Interrelation between the parameters of endogenous vascular regulation, oxidative stress and the markers of inflammatory response in COVID-19 patients while on extracorporeal membrane oxygenation

Introduction. Extracorporeal membrane oxygenation has found wide application in clinical practice during the COVID-19 pandemic. Oxidative stress, endothelial dysfunction, and systemic inflammatory response syndrome play an important role in the pathogenesis of COVID-19. Our research was designed to study correlations in-between those factors and the impact of extracorporeal membrane oxygenation on them. Aim. The study of systemic inflammatory response and endothelial function in patients with COVID-19 during extracorporeal membrane oxygenation. Material and methods. In the course of a prospective study, we examined 100 COVID-19 patients aged 26 to 75 years, median 55 years [47;60], who were treated at the N.V. Sklifosovsky Research Institute for Emergency Medicine, using extracorporeal membrane oxygenation. As a control group (normal), 25 practically healthy people whose median age was 32 years [25;39] were examined. The function of the vascular endothelium was assessed by the content of nitric oxide stable metabolites in the blood serum and the level of angiotensin-converting enzyme. Next, the ratio of nitric oxide metabolite to angiotensin-converting enzyme level was calculated, reflecting the imbalance between endothelium-dependent vasodilation and vasoconstriction. To assess the severity of oxidative stress in blood serum, malondialdehyde was determined as a marker of lipid peroxidation. The state of the antioxidant system was assessed in terms of total antioxidant status of blood serum. The presence of an imbalance in the system of lipid peroxidation and the antioxidant system total antioxidant status was judged by the oxidative stress coefficient, i.e. the ratio of malondialdehyde to the total antioxidant activity. Results. The analysis showed the presence and progression of endothelial dysfunction, impaired vascular regulation, activation of free radical processes, the presence of an imbalance in the prooxidant/antioxidant system, as well as the progression of the inflammatory process with a decrease in the level of markers of the COVID-19 severity. Conclusion. Further studies of the correlation between endothelial damage and the severity of the systemic inflammatory response syndrome may be of fundamental importance for explaining the pathophysiological mechanisms of COVID-19 course and developing new treatments for such patients. © 2023 Sklifosovsky Research Institute for Emergency Medicine. All rights reserved.

Anti-Interferon Alpha Autoantibodies and Their Significance in Covid-19

During the last two years, treatment of patients with novel coronavirus infection COVID-19 remains an urgent health problem. Interferon proteins are known to play a significant role in antiviral immunity. Some pathological conditions are accompanied by production of neutralizing autologous immunoglobulins against own host interferons (autoIFN-Abs). There is evidence that autoantibodies against interferons alpha and omega are detected in patients with life-threatening course of COVID-19 pneumonia. The aim of our study was to analyze prevalence of autoantibodies against interferon alpha in patients with COVID-19 coronavirus infection and assess their impact on clinical course of the disease. We examined 70 patients with severe COVID-19, who received inpatient treatment at the intensive care units. Serum autoantibodies against interferon alpha were determined on day 8-50 after disease onset by using solid-phase enzyme immunoassay ( ELISA). Patients were divided into 2 groups: those with and without (group 2) autoantibodies against interferon alpha (group 1). Anti-COVID serum from 57 donors was used a control. Among patients, autoantibodies against interferon alpha were detected in 13 (18%) subjects, which level ranged from 26.8 to 1000 ng/ml. Among donors, autoIFN-Abs were detected in 5 (8.8%) subjects at trace concentrations (from 1.65 to 12.0 ng/ml). Respiratory failure developed significantly more often in patients with auto-IFN-Abs. While analyzing laboratory parameters, it was noted that the concentration of C-reactive protein was significantly higher in the group of patients with auto-IFN-Abs. Mortality rate of patients with high auto-IFN-Abs levels was 60%. In conclusion, it was found that serum autoantibodies against IFN alpha in COVID-19 patients caused lung damage that significantly more often required hardware respiratory support, so comparable by duration with it for patients without auto-IFN-Abs. High concentrations of auto-IFN-Abs (more than 100 ng/ml) in patients with COVID-19 can be considered as a predictor of unfavorable disease outcome.

Regulation of lymphocyte apoptosis in intensive care patients with COVID-19

Severity of a new coronavirus infection (COVID-19) caused by the SARS-COV-2 virus is largely due to abnormal immune condi-tion in these patients. Lymphopenia is observed in 85% of patients with severe COVID-19 that may be associated with enhanced apoptosis of lymphocytes. Objective. To analyze apoptotic death of lymphocytes and changes in proteins regulating apoptosis in patients with severe COVID-19. Material and methods. We analyzed 93 ICU patients. All patients were divided into three groups depending on severity and outcomes of disease: group 1 consisted of 53 patients with favorable course and outcomes of disease, group 2 included 26 patients with unfavorable course and favorable outcomes of disease, group 3 included 14 patients with unfavorable course and outcomes of disease. Blood sampling for analysis of apoptosis markers was carried out in 5-12 and 14-18 days after clinical manifestation of disease. Quantitative parameters of lymphocyte apoptosis were evaluated using flow cytometry. Regulatory proteins of apop-tosis (phosphorylated AKT, JNK, BAD, BCL-2, p-53, active caspase 8 and 9) were determined on the Luminex platform. We also assessed concentration of leukocytes, relative and absolute lymphocyte count, concentration of C-reactive protein (CRP), procal-citonin and lactate dehydrogenase. Results. Study groups significantly differed in NEWS score (p=0.001), SOFA score (p=0.001), CRP level (p=0.001), severity of lymph-openia (p=0.001) and level of CD14+HLA-DR+ monocytes (p=0.001). Quantitative parameters of lymphocyte apoptosis did not cor-relate with lymphopenia. The highest rates of lymphocyte apoptosis were observed in patients with favorable course and outcomes of disease. There was no correlation between concentration of lymphocytes in venous blood and level of proteins regulating apoptosis. Conclusion. Patients with severe COVID-19 are characterized by abnormal induction of lymphocyte apoptosis through external and internal activation pathways in response to viral aggression. In deceased patients, pro-apoptotic factors prevailed while activity of anti-apoptotic factors was decreased. © 2023, Media Sphera Publishing Group. All rights reserved.

Specific Changes in Hemostasis System Parameters during Extracorporeal Membrane Oxygenation in Patients with a Novel Coronavirus Infection

Extracorporeal membrane oxygenation (ECMO) is a method that makes it possible to compensate for critical changes caused by acute respiratory failure, with the ineffectiveness of treatment with rigid modes of artificial lung ventilation (ventilator) in patients with acute respiratory distress syndrome in intensive care units. The search for the optimal state of the hemostasis system is one of the main tasks in the treatment of critical patients in ECMO conditions. The objective: to study changes in hemostatic parameters in patients with COVID-19 undergoing ECMO and determine the need for their correction. Subjects and Methods. According to the inclusion and exclusion criteria, 100 patients were included in the study: 72 men and 28 women aged 26 to 75 years old, the median age made 55 years [47;60]. VV-ECMO was performed in all observations. In 100% of cases, the cause of respiratory failure which required VV-ECMO was COVID-19-associated pneumonia. Results. 49 episodes of hemorrhagic complications and 76 episodes of thrombotic complications were recorded from the 1st to the 7th day from the moment of ECMO initiation. We found that the chance of developing thrombosis decreased by an average of 0.3% with an increase in the activity of antithrombin-3 by 1%. A statistically significant association of thrombosis risk was also found for prothrombin and prothrombin time. Conclusion. During the first 7 days of ECMO, patients with COVID-19 demonstrate the increase in APTT, prothrombin time and a decrease in the number of platelets, prothrombin activity, and fibrinogen concentration. The risk of thrombosis in this group of patients significantly decreases with the increasing activity of antithrombin-3 and prothrombin and increases with rising need of the higher dose of unfractionated heparin. The tactics of restrictive anticoagulant therapy when using unfractionated heparin can be taken into account as a way to reduce the risk of thrombosis and requires further research. © 2022 The authors.

Effect of vitamin D (25-OH D3 ) concentration on the course and outcomes of COVID-19 in intensive care patients

Objective. To study the effect of vitamin D concentration on the course and outcomes of COVID-19 in intensive care patients. Material and methods. A prospective study included 43 ICU patients admitted to the Sklifosovsky Research Institute for Emergency Care with a confirmed diagnosis of a novel coronavirus infection. Single blood sampling was performed in 1—2 days after admission for analysis of 25-OH D3 concentration. Patients were divided into 2 groups with normal and reduced level of vitamin D. We analyzed chest CT data and laboratory parameters at admission and at the peak of cytokine storm. Administration of IL-6 antagonists and IL-6 receptor blockers was compared. We also compared the need for respiratory support, period between the onset of disease and respiratory therapy, its total duration and type of respiratory support, incidence of complications (sepsis, multiple organ failure, nosocomial pneumonia, acute kidney injury, thrombosis and hemorrhagic events). We analyzed the outcomes of disease, length of ICU-stay and hospital-stay. Results. Patients with normal vitamin D level at admission were characterized by lower serum C-reactive protein (15.41±7.96 vs. 63.271±11.988;p=0.029), while lymphocyte count (1.69±0.49 vs. 0.921±0.0719;p=0.029), leukocyte count (7.88±1.33 vs. 5.305±0.468;p=0.041) and serum lactate dehydrogenase (454.50±102.5 vs. 271.315±16.867;p=0.024) were higher. Minimum daily saturation at the peak of cytokine storm was higher in patients with normal vitamin D level (95.2±1.39 vs. 90.947±0.9585;p=0.044). Conclusion. Patients with vitamin D deficiency have a more pronounced inflammatory response in initial stages of disease and more severe lung damage at the stage of cytokine storm. However, this does not increase aggressiveness and duration of respiratory support, ICU-and hospital-stay. There was no worsening of the outcomes too. © S.S. PETRIKOV1, G.E. SAVKOV1, M.A. GODKOV1, N.V. BOROVKOVA1, A.M. KVASNIKOV1, D.A. LEBEDEV1, K.V. KISELEV2, K.A. POPUGAEV1.

Intensive Care of Patients with COVID-19.

The severe course of COVID-19 requires treatment in emergency and intensive care units. Acute respiratory failure due to the development of pneumonia and acute respiratory distress syndrome is the most common and life-threatening manifestation of the new coronavirus infection. Treatment of patients with severe and extremely severe COVID-19; the use of modern schemes and protocols for drug therapy, mechanical ventilation, and extracorporeal membrane oxygenation; sorption techniques; the use of thermal helium; hemostasis correction; and rehabilitation problems are discussed.

ANTI-INTERFERON ALPHA AUTOANTIBODIES AND THEIR SIGNIFICANCE IN COVID-19

During the last two years, treatment of patients with novel coronavirus infection COVID-19 remains an urgent health problem. Interferon proteins are known to play a significant role in antiviral immunity. Some pathological conditions are accompanied by production of neutralizing autologous immunoglobulins against own host interferons (auto-IFN-Abs). There is evidence that autoantibodies against interferons alpha and omega are detected in patients with life-threatening course of COVID-19 pneumonia. The aim of our study was to analyze prevalence of autoantibodies against interferon alpha in patients with COVID-19 coronavirus infection and assess their impact on clinical course of the disease. We examined 70 patients with severe COVID-19, who received inpatient treatment at the intensive care units. Serum autoantibodies against interferon alpha were determined on day 8–50 after disease onset by using solid-phase enzyme immunoassay (ELISA). Patients were divided into 2 groups: those with and without (group 2) autoantibodies against interferon alpha (group 1). Anti-COVID serum from 57 donors was used a control. Among patients, autoantibodies against interferon alpha were detected in 13 (18%) subjects, which level ranged from 26.8 to 1000 ng/ml. Among donors, auto-IFN-Abs were detected in 5 (8.8%) subjects at trace concentrations (from 1.65 to 12.0 ng/ml). Respiratory failure developed significantly more often in patients with auto-IFN-Abs. While analyzing laboratory parameters, it was noted that the concentration of C-reactive protein was significantly higher in the group of patients with auto-IFN-Abs. Mortality rate of patients with high auto-IFN-Abs levels was 60%. In conclusion, it was found that serum autoantibodies against IFN alpha in COVID-19 patients caused lung damage that significantly more often required hardware respiratory support, so comparable by duration with it for patients without auto-IFN-Abs. High concentrations of auto-IFN-Abs (more than 100 ng/ml) in patients with COVID-19 can be considered as a predictor of unfavorable disease outcome.

Hyperbaric oxygen therapy in patients with COVID-19

The aim of the study is to evaluate the efficacy of hyperbaric oxygen therapy and its effect on oxidative stress and apoptosis in patients with new coronavirus infection COVID-19. Materials and methods. 90 patients diagnosed with new coronavirus infection caused by SARS-CoV-2 virus were examined. Hyperbaric oxygen therapy sessions were conducted in 57 patients (38 in severe condition (CT 3–4), 19 in moderate condition (CT 1–2)). The procedures were performed in 1.4–1.6 ATA mode for 40 min-utes, 247 sessions in total were performed. The effect of hyperbaric oxygenation was assessed by measuring the level of oxygen saturation, the severity of oxidative stress and apoptosis of blood lymphocytes. Results. In all examined patients with new coronavirus infection caused by SARS-CoV-2, positive changes such as dyspnea reduction and improvement of general well-being were registered after hyperbaric oxygen therapy sessions. The level of oxygen saturation after the end of the hyperbaric oxygen therapy course was 95.0±1.6% (before the course — 91.3±5.9%), which allowed to return almost all patients to spontaneous res-piration without the need for further oxygenation therapy. Hyperbaric oxygen therapy did not reduce the total antioxidant activity, however, it was associated with a decrease in the blood malone dialdehyde from 4.34±0.52 µmol/l to 3.98±0.48 µmol/l and a decrease in open circuit potential of platinum electrode from-22.78±24.58 mV to-37.69±17.4 mV. Besides, the positive effect of hyperbaric oxygen therapy was manifested in normalization of blood cell apoptosis. Conclusion. Hyperbaric oxygen therapy in patients with new coronavirus infection caused by the SARS-CoV-2 virus is an effective treatment method with multiple effects resulting in improvement of subjective indicators of the patients' condition, increase of hemoglobin oxygen saturation, decrease of lipid peroxidation intensity, activation of antioxidant system, restoration of pro-and antioxidant balance and apoptosis normalization. © 2020, V.A. Negovsky Research Institute of General Reanimatology. All rights reserved.

Rehabilitation of patients with covid-19 infection at the sklifosovsky research institute for emergency care

Organization of post-infection rehabilitation is an urgent problem in the context of a new coronavirus infection pandemic. Algo-rithm for protection of patients and staff is usually described in the literature. At the same time, rehabilitation process is not ana-lyzed. Therefore, experience exchange is advisable. Objective. To summarize the experience of rehabilitation of patients with COVID-19 infection at the intensive care unit of the Skli-fosovsky Research Institute for Emergency Care. Material and methods. The study included 39 patients with COVID-19 infection in severe and extremely severe condition. Mean age was 60 (52;67.5) years. Mechanical ventilation was required in 14 (35.9%) patients. All patients underwent rehabilitation around the clock. Results. The rehabilitation program was determined for each patient within 48 hours after admission. Rehabilitation measures included positioning (including pron-position), verticalization, mechanotherapy, physiotherapy exercises, breathing exercises, and psychological support. In this manuscript, we describe the organization of rehabilitation and its features. There were 674 physiotherapy exercises (excluding positioning) and 233 physiotherapy procedures. Each patient underwent 2—3 physiotherapy procedures per day. Patients under mechanical ventilation underwent all rehabilitation procedures without any features of toler-ance or effectiveness. Psychological care was required for difficult adaptation to in-hospital conditions, advanced anxiety and im-paired mood. We have developed a guide on stress management for medical staff and effective communication with patients. Conclusion. Organization of the intensive care unit of infectious building at the Sklifosovsky Research Institute for Emergency Care is close to the international recommendations of experts. Specialists have developed the new methods of working with patients. © 2020, Media Sphera. All rights reserved.

The safety of hyperbaric oxygen therapy in the treatment of Covid-19

Relevance Acute respiratory infection COVID-19 caused by the SARS-CoV-2 (2019-nCov) coronavirus is severe and extremely severe in 15-20% of cases, which is accompanied by the need for respiratory support. Hyperbaric oxygenation is recognized as an effective therapy for replenishing any form of oxygen debt. Aim of study To study the safety of HBO use in patients with COVID-19. Materia l and me thods We examined 32 patients with the diagnosis "Coronavirus infection caused by the virus SARS-CoV-2" (10 - moderately severe patients (CT 1-2), 22 - patients in serious condition (CT 3-4), who received course of hyperbaric oxygenation (HBO). The procedures were carried out in a Sechrist 2800 chamber (USA) at a mode of 1.4-1.6 AT for no more than 60 minutes. In total, the patients received 141 HBO sessions. Before and after each HBO session, the subjective indicators of the patient's condition were assessed and the blood oxygen saturation was measured. Res ults An algorithm for HBO course management was developed, which consists in using "soft" modes (up to 1.4 AT) during the first session, followed by pressure adjustment (not higher than 1.6 AT) during the course to achieve maximum therapeutic effect and comfort for the patient. Against the background of the HBO course, the patients showed an increase in blood oxygen saturation in patients in both surveyed groups, as well as positive dynamics in the form of a decrease in shortness of breath, an improvement in general well-being. Conc lusi on The inclusion of daily sessions (at least 4) of hyperbaric oxygenation in "soft" modes (1.4-1.6 ATA) in the complex therapy for COVID-19 has shown its safety and preliminary positive effect on the subjective state of the examined patients and the dynamics of blood oxygen saturation. © 2020 Sklifosovsky Research Institute for Emergency Medicine. All rights reserved.

COMPUTER TOMOGRAPHY IN ASSESSING AND MONITORING THE DEGREE OF LUNG INGURY DUE TO COVID-19

P urpose. To explore the capabilities of CT in assessing the lungs injury degree due to COVID-19 by dynamic observation. Materials and methods. The analysis of 184 chest CT images of 60 patients with a diagnosis of viral pneumonia due to COVID-19. 37 patients were male, 23 patients were female, age from 23 to 74 (49.37 ± 14.2) years. For all patients the level of lungs damage was calculated by using a CT workstation. Results. The majority of patients (70%) suffered mild pneumonia due to COVID-19. Bilateral inflammatory changes (86.67%) are specific signs of pneumonia caused by COVID-19. The first day of examination of CT scans showed that 5% of patients had pathological changes in the lungs, which were not visualized and were only detected on following CT scans. A group of patients (6.67%) with no inflammatory changes on the first CT scan images, did not have any pathological lung changes after repeating CT scan, despite positive results of the SARS-CoV-2 test, which was performed by using RT-PCR method. Dynamic observation of the lungs state with the volume, type and number of inflammatory changes determination allows accurately control the degree and progression of disease, as well as treatment effect. CT scans revealed changes in the pulmonary parenchyma specific to viral etiology in the form of compaction by the type of ground glass opacity (GGO) in 14 cases (23.33%), by the type of GGO with the presence of reticular changes - in 8 (13.33%), the combination of GGO type and consolidation - in 21 (35%), in 10 cases (16.67%) there were only consolidation regions, including perilobular seals. Sensitivity is 93.3%. Conclusions. CT is a method with a high sensitivity, so it makes possible to identify the whole spectrum of pneumonia’s manifestations caused by COVID-19. To determine the degree of lungs injury is necessary to use available solutions that increase the effectiveness of the diagnosis of COVID-19. A wide interval of the lung damage volume (25% on the CT1-CT4 scale) does not always veraciously allowed to estimate the dynamics of the inflammatory process. Ц ель. Изучить возможности КТ в оценке степени поражения легких при COVID-19 в условиях динамического наблюдения. Материалы и методы. Проанализированы результаты 184 исследований КТ грудной клетки 60 пациентов с диагнозом вирусная пневмония COVID-19. Мужчин было 37, женщин - 23, возраст от 23 до 74 (49,37± 14,2) лет. Всем пациентам рассчитали объем поражения легких с помощью программного обеспечения рабочей станции компьютерного томографа. Результаты. Большинство пациентов (70%) перенесли пневмонию COVID-19 в легкой степени тяжести. Для COVID-19 пневмонии характерны двусторонние воспалительные изменения (86,67%). При КТ в первые сутки у 5% пациентов патологические изменения в легких не визуализировались и были выявлены только при динамическом контроле. У 6,67% пациентов с отсутствием воспалительных изменений при первом КТ, несмотря на положительные результаты теста на SARS-CoV-2, выполненные с использованием ОТ-ПЦР, и при повторных КТ патологических изменений легких не было. Динамический контроль состояния легких с определением количественных показателей относительного объема воспалительных изменений позволял точно оценить тяжесть поражения, достоверно осуществить мониторинг прогрессирования и ответных реакций на проводимое лечение при COVID-19. При КТ были обнаружены характерные для вирусной этиологии изменения легочной паренхимы в виде уплотнения по типу «матового стекла» в 14 случаях (23,33%), изменения по типу «матового стекла» с наличием ретикулярных изменений - в 8 (13,33%), сочетание уплотнения по типу «матового стекла» с консолидацией - в 21 (35%), в 10 случаях (16,67%) были только участки консолидации, в том числе с перилобулярными уплотнениями. Чувствительность 93,3%. Выводы. Метод КТ с высокой степенью чувствительности позволяет выявить весь спектр возможных проявлений пневмонии COVID-19. Для определения объема поражения легких необходимо использовать доступные решения, повышающие эффективность диагностики COVID-19. Широкий интервал объема поражения (25% в шкале КТ1-КТ4) не всегда позволяет точно отразить динамику процесса в легких.

Comparison of clinical data and computed tomography semiotics of the lungs in COVID-19

The objective of the study: To compare the degree of lung damage according to chest CT data to the clinical state of COVID-19 patient, to analyze the semiotics and changes in CT data. Subjects and methods. 317 CT scans were retrospectively analyzed;those scans belonged to 98 patients with COVID-19 treated at N.V. Sklifosovsky Research Institute for Emergency Medicine. Patients were divided into 4 groups, depending on the degree of the lungs damage detected by CT during the primary examination, their clinical state was assessed at each subsequent CT scan. To determine the relationship between the degree of pulmonary changes and the clinical status of patients, a correlation analysis was performed using the rank correlation method, significance was assessed using the Student's coefficient. Results. It was found that CT allowed to identify changes in the lungs typical of COVID-19 and assess their degree, as well as to analyze progression or regression lung changes, including comparison with clinical data. A significant correlation was revealed (rs = 0.577) between the growing degree of lung damage, as determined by CT and deterioration of the clinical status of patients. © 2020 New Terra Publishing House. All rights reserved.