov A.A., Lysenko M.A.


Aim. To determine the criteria for the optimal use of IL-6 receptor blockers in patients with COVID-19 community-acquired pneumonia based on predictors of adverse outcomes.

Materials and methods. The single-center, non-randomized prospective study included 190 patients with community-acquired pneumonia caused by coronavirus 2 between the beginning of March and the end of May 2020. Of these, 89 patients received tocilizumab and 101 patients received sarilumab. The study inclusion criterion for the patient was indications for initiating therapy with one of the inhibitors of IL-6 receptors (anti-IL-6R) according to the Interim guidelines (versions 4 and 5). The exclusion criterion was the need to re-prescribe genetically engineered biological therapy (GEBT). The severity of the patient's condition was assessed according to the early warning score (NEWS2), the volume of lung tissue lesions was assessed according to computed tomography (CT). Laboratory monitoring included counting the absolute (abs) number of lymphocytes, serum levels of C-reactive protein (CRP), interleukin 6 (IL-6), D-dimer, lactate dehydrogenase, fibrinogen. Statistical data processing was conducted by nonparametric methods using the IBM SPSS Statistics V-22 software.

Results. The phenotype of a patient with a negative outcome prognosis was described: a male patient over 50 years of age with aggravated premorbid background (with cardiovascular diseases, obesity and/or chronic renal disease), lung lesion CT 3–4, saturation less than 93% upon inhalation of atmospheric air, persisting for 24–48 hours after GEBT. According to the blood test, lymphopenia was below 1000 U/L and CRP levels were above 50 mg/L. The laboratory parameters and clinical picture of the patient progressively worsened after 9–11 days of illness, regardless of the use of Anti-IL-6R. The features of patients monitoring when administering IL-6 receptor blockers have been determined.

Conclusion. IL-6 receptor blockers should be administered to patients hospitalized with severe COVID-19 before the development of hyperinflammatory reactions. The optimal "therapeutic window" is 7–8 days of illness.

Terapevticheskii arkhiv. 2021;93(11):1316-1324
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COVID-19 in haemodialysis patients: result analysis of the first year of the pandemic

Zubkin M.L., Frolova N.F., Kim I.G., Ushakova A.I., Usatiuk S.S., Iskhakov R.T., Diakova E.N., Chervinko V.I., Volodina E.V., Tomilina N.A., Kryukov E.V.


Background. Present concepts of the novel coronavirus infection prognosis in haemodialysis (HD) patients are rather controversial. There is little information on therapy efficiency and safety in such patients. We studied COVID-19 course specifics, prognostic factors associated with fatal outcomes, therapy efficiency and its transformation at different stages of the pandemic first year.

Materials and methods. Single-centre retrospective uncontrolled study included 653 COVID-19 HD-patients treated at Moscow City Nephrology Centre from April 1 to December 31, 2020.

Results. This period mortality rate was 21.0%. Independent predictors of COVID-19 unfavourable outcome in HD patients were pulmonary lesion extension (CT grades 3–4), high comorbidity index, and mechanical ventilation. Approaches to COVID-19 treatment modified significantly at different periods. Immunomodulatory drugs (monoclonal antibodies to IL-6, corticosteroids) were used largely at later stages. With tocilizumab administration, mortality was 15.1%, tocilizumab together with dexamethasone – 13.3%; without them – 37.8% (р<0,001). Tocilizumab administration in the first 3 days after hospitalization of patients with CT grades 1–2 was associated with more favourable outcomes: 1 out of 29 died vs 6 out of 20 (tocilizumab administered at later periods); p<0.04. There was no significant difference in death frequency in patients with CT grades 3–4 depending on tocilizumab administration time.

Conclusion. COVID-19 in HD patients can manifest in a severe course with unfavourable outcome. It is urgent to identify reliable disease outcome predictors and develop efficient treatment in this population.

Terapevticheskii arkhiv. 2021;93(11):1325-1333
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CYP2C8, PTGS-1, 2 gene polymorphisms prevalence associated with sensitivity to non-steroidal anti-inflammatory drugs among North Caucasus ethnic groups

Abdullaev S.P., Denisenko N.P., Mirzaev K.B., Shuev G.N., Sozaeva Z.A., Kachanova A.A., Mammaev S.N., Kasaeva E.A., Gafurov D.M., Grishina E.A., Sychev D.A.


Aim. Find the prevalence of CYP2C8*3 (rs10509681; rs11572080), PTGS-1 (rs10306135; rs12353214) and PTGS-2 (rs20417) alleles and genotypes in four ethnic groups among Laks, Avars, Dargins and Kumyks.

Materials and methods. The study involved 400 volunteers from four ethnic groups living in Republic of Dagestan: 100 participants from each group. Carriage of polymorphic markers was determined by reverse transcription polymerase chain reaction.

Results. Minor allele frequency of the CYP2C8 (rs10509681) was 5.5% in Avars, 10% in Dargins, Laks and Kumyks – 6.5% both; CYP2C8 (rs11572080) was 5.5% in Avars, 9.5% in Dargins, 6.5% in Laks, 8.5% in Kumyks; PTGS-1 (rs10306135) in Avars – 10.5%, in Dargins – 13.0%, in Laks – 9.5% and Kumyks – 7.5%; PTGS-1 (rs12353214) in Avars – 9.0%, in Dargins – 4.5%, in Laks – 7.5%, in Kumyks – 8.0%; PTGS-2 (rs20417) in Avars – 1.0%, in Dargins – 2.5%, in Laks – 3.5%, in Kumyks – 5.0%. There were no significant differences between groups.

Conclusion. The study of CYP2C8 and PTGS-1 and 2 gene polymorphisms is promising for predicting the effectiveness and safety of non-steroidal anti-inflammatory drug therapy, due to the high prevalence of these polymorphisms in ethnic groups in the North Caucasus.

Terapevticheskii arkhiv. 2021;93(11):1334-1339
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The efficacy and safety of eculizumab biosimilar in patients with paroxysmal nocturnal hemoglobinuria. Results of a phase III randomized open-label comparative clinical trial

Kulagin A.D., Bakirov B.A., Davydkin I.L., Elykomov I.V., Konstantinova T.S., Korobkin A.V., Kosinova M.V., Mazurov V.I., Minaeva N.V., Proidakov A.V., Ptushkin V.V., Shatokhin Y.V., Lin'kova Y.N., Zinkina-Orikhan A.V., Morozova M.A.


Aim. To establish the equivalent efficacy and comparable safety profile of biosimilar Acveris and referent eculizumab product Soliris used for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).

Materials and methods. Were included in the phase III multicenter 28 PNH patients, open-label clinical trial. Participants were randomized (1:1) into 2 treatment groups: investigational product (Acveris, n=14) and referent product (Soliris, n=14). Patients received eculizumab as the intravenous infusion 600 mg once a week during the first 4 weeks, 900 mg at week 5 and then 900 mg every 14 days (±2 days) up to week 27 of the study. The efficacy, pharmacokinetics, pharmacodynamics, safety and immunogenicity of the compared products were analyzed after the end of 27 weeks of the study. The primary efficacy endpoint was the area under the curve “LDH concentration–time” (AUCLDH) throughout the study period weeks 5–27.

Results. The difference between the mean AUCLDH values between the Acveris and Soliris groups was 5380.0 [-38 773.87; 49 533.87] U/l×days. The 95% CI limits for the difference in mean AUCLDH values between the groups fit the preset 95% CI [-146 500.9–146 500.9] U/l×days and establish the equivalent efficacy of the biosimilar and referent product according to the primary efficacy endpoint. The safety profile of both Acveris and Soliris was expected and comparable according to the proportion of patients with adverse events. The formation of binding antibodies to eculizumab was not detected in both the groups.

Conclusion. The study established the equivalent efficacy of biosimilar product Acveris and referent eculizumab product with the evidence of effective suppression of intravascular hemolysis in PNH patients along with a comparable favorable safety profile.

Terapevticheskii arkhiv. 2021;93(11):1340-1348
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Neural networks in the predictive diagnosis of cognitive impairment in type 1 and type 2 diabetes mellitus

Samoilova I.G., Matveeva M.V., Kudlay D.A., Tonkikh O.S., Tolmachev I.V.


Background. Cognitive dysfunction, including mild cognitive impairment and dementia, is increasingly recognized as a serious complication of diabetes mellitus (DM) that affects patient well-being and disease management. Magnetic resonance imaging (MRI)-studies have shown varying degrees of cortical atrophy, cerebral infarcts, and deep white matter lesions. To explain the relationship between DM and cognitive decline, several hypotheses have been proposed, based on the variability of glycemia leading to morphometric changes in the brain. The ability to predict cognitive decline even before its clinical development will allow the early prevention of this pathology, as well as to predict the course of the existing pathology and to adjust medication regimens.

Aim. To create a computer neural network model for predicting the development of cognitive impairment in DM on the basis of brain neuroimaging techniques.

Materials and methods. The study was performed in accordance with the standards of good clinical practice; the protocol was approved by the Ethics Committee. The study included 85 patients with type 1 diabetes and 95 patients with type 2 diabetes, who were divided into a group of patients with normal cognitive function and a group with cognitive impairment. The patient groups were comparable in age and duration of disease. Cognitive impairment was screened using the Montreal Cognitive Assessment Scale. Data for glycemic variability were obtained using continuous glucose monitoring (iPro2, Libre). A standard MRI scan of the brain was performed axially, sagittally, and coronally on a Signa Creator “E”, GE Healthcare, 1.5 Tesla, China. For MRI data processing we used Free Surfer program (USA) for analysis and visualization of structural and functional neuroimaging data from cross-sectional or longitudinal studies, and for segmentation we used Recon-all batch program directly. All statistical analyses and data processing were performed using Statistica Statsofi software (version 10) on Windows 7/XP Pro operating systems. The IBM WATSON cognitive system was used to build a neural network model.

Results. As a result of the study, cognitive impairment in DM type 1was predominantly of mild degree 36.9% (n=24) and moderate degree 30.76% (n=20), and in DM type 2 – mild degree 37% (n=30), moderate degree 49.4% (n=40) and severe degree 13.6% (n=11). Cognitive functions in DM type 1 were impaired in memory and attention, whereas in DM type 2 they were also impaired in tasks of visual-constructive skills, fluency, and abstraction (p<0.001). The analysis revealed differences in glycemic variability indices in patients with type 1 and type 2 DM and cognitive impairment. Standard MRI of the brain recorded the presence of white and gray matter changes (gliosis and leukoareosis). General and regional cerebral atrophy is characteristic of type 1 and type 2 DM, which is associated with dysglycemia. When building neural network models for type 1 diabetes, the parameters of decreased volumes of the brain regions determine the development of cognitive impairment by 93.5%, whereas additionally, the coefficients of glycemic variability by 98.5%. The same peculiarity was revealed in type 2 DM – 95.3% and 97.9%, respectively.

Conclusion. In DM type 1 and type 2 with cognitive impairment, elevated coefficients of glycemic variability are more frequently recorded. This publication describes laboratory and instrumental parameters as potential diagnostic options for effective management of DM and prevention of cognitive impairment. Neural network models using glycemic variability coefficients and MR morphometry allow for predictive diagnosis of cognitive disorders in both types of diabetes.

Terapevticheskii arkhiv. 2021;93(11):1349-1358
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Clinical notes

Mixed infection: viral hepatitis A and hemorrhagic fever with renal syndrome. Case report

Bondarenko A.L., Protasov A.V., Rokhin E.A., Slobozhaninova Y.P.


The article considers a case from clinical practice: a mixed infection of viral hepatitis A and hemorrhagic fever with renal syndrome. Hepatitis had a protracted course and proceeded with the development of acute hepatic encephalopathy. Hemorrhagic fever was characterized by an atypical course with lung and heart damage.

Terapevticheskii arkhiv. 2021;93(11):1359-1362
pages 1359-1362 views

Cutaneous and visceral leishmaniasis in patients with HIV infection in Russia. Case report

Ermak T.N., Kravchenko A.V., Pokrovsky V.V., Andreev A.V.


The article contains information on the problem of the combined course of HIV infection and leishmaniasis: a number of statistical and overview data in the world. It also presents a brief description of known cases of HIV patients with leishmaniasis in the Russian Federation. In all cases the diagnostics of leishmaniasis was difficult due to the lack of alertness of physicians to this illness, as well as poor knowledge of epidemiological situation of leishmaniasis. All patients with visceral leishmaniasis but one caught it during their stay in Crimea. Cutaneous leishmaniasis was described in HIV infection in the Russian Federation for the second time and is associated with the patient's residence in the Chechen Republic.

Terapevticheskii arkhiv. 2021;93(11):1363-1367
pages 1363-1367 views

The problem of diagnosis and differential diagnosis of botulism in pregnant women. Case report

Malov V.A., Tsvetkova N.A., Baka K.N., Volchkova E.V., Konnova Y.A., Maleyev V.V., Gruzdeva O.Y., Archngelskaya I.V., Maloletneva N.V., Dmitrieva L.N.


The article describes a clinical observation of a severe course of a sporadic case of foodborne botulism in a woman at 32 weeks gestation with a successful resolution of pregnancy by independent childbirth. No adverse effects of botulism on pregnancy, delivery, and fetal development were noted. Anti-botulinum serum was administered to the patient no earlier than 96 hours from the onset of the disease. The paper analyzes the clinical picture of botulism, on the basis of which it is necessary to carry out a differential diagnosis.

Terapevticheskii arkhiv. 2021;93(11):1368-1374
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Acute disseminated encephalomyelitis and myelitis associated with new coronavirus infection COVID-19. Case report

Akhmedzhanova L.T., Voskresenskaia O.N., Isaikin A.I., Ermilova E.V., Nasonova T.I., Chernousov P.A., Rusin V.V.


Acute disseminated encephalomyelitis (AEM) and acute transverse myelitis (OPM) are autoimmune demyelinating diseases of the central nervous system. Two clinical observations of AEM and OPM developed after suffering acute coronavirus infection (SARS-CoV-2) are presented. Differential diagnosis was carried out with multiple sclerosis, encephalitis of an infectious nature, compressive myelopathy, and opticomyelitis. Both observations show an almost complete recovery of lost functions. The pathogenetic mechanisms of the development of AEM and OPM in patients with coronavirus infection are discussed. The onset of central nervous system dysimmune lesion in the context of coronavirus infection makes it necessary to monitor the clinical situation with the involvement of a neurologist for timely diagnosis and determination of therapeutic tactics that can reduce the degree of disability of patients.

Terapevticheskii arkhiv. 2021;93(11):1375-1380
pages 1375-1380 views


Adrenal incidentaloma. Part 2. Modern concepts of computed tomography semiotics of adrenal gland incidentalomas: algorithm of differential diagnosis

Buryakina S.A., Tarbaeva N.V., Volevodz N.N., Karmazanovsky G.G., Kovalevich L.D., Shestakova M.V., Dedov I.I.


While accidentally detecting an adrenal gland lesion (incidentaloma) during a routine computed tomography (CT) scan, the radiologist should correctly interpret revealed changes. The most common lesion is adenoma with high lipid content, but a lipid poor adenoma, pheochromocytoma, adrenocortical cancer, metastasis and other less common adrenal diseases are also worth of attention and require detailed knowledge of their CT semiotics. The article presents criteria of differential diagnosis of the adrenal incidentalomas on the basis of which an algorithm of differential diagnosis was proposed for the most common adrenal lesions.

Terapevticheskii arkhiv. 2021;93(11):1381-1388
pages 1381-1388 views

Pro-inflammatory cytokines in chronic cardiac failure: state of problem

Korotaeva A.A., Samoilova E.V., Mindzaev D.R., Nasonova S.N., Zhirov I.V., Tereschenko S.N.


Systemic inflammation is characterized by the induction of pro-inflammatory cytokines, the increased level of which in the blood of patients with chronic heart failure (CHF) correlates with unfavorable clinical outcomes. However, it is unclear whether pro-inflammatory cytokines are the cause or the consequence of the disease progression. CHF with preserved ejection fraction and CHF with reduced ejection fraction demonstrate different inflammatory features, which suggests different degrees of pro-inflammatory pathway activation. The review deals with participation of pro-inflammatory cytokines in pathophysiological processes of CHF development, emphasizing the role of interleukin-6 activation and the effects of accompanying diseases on the course of systemic inflammation. The search for new approaches to prevention and therapy of CHF remains actual. The review presents the results of clinical trials of targeted anti-cytokine therapy which have revealed difficulties in controlling inflammation under the conditions of CHF. Identification of specific pro-inflammatory pathways in CHF pathogenesis will allow one to control inflammatory cascades, thus providing a prospective therapeutic strategy.

Terapevticheskii arkhiv. 2021;93(11):1389-1394
pages 1389-1394 views

The role and place of pathogenetic therapy with glucocorticosteroid hormones in the treatment of patients with novel coronavirus infection (COVID-19)

Efremov D.O., Beloborodov V.B.


In December 2019, in Wuhan (PRC), there was an outbreak of a new coronavirus infection (COVID-19) caused by coronavirus type 2 (SARS-CoV-2), which has a zoonotic origin. The World Health Organization announced the COVID-19 pandemic on March 11, 2020. In most cases, the disease is asymptomatic or mild. However, up to 15% of patients require hospitalization, and 5% develop a critical condition. To date, no effective antiviral drug COVID-19 has been found that can reduce mortality. Pathological changes in the lungs are manifested by diffuse alveolar damage, which is clinically manifested by increasing respiratory failure, accompanied by a decrease in saturation and oxygen concentration in arterial blood. It is assumed that autoimmune reactions play an important role in the development of multiple organ failure. Generalized inflammation is characterized by an increase in the concentration of C-reactive protein, ferritin, interleukin-1 and interleukin-6, and other markers. At the stage of development of infection in the form of a cytokine storm, proinflammatory cytokines can themselves become pathogenetic factors in the development of critical conditions, multiple organ failure and deaths. Therefore, a key challenge in treating hospitalized patients with COVID-19 is to control generalized inflammation. Glucocorticosteroid hormones (GCS) are widely used as anti-inflammatory drugs in the clinic of infectious diseases. However, until recently, there was no convincing data on the effectiveness of GCS in patients with COVID-19. Recently published results of a large randomized clinical trial (RECOVERY) showing the efficacy of GCS (dexamethasone) in the treatment of critically ill patients with COVID-19. At the same time, the feasibility and effectiveness of GCS in patients with COVID-19 outside critical conditions, the pathogenetic mechanisms that determine the effectiveness/ineffectiveness of these drugs and the validity of their use remain insufficiently studied.

Terapevticheskii arkhiv. 2021;93(11):1395-1400
pages 1395-1400 views

Varicella-pox virus infection: features of the course, clinical manifestations, complications, and possibilities for prevention

Prikhodchenko N.G.


Varicella zoster virus (VZV) is a pathogenic human herpes virus that causes chickenpox as a primary infection, after which it persists for a long time and latently in the peripheral ganglia. Decades later, the virus can reactivate spontaneously, or after exposure to a number of triggering factors, causing herpes zoster (shingles). The reasons for the long-term persistence of VZV are gradually being revealed, but some issues remain unknown at the moment. Chickenpox and its complications are especially difficult in immunocompromised patients, but they are often found in people without risk factors. The most frequent and important complication of VZV reactivation is postherpetic neuralgia; encephalitis, segmental motor weakness and myelopathy, cranial neuropathies, and gastrointestinal complications often develop. The only scientifically proven effective and affordable way of mass prevention at the moment is vaccination. Chickenpox vaccines are safe and effective in preventing morbidity and mortality associated with the disease.

Terapevticheskii arkhiv. 2021;93(11):1401-1406
pages 1401-1406 views

History of medicine

History of the discovery and study of tick-borne encephalitis in Russia: three Far Eastern expeditions (1937–1939)

Kolyasnikova N.M., Zlobin V.I., Ishmukhametov A.A., Maleev V.V.


The review provides a brief historical outline of the discovery and study of tick-borne encephalitis (TBE) during three expeditions to the Far East (1937–1939). As a result of the Far Eastern expeditions, the TBE virus was discovered, numerous strains were isolated, a vector-borne transmission pathway was established, the main features of epidemiology, clinic and pathomorphology of the disease were described, serotherapy was tested, first inactivated "brain" vaccine against TBE was developed and its effectiveness was proved. The history of the discovery and study of TBE is marked by the heroism of researchers and tragic events – illness of some participants, death during the development of the first vaccine, arrest of L.A. Zilber and two performers.

Terapevticheskii arkhiv. 2021;93(11):1407-1412
pages 1407-1412 views

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