Polypous rhinosinusitis in combination with bronchial asthma: clinical features and cellular characteristics of local and systemic inflammation

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Abstract

Background. The combination of chronic rhinosinusitis with nasal polyps (CRSwNP) and bronchial asthma (BA) is currently considered as a separate phenotype characterized by similar features of inflammatory changes leading to an increase in the clinical course of both CRSwNP and BA. The aim of the study was to investigate the clinical features and characteristics of the local and systemic inflammatory process in patients having a combination of CRSwNP and BA. Materials and methods. The study included 96 volunteers, who were divided into 4 groups: group 1 consisted of healthy volunteers (Normal); group 2 consisted of volunteers with CRSwNP in combination with allergic BA (CRSwNP + aBA); group 3 - volunteers with PRS in combination with non-allergic BA (CRSwNP + nBA); and group 4 - CRSwNP without BA. Clinical, laboratory, instrumental and allergology examination methods were applied for all participants of the study. BA control status was determined using the asthma control questionnaire (ACQ-7), and CRSwNP control status was determined using the nasal and paranasal sinus clinical outcome control questionnaire (SNOT-22). At the same time, the quality of life of the patients was also evaluated using AQLQ (Asthma Quality of Life Questionnaire). Results. The results confirmed the interaction of BA and CRSwNP, where the combination of these diseases led to a more severe and uncontrolled clinical course of BA and CRSwNP based on the assessment using SNOT-22, ACQ-7 and AQLQ questionnaires. These results correlated with an increase in the absolute number of eosinophils in peripheral blood and pronounced eosinophilic cell infiltration of nasal polyp stroma. Data processing demonstrated that the combination of CRSwNP and nBA showed signs of more pronounced eosinophilic inflammation, which is an unfavorable prognostic factor. Conclusions. The comparison of the cellular characteristics of the local and systemic inflammatory process in patients with CRSwNP in combination with BA allowed us to conclude that polyp development follows a local inflammatory process. Further study of the pathogenesis of CRSwNP and BA will help to understand the mechanisms that connect these diseases and consider possible target molecules for biological therapy.

Full Text

Introduction Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease of the upper respiratory tract, the pathogenesis of which is not well understood despite ongoing genetic, immunological and microbiological studies [1]. Every year, the number of patients suffering from CRSwNP is constantly growing. About 1 million 500 thousand people have CRSwNP in Russia, 30-35 million people in the USA, and according to the European recommendations for rhinosinusitis and nasal polyps (EPOS - European position paper on rhinosinusitis and nasal polyposis), CRSwNP is found in 2 to 4.3% of the population of Europe [2, 3]. Polypous rhinosinusitis is one of the most severe forms of chronic rhinosinusitis, which is difficult to For correspondence Статья поступила 03.02.2019 г Kurbacheva Oksana Mikhailovna, Принята к печати 11.02.2020 г MD, PhD, DSc, professor, head of the Asthma Department, NRC Institute of Immunology FMBA of Russia E-mail: kurbacheva@gmail.com Рекомендована к публикации ORCID ID: 0000-0003-3250-0694 Н.М. Ненашевой Russian Journal of Allergy 2020;17(1) 41 ОРИГИНАЛЬНЫЕ СТАТЬИ Полипозный риносинусит в сочетании с бронхиальной астмой treat not only conservatively, but also surgically [4]. In the selection of therapy for this cohort of patients, there are difficulties including those associated with the presence of comorbid diseases of CRSwNP, which significantly affect its clinical presentation, and, most importantly, the further success of CRSwNP therapy. Among the most common diseases in patients with CRSwNP, bronchial asthma (BA) characterized by chronic inflammation of the lower respiratory tract is distinguished [5, 6]. The combination of CRSwNP and BA is characterized by a clinically more severe and uncontrolled course of BA, where the apparent obstruction of the respiratory tract is observed as compared with patients suffering from BA without CRSwNP [7]. In this regard, CRSwNP is considered as a risk factor for the formation of severe and poorly controlled BA. It is believed that in patients with BA the presence of evident inflammation in the lower respiratory tract is caused by CRSwNP, therefore, such patients often need hospitalization to relieve BA exacerbation, and their treatment requires a longer time [8, 9]. Based on the concept of the uniformity of the respiratory system, which implies the implementation of the principle of “one respiratory tract, one disease” [10], CRSwNP and BA should be considered as two pathological conditions that have common features of pathogenesis. Based on this fact, a number of researchers believe that diseases of the upper and lower respiratory tract are a simultaneous manifestation of the same inflammatory process [11, 12]. However, it is worth noting that the inflammatory process with a combination of CRSwNP and BA has certain features that affect the choice of therapy, therefore, knowledge of the mechanisms of inflammation and their triggering factors can ensure successful diagnosis and treatment in the future. Materials and methods The study included 96 adult volunteers who were divided into 4 groups based on inclusion/exclusion criteria. Group 1: healthy volunteers (Normal), group 2: CRSwNP in combination with allergic BA (CRSwNP + aBA), group 3: CRSwNP in combination with non-al-lergic BA (CRSwNP + nBA), and group 4: CRSwNP without BA. Clinical, laboratory, instrumental and allergological examinations including a clinical blood test, spirometry, an allergy history, and skin prick tests using diagnostic allergens were carried out in all studied groups. Water-salt solutions of allergens manufactured by «Biomed» JSC named after I.I. Mechnikov: allergen from house dust, library dust, feather pillows, epidermal allergen from cat and dog hair, allergen D. pteronyssinus, and D. farinae, which had a concentration of 10,000±2500 PNU/ml, were used. Water-salt solutions of allergens by FSUC “SIC “Microgen” JSC: a mixed allergen from pollen of trees, meadow and weeds, which had a concentration of 10,000 PNU/ml were also used. In addition to the water-salt solutions of allergens, a test control fluid by FSUC “SIC “Microgen” JSC and a 0.1% histamine solution by LP Burli were used. The assessment of asthma control status was based on ACQ-7 questionnaire (Asthma Control Questionnaire), and the quality of life of patients was also evaluated using AQLQ (Asthma Quality of Life Questionnaire). The presence of bilateral polypous rhinosinusitis was confirmed by endoscopic examination of the nasal cavity and computed tomography of the paranasal sinuses (PNS). The endoscopic examination of the nasal cavity determined the prevalence of polyposis vegetation according to the recommendations of EPOS (European position paper on rhinosinusitis and nasal polyposis), 2012. Patients with isolated anthrochoanal and unilateral nasal polyps were not included in the study. The CRSwNP control status was assessed using SNOT-22 questionnaire (Sino-nasal outcome test - 22 questions - the questionnaire for controlling the outcome of diseases of the nose and paranasal sinuses). All patients underwent endovideoscopic polypotomy, and a group of healthy volunteers underwent surgical sampling of the fragments of the mucous membrane of the posterior ends of the lower nasal turbinates during a planned conchotomy Histological examination The surgical material was fixed in 10% neutral buffered formalin with pH of 7.2-7.4 for 12-24 hours. Preparation of the material, wrapping in paraffin, preparation of histological specimens, and staining with hematoxylin and eosin were carried out according to the generally accepted technique [13]. For section microtomy, a rotary microtome with a manual drive Leica RM2235 (Germany) was used. The study was carried out on Zeiss Axio Scope A1 microscope (Germany) with x 100 and x400-fold magnifications. The epithelial lining of the polyp or its fragments, the state of the glands, the evidence of stroma edema and fibrosis as well as the density and composition of inflammatory infiltration, which were determined in at least 10 representative fields of view on the microscope with 400-fold magnification, were evaluated. To establish the density of the infiltrate, the following cells (eosinophils, neutrophils, lymphocytes, histiocytes, macrophages, and mast cells) were counted with subsequent calculation of the arithmetic mean value, depending on the value of which three degrees of severity of leukocyte inflammatory infiltration were conditionally distinguished: weak (the 1st degree), moderate (the 2nd degree) and significant (the 3d degree). The first degree (I) included cases in which the arithmetic mean value calculated for 10 fields of view did not exceed 200 cells, at the second degree (II) the arithmetic mean ranged from 201 to 400 cells, and the third degree (III) the arithmetic mean was >400 cells. Using the quantitative indicators of the number of eosinophils and neutrophils in the inflammatory infiltrate, we determined the eosinophil-neutrophil index (ENI), which is equal to the ratio of the arithmetic mean value 42 Российский Аллергологический Журнал 2020;17(1) ORIGINAL ARTICLES Polypous rhinosinusitis in combination with bronchial asthma of eosinophils to the arithmetic mean value of neutrophils in 10 recorded fields of view. The calculation formula is given below. The arithmetic mean value of eosinophils in 10 fields of view ENI =- The arithmetic mean value of neutrophils in 10 fields of view Statistical processing of data Statistical analysis of the actual data was carried out using the statistical software package Statistica 12.0. The data were presented as “an arithmetic mean value” ± “a standard error of mean” [M+m]. The statistical significance of the differences was determined using a nonparametric criterion - Mann-Whitney U test. Differences were considered statistically reliable at P<0.05. To analyze the relationship between two numerical indicators, Spearman rank correlation was used. Correlation was considered reliable at P<0.05. Results Characterization of Patient Groups In all the studied groups women predominated, but in “CRSwNP without BA” group the ratio of women and men was 45.83% and 54.17%, respectively Table 1. Characteristics of the participants of the study (Table 1). The average BA duration was 14.96+2.25 years for CRSwNP + aBA group and 12.46+2.31 years for the CRSwNP + nBA group; at this no statistically significant differences were observed. The average duration of CRSwNP in CRSwNP + aBA group is 11.12+1.97 years, in CRSwNP + nBA group is 12.0+1.97 years, and in “CRSwNP without BA” group is 13.17+2.32 years. In most cases, aBA was diagnosed before CRSwNP, while the average age of the patients was 36.33+3.13 years, and later, with an interval of no more than 5 years, CRSwNP at the age of40.42+3.14 years. In CRSwNP + nBA group, it was revealed that such symptoms as nasal congestion were the first complaints before the diagnosis of bronchial asthma, which indicates the relationship of these diseases. In our study we also analyzed the frequency of exacerbations and hospitalizations due to BA, surgical interventions (endovideoscopic nasal polypotomy - FESS) for the entire period of the disease as suggested by the European Rhinology Research Forum (www.rhinolo-gyresearch.eu), organized by EUFOREA (European Forum for Research and Education in Allergy and Airway Diseases). The total percentage of hospitalizations for BA in CRSwNP + aBA group was 83.43%, which is Characteristics Normal CRSwNP + aBA CRSwNP + nBA CRSwNP without BA A number of people 24 24 24 24 Sex (women/ men, n, %) 13/11 (54.17%/45.83%) 20/4 (83.33%/16.67%) 18/6 (75.0%/25.0%) 11/13 (45.83%/54.17%) Age, years 32.50+2.79 50.63+2.90 52.83+2.94 50.25+2.22 CRSwNP debut, years 40.42+3.14 41.79+2.95 39.13+2.52 BA debut, years 36.33+3.13 40.38+3.19 BA duration, years 14.96+2.25 12.46+2.31 CRSwNP duration, years 11.12+1.97 12.0+1.97 13.17+2.32 BA exacerbations in the past 12 months 1 time, % 50.0% 41.67% 2 times,% 20.83% 25.0% 3 times,% 4.17% 4 times and more, % 20.83% Hospitalizations for BA in the past 12 months 1 time, % 75.1% 41.7% 2 times,% 8.33% 12.5% 3 times,% 8.33% 4 times and more, % 4.17% SGCS courses, % 58.33% 62.5% FESS more than 4 times for the entire disease period, % 66.67% 79.17% 54.17% Intolerance to NSAIDs, % 25.0% 54.17% # 4.17% Note: * - statistically significantly different from the «Normal», P<0.05; 0 - statistically significantly different from « CRSwNP + aBA», P<0.05; ** - statistically significantly different from « CRSwNP without BA», P<0.05. Russian Journal of Allergy 2020;17(1) 43 ОРИГИНАЛЬНЫЕ СТАТЬИ Полипозный риносинусит в сочетании с бронхиальной астмой significantly higher compared to CRSwNP + nBA group (66.7%). At the same time, a high frequency of hospitalizations (more than twice in 12 months) was noted in CRSwNP + nBA group in contrast to CRSwNP + aBA group, where single hospitalizations were mainly registered [75.1%] (Table 1). The above facts confirm the more severe clinical course of non-allergic BA in combination with CRSwNP. The obtained data also correlate with the frequency of BA exacerbations, thus, volunteers with CRSwNP in combination with BA had a severe course contributing to an increase in the volume of treatment with systemic glucocorticosteroids (SGCS) (Table 1), but the combination of nBA and CRSwNP is characterized by a more severe and uncontrolled course of BA, which led to frequent exacerbations and, naturally, hospitalizations. Regarding the frequency of surgical interventions, Table 1 shows that the largest percentage of polypotomies performed more than 4 times was in CRSwNP + nBA group as compared with CRSwNP + aBA and PRS without BA groups, but there were no statistically significant differences. In this case, we can state that BA directly affects CRSwNP leading to the aggressive course of the disease that is resistant to standard therapy. In the peripheral blood of the volunteers with CRSwNP + nBA, the absolute number of eosinophils was statistically significantly higher 5 and 9 times as compared with Normal group [p = 0.00001] and CRSwNP + aBA [p = 0.00002] (Fig. 1). In addition, the level of leukocytes was statistically significantly higher as compared with Normal group in the volunteers with CRSwNP + aBA [p = 0.001] and CRSwNP + nBA [p = 0.00004] (Fig. 2). It should be noted that “CRSwNP + aBA” [p = 0.040] and “CRSwNP + nBA” [p = 0.004] groups also had statistically significant differences as compared with CRSwNP without BA group. When considering the level of monocytes, a statistically significant increase was recorded in CRSwNP + nBA group as compared to Normal group [p = 0.006], CRSwNP + aBA [p = 0.008], CRSwNP without BA [p = 0.002] (Fig. 3). Segmental neutrophils were statistically significantly increased in Eosinophils 1 200 000 000 900 000 000 CD E 600 000 000 _o =□ о о 300 000 000 ** * Normal CRSwNP+aBA CRSwNP+nBA CRSwNP without BA Fig. 1. The level of eosinophils in peripheral blood. Note: * - statistically significantly different from the «Normal», P<0.05; 0 - statistically significantly different from «CRSwNP + aBA», P<0.05; ** - statistically significantly different from «CRSwNP without BA», P<0.05 Leukocytes 10 000 000 000 80 000 000 000 §. 60 000 000 000 .Q £ -§ 40 000 000 000 о о 20 000 000 000 0 Normal CRSwNP+aBA CRSwNP+nBA CRSwNP without BA Fig. 2. The level of leukocytes in peripheral blood. Note: * - statistically significantly different from the «Normal», P<0.05; о - statistically significantly different from «CRSwNP + aBA», P<0.05; ** - statistically significantly different from «CRSwNP without BA», P<0.05 Monocytes 800 000 000 600 000 000 E 400 000 000 200 000 000 Normal CRSwNP+aBA CRSwNP+nBA CRSwNP without BA Fig. 3. The level of monocytes in peripheral blood. Note: * - statistically significantly different from the «Normal», P<0.05; о - statistically significantly different from «CRSwNP + aBA», P<0.05; ** -statistically significantly different from «CRSwNP without BA», P<0.05 CRSwNP group in combination with allergic and non-al-lergic BA as compared with Normal group [p = 0.042 and p = 0.012, respectively], and CRSwNP without BA group [p = 0.049 and p = 0.017, respectively] (Fig. 4). Moreover, stab neutrophils were statistically significantly increased mainly in CRSwNP + aBA group as compared to Norm group [p = 0.041] and CRSwNP without BA group [p = 0.018] (Fig. 5). Segmental neutrophils 6 000 000 000 4 500 000 000 £ E 3 000 000 000 о ID О ° 1 500 000 000 0 Normal CRSwNP+aBA CRSwNP+nBA CRSwNP without BA Fig. 4. The level of segmental neutrophils in peripheral blood. Note: * - statistically significantly different from the «Normal», P<0.05; о - statistically significantly different from «CRSwNP + aBA», P<0.05; ** -statistically significantly different from «CRSwNP without BA», P<0.05 0 0 44 Российский Аллергологический Журнал 2020;17(1) ORIGINAL ARTICLES Polypous rhinosinusitis in combination with bronchial asthma 400 000 000 300 000 000 £ E 200 000 000 о ID О 100 000 000 0 Fig. 5. The level of stab neutrophils in peripheral blood. Note: * - statistically significantly different from the «Normal», P<0.05; 0 - statistically significantly different from «CRSwNP + aBA», P<0.05; ** - statistically significantly different from «CRSwNP without BA», P<0.05 According to spirometry data (Table 2), FEV1 (Forced expiratory volume) in “CRSwNP + aBA” and “CRSwNP + nBA” groups was statistically significantly lower as compared with “Normal” group [p = 0.0003 and p = 0.00002, respectively] and “CRSwNP without BA” group [p = 0.001 and p = 0.00004, respectively]. The ratio of FEV1/FVC (Forced lung capacity) in “CRSwNP + aBA” group also decreased, which indicates an increase in the clinical course of BA in combination with CRSwNP On the other hand, the greatest decrease in CRSwNP + nBA group was revealed in comparison with the patients of CRSwNP + aBA group. This fact is explained by a more pronounced inflammation and, therefore, a severe clinical course of non-allergic BA. There was a statistically significant decrease in FEV1/FVC ratio in CRSwNP without BA group as compared with Norm group [p = 0.004], which may indicate the already existing effect of inflammation in CRSwNP on the lower respiratory tract confirming the concept of the united respiratory tract. Allergological examination Polysensitization (year-round and pollen allergens) prevailed in the group of volunteers with CRSwNP + aBA - 41%, sensitization to pollen allergens was 32%, and to year-round allergens - 27%. The level of total IgE in the blood serum of volunteers with CRSwNP + nBA [165.11+72.26 IU/ml] was significantly higher as compared with other groups, while statistically significant differences [p = 0.021] were observed when Table 2. Spirometric data of the participants of the study Stab neutrophils Normal CRSwNP+aBA CRSwNP+nBA CRSwNP without BA comparing “CRSwNP + nBA” [165.11+72.26 IU/ml] and CRSwNP without BA [38.76+11.03 IU/ml] groups (Fig. 6). It is known that innate lymphoid cells of type 2 (ILC2) have a leading role in the pathogenesis of non-allergic BA and there is no mechanism for switching over B cells to IgE secretion. However, B cells play an equally important role in maintaining inflammation in case of BA and CRSwNP, and at this, in previous studies a significant number of B cells were found in polyp tissue locally producing antibodies of IgG1, IgG2, IgG4, IgA, IgE, and IgM classes. This may explain the increase in total IgE in the blood serum of the volunteers with CRSwNP in the absence of IgE-dependent allergy IgE 300 250 200 1. 150 100 50 0 Fig. 6. The level of total IgE in the blood serum. Note: * - statistically significantly different from the «Normal», P<0.05; о - statistically significantly different from «CRSwNP + aBA», P<0.05; ** - statistically significantly different from «CRSwNP without BA», P<0.05 Assessment of asthma and polypous rhinosinusitis control status According to ACQ-7 questionnaire, BA was uncontrolled in all studied groups when comparing volunteers with allergic and non-allergic BA, both in combination with CRSwNP and without it. The highest scores were noted in “CRSwNP + nBA” group [2.22+0.16 scores], while being statistically significantly different from “CRSwNP + aBA” group [p = 0.038] (Table 3). When assessing the evidence of rhinosinusitis symptoms according to SNOT-22 questionnaire, where the severity of the status is directly proportional to a number of scores, no statistically significant changes were detected, and SNOT-22 was 54.63+2.83 scores in the CRSwNP + aBA group, which is higher relative to other study groups. Studying of life quality by means .11. Normal CRSwNP+aBA CRSwNP+nBA CRSwNP without BA Characteristics Normal CRSwNP + aBA CRSwNP + nBA CRSwNP without BA FEV1, litres 3.55+0.19 2.49+0.15*, ** 2.03+0.14*, °, ** 3.53+0.21 FEV1, % of due values 109.05+2.96 86.04+3.69*, ** 74.1+3.83*, ** 109.44+3.57 FEV1/FVC , % of due values 83.14+1.58 67.88+1.69*, ** 63.65+2.17*, ** 77.41+1.22* Note: * - statistically significantly different from «Normal», P<0.05; о - statistically significantly different from «CRSwNP + aBA», P<0.05; ** - statistically significantly different from «CRSwNp without BA», P<0.05. Russian Journal of Allergy 2020;17(1) 45 ОРИГИНАЛЬНЫЕ СТАТЬИ Полипозный риносинусит в сочетании с бронхиальной астмой of AQLQ questionnaire revealed the lowest values of all life quality scales for the volunteers of “CRSwNP + nBA” group as compared with other studied groups (Table 3). Volunteers noted restrictions in their daily activities, suffered from the symptoms of the disease, experienced stress due to suffocation, dyspnea, and coughing, and heavily tolerated the negative impact of environmental factors. Processing the data, we obtained the results indicating that in combination with CRSwNP, the clinical course of BA becomes less controlled, confirmed by ACQ-7 and AQLQ data, while according to SNOT-22 questionnaire, where an increase was observed in “CRSwNP + aBA ” and “CRSwNP + nBA ” groups in comparison with other groups, BA complicates the clinical course of CRSwNP. Histological examination of the polyp biopsy material of the nasal mucosa When performing a pathomorphological study of polyp tissue depending on the predominance of cells, all polyps were divided into eosinophilic, neutrophilic, and, in case of an equal number of eosinophils and neutrophils, mixed. In this case the assessment was based on the predominance of eosinophils and neutrophils in 10 representative fields of view with 400-fold magnification. In CRSwNP + aBA group, 70.83% of eosinophilic and 4.17% of mixed polyps were diagnosed, but polyps with a predominance of neutrophils were not detected. In “CRSwNP + nBA” group, 62.50% of eosinophilic polyps, 8.33% of neutrophilic and 8.33% of mixed polyps were observed (Table 4). In “CRSwNP without BA” group, 58.33% of eosinophilic, 8.33% of neutrophilic and 8.34% of mixed polyps were detected. When studying ENI in polypous tissue, an increase in this ratio was revealed in all studied groups (CRSwNP in combination with allergic and non-allergic BA and CRSwNP without BA), without statistically significant differences (Table 4). Figures 7 and 8 show the degree of cell infiltration, which characterizes the intensity of the local inflammatory reaction. It should also be emphasized that, in contrast to the previously proven relationship between the level of eosinophils in blood and sputum with BA, a correlation analysis with the calculation of Spearman’s rank correlation did not reveal reliable correlations between the absolute or relative eosinophils values in peripheral blood and polyp tissue indicating the absence of the interdependence of the content of eosinophils in the polyp stroma and peripheral blood. Thus, in order to assess the intensity of inflammation in polyps, we cannot use the eosinophil value in the systemic blood flow, and it is necessary to rely mainly on the characteristics of the local inflammatory process. This confirms once again the need to study the indices Table 3. Questionnaires of BA and CRSwNP control Questionnaires CRSwNP + aBA CRSwNP + nBA CRSwNP without BA ACQ-7 1.81+0.15 2.22+0.16° SNOT-22 54.63+2.83 52.58+4.09 50.96+3.67 AQLQ Activity 3.23+0.47 3.03+0.38 Symptoms 2.44+0.26 2.11+0.18 Emotions 2.90+0.42 2.31+0.34 Environment 3.94+0.41 3.35+0.57 Note: о - statistically significantly different from «CRSwNP + aBA», P<0.05, ** - statistically significantly different from «CRSwNP without BA», P<0.05. Table 4. Histological examination data Indexes CRSwNP + aBA CRSwNP + nBA CRSwNP without BA ENI 13.88+4.06 11.35+3.49 14.72+4.09 Type of polypous tissue Eosinophilic 70.83% 62.50% 58.33% Neutrophilic - 8.33% 8.33% Mixed 4.17% 8.33% 8.34% 46 Российский Аллергологический Журнал 2020;17(1) ORIGINAL ARTICLES Polypous rhinosinusitis in combination with bronchial asthma 1 degree 2 degree 3 degree Fig. 7. The degree of manifestation of leukocyte inflammatory infiltration of the nasal polyp stroma. Note: Hematoxylin and eosin staining, 400-multiple magnification CRSwNP without BA CRSwNP + nBA CRSwNP + aBA 3 degree 2 degree 1 degree 0,00 5,00 10,00 15,00 20,00 25,00 30,00 35,00 40,00 45,00 Fig. 8. The degree of cell infiltration of polypous tissue in “CRSwNP + aBA”, “CRSwNP + nBA” and “CRSwNP without BA” groups of the local inflammatory response at the level of the mucous membrane of the upper respiratory tract, the state of which is the most significant diagnostic criterion for CRSwNP. Discussion The mutual influence of the two pathologies (CRSwNP and BA) has been too little studied, and these diseases are traditionally regarded as independent, as previously confirmed by many experiments. Initially, there was no increase in the frequency of allergic pathologies (including BA) among patients with CRSwNP, nor was their effect on the severity of CRSwNP symptoms and the probability of surgery to remove polyps. However, in recent years some publications have appeared in the world scientific literature, which prove the close relationship of CRSwNP and BA. Lin et al. [14-16] revealed the increased frequency of polyps in patients with BA, which was 31.4% for mild BA, and in the groups of patients with moderate and severe BA - 48.3% and 94.4%, respectively. Russian researchers also confirmed the existence of a relationship between BA and CRSwNP, and their study including 411 volunteers demonstrated the increased occurrence of polyps in patients with moderate (47.9%) and severe (41.2%) BA [17]. Processing the data, we obtained the results that indicated an uncontrolled course of asthma in combination with CRSwNP confirmed by ACQ-7 and AQLQ data, and a decrease in FEV1 and FEV1/FVC ratio in comparison with both Normal and CRSwNP without BA groups. Meanwhile, according to SNOT-22 questionnaire, BA complicates the clinical course of CRSwNP, which is also confirmed by the increased need for surgical treatment of endovideoscopic nasal polypotomy. According to EUFOREA recommendations, the clinical course of CRSwNP can be considered aggressive during nasal polypotomy more than 4 times during the entire period of the disease, and subsequent polypotomies are not effective for this category of patients. Patients with CRSwNP in combination with non-allergic and allergic BA had a greater percentage of polypotomies performed more than 4 times, which indicates a more severe and aggressive clinical course of CRSwNP. The obtained results are also confirmed by significant changes in the cellular composition of blood expressed in the largest deviation in the absolute number of eosinophils, leukocytes, segmented and stab neutrophils, and blood monocytes, which proves the fact of a more pronounced inflammation with a combination of CRSwNP and BA. Russian Journal of Allergy 2020;17(1) 47 оригинальные статьи Полипозный риносинусит в сочетании с бронхиальной астмой The results of our study refute the hypothesis of the occurrence of eosinophilic process only in the presence of allergies. In this case, eosinophilia can be explained by the activation of inflammation, developing with the participation of ILC2 type, which, producing IL-5, attract eosinophils to a local reaction zone. According to many authors, the predominance of the eosinophilic type of inflammation has a prognostically more severe clinical course and resistance to the therapy. In this case, the volunteers with CRSwNP in combination with nBA had more severe and uncontrolled clinical course of both diseases, which required the use of a larger volume of GCS. Our results showed that CRSwNP is a key predictor of an increase in BA severity reflected in a number of randomized studies where the severity of BA course had direct correlations with the severity of CRSwNP [18, 19]. Thus, CRSwNP and BA are heterogeneous diseases including many phenotypes that develop by various molecular mechanisms. Our study confirms the mutual influence of CRSwNP and BA, therefore, choosing the tactics of managing such patients, it is necessary to understand that therapy should be aimed at both CRSwNP and BA. If the inflammatory process in the upper and lower respiratory tract is controlled, then exacerbations will be much less frequent, and their clinical course will be less severe. Conclusion The frequent combination of CRSwNP and BA creates significant problems in their diagnosis and treatment, therefore, the study of the molecular mechanisms of the pathogenesis of these pathologies is a priority task in numerous studies around the world. The understanding the fact that inflammation in the upper respiratory tract supports inflammation of the lower respiratory tract and vice versa contributed to the concept of uniformity of the respiratory tract. However, our study confirmed not only the mutual influence of CRSwNP and BA, but also a significant predominance of the local inflammatory process, thus polyp development follows the local dysregulation of pro- and anti-inflammatory factors, while systemic disorders are secondary in the immune system.
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About the authors

Oksana Mikhailovna Kurbacheva

NRC Institute of Immunology FMBA of Russia

Email: kurbacheva@gmail.com

Miramgul Esengeldyevna Dyneva

NRC Institute of Immunology FMBA of Russia

Email: amanturliva.miramgul@mail.ru

Igor Petrovich Shilovskii

NRC Institute of Immunology FMBA of Russia

Email: igorshilovski@gmail.com

Elena Leonidovna Savlevich

Federal State Budgetary Institution of Higher Professional Education “Central State Medical Academy” of the Office of the President of the Russian Federation

Email: savllena@gmail.com

Valeriia Ivanovna Kovchina

NRC Institute of Immunology FMBA of Russia

Email: kvi91@mail.ru

Aleksandr Arkadevich Nikolskii

NRC Institute of Immunology FMBA of Russia

Email: aa.nikolskii@nrcii.ru

Elizaveta Iurevna Savushkina

Federal State Budgetary Institution of Higher Professional Education “Central State Medical Academy” of the Office of the President of the Russian Federation

Email: lizasavushkina@mail.ru

Musa Rakhimovich Khaitov

National Research Center - Institute of Immunology Federal Medical-Biological Agency of Russia

Email: mr.khaitov@nrcii.ru

References

  1. Kim DW, Cho SH. Emerging endotypes of chronic rhinosinusitis and its application to precision medicine. Allergy Asthma Immunol Res. 2017;9(4):299-306. DOI: 10.4168/ aair.2017.9.4.299.
  2. Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I et al. European position paper on rhinosinusitis and nasal polyps. Rhinol Suppl. 2012;50(23):1-298. DOI: 10.2500/ ajra.2013.27.3925.
  3. Serrano E, Neukirch F, Pribil C, Jankowski R, Klossek JM et al. Nasal polyposis in France: impact on sleep and quality of life. J Laryngol Otol. 2005;119(7):543-549. doi: 10.1258/0022215054352108.
  4. Савлевич ЕЛ, Гаганов ЛЕ, Егоров ВИ, Курбачева ОМ, Герасимов АН, Шачнев КН. Сравнительное пилотное исследование эндотипов хронического полипозного риносинусита у пациентов, проживающих в разных географических регионах Российской Федерации. Иммунология. 2018;39(4):208-213. doi: 10.18821/0206-49522018-39-4-208-213.
  5. Шиловский ИП, Дынева МЕ, Курбачева ОМ, Кудлай ДА, Хаитов МЕ Роль интерлейкина-37 в патогенезе аллергических заболеваний. ACTA NATURAE. 2019;4(43):54-64. doi: 10.32607/20758251-2019-11-4-54-64.
  6. Курбачева ОМ, Павлова КС. Фенотипы и эндотипы бронхиальной астмы: от патогенеза и клинической картины к выбору терапии. Российский Аллергологический Журнал. 2013;10(1):15-24.
  7. Chaaban MR, Walsh EM, Erika M, Woodworth BA et al. Epidemiology and differential diagnosis of nasal polyps. Am J Rhinol Allergy. 2013;27(6):473-478.
  8. Савлевич ЕЛ, Дынева МЕ, Гаганов ЛЕ, Егоров ВИ, Герасимов АН, Курбачева ОМ. Лечебно-диагностический алгоритм при разных фенотипах полипозного риносинусита. Российский Аллергологический Журнал. 2019;16(2):50-61.
  9. Soler ZM, Mace JC, Litvack JR, Smith TL. Chronic rhinosinusitis, race, and ethnicity. Am J Rhinol Allergy. 2012;26:110-116. doi: 10.2500/ajra.2012.26.3741.
  10. Дынева МЕ, Курбачёва ОМ, Савлевич ЕЛ. Бронхиальная астма в сочетании с хроническим полипозным риносинуситом: эпидемиология, распространенность и особенности их взаимоотношения. Российский Аллергологический Журнал. 2018;15(1):16-25.
  11. Stevens WW, Peters AT, Hirsch aG, Nordberg CM, Schwartz BS et al. Clinical Characteristics of Patients with Chronic Rhinosinusitis with Nasal Polyps, Asthma, and Aspirin-Exacerbated Rbiespiratory Disease. J Allergy Clin Immunol Pract. 2017;5(4):1061-1070. doi: 10.1016/j.jaip.2016.12.027.
  12. Mortuaire G, Gengler I, Balden M, Capron M, Lefevre G. Impact of allergy on phenotypic and endotypic profiles of nasal polyposis. European Annals of Otorhinolaryngology Head and Neck Diseases. 2017;135:159-162. DOI: 10.1016/j. anorl.2017.11.005.
  13. Курс патогистологической техники. Под ред. Меркулова ГА. Л.: Медгиз; 1961.
  14. Yeganeh C, Xia H, Movassagh C, Koziol-White Chang Y et al. Emerging mediators of airway smooth muscle dysfunction in asthma. Pulm Pharmacol Ther. 2013;26(1):105-111. doi: 10.1016/j.pupt.2012.06.011.
  15. Raedler D, Ballenberger N, Klucker E, Bock A et al. Identification of novel immune phenotypes for allergic and nonallergic childhood asthma. J Allergy Clin Immunol. 2015;135(1):81-91. doi: 10.1016/j.jaci.2014.07.046.
  16. Lin DC, Chandra RK, Tan BK, Zirkle W Conley DB et al. Association between severity of asthma and degree of chronic rhinosinusitis. Am J Rhinol Allergy. 2011;25:205-208. doi: 10.2500/ajra.2011.25.3613.
  17. Чичкова НВ. Бронхиальная астма и полипозный риносинусит: особенности клинического течения и тактика ведения больных. Астма и аллергия. 2015;1:19-22.
  18. Yacoub MR, Trimarchi M, Cremona G, Dal Farra S et al. Are atopy and eosinophilic bronchial inflammation associated with relapsing forms of chronic rhinosinusitis with nasal polyps? Clin Mol Allergy. 2015; 13(1):1-6. doi: 10.1186/s12948-015-0026-8.
  19. Pearlman AN, Chandra RK, Chang D, Conley DB et al. Relationships between severity of chronic rhinosinusitis and nasal polyposis, asthma, and atopy. Am J Rhinol Allergy 2009;23(2):145-148. doi: 10.2500/ajra.2009.23.3284.

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