Elena Shilova’s research while affiliated with Russian Research Institute of Hematology and Transfusiology and other places

Background. The role for the HLA complex in SARS-CoV-2 immunosurveillance, resistance to virus infection and type of the individual immune response is accounted for by the extraordinary variability of HLA-genotypes as well as involvement of HLA-molecules in the mechanisms behind both cellular and humoral immunity. The aim of our study was to identify HLA-genetic factors underling severe COVID-19 course in St. Petersburg residents. Materials and Methods. The study included 78 St. Petersburg residents aged 20 to 84 years (median – 55 years) recovered after COVID-19 in 2020-2022. The distribution of the examined persons based on COVID-19 severity was as follows: mild – 41, moderate – 32, severe – 5 persons. For further analysis, subjects with moderate-to-severe disease were included into a single group (37 persons). The control group consisted of 1,563 St. Petersburg residents who were potential hematopoietic stem cell donors, aged 18 to 60 years (median – 32 years). The low resolution HLA typing was performed by polymerase chain reaction using sequence-specific primers and sequence-specific oligonucleotide probes. HLA typing in control group was performed prior to SARS-CoV-2 pandemic. Results. A lower frequency of HLA-A*01 group was found in individuals with mild vs. moderate/severe COVID-19 (0.0366 vs. 0.1351; p=0.04) and control group (0.0366 vs. 0.1193; p=0.02). A higher frequency of HLA-A*11 group was found in moderate/severe course compared to mild COVID-19 (0.1081 vs. 0.0244; p=0.048). Compared to control group, HLA-A*11 frequency in moderate/severe course (0.1081 vs. 0.0582; p=0.08) tended to increase. According to multivariate analysis, the risk of severe COVID-19 course in St. Petersburg residents was significantly associated with detected HLA-A*11 allele group (OR 7.38; CI 1.15-47.3; p=0.032) and age (OR 1.05; CI 1.01-1.09; p=0.008) along with an effect from HLA-A*01 tending to contribute to a risk of developing severe COVID-19 (OR 3.88; CI 0.88-17.09; p=0.068). Conclusion. HLA markers for severe COVID-19 in St. Petersburg residents was identified providing deeper insight into a role played by HLA system in COVID-19 outcomes.

The specifics of individual immune reactions after COVID-19 have not been studied sufficiently. This study aimed to describe the changes in indicators of cellular and humoral levels of immunity after COVID-19, and gage general trends and individual characteristics. We sampled blood of 125 unvaccinated COVID-19 patients (29 men and 96 women, median age 53 years) 1 to 4 months after recovery, and determined the relative content of T-lymphocytes (CD3+), B-lymphocytes (CD19+), and cells with late activation markers (CD3+HLA–DR+) in them using flow cytometry. With the help of ELISA, we have registered the level of circulating immune complexes, which can be medium molecular weight (CICmed) and low molecular weight (CIClow), and the content of antibodies to SARS-CoV-2. In the mild course group, significant differences from the normal values (p < 0.001) were found for T cells (growth, 74.4 ± 1.2% vs. 68.6 ± 1.1%) and B cells (decline, 10.2 ± 0.7% vs. 13.9 ± 0.9%). In the moderately severe course and severe course groups, the level of CD3+HLA–DR+ lymphocytes was increased (7.7 ± 0.4% and 15.7 ± 2.5%, respectively, versus 3.9 ± 0.8% in the control group; p < 0.01). All the examined patients had high levels of CIClow (2.6-2.9-fold increase) and CICmed (1.6–1.8-fold increase). The protective level of antibodies to SARS-CoV-2 above 150 BAU/ml was registered in about 50% of the mild group participants, 75% of the moderately severe group members, and 100% of patients who had the disease in a severe form. We detected no connections between immune disorders and clinical features of the course of the disease and the period thereafter, with the exception of abdominal syndrome peculiar to the acute stage of the disease. The article also describes a clinical case of detection in the early post-COVID-19 period of a pathological clone characteristic of B cell chronic lymphocytic leukemia, and its subsequent disappearance and normalization of the immunophenotype as registered during a follow-up 1.5 years after recovery. The persistent immunological shifts should be taken into account when assessing the risks of reinfection and possible complications.

The treatment of multiple myeloma is inextricably linked to the need for assessment and monitoring of the minimal residual disease (MRD). Assessment of the MRD allows evaluating the efficacy of therapy and obtaining significant prognostic information; it is an indicator of the degree of eradication of the tumor clone. The methods for detecting residual tumor cells evolve constantly, which translates into updates of the criteria reflecting the scale of response to therapy. There is no single MRD detection technique; common recommendations suggest seeking for pathological cells both intramedullary and extramedullary. This review describes current MDR determination methods, including imaging, next generation multiparametric flow cytometry, and methods based on DNA analysis — allele-specific oligonucleotide polymerase chain reaction and next generation sequencing. We compare their advantages, limitations, disadvantages, clinical significance, and show the necessary sensitivity thresholds of the described methods and the conditions that make this or that approach ideal in the context of detection of MRD.

Recent studies devoted to the patterns of the COVID-19 course in patients of various groups indicate a significant role of the immunity state in the disease development. Risk groups of severe disease course, including senile age, obesity and immunodeficiency conditions, have been identified. Research is underway to identify the genetic predisposition to SARS-CoV-2 infection and determine the poor prognosis in COVID-19. The presented article examines the immunological aspects of pathological conditions associated with an unfavorable prognosis of COVID-19. A complex immune response (including both innate immune mechanisms and an adaptive systemic response) develops in response to SARS-CoV-2 infection. The key mechanism of multisystem organ failure is a hyperimmune reaction with the development of a systemic inflammatory response, the so-called "cytokine storm", and the characteristics of the immune response largely determine the disease severity. In this regard, the immune response characteristics in patients at risk are of particular interest, including studies concerning the immunological aspects of a more severe disease course depending on age, the history of obesity, diabetes mellitus and other pathological conditions, as well as various genetic factors, which is the subject of active study at present. KEYWORDS: immune system, COVID-19, SARS-CoV-2, risk factors, obesity, oncological diseases, genetic predisposition, immune response. FOR CITATION: Glazanova T.V., Shilova E.R., Pavlova I.E. Risk factors of COVID-19: immunological aspects. Russian Medical Inquiry. 2023;7(11). (in Russ.). DOI: 10.32364/2587-6821-2023-7-11-5.

During the pandemic, a large number of works devoted to COVID infection have appeared, which have made it possible to understand the pathogenetic features of the disease and to accumulate significant clinical experience. However, the question remains about the degree of participation of humoral and cellular (primarily T-cell) immunity in the mechanisms of immune defense and resistance to COVID-19, the individual features of the immune response in different subjects. Post-COVID syndrome is currently a separate diagnosis included in the ICD-10 International Classification of Diseases, but the long-term effects of the SARS-CoV-2 on the immune system are not yet well established. At the same time, a long-term increased activity of the immune system can contribute to the development of autoimmune reactions. The review of the literature presents the results of studies, mainly devoted to immune system disorders after COVID infection. The changes in subpopulations of T-lymphocytes, B-lymphocytes, their functional properties, the complement system and other factors of humoral immunity, as well as the production of a number of cytokines are described. Data on immune disorders in post-COVID syndrome and during the convalescence period are presented in detail. Since COVID-19 is an infection that has a significant impact on the hematopoietic system and hemostasis, special attention is paid to the category of subjects with an increased risk of severe complications. Among the latter are elderly patients, persons suffering from diabetes mellitus, oncological and oncohematological patients, in particular, with hematopoietic and lymphoid tissue neoplasia, such as chronic lymphocytic leukemia, lymphoma, multiple myeloma. The review pays special attention to the peculiarities of the course of COVID-19 and the response of the immune system to vaccination in patients with oncohematological diseases. Deciphering the significance of individual links of cellular and humoral immunity in patients who have undergone COVID-19 is an important issue in creating effective vaccines and improving therapeutic methods.

Aplastic anemia (AA) is a non-neoplastic hematological disease closely associated with bone marrow failure which is typical of paroxysmal nocturnal hemoglobinuria (PNH) and myelodysplastic syndrome (MDS). The PNH clones can be detected in more than a half of AA patients at onset of the disease, and there is a probability for AA/PNH co-variants to progress to classic hemolytic PNH. At the same time, the AA patients treated by immunosuppressive therapy undergo the risk of disease transformation to MDS and acute myeloid leukemia. Currently known risk factors and possible precursors of such transformation are considered in the brief literature review. In addition to that, the paper provides a case report of AA/PNH transformation to MDS during complete AA remission after immunosuppressive therapy combined with a successful haploidentical transplantation of hematopoietic stem cells.

The OBJECTIVE of the study was to reveal the causes of anemia in patients with gastric cancer in the perioperative period. METHODS AND MATERIALS . The object of the study were 700 patients with gastric cancer who underwent surgical treatment. All patients underwent clinical and biochemical blood test, indicators characterizing iron metabolism in the body (serum iron, ferritin, transferrin), and the level of endogenous erythropoietin during the perioperative period. The comparison group included 20 patients with gastric bleeding of non-neoplastic etiology. Both groups were comparable in age (median was 60 and 62 years old) and hemoglobin level (median Hb 95.3 g/l and 94.5 g/l). RESULTS. Anemia was diagnosed in 15 % of patients (n=105) in the perioperative period. Mild anemia was more often detected (hemoglobin level 95–110 g/l) – in 47.6 % of patients. Moderate anemia (80–94 g/l) was observed in 24.0 % of patients, severe anemia (65–79 g/l) – in 18.1 % of patients, severe (hemoglobin level below 65 g/l) – in 10.3 % of patients. A strong correlation (r=0.89; P<0.05) was observed between the stage at the tumor process and the severity of anemia. At the same time, no connection was found between the macroscopic form of a stomach tumor and the severity of anemia. The analysis of the indicators of iron metabolism allowed to confirm the true iron deficiency in this category of patients, which was characterized by a decrease in the level of serum iron in patients with gastric cancer to (7.8±1.6) μmol/L (from 4.7 to 8.2 μmol/L). Comparative analysis of the level of endogenous erythropoietin in the group of patients with gastric cancer (n=20) and patients with gastrointestinal bleedings of non-neoplastic etiology (n=20) showed significantly lower values with a difference of 27.7 % in the first group of patients ((66.9±28.2) mIU/ml versus (95.6±36.7) mIU/ml; P<0.05), which indicated inadequate production of erythropoietin in patients with gastric cancer. CONCLUSION . The main causes of anemia in patients with gastric cancer in the perioperative period should be considered a true iron deficiency, as well as inadequate production of endogenous erythropoietin.

Anemia in patients with malignant neoplasms affects the quality of life of the patient and sometimes limits the timely implementation of antitumor treatment. In the pathogenesis of anemia of the malignant neoplasms the largest role play infiltration of the bone marrow by tumor cells, suppression of hematopoiesis by inflammation cytokines, development of functional iron deficiency, reduction of sensitivity of receptors to erythropoietin or its synthesis. The doctor can prescribe effective pathogenetic therapy after evaluating the mechanisms of anemia development in this category of patients. In the article are described in detail the methods of pathogenetic correction of anemic syndrome using parenteral iron preparations, recombinant erythropoietin, indications for their appointment, effectiveness in patients with cancer, as well as possible side effects and complications of therapy. The mechanisms of action, pharmacokinetics, and features of the use of different erythropoietin adents are described. It is shown the effectiveness of erythropoietin preparations in patients with lymphoproliferative disorders based on the results of our own study. A positive response was observed in 77.3 % of patients with non-Hodgkin’s lymphomas, in 61.8 % – with multiple myeloma and 60.9 % with chronic lymphocytic leukemia. It is presented the prognostic factors for the response to erythropoietin therapy and showed own datum in patients with myelodysplastic syndrome (in case of the serum erythropoietin <500 mMU / ml a positive response was found in 35.6 %, with higher level – no response) and with lymphoproliferative disorders (in case of erythropoietin was <130 mMU / ml, the positive response was 80 %, at 130–499 mMU / ml – 63.6 %, and at ≥500 mMU / ml – 25 %). In the article are described the principles of anemia correction using red blood cells transfusions and features of their use in patients with cancer. Special attention is paid to the study of blood saturation as one of the indicators that allow us to assess the adequacy of the gas transport function of blood during red blood cells transfusions. The algorithm for correcting anemia in malignant neoplasms using red blood cells transfusions and erythropoietin agents are presented. It is shown low blood saturation (<60 %) in 32 % hematological malignancie’s patients with a hemoglobin 8.0 g / dL. This datum suggests presence of tissue hypoxia and gives approval to expand the threshold for red blood cells transfusions

Anemia is considered one of the manifistations of many neoplasms affecting the overall survival and reducing the quality of life of patients. The prevalence of anemia varies from 20 to 90% depending on the nosology, the stage of the disease, antitumor treatment. The pathogenesis of anemia in cancer patients is complex. Among pathogenetic factors, such factors are distinguished as tumor infiltration of the bone marrow by malignant cells, inhibition of erythroid growth by cytokines of inflammation, decreased sensitivity of receptors to erythropoietin and its production, increased levels of hepcidin, defects of nutrition, increased deposition and sequestration of blood cells in the spleen, excessive bone fibrosis, hemorrhagic syndrome, antitumor therapy. The article presents the pathogenesis of anemia in oncological disease with a detailed description of the suppressive effect on hematopoiesis of a number of proinflammatory cytokines (interleukin-1, interleukin-6, tumor necrosis factor-, interferon-) produced by cells of the immune system. The mechanism of influence of cytokines on erythropoiesis, synthesis of erythropoietin as well as on the enhancement of hepcidin production in the body is presented in detail. The article also describes the mechanism of impairment of iron kinetics in the body in patients with cancer and subsequent development of functional deficiency. This review of the literature contains up-to-date information about the factors involved in the pathogenesis of anemia in cancer patients, understanding of which will allow the clinical physician to choose a rational way of pathogenetic or substitution correction of anemic syndrome, taking into account the personalized approach to treatment and prevention, especially in patients receiving surgical, chemotherapy, radiation treatment.