RU2796386C1 - Method for predicting exacerbations of bronchial asthma over the next year in patients with concomitant multimorbid pathology - Google Patents

Abstract

FIELD: medicine; therapy; pulmonology.

SUBSTANCE: invention can be used to predict exacerbations of bronchial asthma (BA) over the next year in patients with concomitant multimorbid pathology. Diagnostic indicators are determined as follows: the level of physical activity according to the ODA23+ questionnaire, forced expiratory volume in 1 second of the maneuver, forced expiratory lung capacity (FEV₁), the level of blood serum peroxides, the level of activity of patients according to the Lequesne scale, the level of leptin venous blood, body mass index (BMI), interleukin-6 (IL-6), cumulative disease index CIRS. Based on the data obtained, the probability index of the frequency of BA exacerbation over the next year in patients with concomitant multimorbid pathology (ExacBA) is calculated using the following formula:

ExacBA = 7,57567 - 0,105518×FEV₁ - 0,144268×CIRS - 0,000172187×ODA23⁺×FEV₁ - 0,000901236×ODA23⁺×Leken + 0,00038601×ODA23⁺×BMI - 0,000426185×ODA23⁺×IL6 + 0,00135395×ODA23⁺×CIRS + 0,000477974×FEV₁ ² + 0,000968334×FEV₁×Leken - 0,000180234×FEV₁×Leptin + 0,000369123×FEV₁×IL6 - 0,00000330283×PerOx×IL6 + 0,000376305×Leptin×BMI - 0,000246557×Leptin×IL6 - 0,000365621×BMI² + 0,000185599×IL6² + 0,00290871×CIRS²,

where ODA23⁺ is the result according to the ODA23+ motor activity questionnaire, in points, FEV₁ is the forced expiratory volume in 1 second, in percent, PerOx is the level of blood serum peroxides, µmol/l, Leken is the result of assessing the dynamics of patients' activity according to the Leken scale, points, Leptin — venous blood leptin level, ng/ml, BMI — body mass index, kg/m², IL6 — IL-6 level, pg/ml, CIRS — cumulative disease index, points. If the ExacBA value is less than 2, a low risk of developing BA exacerbations is predicted, with the number of exacerbations once a year. With an ExacBA value of 2 or more, a high risk of exacerbations is predicted, with the number of exacerbations per year 2 or more times.

EFFECT: method makes it possible to obtain a reliable prognosis for the development of BA exacerbations in patients with concomitant multimorbid pathology over the next year by studying a complex of factors using the mathematical apparatus of multivariate regression analysis.

1 cl, 2 tbl, 2 ex

Description

The invention relates to medicine, namely to therapy and pulmonology, and can be used for a personalized program for the management of patients with bronchial asthma (BA) with concomitant multimorbid pathology, taking into account the individual risk of exacerbations of the disease during the next year of observation.

In recent years, the number of patients with comorbid, polymorbid or multimorbid diseases has been steadily growing (Cardiovascular Therapy and Prevention. 2019;18(1):5-66. http://dx.doi.org/10.15829/1728-8800-2019- 1-5-66). According to recent publications, the most common multimorbid conditions in AD are upper respiratory tract disease, chronic sinusitis, gastroesophageal reflux disease (GERD), obesity, and depression. GINA (Global Initiative for Asthma 2022) experts believe that the main comorbid diseases of asthma to pay attention to are rhinosinusitis, obesity and GERD. But, at the same time, GINA points out that in patients with AD, especially those with difficult to control or severe AD, there are usually several comorbidities and active treatment of comorbidities is recommended, as they can exacerbate the burden of symptoms, impair quality of life and lead to to drug interactions, and some comorbidities also impair asthma control. Many researchers pay great attention to comorbid diseases in patients with asthma, analyze their impact on the prognosis and treatment of asthma (Uryasiev O.M., Panfilov Yu.A. Effect of obesity on clinical and functional parameters and the effectiveness of anti-asthma therapy in patients with bronchial asthma. Science young (Eruditio Juvenium) 2013;4:79-88). To identify the most common comorbidities in AD, Su X. et al. conducted an extensive meta-analysis of the available literature data, which showed that the following diseases were more common in patients with BA compared to those without this diagnosis: cardiovascular pathology, including arterial hypertension and cerebrovascular disease; obesity, diabetes mellitus and other metabolic and endocrine diseases; as well as mental and neurological disorders, diseases of the intestines and urinary tract, cancer and other bronchopulmonary diseases (Su X., Ren Y., Li M., et al. Prevalence of Comorbidities in Asthma and Nonasthma Patients: A Meta-analysis / / Medicine 2016 Vol 95 No 22 P e3459 doi:10.1097/MD.0000000000003459). It is also important that comorbidities occur in patients with asthma much more often than in the general population (Karlstad 0., Nafstad P., Tverdal A., et al. Comorbidities in an asthma population 8-29 years old: a study from the Norwegian Prescription Database // Pharmacoepidemiology and Drug Safety 2012 Vol 21 No 10 P 1045-1052 doi:10.1002/pds.2233). A population-based study conducted in Scotland showed that 62.6% of patients with asthma had at least 1 comorbidity, and 16.3% had 4 or more (Weatherburn C.J., Guthrie B., Mercer S.W., et al. Comorbidities in adults with asthma: Population based cross-sectional analysis of 1.4 million adults in Scotland Clinical and Experimental Allergy 2017 Vol 47 No 10 pp 1246-1252 doi:10.1111/cea 12971). American authors Ir. Mindlis et al. showed that elderly AD patients have 2 or more comorbidities, with a median of 5.3 (SD=2.3; range 0-12) (Mindlis I, Wisnivesky JP, Wolf MS, et al. Comorbidities and depressive symptoms among older adults with asthma J Asthma 2022;59(5):910-916 doi: 10.1080/02770903.2021.1887890). Recent meta-analyses have reported a prevalence of 49.5% (95% CI, 36.4%-6.6%) of osteoarthritis in patients with AD (Althoff MD, Ghincea A, Wood LG, et al. Asthma and Three Colinear Comorbidities: Obesity, OS A, and GERD J Allergy Clin Immunol Pract. 2021;9(11):3877-3884 doi: 10.1016/j.jaip.2021.09.003.). Korean researchers showed that arthritis, rhinitis, depression, and obesity were independently associated with asthma in Korean patients over 40 years of age (Park J, Kim TV, Joo Η, Lee JS, Lee SD, Oh YM. Diseases Concomitant With Asthma in Middle-Aged and Elderly Subjects in Korea: A Population-Based Study Allergy Asthma Immunol Res 2013 Jan;5(l): 16-25 https://doi.org/10.4168/aair.2013.5.l.16).

When assessing the impact of comorbid diseases on BA control, it was shown that 92% of patients with difficult-to-control BA had at least 1 comorbid disease. The number of comorbidities is inversely proportional to the level of asthma control, the more diseases, the worse the control (Hekking RR, Amelink M, Wener RR, et al. Comorbidities in Difficult-to-Control Asthma. J Allergy Clin Immunol Pract. 2018;6(1) : 108-113 doi: 10.1016/j.jaip.2017.06.008). D.A. Beuther et al. also showed that patients with difficult or uncontrolled asthma have a high prevalence of comorbid diseases and concomitant obesity (Beuther D. A., Sutherland E. R. Overweight, obesity, and incident asthma: a meta-analysis of prospective epidemiologic studies. Am. J. Respir. Crit. Care Med. 2007; 175:661-666). When BA is combined with comorbid diseases and obesity, the achievement of control over the disease worsens, the response to standard therapy decreases (Ermolova A.V., Budnevsky A.V., Malysh E.Yu., etc. Clinical and functional features of bronchial asthma in patients with metabolic syndrome Clinical medical 2015;93(6):44-49). Thus, comorbidities should be considered with greater attention in AD strategies and should be an important component of analysis of covariance in studies with subjective health outcomes (Wijnhoven HA, Kriegsman DM, Hesselink AE, de Haan Μ, Schellevis FG. The influence of co -morbidity on health-related quality of life in asthma and COPD patients. Respir Med. 2003 May;97(5):468-75. doi: 10.1053/rmed.2002.1463. PMID: 12735662.).

Existing methods for predicting exacerbation of BA can be divided into two groups.

1. Methods for determining, as such, the prognosis of exacerbation of BA

For example, the “Method for predicting an exacerbation of bronchial asthma” is known (RF patent No. 2563998 dated September 27, 2015), which consists in the collection and study of peripheral blood at the stage of remission of BA. The resulting blood is divided into 2 samples, while ultraviolet irradiation of one of the samples is carried out for 60 seconds, blood serum samples are obtained from them, which are examined by the method of marginal dehydration in polarized light, and upon detection of aggregations of a spherulite crystal and a spherical accumulation of small particles embedded in it weakly anisotropic granules in a sample not exposed to irradiation, and spherulite crystals surrounded by loosely arranged clusters of weakly anisotropic granules in a sample exposed to irradiation, exacerbation of bronchial asthma is predicted. EFFECT: method makes it possible to predict exacerbation of BA at the preclinical stage, when preventive measures will be timely and will not allow the disease to go into an exacerbation stage.

The disadvantages of the method are the determination of the stage of remission or exacerbation at the current time and the inability to predict the number of exacerbations of BA over the next year, the method is difficult to apply in routine clinical practice in the provision of primary health care, comorbid pathology is not taken into account.

Also known is the “Method for predicting the number of exacerbations in patients with bronchial asthma” (RF patent No. 2458347 dated August 10, 2012), which consists in the fact that on the ficoll-verografin density gradient, lymphocytes are isolated by centrifugation from the patient’s whole blood taken from the cubital veins in the morning on an empty stomach, during exacerbations of BA and after its relief. A suspension of lymphocytes is applied to a glass slide as a “thick drop”, dried at room temperature, and CD38+ lymphocytes are counted per 300 cells in the field of view by an immunocytochemical method using mouse anti-human CD38 antibodies, anti-mouse FITC-labeled antibodies and fluorescent microscopy. With a decrease in their number in the second sample relative to the first by 4 cells or more, the absence of exacerbations of BA during the year is predicted, with an increase by 4 or more cells - at least 2 exacerbations, the absence of dynamics in the change in the number of CD38+ lymphocytes or fluctuations within 3 cells provides for 1 exacerbation . The method allows to predict the number of BA exacerbations within a year after hospitalization.

The disadvantage of this method is the complexity of the use in routine clinical practice of immunocytochemical blood tests, comorbid pathology is not taken into account.

2. Methods for determining the prognosis of exacerbation of asthma, taking into account the comorbid condition of the patient

Previously, we developed a “Method for predicting exacerbations of bronchial asthma over the next year in patients with concomitant obesity” (RF patent No. blood, the level of adiponectin in venous blood, patient compliance using the “Compliance Scale for Patients with Chronic Nonspecific Lung Diseases”, the level of situational anxiety on the Spielberger Anxiety Scale, the level of depression on the Zung Self-Assessed Depression Scale. The method allows to calculate the index of the probability of exacerbation of BA within 1 year of observation using the developed formula. The disadvantages of this method is that only obesity is taken into account, other comorbid pathologies are not taken into account, which can act as trigger factors and increase the risk of BA exacerbations over the next year.

According to the World Health Organization (WHO), asthma is one of the main common chronic non-communicable diseases (CNCDs), which affects not only adults but also children (https://www.who.int/news-room/fact-sheets/detail /noncommunicable-diseases).

Insufficient physical activity (PA) is associated with the risk of developing chronic NCDs, including overweight, obesity (Bobrik Yu.V., Moroz G.A., Ponomarev V.A. The role of physical culture in the primary prevention of chronic non-communicable diseases and improving the quality life of the population, Scientific Bulletin of Crimea, 2018;6(17): 19-23).

Asthma is characterized by variability in respiratory symptoms, manifested in varying intensity, duration, frequency, as well as reversibility of bronchial obstruction (2022 GINA Report, Global Strategy for Asthma Management and Prevention. https: //ginasthma.org/gina-reports/).

With such a variable course of BA, patients often limit their activity, lead a sedentary lifestyle, do not increase the intensity and duration of FA, believing that FA provokes BA symptoms (Dobrynina E.A. Bronchial asthma and exercise. Bulletin of Science and Education. 2017; 1 (12(36)), 102-105). Indeed, high-intensity FA can be one of the triggers of acute bronchospasm (Tsarev S.V. Exercise-induced bronchospasm. Asthma and allergy. 2018;(4):3-6), but, according to the literature, dosed training under optimal conditions (air humidity, temperature), on the contrary, help to reduce the frequency and severity of seizures (Tribuntseva L.V., Budnevsky A.V., Shkatova Y.S., Ivanchuk Yu.S., Tokmachev R.E. The importance of physical activity for the clinical course bronchial asthma: a review of the literature, Academician I.P. Pavlov Russian Biomedical Bulletin, 2021;29(1): 161-170. In patients with asthma, exercise-induced bronchospasm (EF) is often associated with poor disease control. The occurrence of bronchoconstriction associated with physical activity limits further exercise, which in turn negatively affects the quality of life (QoL) of patients. (Mancuso SA, Sayles W, Robbins L, Phillips EG, Ravenell K, Duffy C, et al. Barriers and facilitators to healthy physical activity in asthma patients. The Journal of asthma: official journal of the Association for the Care of Asthma. 2006 ;43(2): 137-43.). In addition, the restriction of ΦΑ can lead to overweight, obesity.

The impact on AD of multimorbid diseases such as: cardiovascular disease, depression, diabetes mellitus, dyslipidemia, osteoporosis, rhinosinusitis, chronic obstructive pulmonary disease, obesity, arthritis, cancer, GERD, is being actively studied (Park J, Kim TV, Joo Η, Lee JS , Lee SD, Oh YM. Diseases concomitant with asthma in middle-aged and elderly subjects in Korea: a population-based study. Allergy Asthma Immunol Res 2013;5:16-25). Excessive deposition of adipose tissue, even in the absence of asthma, leads to physiological changes in lung function, for example, a decrease in lung volumes, an increase in chest rigidity, and the formation of dyspnea (Beuther DA, Sutherland ER. Obesity and pulmonary function testing. J Allergy Clin Immunol. 2005;115 :1100-1101). Due to the deposition of fat in the chest, its rigidity develops and, as a result, difficulty in breathing. The deposition of fat in the abdominal cavity leads to a limitation of diaphragm mobility due to overstretching of muscle fibers (Pertseva T.A., Nudga N.P. Asthma and obesity: what is the relationship. Ukrainian Pulmonological Journal. 2011; 1: 61-64).

Systemic inflammation is a common pathogenetic mechanism for most AD phenotypes, as well as for obesity, diabetes mellitus, depression, and explains the possible relationship between these diseases (Kapadia S.G., Wei C, Bartlett S.J., et al. Obesity and symptoms of depression contribute inde- pendently to the poor asthma control of obesity // Respiratory Medicine 2014 Vol 108 No 8 P 1100-1107 doi:10.1016/j.rmed.2014.05.012). It is known that obesity increases the risk of developing BA, and also aggravates its course, reducing the level of symptom control, increasing the risk of exacerbations (Solovyova I.A., Sobko E.A., Demko I.V., Kraposhina A.Yu., Gordeeva N.V. ., Loktionova M. M. Bronchial asthma and obesity Therapeutic archive 2017; 89 (3), 116-120. Obesity is directly related to chronic systemic inflammation. Performing the functions of an endocrine organ, adipose tissue produces various biologically active substances, such as leptin, adiponectin, as well as pro-inflammatory mediators - interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α). Asthma is considered as a chronic inflammatory disease of the airways, which leads to bronchial hyperreactivity. Therefore, obesity, by increasing airway inflammation, may affect asthma. It has been proven that a high level of IL-6 associated with obesity contributes to the intensification and maintenance of inflammation in the lungs, and, as a result, the intensification and maintenance of asthma symptoms (Kytikova O.Yu., Gvozdenko T.A., Antonyuk M.V. The role of systemic inflammation in bronchial asthma and obesity Clinical Medicine 2018;96(9):784-790).

In addition, in obesity, as a result of the toxic effects of intermediate products of fatty acid metabolism, the structural elements of adipose tissue are in a state of constant oxidative stress, which in turn activates intracellular signaling systems in adipocytes. This leads to an increase in the expression of intermediate products of fatty acid metabolism, an increase in inflammatory processes in the entire adipose tissue of the body. Generalization of inflammation is accompanied by increased synthesis of pro-inflammatory cytokines, including IL-6, TNF-α.

Common molecular-cellular pathogenetic mechanisms of AD and obesity determine more pronounced clinical symptoms, frequent exacerbations, and, as a result, a low level of control, resistance to basic therapy in combination with more frequent use of β-agonists to relieve symptoms, severity of asthma, frequent hospitalizations with an exacerbation of the disease (Markova T.N., Fomina D.S., Kostenko A. A., Bobrikova E.N. Obesity and bronchial asthma: two diseases with common aspects of pathogenesis. Preventive medicine. 2020;23(4): 126 -132).

Researchers indicate certain relationships between the activity of the immune system and psychological state. For example, cytokines such as IL-1, -2 and -6 and TNF-α are involved in the regulation of affective behavior. An animal study has shown that an acute immune problem has an effect similar to that of a major depressive disorder. In addition, chronic stress can lead to dysregulation of the hypothalamic-pituitary-adrenal axis, excessive production of cortisol levels, resistance to glucocorticosteroids, and the development of systemic inflammation. Systemic inflammation is characterized by elevated levels of inflammatory markers such as C-reactive protein (CRP), IL-6, IL-1β, TNF-α, and leptin. Elevated levels of IL-6, CRP and CD 163 (macrophage activation marker) have been associated with decreased lung function (especially in severe AD) and neutrophilic airway inflammation (Zhang L., Zhang X., Zheng J., et al. Depressive symptom -associated IL-1β and TNF-α release correlates with impaired broncho dilator response and neutrophilic airway inflammation in asthma Clinical and Experimental Allergy 2019 Vol 49 No 6 P 770-780 doi: 10.1111/cea. 13346). Aging is also associated with a chronic pro-inflammatory state, with elevated concentrations of IL-1, IL-6 and TNF-α. Various inflammatory mediators, including IL-1, IL-6, IL-8, TNF-α, and other cytokines, are known to be elevated in patients with osteoarthritis. In addition, obese patients are known to consume more calories, which leads to mitochondrial overload, overproduction of reactive oxygen species, damage to mitochondrial (and cellular) components, and mitochondrial loss. Mitochondrial dysfunction leads to incomplete oxidation of fatty acids and an increase in circulating lipids. Some metabolically active lipids inhibit insulin signaling and may contribute to the development of insulin resistance. The situation is aggravated by inactivity, since physical activity is a way to increase mitochondrial activity (Aguilera-Aguirre L., Bacsi A., Saavedra-Molina A., et al. Mitochondrial dysfunction increases allergic airway inflammation // Journal of Immunology. 2009. Vol. 183, No. 8. P. 5379-5387. doi: 10.4049/jimmunol.0900228). Asthma is associated with oxidative stress, which may be partially caused by mitochondrial dysfunction, but also accelerates mitochondrial dysfunction (Sahiner U.M., Birben E., Erzurum S., et al. Oxidative stress in asthma: Part of the puzzle // Pediatric Allergy and Immunology. 2018. Vol.29, No. 8. P. 789-800. doi: 10.1111/pai. 12965).

Thus, patients with asthma and concomitant multimorbid pathology require a personalized management program to prevent exacerbations in a timely manner.

The task to be solved by this invention is the possibility of predicting exacerbations of BA in the coming year in patients with concomitant multimorbid pathology.

Achievable technical result is to obtain a reliable forecast of the development of BA exacerbations in patients with concomitant multimorbid pathology.

The technical result is achieved through the following methods.

In a patient with bronchial asthma with concomitant multimorbid pathology, indicators such as the level of physical activity according to the ODA23+ questionnaire, forced expiratory volume in 1 second of the maneuver, forced expiratory lung capacity (-FEV ₁ -), the level of blood serum peroxides, the level of activity of patients are determined according to the Lequesne scale, venous blood leptin level, body mass index (BMI), interleukin-6 (IL-6) level, CIRS cumulative disease index.

Then, based on the data obtained, the probability index of the frequency of exacerbation of BA over the next year in patients with concomitant multimorbid pathology (ExacBA) is calculated using the formula:

где ODA23⁺ - результат по опроснику двигательной активности ODA23+, в баллах,

where ODA23 ⁺ is the result of the ODA23+ motor activity questionnaire, in points,

FEV ₁ - forced expiratory volume in 1 second, in percent,

PerOx - the level of blood serum peroxides, µmol/l,

Leken is the result of assessing the dynamics of patients' activity on the Leken scale, in points,

Leptin - venous blood leptin level, ng/ml,

BMI - body mass index, kg / m ² ,

IL6 - IL-6 level, pg/ml,

CIRS - cumulative disease index, in points.

If the value of ExacBA is less than 2, a low risk of developing exacerbations of BA is predicted, with the number of exacerbations 1 time per year. With an ExacBA value of 2 or more, a high risk of exacerbations is predicted, with the number of exacerbations per year 2 or more times.

We have developed a predictive model for the frequency of BA exacerbations in patients with concomitant multimorbid pathology.

To calculate the parameters of the model, we analyzed the data of 237 patients with asthma aged 18 to 78 years: men - 51 (21.5%), women - 186 (78.5%), mean age 52.6 ± 1.3 years. Patients were under observation for 12 months, a comprehensive examination was performed at the stage of inclusion in the study and after 12 months.

The diagnosis of asthma was established in accordance with the GINA 2022 criteria.

All patients underwent a comprehensive examination, which included collecting complaints and anamnesis, assessing the objective status, and determining laboratory parameters of venous blood.

BMI was calculated using the formula BMI=Macca/height ² (kg/m ² ): BMI 18.5-25 kg/m ² - norm, BMI 25-30 kg/m ² - overweight BMI > 30 kg/m ² - obesity.

Based on the anamnesis data, outpatient card data, data from additional research methods conducted by patients, the existing comorbidities were analyzed and evaluated. Multimorbid pathology was assessed using the CIRS (Cumulative Illness Rating Scale) pathology rating scale (Miller MD, Paradis CF, Houck PR, et al. Rating chronic medical illness burden in geropsychiatric practice and research: application of the Cumulative Illness Rating Scale // Psychiatry Res. 1992;41(3):237-48) The mean number of comorbidities was 4.8±0.61. The average score of the CIRS index was 7.44±0.95 points, the maximum score was 19, the minimum was 2. The CIRS index value was significantly higher among patients with obesity and amounted to 10.1±1.9 points, while in patients without obesity it was 4.68±0.31 points. There were significant differences in the values of the CIRS index depending on the presence or absence of obesity (p<0.0001).

The level of motor activity was assessed using the ODA23+ motor activity questionnaire developed at the Federal State Budgetary Institution “GNITsPM” of the Ministry of Health of Russia (Aronov D.M., Krasnitsky V.B., Bubnova M.G., 2013). Motor activity was assessed as "Very high" at ≥109 points, "High" at 85-108 points, "Moderate" at 62-84 points, "Low" at 39-61 points, "Very low" at ≤38 points.

The dynamics of patients' activity in everyday life was assessed using the Leken's functional index. With a result of 0 points - there was no disability, the degree of disability was assessed as "Mild" at 1-4 points, "Moderate" at 5-7 points, "Severe" at 8-10 points, "Sharply pronounced" at 11-13 points, "Extremely pronounced" at ≥14 points (Lequesne M. Indices of severity and disease activity for osteoarthritis. Semin Arthritis Rheum. 1991;20(6(2)):48-54).

The study of parameters of respiratory function (RF) was carried out on the spirograph "Diamant-S" (Russia) with the registration of the "flow-volume" loop. The FEV ₁ indicator was analyzed - the volume of forced expiratory flow in the 1st second of the forced vital capacity (FVC) maneuver of exhalation. The proper values of the spirometric indicator were recorded, expressed as a percentage of the standard for the corresponding age, height and sex.

The level of oxidative stress was determined by the level of peroxides by enzyme immunoassay (ELISA) using the PerOx kit from Immundiagnostik (Germany). The level of oxidative stress was assessed as "Low" at the level of hydrogen peroxide <180 µmol/l, "Medium" at 180-310 µmol/l, "High" at >310 µmol/l.

The level of the leptin adipocytokine profile was determined by ELISA using the LEPTIN-Sensitive-ELISA reagent kit from Mediagnost GmbH (Germany). Reference values for men: 2.0-5.6 ng/ml, for women 3.7-11.1 ng/ml.

The level of the pro-inflammatory profile indicator - interleukin (IL)-6 was determined using the "sandwich" variant of solid-phase ELISA with a set of reagents "INTERLEUKIN-6-ELISA-BEST" company VECTOR-BEST (Russia). Reference values <7.0 pg/ml.

Statistical data processing was carried out using the STATGRAPHICS 18 for Windows software package.

Using the apparatus of multivariate regression analysis, a model was constructed that describes the dependence of the frequency of BA exacerbations over the next year in patients with concomitant multimorbid pathology on the studied factors.

Thus, the index of the probability of BA exacerbation over the next year (ExacBA) in c.u. was chosen as a predictive variable, as dependent variables:

- ODA23 ⁺ result on the ODA23+ motor activity questionnaire (points);

- FEV ₁ - forced expiratory volume for the 1st second of the expiratory FVC maneuver (% of due);

- PerOx - the level of blood serum peroxides (µmol/l);

- Leken - the result of assessing the activity of patients on the Leken scale (points);

- Leptin venous blood leptin level (ng/ml);

- BMI - body mass index (kg/cm ² );

- IL-6 - level of pro-inflammatory profile - IL-6 (pg/ml);

- CIRS - cumulative disease index CIRS (Cumulative Illness Rating Scale).

When constructing the model, not only the influence of each factor separately on the frequency of BA exacerbations was taken into account, but also their combined (paired) effect. The assessment of the significance of the coefficients of the regression equation was evaluated based on the Student's t-test. At the same time, insignificant (p>0.05) coefficients (and their corresponding indicators) were sequentially (starting from the coefficient with the worst estimate) excluded from the model and the remaining coefficients were recalculated. This process was repeated until only significant coefficients remained in the model (with the corresponding indicators and their pair interactions).

The model thus constructed has the following form:

Scale for assessing the risk of BA exacerbations:

ExacBA <2 - low risk of developing exacerbations of BA, with the number of exacerbations 1 time per year,

ExacVA>2 - high risk of exacerbations, with the number of exacerbations per year 2 or more times.

In table. 1 shows estimates of the parameters of the resulting model.

Table 2 presents the results of assessing the adequacy of the model.

As follows from Table 2, the model adequately (F=83.96, p<0.0001) describes the existing relationship between the frequency of BA exacerbations and the studied parameters included in the model as independent variables.

Example 1

Patient C, 48 years old, with allergic bronchial asthma, mild severity, partially controlled by DN0. Gastroesophageal reflux disease, endoscopically negative. Pollinosis. Seasonal allergic rhinoconjunctivitis. Uterine fibromyoma, submycotic. Data from a comprehensive clinical, instrumental and laboratory examination: the result of ODA23+ was 79.7 points, FEV ₁ - 75% of the predicted value, PerOx level - 406.02 μmol/l, the result of patients' activity on the Lequesne scale - 3.5 points, venous leptin level blood - 4.73 ng/ml, BMI - 24.01 kg/cm ² , IL-6 level - 9.42 pg/ml, cumulative disease index CIRS 5 points.

The frequency of exacerbations of BA, calculated using our prognostic model, over the next year:

That is, ExacBA <2 (low risk of exacerbations).

Observation of the patient during the year revealed 1 exacerbation of BA. Thus, our prediction came true.

Example 2

Patient R., aged 68, diagnosed with Bronchial asthma of mixed origin, moderate severity, not controlled by VNO. Obesity 2 degrees, exogenous-constitutional genesis. Generalized osteoarthritis: bilateral osteoarthritis of the knee joints 1 tbsp. right and 2 tbsp. on the left, coxarthrosis on the right 2 tbsp. FN 2. Stage 2 hypertension, drug-controlled course, dyslipidemia, risk of CVD, 3 target BP level <130/80 mm. rt. Art.

Data from a comprehensive clinical, instrumental and laboratory examination: the result of ODA23+ was 87.5 points, FEV ₁ - 51.8% of the predicted value, PerOx level - 2014.34 µmol/l, the result of patients' activity on the Lequesne scale - 8.7 points, the level venous blood leptin - 28.97 ng/ml, BMI - 33.75 kg/cm ² , IL-6 level - 37.33 pg/ml, cumulative disease index CIRS 6 points.

The frequency of exacerbations of BA, calculated using our prognostic model, over the next year:

That is, ExacBA ≥2 (high risk of exacerbations).

The observation of the patient during the year revealed 3 exacerbations of BA. Thus, our prediction came true.

The developed method for predicting the frequency of BA exacerbations makes it possible to predict the frequency of exacerbations of the disease (high risk, low risk) in patients with concomitant multimorbid pathology.

Claims (11)

A method for predicting exacerbations of bronchial asthma (BA) over the next year in patients with concomitant multimorbid pathology, including the determination of diagnostic indicators, characterized in that the indicators determine: the level of motor activity according to the ODA23+ questionnaire, forced expiratory volume in the 1st second of forced maneuver expiratory lung capacity (FEV ₁ ), serum peroxide level, patient activity level on the Lequesne scale, venous blood leptin level, body mass index (BMI), interleukin-6 (IL-6) level, cumulative disease index CIRS, based on obtained data, the probability index of the frequency of BA exacerbation over the next year in patients with concomitant multimorbid pathology (ExacBA) is calculated using the formula: ExacBA = 7.57567 - 0.105518×FEV ₁ - 0.144268×CIRS - 0.000172187× ODA23 ⁺ ×FEV ₁ - 0.000901236×ODA23 ⁺ ×Leken + 0.00038601×ODA23 ⁺ ×BMI - 0.000426185 ×ODA23 ⁺ ×IL6 + 0.00135395×ODA23 ⁺ ×CIRS + 0.000477974×FEV ₁ ² + 0.000968334×FEV ₁ ×Leken - 0.000180234×FEV ₁ ×Leptin + 0.000369123×FEV ₁ ×IL6 - 0.00000330283×PerOx×IL6 + 0.000376305×Leptin×BMI - 0.000246557×Leptin×IL6 - 0.000365621×BMI ² + 0.000185599×IL6 ² + 0.00290871×CIRS ² , where ODA23 ⁺ is the result of the ODA23+ motor activity questionnaire, in points, FEV ₁ - forced expiratory volume in 1 second, in percent, PerOx is the level of blood serum peroxides, µmol/l, Leken - the result of assessing the dynamics of patients' activity on the Leken scale, in points, Leptin - venous blood leptin level, ng/ml, BMI - body mass index, kg / m ² , IL6 - IL-6 level, pg/ml, CIRS - cumulative disease index, in points, and with an ExacBA value of less than 2, a low risk of developing BA exacerbations is predicted, with the number of exacerbations 1 time per year; and with an ExacBA value of 2 or more, a high risk of exacerbations is predicted, with the number of exacerbations per year 2 or more times.