Rare variants affecting host defense against pathogens may be involved in COVID-19 severity, but most rare variants are not expected to have a major impact on the course of COVID-19. We hypothesized that the accumulation of weak effects of many rare functional variants throughout the exome may contribute to the overall risk in patients with severe disease. This assumption is consistent with the omnigenic model of the relationship between genetic and phenotypic variation in complex traits, according to which association signals tend to spread across most of the genome through gene regulatory networks from genes outside the major pathways to disease-related genes. We performed whole-exome sequencing and compared the burden of rare variants in 57 patients with severe and 29 patients with mild/moderate COVID-19. At the whole-exome level, we observed an excess of rare, predominantly high-impact (HI) variants in the group with severe COVID-19. Restriction to genes intolerant to HI or damaging missense variants increased enrichment for these classes of variants. Among various sets of genes, an increased signal of rare HI variants was demonstrated predominantly for primary immunodeficiency genes and the entire set of genes associated with immune diseases, as well as for genes associated with respiratory diseases. We advocate taking the ideas of the omnigenic model into account in COVID-19 studies.

COVID-19 patients with acute respiratory distress syndrome (ARDS) have an immune imbalance when systemic inflammation and dysfunction of circulating T and B cells lead to a more severe disease. Using TREC/KREC analysis, we studied the level of mature naive T and B cells in peripheral blood of COVID-19 patients and its relationship with clinical and laboratory data. TREC/KREC analysis was performed by multiplex real-time quantitative PCR on a sample of 36 patients aged 45 years or younger. The reduced TREC/KREC level was observed in ARDS patients compared with non-ARDS patients, and similar results were found for the deceased patients. During days 6 to 20 of hospitalization, a higher neutrophil-to-lymphocyte ratio (NLR) was detected in ARDS patients compared with non-ARDS patients. TREC/KREC negatively correlated with NLR; the highest correlation was recorded for TREC per 100,000 cells with the coefficient of determination R2 = 0.527. Thus, TREC/KREC analysis is a potential prognostic marker for assessing the severity and outcome in COVID-19.

The aim of the study was to investigate the serial changes in inflammatory indices derived from blood cell counts and C-reactive protein (CRP) levels in COVID-19 patients with good and poor outcomes. We retrospectively analyzed the serial changes in the inflammatory indices in 169 COVID-19 patients. Comparative analyses were performed on the first and last days of a hospital stay or death and serially from day 1 to day 30 from the symptom onset. On admission, non-survivors had higher CRP to lymphocytes ratio (CLR) and multi-inflammatory index (MII) values than survivors, while at the time of discharge/death, the largest differences were found for the neutrophil to lymphocyte ratio (NLR), systemic inflammation response index (SIRI), and MII. A significant decrease in NLR, CLR, and MII by the time of discharge was documented in the survivors, and a significant increase in NLR was documented in the non-survivors. The NLR was the only one that remained significant from days 7–30 of disease in intergroup comparisons. The correlation between the indices and the outcome was observed starting from days 13–15. The changes in the index values over time proved to be more helpful in predicting COVID-19 outcomes than those measured on admission. The values of the inflammatory indices could reliably predict the outcome no earlier than days 13–15 of the disease.

Aim. To evaluate the safety and efficacy of the adaptive phage therapy technique in patients with recurrent pneumonia in neurological critical care.Material and methods. The clinical study included 83 chronically critically ill patients with severe brain damage. The bacteriophage cocktail selected against specific hospital strains was administered by inhalation to 43 patients. The control group included 40 patients who received conventional antimicrobial therapy. The changes in clinical, laboratory and instrumental parameters, levels of biomarkers, microbiological and PCR tests of bronchoalveolar lavage fluid were assessed, including those in the «phage therapy with antibiotics» (n=29) and «phage therapy without antibiotics» (n=14) subgroups.Results. The groups were comparable in terms of basic parameters (age, sex, diagnosis, organ dysfunction according to APACHE II, use of vasoactive drugs) and the level of airway colonization with antibioticresistant bacterial strains. Good tolerability and absence of clinically significant side effects were observed during inhaled administration of the bacteriophage cocktail. Computed tomography on day 21 showed a significant reduction in lung damage in patients who received bacteriophages. Patients treated with bacteriophages without antibiotics had significantly lower need for mechanical ventilation. The mortality rate on day 28 did not differ significantly and was 4.7% (2/43) in the bacteriophage-treated group vs 5% (2/40) in the control group.Conclusion. The first experience of using the adaptive phage therapy technique in chronically critically ill patients in neurological intensive care demonstrated the safety of inhalational administration of the bacteriophage cocktail. The efficacy of the technique was confirmed by the treatment results obtained in the phage therapy group, which were not inferior to those in the group with conventional antibiotic therapy, while several clinical and laboratory parameters tended to improve even in patients who received bacteriophages and did not receive antibiotics.

Антитромбин (АТ) является одним из ключевых факторов-регуляторов гемостаза, активность которого существенно снижается при SIRS� Цель работы: изучить возможность и целесообразность определения уровня AT в плазме крови для прогнозирования результатов лечения септических больных� Методы. У 83 больных сепсисом определяли содержание АТ в начале и на пике заболевания� Проведено сравнение прогностических возмож-ностей определения уровня АТ, некоторых других показателей коагулограммы и клинических шкал оценки тяжести состояния при сепсисе� Результаты. На 5-е сут заболевания выявлены наиболее значимые предикторы неблагоприятного исхода сепсиса: уровень фибриногена 42 [0,33]; p = 0,0722); уровень АТ 4 [8,02 86,86]; p < 0,0001)� Попарное сравнение ROC-кривых фибриногена и АТ в конечной точке исследования показало различие между площадями AUC (Area Under Curve), которое составило 0,337 [95%-ный ДИ 0,154-0,520] при p = 0,0003, что подтвердило предположение о высокой значимости теста с АТ� С точкой отсечения ≤ 61% данный тест продемонстрировал соотношение чувствительности и специфичности 79 и 88% соответственно� TESTING ANTITHROMBIN LEVEL ALLOWS PREDICTING A CLINICAL OUTCOME OF SEPSIS I. V. REDKIN, А. F. LOPАTIN, YU. V. SKRIPKIN, V. V. SАMOYLENKO, V. V. LIKHVАNTSEV Moscow Regional Research Clinical Institute named after M. F. Vladimirsky, Moscow, RussiaAntithrombin is one of the key regulating factors of homeostasis, which activity significantly reduces in SIRS� The objective of the study: to investigate possibility and feasibility to test antithrombin level in blood plasma in order to predict treatment outcomes in patients with sepsis� Subjects. The level of antithrombin was tested in 83 patients by the start and at the peak of the disease� Predictive value was compared for antithrombin tests, some other parameters of coagulogram, and clinical severity scales in sepsis� Results. On the 5th day of the disease, the most significant predictors of the unfavorable outcome of sepsis were identified: fibrinogen level (Odds ratio -2�42 [0�92-6�33]; p = 0�0722); and antithrombin level (Odds ratio -26�4 [8�02 86�86]; p < 0�0001)� Pair-wise comparison of ROC-curves of fibrinogen and antithrombin at the final point of the study demonstrated differences between areas under curve (AUC), which made 0�337 [95% CI 0�154-0�520] with p = 0�0003, which confirmed the assumption of the high predictive value of antithrombin level� With the cut-off point at ≤ 61% this test demonstrated the sensitivity and specificity of 79% and 88% respectively� Conclusion: In order to predict severity and potential outcome of sepsis, it is recommended to test antithrombin level at the peak of the disease� Key words: antithrombin� sepsis, fibrogen /2078-5658-2018-15-3-41-46 Полиорганная недостаточность, в том числе и нарушение системы свертывания крови, являют-ся неотъемлемыми атрибутами сепсиса [10, 17,23]� Диссеминированное внутрисосудистое свертыва-ние крови (ДВС-синдром) предстает как следствие и одновременно как причина (взаимоотягощение, «порочный круг»...