Results of the work of the Military medical academy research institute of novel coronavirus infection problems through 2020–2021

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Abstract

Novel coronavirus infection COVID-19 pandemic has become a serious test for the world’s population across the board — from individual to population. Introduced restrictive measures of self-isolation, observation, and quarantine, mostly known before the pandemic only to medical specialists, have become a forced “lifestyle” for most of the people across the globe, their specific adaptation to the new, unusual conditions of the existence and communication. Healthcare has faced off with an unknown infection, while traditional methods of the treatment showed their ineffectiveness at the initial stage. The results of the Research Institute of Problems of New Coronavirus Infection of the Military Medical Academy named after S.M. Kirov from April 2020 to present are listed. Work basis is formed by the scientific and clinical results of the Academy’s work during the COVID-19 pandemic. The experience of organizing sanitary, antiepidemic and preventive measures at the permanent disposition and in the field in the regions of Russia and abroad is presented. Developed, improved, and put into the practice methods of diagnosis and treatment of the patients, including the electron microscopic diagnostics of long-term carrier, ultrasound examination of the lungs, glucocorticosteroid therapy, helium–oxygen therapy, risk prediction algorithms and computer-aided evaluation of the degree of lung tissue damage, evaluation of the drug effectiveness are listed. In a separate section study related to the Russian vaccine “Gam-COVID-Vac,” the assessment of immunity after the disease, complex disorders, and in postvaccination cases, the use of the immune pathogen-reduced plasma, the mutual influence of various vaccines are presented. Methods of rehabilitation of convalescents, dispensary-dynamic observation, and military medical examination are studied and developed.

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BACKGROUND

On February 11, 2020, the World Health Organization declared the coronavirus infection (COVID-19) a pandemic. In March, the infection was registered in Russia, and in April, the Research Institute (RI) of Novel Coronavirus Infection Problems was established following the admission of the first patients at the S.M. Kirov Military Medical Academy (MMA). It attracted the attention of all departments, and scientific and auxiliary units as they offered medical care and performed high-quality research. The institute was headed by the deputy head of the academy for educational and scientific work; the head of the department for organizing scientific work and training personnel was appointed the deputy head. A register of military personnel infected with SARS-CoV-2 and those treated at the academy was created as of October 2021, containing about 2500 entries [1].

The Academy specialists studied the diagnosis and treatment of COVID-19 in patients from different countries. Assistance to patients with a new coronavirus infection was organized and provided by the Academy staff from the academy and beyond (Moscow, Kurga, Tyva, and Dagestan), even from other countries (Serbia, and Italy). Moreover, aeromedical transportation and telemedicine consultations were performed [2–6]. Aspects of the use of personal protective equipment in the foci of a new coronavirus infection were developed [7]. For a differentiated approach to the implementation of preventive and anti-epidemic measures among military personnel, risk factors for COVID-19 disease were explored, and a disease risk assessment scale was developed. The result obtained correlated with recommendations on the scope of preventive and anti-epidemic measures [8].

The specialists equally analyzed the characteristics of immunopathogenesis associated with infections caused by the Coronaviridae family and their differences from a new coronavirus infection. It is known that in upper respiratory tract morbidity in adults, 10–30% of cases are associated with coronaviruses. Besides, 2019-nCoV has the ability to bind to angiotensin-converting enzyme 2 receptors, making it easily accessible to cells at low viral loads. SARS-CoV-2 refers to “superantigens” which manifests by suppressing non-specific resistance factors and inhibiting innate immunity mechanisms associated with a systemic inflammatory reaction in the form of a “cytokine storm”. It also activates phagocytes in the lung tissue and alters the parenchymal structure and causing fibrosis. The immunogenic properties of the virus, and unique structure (responsible for the formation of specific immunity) are target points for managing patients and developing vaccines. The studies continued with the participation of the academy employees in testing a vaccine against coronavirus [9–12].

One of the urgent burdens of health care is the issue of the formation of immunity in people with previous COVID-19 infection, the possibility of a re-infection, and the effectiveness of vaccination. In a joint project of the academy and the Helix laboratory service, the mechanisms underlying the formation of neutralizing antibodies to the SARS-CoV-2 spike (S) protein and the aspects of humoral immunity in people with mild or asymptomatic COVID-19 were studied based on age and sex.

Thus, we aimed at elucidating the results of the work of the RI on Novel Coronavirus Infection Problems of the MMA from April 2020 till date.

MATERIALS AND METHODS

We included 1109 patients aged 18 to 70 years (mean age: 38.2 years) who received outpatient treatment for mild or asymptomatic disease. All patients included in the study underwent quantitative determination of IgG to the S-protein of the pathogen SARS-CoV-2 in venous blood on the days 30, 45, 60, and 90 from the most recent positive reverse transcription polymerase chain reaction (RT-PCR) for SARS-CoV-2 nucleic acid, determined by immunochemiluminescent analysis (LIAISON XL, DiaSorin S.p.A., Italy). In project 2, an epidemiological study of collective immunity to SARS-CoV-2 was performed against the vaccination among members of military educational organizations. They enrolled 497 people stratified according to epidemiological and vaccination history of COVID-19, blood groups, and Rhesus factor. The immunity was assessed using serum IgG levels of SARS-CoV-2 in through enzyme-linked immunosorbent assay.

RESULTS AND DISCUSSION

Post-infectious humoral immunity is established with mild or asymptomatic COVID-19, persisted in patients for at least 3 months. The formation of combined immunity with the highest concentrations of specific antibodies in recovered and vaccinated individuals was revealed. Thus, vaccination to those who have recovered from COVID-19 can be recommended. The emergence of post-infectious immunity in those with a latent epidemic process has also been established1 [13].

The study of ultrastructural changes in biopsies of the nasopharyngeal mucosa using electron microscopy revealed a number of patterns. In all clinical forms of COVID-19, signs of viral damage were noted in the cells. However, in the inapparent form, no viral particles were detected; in acute respiratory disease (ARD), the virus was detected in the initial, peak, and convalescence periods. Meanwhile, in cases of viral lung lesion (VLL), it was registered only in the initial period. However, it was in this form that the highest concentration of SARS-CoV-2 viral particles in vesicles and cells was observed. The data obtained indicate that due to active cell damage, the formation of vesicles with the virus and its subsequent release from cells. The localized form of infection is mediated, while the formation of a generalized form (viral lung lesion) causes the virus should probably accumulate in high concentrations in vesicles. After that, when smooth vesicles merge with the plasma membrane, a significantly larger number of virions (compared to ARD) is simultaneously released from the cell, thereby contributing to a high probability of hematogenous dissemination of the virus. The virus localization outside the vesicles in the cell requires further study [14].

Much attention is paid to the study of the disease pathogenesis, where four key links were distinguished:

Direct cytopathic effect that damages target organ cells and the development of clinical symptoms in the initial period of the disease (rhinitis, pharyngitis, anosmia, ageusia, lung damage, vasopathy and vasculitis, dermatological, and neurological manifestations).

Dysregulation of the renin-angiotensin-aldosterone system (RAAS) toward clinically significant effects of type 1 angiotensin-converting enzyme (ACE). Under homeostasis, the antagonism of ACE-1 is the main function of ACE-2. SARS-CoV-2 blocks ACE-2 receptors, shifting the physiological balance of RAAS toward ACE-1 mediated effects (vasoconstriction of microvasculature vessels, increased permeability of arterioles and venules in case of direct damage to the vascular endothelium, which causes interstitial edema, which increases inflammatory process in the lungs, which reduces the perfusion-ventilation ratio and aggravates the course of acute respiratory distress syndrome (ARDS), comorbid metabolic, and cardiovascular pathology).

Endothelial dysfunction, and RAAS dysregulation toward hypertensive effects, activates the pro-coagulative hemostatic links (thrombin synthesis increases, fibrinolysis efficiency decreases), which ultimately contributes to the development of local disseminated intravascular blood coagulation syndrome (DIC syndrome), and subsequently that turning into a generalized form, clinically manifested by thromboembolic complications (acute coronary syndrome, thrombosis of the pulmonary artery tree, infectious-toxic encephalopathy, acute cerebrovascular accidents, vasculitis) and increased ARDS.

In addition to these key links, excessive platelet consumption enhances the inflammatory potential of neutrophils and promotes additional hyperactivation of macrophages, which naturally accelerates the release of pro-inflammatory cytokines and the formation of so-called neutrophil extracellular traps (nets) with an increased content of fibrinogen, fibrin, and/or microthrombi. Neutrophil networks further damage the endothelium and activate both external and internal mechanisms of hemostasis, causing hypercoagulability. Concurrently, hypoxemia leads to the development of systemic hypoxia and, through the activation of hypoxia-induced factor-1 alpha (HIF-1α), contributes to the progression of ARDS, DIC syndrome, and subsequently fibrosis of the lung tissue [15–17].

The diagnosis of acute infectious diseases at their initial stages, based on the sometimes scanty and indolent clinical presentation, allows for the early identification of infectious patients, which would lead to their early isolation, thereby fulfilling the key epidemiological objective of excluding the source of infection from the epidemic process. Most acute infectious diseases that can cause an international emergency have a short initial period and can rapidly spread to reach its peak (cholera, pneumonic plague and pulmonary anthrax, influenza, typhoid fever, etc.), which necessitates emergency or urgent care or prevention of complications as early as possible. The current threat of infection caused by the SARS-CoV-2 virus differs considerably from classical acute infectious diseases.

The entire scope of therapeutic and diagnostic measures, of course, is most effective when infection caused by SARS-CoV-2 is diagnosed early. Concurrently, the initial period of this disease can last for 6–8 days, during which the patient often feels relatively well and significant clinically changes in the lungs are not detected during examination of the chest organs. This sequence of events, first of all, lowers the guard of primary care medical personnel, leading to the inadequate prescription of diagnostic studies (coagulogram, D-dimer, fibrinogen, C-reactive protein, ferritin, and albumin) and therapeutic measures (antiviral, preventive anti-inflammatory, and anticoagulant therapies). As such, numerous patients are admitted to hospitals later than 8 days from the onset of the disease and often with a clinical presentation of acute respiratory failure, that is, in the period of pulmonary infection and hyperinflammation. This leads to the rapid depletion of health care resources and, in some cases, to unfavorable outcomes for the patient. Both rather well-known research methods are widely used, together with relatively rarer and newer ones, such as ultrasound examination (US) for the quick assessment of the state of the lungs. A comparison of the data obtained from computed tomography (CT) and US of the lungs revealed a high degree of agreement. If CT showed signs of lung tissue infiltration, up to “ground glass opacity”, then US revealed B-lines of varying intensity, up to “white lung”. Moreover, if consolidation was detected on CT, then it was also determined on US. Free fluid in the pleural cavity was detected at equal rates by both CT and US [18–30].

There is very little evidence for the undisputed clinical effectiveness of any drugs for COVID-19. A literature analysis on the experience of treating patients with atypical pneumonia associated with the SARS-CoV and MERS-CoV coronaviruses, as well as the experience gained in the treatment of patients infected with SARS-CoV-2, allowed for the identification of several drugs from different groups. These include favipiravir, remdesivir, umifenovir, riamilovir, ribavirin, hydroxychloroquine, azithromycin (in combination with hydroxychloroquine), as well as interferon-alpha preparations and anti-COVID plasma.

The academy departments also conducted studies to evaluate the clinical efficacy and safety of various etiotropic antiviral drugs with a direct mechanism of action in the treatment of patients with moderate SARS-CoV-2. Accordingly, studies on various drugs showed a statistically significant reduction in the duration of fever, cough, and anosmia, as well as faster elimination of the virus from the body [31–34].

The use of convalescent plasma in the early stages of the disease reduces the number of patients requiring mechanical lung ventilation. However, not all convalescent patients have a high titer of antiviral antibodies. Fortunately, the advent of the Russian vaccine Gam-COVID-Vac made it possible to obtain immune plasma from vaccinated individuals. Notably, related studies revealed that the level of antiviral antibodies in the plasma of convalescent patients significantly exceeded that in their plasma.

Anti-COVID plasma is prescribed in cases wherein the potential efficiency of transfusion therapy outweighs the potential risks (primarily acute functional disorders of the circulatory system), at a dose of at least 3.125 mL per 1 kg of body weight once (the total volume of transfusion should not exceed 20 mL per 1 kg of body weight).

Experience with using immune anti-COVID, pathogen-reduced plasma in MMA clinics treating infectious diseases has demonstrated the clinical efficacy of this immunobiological preparation in the treatment of severe infection caused by SARS-CoV-2. Accordingly, patients receiving anti-COVID plasma exhibited significantly faster elimination of the virus from their body based on the results of PCR of nasopharyngeal swabs than the control group (8.8 vs. 13.3 days). In addition, severe patients administered immune anti-COVID, pathogen-reduced plasma showed faster restoration of normal arterial blood oxygen levels and required shorter periods of oxygen therapy [35, 36].

Glucocorticosteroids (GCS) are the first choice for anti-inflammatory therapy in COVID-19 patients. Recent clinical studies in Europe have shown that the use of dexamethasone at a dose of 6 mg once a day for 10 days promoted a significant decrease in mortality during the follow-up period (28 days) in a group of COVID-19 patients who received invasive mechanical lung ventilation or oxygen support. Concurrently, the use of GCS is not recommended for the prevention or treatment of mild to moderate coronavirus infection (in patients not receiving oxygen).

Experience with using these drugs in MMA clinics for patients with moderate and severe infection caused by SARS-CoV-2 showed that preemptive anti-inflammatory therapy should be performed as early as possible (on days 7–8 of the illness on average) until the symptoms of life-threatening conditions develop completely, namely specific viral lung disease, ARDS, DIC syndrome, and multiple organ failure. Evaluation of the efficiency of complex anti-inflammatory therapy with GCSs, interleukin-6, and Janus kinase inhibitors in the treatment of patients with a new coronavirus infection in MMA clinics for infectious diseases showed that patients with a pronounced pro-inflammatory response, who received this therapy in a timely manner, demonstrated statistically significant lower mortality rates (7.4% vs. 23%) compared to those treated with GCSs only [37–39].

Given the release of cytokines during SARS-COV-2 infection, blood clotting disorders have often been encountered. The development of hypercoagulation and DIC is characteristic in the initial stages of the disease. Coagulopathy in COVID-19 is characterized by the activation of the blood coagulation system in the form of a significant increase in the blood concentration of D-dimer without significant signs of consumption of fibrinogen and platelets. As a rule, DIC syndrome develops at the later stages of the disease. It is registered only in 0.6% of surviving patients and 71.4% of deceased patients. The development of hypercoagulation is associated with the risk of thrombotic complications. Electron microscopy data indicate the presence of pronounced damage to endothelial cells associated with the penetration of SARS-CoV-2 viruses into the cells, generalized thrombosis of small vessels, microangiopathy, occlusion of alveolar capillaries, and signs of neoangiogenesis [40, 41].

When blood oxygen saturation (SpO2) when breathing atmospheric air falls below 93%, oxygen therapy using nasal cannulas (oxygen flow at a low rate of 3–15 L) is recommended until SpO2 reaches 96%–98%. In the absence of a response at the stage 1, high-flow oxygenation with a flow of 30–60 L/min instead of standard oxygen therapy or non-invasive lung ventilation is recommended due to its advantage in providing adequate oxygenation and minimal risk of infection transmission. When using high-flow oxygen therapy, it is advisable to put a protective mask on the patient. It is recommended to combine oxygen therapy (standard or high-flow) with the patient’s prone position for at least 12–16 h a day, which leads to improved oxygenation. In the absence of an effect following oxygen therapy for 2 h and an increase in respiratory failure, it is necessary to transfer the patient to the resuscitation and intensive care unit [42].

An important aspect was our study on the impact of the pandemic on the psychological state of the population. Throughout the unfavorable epidemiological period, the characteristics of the psychological response of the population ranged from hypersensitive (anxious) to displacing poles. The initial period (January 2020) was characterized by the appearance of information regarding a new coronavirus infection in Wuhan (People’s Republic of China) in the media. In this regard, the emergence of COVID-19 was not perceived as a serious potential threat by most global countries, and psychological response patterns were characterized by minimal anxiety and, for the most part, denial (non-acceptance) of possible serious consequences.

The period of distant (outside of the country) epidemic outbreaks (spread beyond the primary focus) and gradual “information saturation” (February–March 2020) was characterized by the appearance of new and often conflicting data on the rapid spread of COVID-19, the degree of its hazardous nature to life, as well as the first restrictions imposed on Russian citizens (usually related to the prohibition of travel to a number of countries) across information resources. The psychological response of the population at that time were manifested by two polar opposites, namely undifferentiated, weakly expressed intermittent anxiety and almost complete denial of a serious threat to health (due to the absence of lethal outcomes at the beginning of the epidemic and their relatively small number in the first weeks).

The period of growth in incidence and initial (primary) psychological response (latter half of March 2020) was marked by an increase in the incidence of morbidity and mortality from COVID-19 in the Russian Federation, which prompted two main response options. Option 1 was represented by a clearer specification of the content of anxious experiences (“crystallization” of the threat), which was accompanied by various “protective” activities, such as moving out of town, buying medicines, food, and household goods (a week of “buckwheat and toilet paper”) aimed at reducing the level of internal stress and concern for relatives. The option 2, which was no less common, was the psychological displacement of the threat significance. This was largely due to the influence of the media, media space, social networks, and instant messengers (publications about “special immunity of the Russian population,” “genetic and age characteristics,” etc.), contradictory information (even provocative), disavowal of preventive measures taken in various entertainment shows broadcast in prime time. Such forms of response were especially typical for the younger generation.

Psychological and psychopathological phenomena during the height of the epidemic and self-isolation (since the end of March 2020) had the highest polymorphism and were determined by various circumstances, first of all, by the nature of compliance with restrictive measures, the age and sex characteristics of a person, the characteristics of his professional activity, as well as other medical, biological, and social factors.

Psychological and psychopathological phenomena of the period of exit from self-isolation (since June 09, 2020) and gradual “re-adaptation” to a normal lifestyle are currently the least studied. During the self-isolation period, many have developed an “acquired adaptation” to new (previously unusual) conditions and lifestyles (lack of regimen, loads, professional responsibility). Therefore, the return to the “pre-epidemic” style of life causes an additional psychological stress that can be assessed only after a certain time [43–45].

Measures for the medical rehabilitation of patients who have undergone COVID-19 are aimed at restoring the immunity of the patient, namely improving lung ventilation, gas exchange, and bronchial clearance; continued nutritional support; increase in overall physical endurance; correction of disorders of memory, attention, sleep, and muscle weakness; increase in mobility; overcoming stress, anxiety, or depression.

The specific composition of an individual’s rehabilitation program is based on the degree of dysfunction of various organs with a new coronavirus infection, and includes the rehabilitation technologies (therapeutic physical factors, therapeutic physical culture, medical massage, psychological correction methods, nutritional support, pharmacological correction, training and occupational therapy, the use of technical means of rehabilitation, and other technologies). The results of previous studies [46–52] were important in the development of these measures.

CONCLUSION

In general, comprehensive research within the RI of Novel Coronavirus Infection Problems provided necessary information related to organizing the provision of medical care, quickly communicate in the Armed Forces in the form of guidelines prepared in accordance with current thinking [53], and in the scientific and medical field of Russia in the form articles. The results related to the development and use of the Russian vaccine Gam-COVID-Vac are the most priority.

1 A number of articles by the Academy staff on the issues presented in the article are still at the stage of publication.

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About the authors

Evgeniy V. Ivchenko

Military Medical Academy named after S.M. Kirov of the Ministry of Defense of the Russian Federation

Email: 8333535@mail.ru
ORCID iD: 0000-0001-5582-1111
SPIN-code: 5228-1527

doctor of medical sciences, associate professor

Russian Federation, Saint Petersburg

Bogdan N. Kotiv

Military Medical Academy named after S.M. Kirov of the Ministry of Defense of the Russian Federation

Email: kotivbn@gmil.com
ORCID iD: 0000-0001-5609-0517
SPIN-code: 4038-0855

doctor of medical sciences, professor

Russian Federation, Saint Petersburg

Dmitrii V. Ovchinnikov

Military Medical Academy named after S.M. Kirov of the Ministry of Defense of the Russian Federation

Author for correspondence.
Email: 79112998764@yandex.ru
ORCID iD: 0000-0001-8408-5301
SPIN-code: 5437-3457
Scopus Author ID: 36185599800

candidate of medical sciences, associate professor

Russian Federation, Saint Petersburg

Sergey A. Bucenko

Military Medical Academy named after S.M. Kirov of the Ministry of Defense of the Russian Federation

Email: bucenko78@mail.ru
Russian Federation, Saint Petersburg

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