Method for predicting risk of severe bronchial asthma in children

Abstract

FIELD: pediatrics and pulmonology.SUBSTANCE: used to predict the risk of severe bronchial asthma in children. Anamnesis is collected, blood is taken, and the child's blood is tested in a laboratory. From the anamnesis, the duration of the disease in years and the number of exacerbations over the current 12 months in points are specified. The peak expiratory flow rate is measured using a peak flow meter, %. The concentration of connexin 43 (CX43), ng / ml, is determined in the child’s blood serum at the time of inclusion in the study. The prognosis for the risk of severe bronchial asthma in children P is calculated using the stated formula. If the P value is 0.52 or higher, a high risk of severe bronchial asthma is predicted.EFFECT: method provides the possibility of increasing the accuracy and reliability of the prognosis of the severity of bronchial asthma in children by taking into account the declared clinical symptoms and risk factors for bronchial asthma in children and adolescents of both sexes who do not have signs of a severe course of the disease at the time of examination.1 cl, 4 ex

Description

[0001] The invention relates to medicine, namely to pediatrics, pulmonology, and can be used to predict the risk of severe bronchial asthma (BA) in children.

[0002] Bronchial asthma (BA) is one of the leading diseases of the late 20th and early 21st centuries, with a steady exponential increase in its prevalence observed alongside global industrialization. Childhood asthma is an extremely serious medical problem worldwide, affecting approximately 24% of the child population, with approximately 19% occurring in adolescents. This chronic respiratory disease significantly impacts the lives of millions of children, causing limited physical activity and missed school days. This can deprive children of both academic achievement and social interaction, especially among low-income and minority populations. Severe asthma poses a significant burden to both patients and societies. Predicting a more severe course of the disease in patients will allow for timely adjustments to treatment and prevent complications.Therefore, the study of various external and internal factors influencing the course of the disease is of great importance for science and practice.

[0003] A method for predicting severe bronchial asthma in children and adolescents with a history of the disease is known from the current state of the art. Clinical symptoms and risk factors are determined: disease duration, high bronchial hyperreactivity in the methacholine test, total serum immunoglobulin E level, polypous rhinosinusitis, atopic dermatitis, moderate bronchial hyperreactivity in the methacholine test, passive smoking, food intolerance with respiratory manifestations, and patient compliance with a hypoallergenic environment. These factors are then graded and numerically calculated. Prognostic coefficients are then determined, allowing for the prediction of high and low risks of severe bronchial asthma (RU Patent No. 2340285, published December 10, 2008).

[0004] The disadvantage of this technical solution is the limited functionality of the method due to the fact that the methacholine test can only be performed on patients over 5 years of age, and the level of total IgE has clinical significance only in the atopic variant of bronchial asthma.

[0005] A known method for predicting the uncontrolled course of bronchial asthma in children with obesity consists in conducting a study of polymorphic variants of metabolic genes - rs1042713 (Arg16Gly) in the ADRB2 gene and rs1801282 (Pko12Ala) in the PPARG gene using real-time PCR analysis, and upon detection of a combination of the AG or GG genotype of the polymorphic variant rs1042713 (Arg16Gly) of the ADRB2 gene and the CG or GG genotype of the polymorphic variant rs1801282 (Pro12Ala) of the PPARG gene, the uncontrolled course of bronchial asthma in children with obesity is predicted (RU Patent No. 2805825, published on 2023.10.24).

[0006] The disadvantages of this technical solution are its limited functionality, associated with its use only in children with bronchial asthma and obesity, its labor intensity and complexity, due to the need for specialized equipment and highly qualified medical personnel to conduct genetic research, as well as insufficient reliability, due to the fact that individual and such clinical parameters important for determining the severity of bronchial asthma as the duration of the disease, the number of exacerbations in the year preceding the examination and indicators of external respiratory function in the child are not taken into account.

[0007] A known method for assessing the severity of bronchial asthma in children includes measuring the level of total immunoglobulin E in blood plasma, the number of eosinophils in a peripheral blood smear and nasal cavity, and positive scarification tests with any of the allergens (house and library dust mites, mold, cat or dog epidermis). The indicators are scaled, resulting in a summed value of the integral sensitization index, and the severity of bronchial asthma is determined based on the total score (RU Patent No. 2355317, published May 20, 2009).

[0008] Its disadvantages: this method takes into account reliable indicators for the atopic process, sufficient to verify the severity of the disease, but is not intended to predict the course of bronchial asthma.

[0009] A method is known for predicting the severity of bronchial asthma in children aged 2-17 years, which consists in examining peripheral blood using light microscopy, with the determination of the intensity of intercellular interactions of neutrophils and eosinophils with erythrocytes, characterized in that the study is carried out at least twice during the period of remission with an interval between studies of at least 3 months, the counting of cellular associations of neutrophils with erythrocytes and eosinophils with erythrocytes is carried out in native blood, a high risk of developing a severe course of bronchial asthma is detected with the content of neutrophil associations with erythrocytes of more than 70% and the content of eosinophil associations with erythrocytes of less than 8% in both studies, and with the content of neutrophil associations less than 70% and eosinophil associations more than 8% in both studies, mild or moderate course of the disease (RU Patent No. 2469329, published on 10.12.2012).

[0010] A disadvantage of this method is the length of the study. Furthermore, it is impossible to conduct studies in children with persistent disease.

[0011] A method for predicting the uncontrolled course of severe bronchial asthma is known (RU Patent No. 2470582, published on July 28, 2011), which consists of conducting spirometry and determining the peak expiratory flow rate, forced expiratory volume in the first second (FEV1) and FEV1 after a test with salbutamol, calculating ΔFEV1, forced vital capacity of the lungs (FVC), the indicator of the maximum volumetric speed at the expiration level of 25.0% of FVC (MOC 25 ), the maximum expiratory flow rate at the expiratory level of 50.0% of the FVC (FVC) 50 ), the maximum expiratory flow rate of 75.0% of the FVC (FVC) 75), the AsthmaControlTest (AST) values ​​and exhaled air gas concentration indicators (CO, NO, NO2), and the probability indicators of classifying an individual into a group with a high (R1) and low (R2) risk of developing uncontrolled severe asthma according to certain mathematical formulas. If R1>R2, a high risk of development is predicted, if R1 <R2 - низкий риск развития неконтролируемого течения данного заболевания.

[0012] The disadvantage of this method is that it predicts exacerbations only in adult patients with severe asthma and is not applicable to children.

[0013] A method for differential diagnosis of the severity of bronchial asthma is known, based on the study of the severity of the direct correlation between the content of interferon-γ and interleukin-1α? in the blood serum, which is inversely proportional to the severity of bronchial asthma (Zaitseva O.V., Lavrentiev A.V., Zaitseva S.V., Samsygina G.A. Interleukin-1 alpha, tumor necrosis factor-alpha and interferon-gamma in the blood serum of children with bronchial asthma at different periods of the disease / / Allergology. - 2000. - No. 3. - P. 8-12).

[0014] The disadvantages of this method are the high cost and complexity of research, the need to determine the content of the specified biologically active substances in the serum of patients during an attack of suffocation.

[0015] The closest to the claimed technical solution is a method for predicting the severe course of bronchial asthma in children, including collecting anamnesis and laboratory blood testing, characterized in that the age of onset of the disease, the frequency of acute respiratory infections in the first 3 years of life are specified from the anamnesis, the level of vascular endothelial growth factor, the concentration of hydroxycholecalciferol are determined in the blood serum and the prognostic coefficient Kpr (TBA) is calculated using the formula:

[0016] ,

[0017] where K пр (TBA) is a prognostic coefficient for severe bronchial asthma, VEGF-A is the level of vascular endothelial growth factor (pg / ml), 25(OH)D is the concentration of hydroxycholecalciferol (nmol / l), D is the age of onset of bronchial asthma (year), ARI is the frequency of acute respiratory infections in the first 3 years of life (times / month), e is the exponent=2.718, and with the value of the prognostic coefficient K пр(TBA)>0.4 predicts severe bronchial asthma (RU Patent No. 2764364, published 2022.01.17).

[0018] The disadvantages of this method are its labor intensity and complexity, due to the need for additional determination of the level of hydroxycholecalciferol and the level of vascular endothelial growth factor in children, as well as its insufficient reliability, due to the fact that individual and such important clinical parameters for determining the severity of bronchial asthma as the number of exacerbations in the year preceding the examination are not taken into account.

[0019] The objective of the claimed invention is to expand the range of methods for predicting the risk of severe asthma in children, which will improve the quality of treatment for these groups of patients by personalizing the therapeutic strategy taking into account the established characteristics.

[0020] This problem is solved by determining the anamnestic data of a child with bronchial asthma: duration of the disease, in years, number of exacerbations over the current 12 months, in points: 1 point - 1-2 times a year, 2 points - 3-4 times a year, 3 points - 5 times or more per year; peak expiratory flow rate is examined using a peak flow meter, in %; in addition, the concentration of connexin CX43 in the child's blood serum is determined, in ng / ml at the time of inclusion in the study, after which the risk prognosis of severe bronchial asthma in children is calculated using the mathematical expression:

[0021]

[0022] where P is the probability of severe asthma,

[0023] exp - exponent e=2.718,

[0024] Z is the multiple regression coefficient, which has a mathematical expression

[0025] Z=11.8*СХ43+0.26*ПЗ+0.71*КО-0.16*ПСВ+6.7,

[0026] where CX43 is the concentration of connexin CX43 in the blood serum in ng / ml,

[0027] PZ - duration of BA in years,

[0028] KO - the number of exacerbations in the current 12 months in points: 1 point - 1-2 times a year, 2 points - 3-4 times a year, 3 points - 5 times or more a year.

[0029] PEF - peak expiratory flow rate in %,

[0030] The P value reflects the probability of developing a severe course: a P value of 0.52 or higher predicts a high risk of severe asthma, while a P value of less than 0.52 predicts a low risk of severe asthma.

[0031] The technical result provided by the given set of features is an increase in the accuracy and reliability of the prognosis of the severity of asthma in children by determining anamnestic data (duration of the disease, number of exacerbations of asthma over the current 12 months), determining the peak expiratory flow rate (PEF) and studying the initial concentrations of connexin CX43 in the blood serum at the time of inclusion of the patient in the study.

[0032] The results of our study allowed us to identify the most important factors and criteria that increase the risk of severe asthma and to develop a formula for predicting the risk of severe asthma in children based on a combination of different indicators.

[0033] The technical result of the claimed method is achieved by taking into account specific clinical symptoms and risk factors for bronchial asthma in children and adolescents of both sexes who do not have signs of severe disease at the time of examination. Determining the disease duration (D) and the number of exacerbations (NE) over the past 12 months is important for verifying the severity of bronchial asthma, as long-term chronic inflammation in the bronchopulmonary system can lead to structural changes in tissues (remodeling). Bronchial remodeling in bronchial asthma is accompanied by hypertrophy and hyperplasia of the smooth muscle layer, leading to increased bronchospasm, goblet cell hyperplasia with mucus hyperproduction, epithelial damage, fibrotic changes, and, consequently, a decreased response to therapy. All of the above leads to increased bronchoobstruction in patients and a more severe course of the disease.The study of peak expiratory flow rate (PEF) allows us to assess the severity of morphological changes in the bronchi at the time of the study and determine the degree of its disturbances.

[0034] The respiratory epithelium plays a significant role in the pathogenesis of asthma. It serves as a physical barrier protecting the body from allergens and pollutants and maintains immune homeostasis by regulating airway inflammation. The gap junction protein connexin 43 (Cx43) plays a key role in this barrier. Disruption of its structure and function leads to increased permeability of the respiratory epithelium and disruption of cell-cell interactions. This protein is tissue-specific, so measuring its serum levels allows one to assess the severity of disorders in the bronchopulmonary system and thereby predict the severity of asthma.

[0035] To assess the risk of severe asthma in children, a study of 125 patients was conducted. In all children, the duration of the disease and the number of exacerbations over the past year were determined. Peak expiratory flow rate was measured using an Omron PFM-20 peak flow meter (Omron Corporation, Japan). Baseline serum connexin CX43 concentrations at the time of study inclusion were determined. Then, the severity of asthma was assessed. The severity of the disease was determined according to the provisions of the National Program "Bronchial Asthma in Children. Treatment Strategy and Prevention", 2021. Moderate and severe asthma were assigned a rank of 1, and mild asthma was assigned a rank of 0. Next, ROC analysis was used to determine the levels of the studied indicators, changes in which were associated with a severe course of the disease, and a prediction model was developed. The mathematical expression of the model was as follows:

[0036]

[0037] where P is the probability of severe asthma,

[0038] exp - exponent e=2.718,

[0039] Z is the multiple regression coefficient, which has a mathematical expression

[0040] Z=11.8*СХ43+0.26*ПЗ+0.71*КО - 0.16*ПСВ+6.7,

[0041] where CX43 is the concentration of connexin CX43 in the blood serum, in ng / ml,

[0042] PZ - duration of BA, in years,

[0043] KO - the number of exacerbations over the current 12 months, in points: 1 point - 1-2 times a year, 2 points - 3-4 times a year, 3 points - 5 times or more per year

[0044] PEF - peak expiratory flow rate, in %.

[0045] After calculating the probability of severe asthma in each patient based on the results of ROC analysis, it was found that if the P value exceeds 0.52 inclusive, with a diagnostic sensitivity of 70.18% and a diagnostic specificity of 95.59%, a high risk of severe asthma can be predicted.

[0046] The overall statistical significance of the model was high, the Chi square test corresponded to χ 2=72.7 at p<0.0001. The area under the ROC curve was 0.892±0.0279 (confidence interval from 0.824 to 0.941) and differed from the reference diagonal line (z=14.078; p<0.001).

[0047] Detailed description of the method and examples of its clinical implementation

[0048] Children with asthma who do not have signs of severe disease at the time of examination are examined. The diagnosis is established based on a survey and clinical examination in accordance with the "Clinical Guidelines for the Diagnosis and Treatment of Bronchial Asthma", 2024 and the National Program "Bronchial Asthma in Children. Treatment Strategy and Prevention", 2021.

[0049] Next, based on the anamnesis data, the duration of the disease (DD) and the number of exacerbations (NE) over the current 12 months are determined in points: 1 point - 1-2 times a year, 2 points - 3-4 times a year, 3 points - 5 or more times a year.

[0050] A study of peak expiratory flow rate is carried out using the Omron RBM-20 peak flow meter (Omron Corporation, Japan), in %.

[0051] An additional 10 ml of blood is collected from the cubital vein to obtain serum. The serum concentration of connexin 43 CX43 (ng / ml) is determined by enzyme-linked immunosorbent assay using the SEA277Hu kit (Cloud-Clone Corporation, Wuhan, China).

[0052] Next, the value of the forecast criterion P is calculated using the formula:

[0053]

[0054] where P is the probability of severe asthma,

[0055] exp - exponent e=2.718,

[0056] Z is the multiple regression coefficient, which has a mathematical expression

[0057] Z=11.8*СХ43+0.26*ПЗ+0.71*КО - 0.16*ПСВ+6.7,

[0058] where CX43 is the concentration of connexinCX43 in the blood serum in ng / ml,

[0059] PZ - duration of BA in years,

[0060] KO - number of exacerbations over the current 12 months, in points: 1 point - 1-2 times a year, 2 points - 3-4 times a year, 3 points - 5 or more times a year.

[0061] PEF - peak expiratory flow rate in %.

[0062] If the P value is equal to 0.52 or higher, a prediction is made about a high risk of severe asthma; if the P value is less than 0.52, a low risk of severe asthma is made.

[0063] The effectiveness of the claimed method is confirmed by the following clinical examples:

[0064] Example 1.

[0065] Patient M., 10 years old. Asthma was diagnosed 3 years ago (asthma duration in years). Over the past 12 months, asthma attacks have occurred 4 times (number of exacerbations - 2 points). Peak flowmetry revealed a peak expiratory flow rate (PEF) of 71%. At study entry, the serum connexin CX43 concentration was 0.75 ng / ml.

[0066] Thus, this patient has: PZ = 3, KO = 2, PSV = 71%, CX43 = 0.75 ng / ml.

[0067] To calculate the prediction P, the criteria obtained as a result of the above studies and measurements were substituted into the formula:

[0068]

[0069] where P is the probability of severe asthma,

[0070] exp - exponent e = 2.718,

[0071] Z is the multiple regression coefficient, which has a mathematical expression:

[0072] Z=11.8*СХ43+0.26*PZ+0.71 *KO-

[0073] 0.16*PSV+6.7=11.8*0.75+0.26*3+0.71*2-0.16*71+6.7 = 6.39,

[0074]

[0075] Since the P value is higher than 0.52, a high risk of severe asthma is predicted.

[0076] This patient was prescribed low-dose inhaled glucocorticosteroids. However, she experienced recurrent episodes of bronchoconstriction, so her background therapy was revised and she was switched to combination therapy with an ICS and a LABA.

[0077] Thus, this clinical example demonstrated the high informative value of the developed method, which allows for the recognition of significant disease progression over a short period of time. The child's improvement in condition during asthma therapy confirms the effectiveness of the proposed prognostic method.

[0078] Example 2.

[0079] Patient I., 15 years old. Asthma was diagnosed 7 years ago (asthma duration in years). Over the past 12 months, asthma attacks have occurred twice (number of exacerbations - 1 point). Peak flowmetry revealed a peak expiratory flow rate (PEF) of 73%. At study inclusion, the serum connexin CX43 concentration was 0.21 ng / ml.

[0080] Thus, this patient has: PZ = 7, KO = 1, PSV = 73%, CX43 = 0.21 ng / ml.

[0081] To calculate the prediction criterion P, the values ​​obtained as a result of the studies and measurements described above were substituted into the formula:

[0082]

[0083] where p is the probability of severe asthma,

[0084] exp - exponent e = 2.718,

[0085] Z is the multiple regression coefficient, which has a mathematical expression:

[0086] Z=11.8*CX43+0.26*n3+0.71*KO- 0.16*PSV+6.7=11.8*0.21+0.26*7+0.71*1-0.16*73+6.7 = 0.028,

[0087]

[0088] Since the P value is below 0.52, the risk of severe asthma is predicted to be low.

[0089] Given the low probability of developing a severe course of BA in this patient, treatment with low-dose inhaled glucocorticosteroids alone was recommended. This therapy allowed for symptomatic control within a short period of time, demonstrating the effectiveness of the developed method in practice.

[0090] Thus, this clinical example demonstrated the possibility of controlling the disease even with the use of a minimal amount of therapy in this patient and to evaluate the reliability of the claimed method in determining the risk of severe disease progression.

[0091] Example 3.

[0092] Patient K., 15 years old. Asthma was diagnosed 7 years ago (asthma duration in years). Over the past 12 months, asthma attacks have occurred 10 times (number of exacerbations - 3 points). Peak flowmetry revealed a peak expiratory flow rate (PEF) of 67%. At study inclusion, the serum connexin CX43 concentration was 0.48 ng / mL.

[0093] Thus, this patient has: PZ=7, KO=3, PSV=67%, CX43=0.48 ng / ml.

[0094] To calculate the prediction criterion P, the values ​​obtained as a result of the studies and measurements described above were substituted into the formula:

[0095]

[0096] where p is the probability of severe asthma,

[0097] exp - exponent e=2.718,

[0098] Z is the multiple regression coefficient, which has a mathematical expression:

[0099] Z=11.8*CX43+0.26*PZ+0.71*KO-0.16*PSV+6.7=11.8*0.48+0.26*7+0.71*3-0.16*67+6.7=5.594,

[0100]

[0101] Since the P value is higher than 0.52, a high risk of severe asthma is predicted.

[0102] This patient was prescribed combination therapy with ICS and LABA in high doses, which led to stabilization of the condition and the absence of clinical manifestations of the disease.

[0103] Considering that this method made it possible to identify in advance a high risk of a severe course of the disease and to prescribe in a timely manner the necessary amount of basic therapy, which led to an improvement in the patient's condition, we can judge the high reliability and effectiveness of the proposed forecasting method.

[0104] Example 4.

[0105] Patient A., 11 years old. Asthma was diagnosed 4 years ago (asthma duration in years). Over the past 12 months, asthma attacks have occurred 4 times (number of exacerbations - 2 points). Peak flowmetry revealed a peak expiratory flow rate (PEF) of 70%. At study inclusion, the serum connexin CX43 concentration was 0.18 ng / ml.

[0106] Thus, this patient has: PZ=4, KO=2, PSV=70%, CX43=0.18 ng / ml.

[0107] To calculate the prediction criterion P, the values ​​obtained as a result of the studies and measurements described above were substituted into the formula:

[0108]

[0109] where p is the probability of severe asthma,

[0110] exp - exponent e=2.718,

[0111] Z is the multiple regression coefficient, which has a mathematical expression:

[0112] Z=11.8*CX43+0.26*PZ+0.71*KO-0.16*PSV+6.7=11.8*0.18+0.26*4+0.71*2-0.16*70+6.7=0.084,

[0113]

[0114] Since the P value is 0.52, we conclude that there is a high risk of severe asthma.

[0115] This patient was prescribed combination therapy with high-dose ICS and LABA, which resulted in stabilization of his condition and the absence of clinical manifestations. Given the positive effect of the treatment, the proposed prognostic method is highly effective.

[0116] Using our developed method, we obtained a reliable prediction of the risk of developing severe asthma in 94.4% of patients. All patients were prescribed background therapy according to the 2024 Clinical Guidelines for the Diagnosis and Treatment of Bronchial Asthma. A follow-up examination conducted one year later showed that the diagnostic specificity was 87.5%, and the diagnostic efficiency of the model was 92.3%.

[0117] Advantages of the method:

[0118] The proposed method for predicting the risk of severe bronchial asthma in children is simple, cost-effective, safe, and accurate. This allows for the selection of appropriate, personalized patient management strategies, reduction of medication burden, and improvement of the child's quality of life.

[0119] The method we developed for predicting the risk of severe bronchial asthma in children has been tested on a significant amount of clinical material, has demonstrated its advantages, and can be recommended for widespread use in pediatric practice.

Claims

A method for predicting the risk of severe bronchial asthma in children, including collecting anamnesis and blood sampling, laboratory testing of the child's blood, characterized in that the anamnesis specifies the duration of the disease in years, the number of exacerbations over the current 12 months in points; the peak expiratory flow rate is measured in % using a peak flow meter, the concentration of connexin 43 (CX43) in the child's blood serum is determined in ng / ml at the time of inclusion in the study and the prognosis of the risk of severe bronchial asthma (BA) in children is calculated using the formula: where P is the probability of severe asthma, exp - exponent e=2.718, Z is the multiple regression coefficient, which has a mathematical expression Z=11.8*СХ43+0.26*ПЗ+0.71*КО-0.16*ПСВ+6.7, СХ43 – concentration of connexin 43 in blood serum in ng / ml; ПЗ – duration of BA in years; KO - the number of exacerbations over the current 12 months in points: 1 point - 1-2 times a year, 2 points - 3-4 times a year, 3 points - 5 or more times a year; PSV - peak expiratory flow rate in %; and if the P value is 0.52 or higher, a high risk of severe bronchial asthma is predicted.

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