PATHOLOGICAL IMMUNITY CHANGES IN COMORBID PATIENTS WITH EXACERBATION OF BRONCHIAL ASTHMA

The aim of the study – to investigate immunological changes in patients with exacerbation of bronchial asthma with different severity and controllability depending on the presence of comorbid pathology. Materials and methods of research. The work is based on the analysis of data from a comprehensive clinical and laboratory examination of 190 patients with exacerbation of asthma. The relative content of T–lymphocytes and their main subpopulations was determined on a flow cytofluorimeter FACS Calibur (Canada) by phenotyping lymphocytes with monoclonal antibodies (BECKMAN COULTER, USA) to surface membrane differentiation antigens (CD): CD3+19– (pan T-cells), CD4+–8+– (T−helpers/inducers), CD4–8+ (cytotoxic T lymphocytes), CD3–16+ (natural killers). To identify the imbalance of immunoregulatory subpopulations of T cells, the immunoregulatory index was calculated – the ratio of the number of CD4+8– Lf and CD4-8+ Lf. To calculate the absolute content in the peripheral blood of individual populations of Lf, leukogram indicators determined on the hematological analyzer ABH-miscros60, France were used. The proliferative activity of lymphocytes was evaluated in cultures of whole blood in the reaction of blast transformation of these cells with morphological accounting of the results. Statistical processing of the obtained data was carried out using


Introduction
In the last two decades, researchers have paid considerable attention to the problem of comorbidity in bronchial asthma BA (Global Initiative for Asthma, 2021; Ilʹyinsʹka, 2021;Kuryk, 2018). Comorbidity is a combination of several chronic diseases in one patient, which mutually affect each other. It has been proven that the interaction of diseases, their pathomorphosis and age significantly changes the course of the main disease, the nature and severity of complications, worsens the patient's quality of life, limits or complicates the treatment and diagnostic process. It is known that patients with comorbid pathology, including the gastrointestinal tract, which is very common among this category of patients, have an increased risk of developing asthma exacerbations and a greater severity of their course. Comorbidity negatively affects the prognosis of the disease and significantly increases the probability of a fatal outcome. The presence of comorbid diseases leads to an increase in the length of hospitalization, causes disability, and prevents the implementation of rehabilitation measures (Nenasheva, 2016;Yermolkevich, 2011;Velychko, 2019;Galimova, 2010;Cazzola, Chumak (2013), Alekseyev, Vertki, 2015). Discrepancies in the data of different authors regarding the prevalence of comorbid pathology in patients with asthma, in particular the digestive organs, and its influence on the course of asthma and the features of immunological changes determined the purpose of the work -to investigate immunological changes in patients with exacerbation of bronchial asthma with different severity and controllability depending on the presence comorbid pathology.

Materials and methods
The work is based on the analysis of the anamnesis data and comprehensive clinical examination of 337 patients with exacerbation of BA and 255 patients who underwent immunological research in the laboratory of clinical immunology. The distribution of patients with exacerbation of BA with different severity and controllability by gender and age is presented in the table 1. The analysis of these data showed that in all groups the majority of patients were women, which corresponds to the gender characteristics of this disease. Most of the examined patients with moderate and severe asthma were of working age (86.3% and 87.2%, respectively), while with mild BA -only 46.7% (p < 0.05).  There was no statistical difference between the fates of patients of different age categories with controlled and partially controlled asthma, however, in the group of patients with an uncontrolled course of the disease, there was a 2.4-fold decrease in the percentage of young and middle-aged patients and a 1.3-fold increase in the number of people elderly (p < 0.05), which corresponds to the well-known features of ВА. Concomitant diseases were recorded in 252 of 337 (74.8%) people, 144 (42.7%) of them had pathology of the digestive organs, and the absence of comorbidity was observed in 85 (25.2%) patients. Among this group, there were 15.4% more men than among the group of patients with concomitant diseases (40.0% and 24.6%, respectively; p < 0.05). There was no difference in the age composition between the groups ( Table 2).
Рatients had a combined pathology of the digestive organs. The remaining 107 (56.3%) persons with exacerbation of asthma had no comorbid diseases. They were included in the  Statistical processing of the obtained data was carried out using licensed software products that were included in the Microsoft Office Professional 2007 package, license OPEN No Level No. 43437596. To confirm the reliability of the difference in the obtained frequency indicators, the method of alternative variation was used with the determination of the student's two-tailed t -test. The level of probability was taken as the value of the probability indicator (p) between groups, which was equal to or less than 0.05 (Babich, 2005;Lapach, 2001).

Results and their discussion
With ВА of moderate severity, an increase in the content of pan-T cells was found in 37.7% of patients, and its frequency did not depend on the presence of concomitant diseases. An increase in the content of T-helpers occurred in 22.9% of patients without comorbid pathology, and in its presence, an insignificant increase in the frequency of high content of T-helpers was observed, table. 3.
A decrease in the content of cytotoxic T-lymphocytes was observed in 27.7% of patients with BA of moderate severity without concomitant pathology and 23.5% of patients with concomitant diseases (p < 0.05), including one in four patients with diseases of the digestive organs. A high immunoregulatory index was recorded in (14.5 ± 15.6) % of patients with BA of moderate severity, and dependence on the presence of comorbid pathology was not detected.
Every tenth patient with moderate asthma had an increased proliferative response of T cells to mitogen, regardless of the presence of concomitant diseases. In severe asthma, an increase in the content of pan-T cells occurred in 41.4% of patients without concomitant diseases, i. e. 1.2 times more often than in moderate asthma, in 35.6% of patients with comorbid pathology -(p < 0, 05) and in 40.0% of people with diseases of the digestive organs.
In patients with severe asthma, a decrease in the content of T-helpers was recorded only in 15.0% of cases in the absence of concomitant diseases (p < 0.05), in almost the same number of patients with comorbid pathology and in 12.5% -of people with concomitant diseases digestive organs (p < 0.05). A decrease in the number of cytotoxic T cells in severe ВА was more frequent than in patients with a moderate-severe course of the disease -1.3 times in people without concomitant diseases (p < 0.05) and 1.4 times in its presence (p < 0.05). There was no difference in the frequency of reduction in the content of cytotoxic T-lymphocytes in groups of patients with BA with different severity in the presence of concomitant pathology of the digestive organs, but it was significantly lower than in the other two groups of patients with severe (table 3). Table 3 Pathological changes of the  Table 4 Pathological changes in the The frequency of pathological changes in the T-system of immunity in patients with exacerbation of BA with different controllability depending on the presence of comorbid pathology is presented in the table. 4.
No patient with controlled BA showed an increase in the content of T-helpers. A decrease in the content of cytotoxic T-lymphocytes in this group was determined in one patient out of two in the presence of concomitant diseases, and in none -in their absence. An increase in the reaction of ballast transformation in patients with controlled asthma was recorded in 1 of six patients without comorbid pathology (16.7%), in 2 of 20 patients with its presence (10.0%; p < 0.05), in including in one out of 6 patients with concomitant diseases of the digestive organs.
In patients with partially controlled BA, a high content of T -cells, was recorded 1.5 times more often in patients without accompanying pathology than in the case of a controlled course of the disease (in 29.9%; p < 0.05), and in patients with its presence, -1.2 times less (p < 0.05). In 33.3% of patients with partially controlled BA, in the presence of diseases of the digestive organs, there was an increase in the content of pan-T lymphocytes, which was significantly lower than in controlled BA. In this group, high levels of T-helper cells were determined in every fourth patient, and dependence on the presence of concomitant diseases was not observed.
A decrease in the content of cytotoxic T cells was observed in one third of patients without concomitant diseases and with pathology of digestive organs (p < 0.05) and in 25.5% of patients with concomitant diseases (p < 0.05). The increased immunoregulatory index occurred in 15.9% of people without concomitant diseases and 24% more often than in patients with comorbid pathology (p < 0.05), and the difference in the frequency of this indicator increase in patients with diseases of the digestive organs in comparison with the frequency in the group of patients with controlled asthma without comorbidities, none were identified. An increase in the proliferative response of lymphocytes to FHA was registered in (8.1±10.9)% of patients with partially controlled asthma, and its dependence on the presence of concomitant diseases was not determined.
In patients with uncontrolled BA, the frequency of pathological changes of the T-immune system was much higher than in controlled and partially controlled disease, with maximum indicators in patients without concomitant diseases, while in patients with comorbid pathology, it was, as a rule, significantly lower. However, the frequency of growth of the immunoregulatory index in patients with uncontrolled BA was low and amounted to 7.7%, but in patients with concomitant diseases it was 2.8 times higher, including 2.4 times higher in the presence of diseases of the digestive organs. It was established that in patients with concomitant diseases, high rates of RBTL with FGA were (2.2 and 2.4) times higher than in patients without concomitant pathology.

Conclusions
In moderate BA, the frequency of pathological changes in the T-system of immunity did not depend on the presence of comorbid pathology, as a rule. In severe BA, an increase in the content of pan-T cells occurred 1.2 times more often than in moderate AD, but this was not observed in people with concomitant pathology. In this group, the frequency of increasing the content of T-helpers and decreasing the content of cytotoxic T cells in patients with severe BA without concomitant diseases was 1.3 times more frequent than in patients with comorbid pathology. No pathological changes in the T-system were detected in patients with controlled BA. In partially controlled BA, these changes were registered 1.5 times more often than in controlled BA, and in its uncontrolled course, the prevalence of pathological changes in the T immune system was much higher than in the two previous groups. In patients with concomitant diseases, these changes, as a rule, had a higher frequency than in patients without comorbid pathology.