Introduction The COVID-19 pandemic at the present stage is one of the most dangerous and serious global problems [1, 2, 3]. The rapid spread of the SARS-COV-2 virus from China to almost all countries of the world, has reached the number of infections of more than 3,236,787. In Russia alone, 24,150 patients are registered per day, 19,847 recovering daily and daily deaths 504. Lack of real etiotropic treatment, the inability to predict the outcome of the disease, high mortality from COVID-19, as well as little-studied consequences for patients who have undergone SARS-COV-2 infection, depending on the severity of the course of the disease, indicate the importance and high relevance of research conducted in the direction of studying the mechanisms of pathogenesis of COVID-19 [4, 5, 6]. The consequences of the postponed COVID-19 infection at the present stage are not known, however, the results of numerous studies have indicated the role of microorganisms, especially viruses, as promoters of tissue malignancy, inducing carcinogenesis in various systems of human organs [7, 8, 9]. At the same time, the authors associate tissue malignancy with impaired iron metabolism in the body of virus-infected patients, which leads to hypoxia and anemia. These data determined the direction of our research in terms of studying the mechanisms of hypoxia during SARS-COV-2 infection.
The aim of the study was to study the mechanisms of hypoxia during SARS-COV-2 infection.
Material and methods. The material for the research was the results of observations and data from clinical and biochemical studies in patients undergoing inpatient treatment in infectious diseases hospitals in the Primorsky Territory. The paper analyzes and discusses the results of our own blood tests of patients who died from COVID-19 caused by SARS-COV-2, with PCR confirmation. To obtain data on the distribution of erythrocytes in the blood vessels of the tissues of deceased patients, a biopsy material was examined, obtained in accordance with the order of the Ministry of Healthcare of the Russian Federation dated 04.29.94 N 82 "On the procedure for conducting pathological autopsies", according to the rules of the instructions governing the procedure for autopsies in medical institutions. The control group consisted of 14 patients who died as a result of injuries incompatible with life, presumably without somatic pathology at the age of 24 to 76 years. The results obtained in age groups in which the age of patients ranged from 21 to 91 years are considered. The clinical material was divided by sex and age groups; a total of 61 patients were considered, of which 33 were men and 28 were women. As a result of treatment, 29 people (15 men, 14 women) were discharged for outpatient treatment and observation, 32 people died (17 men and 14 women). The biopsy material was recorded according to the prescription for preparation for histological examinations immediately after collection. The exclusion of possible artifacts is based on data obtained during a special study on dogs, indicating that when corpses are stored at a temperature of 4 ° -7 ° C for 24-26 hours, microscopically visible changes in the morphology of various organ systems are not observed, except for a slight decrease in the intensity of specific reactions to enzymatic activity. We used classical histological research methods with staining with hematoxylin and eosin to obtain a general morphological picture. The morphological method of the study consisted in the preparation of sections from paraffin blocks of biopsies of the lung, liver, heart, spleen, kidneys of the victims of SARS-COV-2, followed by staining with hematoxylin and eosin in accordance with the classical protocol. Analysis of preparations and production of illustrations were performed using an Olympus Bx52 microscope and a DP25 digital camera with proprietary software.
Research results and their discussion. Coronavirus disease, COVID-19, refers to infectious and inflammatory diseases that mainly affect the respiratory system. However, an analysis of scientific information from the available literature and data from our own studies indicate two key pathogenetic mechanisms in the development of hypoxia in patients infected with SARS-CoV-2: 1) the development of severe acute respiratory syndrome as a result of damage by the SARS-CoV-2 coronavirus to structures in the composition airborne barrier: respiratory epithelium in the alveolar wall, as well as endothelium (Fig. 1 a) and 2) the appearance of pathological forms of erythrocytes with an increase in the number of hypochromic red blood cells (Fig. 1 b, c).
Figure 1. Lung of a person infected with SARS-CoV-2. Staining with hematoxylin and eosin. Microphoto. Uv.x400.
a blood vessel with damaged endothelium; b) hypochromic erythrocytes; c) macrophage with hemosiderin.
In the field of view, hypochromic erythrocytes are identified (indicated by an asterisk), echinocytes are observed in the lumen of the vessels, as well as erythrocytes with Jolly bodies. The presence of an excess of normal numbers of altered forms and sizes of erythrocytes indicates anisocytosis and poikilocytosis. Also, macrophages with phagocytosed hemosiderin are identified (Fig. 1c, indicated by an arrow). The presence of hemosiderin granules in the cytoplasm of macrophages may indicate blocking of the transport protein for iron, which is required for the synthesis of hemoglobin in the red bone marrow [10, 11]. The destruction of red blood cells in tissues outside the spleen also indicates a violation of hematopoiesis in the direction of the erythroid lineage and changes in iron metabolism in the body of patients infected with SARS-CoV-2. We also noted that hemoglobin levels were lower in the older age group, among them there was a higher percentage of patients with diabetes, hypertension and general concomitant diseases, which contributed to a greater severity of clinical manifestations in older patients.
Considering the high importance in hematopoiesis of the mechanisms for the induction of iron transport into the red bone marrow, cellular signaling interactions in this process, the role of ferritin and its regulation in the hematopoietic system, it is necessary to note the insufficient study of these issues. The concept is known according to which SARS-CoV-2 interacts with the hemoglobin molecule through CD147, CD26 and other receptors located on the precursors of erythrocytes and other blood cells, inducing the hepcidin-mimetic action of the viral spike protein, which causes the blocking of ferroportin .
The following pathological pathways of metabolism, resulting from denaturation of hemoglobin and dysregulation of iron metabolism, have been identified: 1) decrease in the level of functioning hemoglobin; 2) iron overload of tissues and hyperferritinemia; 3) the release of free circulating iron and its release into tissues with a toxic effect on cells; 4) hypoxemia, local and systemic hypoxia; 5) ferroptosis with oxidative stress. 6) mitochondrial degeneration and apoptosis. At the same time, several clinical syndromes begin to develop, such as pulmonary edema due to vasoconstriction in the pulmonary artery system against the background of changes in the structures of the air-blood barrier, sideroblast-like anemia, endotheliitis, vasospastic acrosyndrome and arteriovenous thromboembolism.
Thus, we believe that in COVID-19, in addition to the classical point of view on pulmonary immune inflammation, it is necessary to take into account the mechanisms of hypoxia due to the dysregulation of iron metabolism. A more comprehensive diagnostic and therapeutic approach to COVID-19 is proposed, which will use the necessary adjuvant conservative methods in order to increase the hemoglobin content, reduce excess iron deposition in the tissues of various organs, control its delivery to the spleen, and also search for methods to relieve the general hypoxic state. in addition to artificial ventilation.
Conclusions 1. The number of hypochromic erythrocytes, as well as parameters of the level of hemoglobin concentration, poikilocytosis and anisocytosis of erythrocytes are one of the key indicators in assessing anemia and hypoxia in COVID-19, and also serve as prognostic markers in assessing the severity of the prognosis.
2. Patients with low hemoglobin and hypochromic anemia require intensive therapy with oxygenation through the mechanisms of erythropoiesis.
The study was financially supported by the International Medical Research and Education Center (Vladivostok, Russia).
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