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Журнал «Здоровье ребенка» Том 18, №2, 2023

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Прогнозування переносимості інгаляційної терапії як етап персоніфікованого підходу в лікуванні дітей, хворих на муковісцидоз

Прогнозування переносимості інгаляційної терапії як етап персоніфікованого підходу в лікуванні дітей, хворих на муковісцидоз

Авторы: K.V. Skriabinа, S.I. Ilchenko, A.O. Fialkovska
Dnipro State Medical University, Dnipro, Ukraine

Рубрики: Педиатрия/Неонатология

Разделы: Клинические исследования

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Резюме

Актуальність. Враховуючи особливості базисної терапії хронічного запального бронхолегеневого процесу при муковісцидозі (МВ), що включає практично щоденні інгаляції фармакологічних препаратів (муколітики, гіпертонічні розчини хлориду натрію (ГРХН), антибіотики), на практиці актуальним є визначення їх переносимості. Мета дослідження: створення зручної для застосування в практичній медицині прогностичної шкали, що дозволяла б прогнозувати розвиток синдрому гіперреактивності бронхів у дітей із МВ, на підставі клініко-анамнестичних даних, результатів молекулярно-генетичного дослідження й інгаляційних тестів зі зростаючими концентраціями ГРХН для призначення персоніфікованого лікування. Матеріали та методи. Проаналізовано результати клініко-анамнестичних, мікробіологічних, біохімічних, молекулярно-генетичних досліджень та інгаляційних тестів зі зростаючими концентраціями ГРХН у 40 дітей із МВ. При розробці алгоритму прогнозування застосовували кореляційний аналіз, ROC-аналіз, метод бінарної логістичної регресії, методики Вальда і Кульбака. Результати. Створено дві прогностичні моделі, що можуть використовуватися на різних етапах надання медичної допомоги. Для амбулаторного етапу надання медичної допомоги хворим на МВ була побудована модель 1, що враховує клініко-анамнестичні дані, молекулярно-генетичні предиктори, а також клінічні симптоми під час інгаляційних тестів зі зростаючими концентраціями ГРХН. Ця модель також може використовуватись у дітей раннього віку, у яких неможливо провести спірометрію та оцінити показники функції зовнішнього дихання. Для етапу високоспеціалізованої медичної допомоги була створена модель 2, що включає показники спірометричних даних інгаляційних тестів зі зростаючими концентраціями ГРХН та рівня монооксиду азоту в конденсаті повітря, що видихається. Висновки. Розроблені моделі дозволяють з високою вірогідністю розрахувати ризик розвитку синдрому гіперреактивності бронхів для персоніфікованого підбору ГРХН та вибору превентивної брохолітичної терапії за потребою.

Background. Considering the features of basic therapy for chronic inflammatory bronchopulmonary process in cystic fibrosis (CF), which includes almost daily inhalation of pharmacological drugs (mucolytics, hypertonic saline (HS), antibiotics), evaluation of their tolerability is relevant in practice. The purpose of the study is to create a prognostic scale convenient for use in practical medicine, which would predict development of bronchial hyperreactivity syndrome in children with CF, based on clinical and anamnestic data, the results of molecular genetic research and inhalation tests with increasing concentrations of HS to prescribe personalized treatment. Materials and methods. The results of clinical and anamnestic, microbiological, biochemical, molecular and genetic studies and inhalation tests with increasing concentrations of HS were analyzed in 40 children with CF. The creation of the predictive algorithm was based on the application of correlation analysis, receiver operating characteristic analysis, binary logistic regression, Wald and Kullback method. Results. Two prognostic models have been created that can be used at different stages of providing medical care. Model 1 was built for the ambulatory stage of providing medical care to patients with CF, considering clinical and anamnestic data, molecular genetic predictors, as well as clinical symptoms during inhalation tests with increasing concentrations of HS. This model also can be used in young children who cannot perform spirometry to assess their external breathing function. For the highly specialized medical care, model 2 was created, which considers indicators of spirometric data of inhalation tests with increasing concentrations of HS and the level of exhaled nitric oxide. Conclusions. The developed models make it possible to calculate with high probability the risk of developing bronchial hyperreactivity to perform a personalized selection of HS and choose preventive brocholytic therapy as needed.


Ключевые слова

муковісцидоз; гіпертонічний розчин хлориду натрію; гіперреактивність бронхів; прогнозування; діти

cystic fibrosis; hypertonic solutions of sodium chloride; bronchial hyperreactivity; prognosis; children

doi: http://dx.doi.org/10.22141/2224-0551.18.2.2023.1569

Introduction

Cystic fibrosis (CF) is a complex genetic disease with various manifestations, the most important of which is a chronic inflammatory bronchopulmonary process that leads to terminal respiratory failure [1]. Considering the features of the basic therapy for chronic inflammatory bronchopulmonary process in CF, which includes almost daily inhalation of pharmacological drugs (mucolytics, hypertonic saline (HS), antibiotics), determining their tolerability is relevant in practice. As defined earlier, the tolerability of inhalation therapy depends on the genotypic and phenotypic characteristics of the course of the disease (including the level of bronchial sensitivity), comorbid conditions [2–4]. When prescribing basic CF therapy, a practicing physician should take into account the possibility of reducing the effectiveness of therapy due to the presence of the phenomenon of bronchial hyperreactivity (BHR) [5, 6]. The patient’s subjective feeling of difficulty breathing and discomfort during inhalation can be associated with increased sputum production, i.e., the effect of the drug itself, and with bronchospasm as one of the visual manifestations of chronic obstructive pulmonary disease. Bronchospasm can be provoked by any inhalation agent, but its risk is higher when using solutions whose osmolarity differs significantly from that of bronchial secretion. Among them, the most common trigger is HS, which is part of the treatment protocol for patients with CF [7–9]. BHR to inhaled HS is quite common (from 10 to 50 % according to various studies) in CF patients, manifests itself in various symptoms (sore throat, difficulty breathing, spastic cough, hyperactive secretion of induced sputum, auscultative signs of broncho-obstruction) and can interfere with adequate implementation of basic therapy by the inhalation method [3, 4, 8]. The presence of BHR in CF patients depends on many factors, including severity of the course of the disease, damage to the bronchopulmonary system, chronic colonization of the respiratory tract by Pseudomonas aeruginosa, allergic bronchopulmonary aspergillosis (ABPA) [10, 11]. BHR in CF may be the cause of low patient compliance and self-discontinuation of inhalation therapy, which violates the treatment protocol. Despite the conflicting knowledge about the mechanisms of development of chronic obstructive pulmonary disease and bronchial obstruction in CF, there are recommendations for prescribing inhaled bronchodilators to prevent complications in patients with chronic obstructive pulmonary disease [12, 13]. Today, these recommendations are only general in nature and do account for genotypic-phenotypic features of CF course [14, 15]. Unsolved issues are, firstly, those regarding the choice of HS concentration (a 3% solution is less often cause undesirable effects than a 7% solution, but the latter is more effective), and secondly, regarding the choice and prescription of bronchodilators (beta-agonists or long-acting, combined agents including ipratropium bromide and fenoterol bromide). Therefore, the possibility of predicting adverse events at the beginning of basic inhalation therapy and their rational prevention is an important step in personalizing the treatment of patients with CF.
The purpose of the study is to create a prognostic scale convenient for use in practical medicine, which would allow predicting the development of the BHR syndrome in children with CF, based on clinical and anamnestic data, the results of a molecular genetic study, and inhalation tests with increasing concentrations of HS for prescribing persona–lized treatment.

Materials and methods

To achieve the goal, the results of clinical and anamnestic, microbiological, biochemical, molecular genetic studies and inhalation tests with increasing concentrations of HS were analyzed in 40 children with CF who were treated at the Dnipro City Children’s Pulmonology Center.
The research was carried out within the framework of the joint research project of the Department of Propaedeutics of Children’s Diseases and the Department of Microbio–logy, Virology, Immunology and Epidemiology of the Dnipro State Medical University: “Bronchitis in children with comorbid conditions: clinical course and their modern etio–logy”, state registration number 0116U004962.
There were 17 boys (42.5 %) and 23 girls (57.5 %) among the examined children. The average age of boys was 12.4 ± 0.7 years, girls — 11.3 ± 0.9 years. The average age in the general group was 12.0 ± 0.6 years.
The criteria for inclusion in the study were: age from 6 to 18 years, a confirmed diagnosis of CF, ability to perform spirometry, the consent of a patient and parents to participate in the study. The diagnosis of CF was verified based on diagnostic criteria, according to the Unified clinical protocol of primary, secondary (specialized) and tertiary (highly specialized) medi–cal care. Cystic fibrosis (Оrder of the Ministry of Health of Ukraine No. 723 of 07/15/2016). CFTR gene mutations were found in 33 (82.5 %) patients as result of a molecular genetic study. Mutations were not identified in 7 (17.5%) children, but the diagnosis was made due to typical clinical picture and two positive sweat samples, which corresponds to modern criteria for diagnosis of CF. The most common mutation among children with CF was F508del (57.5 %), which was detected in 9 (22.5 %) patients in the homozygous state, in 14 (35.0 %) — in the compound he–terozygous state. Exclusion criteria from the study were: the presence of an episode of hemoptysis/pulmonary bleeding in the anamnesis, FEV1 < 50 % of normal, impossibility of performing spirometry, and previously detected intolerance to hypertonic saline.
Statistical processing of the obtained results was carried out using the Statistica 6.1 application program package (serial number AGAR909E415822FA). When creating the prognostic scale, we focused on its simplicity and convenience for use in the doctor’s practice.
The general algorithm for creating the scale was as follows:
1) based on correlation analysis, to create a list of potential predictors;
2) carrying out the receiver operating characteristic (ROC) analysis to assess the prognostic value of each predictor and select optimal threshold values for its levels (cut-off point) that provide the best operational characteristics of the one-factor model (area under the ROC curve — AUC, sensitivity indicators — S, specificity — SP, diagnostic efficiency — DE);
3) construction of univariate logistic regression models to assess the probability of increased bronchial sensitivity under conditions of achievement/presence (Pmax) or non-achievement/absence (Pmin) of the optimal threshold va–lues of a predictor determined at the previous stage;
4) to increase the effectiveness of the prognosis, a multifactorial approach was used to assess the probability of increased bronchial sensitivity, which considers the combined effect of several factors. For this purpose, for each predictor (provided that the threshold level is reached), the predictive coefficient (PC) was calculated according to the Wald method, based on the Bayes formula, and the measure of Kullback’s informativeness;
5) to determine the critical levels of the probability of bronchial hypersensitivity, which considers the combined effect of several predictors, the sum of points (SPC) was calculated for each observation (patient), which, in turn, acted as a predictor for the logistic regression equation (1), and the dependent variable remained the same (there is a BHR, there is no BHR):
 
Р = exp(z) / (1 + exp(z)), z = B0 + B1 × x (1),
 
where B0, B1 — calculated coefficients of the regression equation;
x — the sum of points (ΣPC) in a specific patient;
Р — theoretical probability of BHR;
6) determination of the threshold values of the total score (according to the constructed regression) for the classification of the probability of increased sensitivity of the bronchi in 3–4 gradations (from low to high — very high). The criterion for assigning a patient to the high-risk group of BHR was considered to be the value of the calculated pro–bability P of more than 0.50 or 50 %;
7) verification of the effectiveness of the model by comparing the actual and predicted frequency of BHR in groups of patients with a total score less than or greater than the threshold according to indicators of sensitivity, specificity and diagnostic efficiency.
Given the existing limitations in the availability of obtaining the necessary data on the course of the patient’s di–sease (time, age, need for special equipment, etc.), several model options were calculated.
The study was conducted with the permission of the local Commission on Biomedical Ethics in accordance with the basic moral and ethical principles, the requirements for observing the rights, interests and personal dignity of the study participants, which are provided by the follo–wing normative documents: the Declaration of Helsinki, the Convention of the Council of Europe on Human Rights and Biomedicine, Good Clinical Practice, UNESCO Universal Declaration on Bioethics and Human Rights, the Constitution of Ukraine (Articles 3, 21, 24, 28, 32), Fundamentals of Ukrainian legislation on health care (Articles 43.1, 44.1).

Results

Seventy-two factors that can affect the tolerability of inhalation therapy in CF patients were analyzed. Further, using correlation and ROC analysis, uninformative signs were excluded from the work, and the most significant predictors of BHR were included in the prognostic table. The diagnostically significant predictors of BHR in CF patients were found among the genotypic-phenotypic features of the course of the disease such as age at diagnosis of CF less than 10 months; the presence of a severe genotype; more than 2 exacerbations of the disease per year; dry paroxysmal cough during remission; the presence of bronchiectasis according to the computed tomography (CT) scan of the chest, the presence of purulent sputum; chronic purulent infection; ABPA. Among the clinical symptoms that occur during inhalation tests with increasing concentrations of HS (3% and 7% NaCl), a sore throat, a significant increase in wet cough, the appearance of dry whistling rales in the lungs during auscultation were diagnostically significant. The spirometry data during the inhalation tests with increasing concentrations of HS confirmed the reliability of prognosis. Models have been created for various stages of providing medical care to the patients with CF, from ambulatory stage to highly specialized care. Indicators for assessing the pro–bability of BHR syndrome in the examined children depen–ding on the main factors with the determination of the PC are shown in the Table 1.
The univariate regression analysis found that the pro–bability of HBV in patients with CF increases to 0.811 or 81.1 % (high probability) in the presence of dry paroxysmal cough in the remission period, in other cases (absence or other nature of cough), the risk is 0.296 or 29.6 % –(Table 1). The presence of purulent sputum in a child during disease exacerbation can also indicate increased bronchial sensitivity (Рmax = 0.619), but in the absence of this sign, the probability remains significant (Рmin = 0.211), which is explained by its dependence on other factors. In addition, operational characteristics of the prognostic value of these criteria (AUC, sensitivity, specificity) mostly correspond to average (AUC 0.6–0.7) or good (AUC 0.7–0.8) ratings, and their diagnostic/prognostic efficiency (predictive accuracy) does not exceed 70 %.
The maximum probability (Рmax = 1.0) of BHR and –excellent characteristics of the prognostic value of the crite–rion (AUC in the range of 0.9–1.0) were specific for indicators such as the presence of ABPA (AUC = 0.912, DE = 92.5 %), reduction of FEV1 after inhalation of 3% NaCl solution by 7 % or more from the baseline (AUC = 0.980, DE = 92.5 %), and when using 7% NaCl solution — by 10 % or more (AUC = 1.0, DE = 100 %). This makes it possible to use the specified criteria as prognostic markers of BHR, which may require the use of short-acting β2-agonists for the period of BHR treatment in children with CF.
It is worth noting that in the absence of ABPA, the pro–bability of BHR in a CF patient remains higher than 10 % (Рmin = 0.115). In such cases, it is advisable to additionally consider 1–2 more criteria to reduce uncertainty. If there is no ABPA and the number of CF exacerbations < 2 times a year, Рmin is 0.056, and in the absence of one more symptom — a dry or low-productive cough at the time of exacerbation, Рmin is 0.042 (less than 5 %).
Based on a multifactorial approach to assess the pro–bability of BHR, which takes into account the combined effect of several factors, the most informative for predicting BHR are the following indicators, which can be independent criteria: the presence of ABPA (I = 6.18), a decrease in FEV1 by 7 % and more from the baseline after inhalation of 3% NaCl solution (I = 6.18) and by 10 % or more after inhalation of 7% NaCl solution (I = 7.12) with PC of 16 points. The other most informative indicators were clinical and spirometric data of inhalation tests with increasing concentrations of HS, according to the rank arrangement of Kullback coefficients. This is best seen when using a 7% NaCl solution: a decrease in FEF25 (an indicator of air passage speed at the level of small bronchi) by 17 % or higher from the baseline (I = 4.47), the appearance of dry whistling rales in the lungs during auscultation (I = 3.76), an increase in the level of FeNO by more than 8 % from the baseline (I = 2.77). Informativeness of clinical and anamnestic data for prediction in general did not exceed 0.95 cu.
Model 1 was built for the ambulatory stage of providing medical care to CF patients, taking into account clinical and anamnestic data and genetic predictors, as well as clinical symptoms during inhalation tests with increasing concentrations of HS (Table 1). The logistic regression model based on the sum of PC scores of 13 parameters was adequate: χ2 = 32.03 (p < 0.001), the significance of regression coefficients B0 and B1 according to the Wald test was р = 0.006. Coefficients of the regression equation: B0 = –5.0421; B1 = 0.1747. Dependence of the theoretical probability of BHR on the total PC score is presented in Fig. 1.
A high risk of BHR (P > 0.5) is predicted if ΣPC accor–ding to 13 parameters is equal to or exceeds 30 points as can be seen from Fig. 1. At the minimum sum of points (ΣPC = 0), the probability of BHR is Р = 0.006, at the maximum (ΣPC = 73) Р = 1.0. The distribution of patients according to the degree of risk was as follows: if ΣPC ≤ 12 points, then the risk is very low (Р < 0.05), with 13 ≤ ΣPC ≤ 22 points — low (Р ≤ 0.25), with 23 ≤ ΣPC ≤ 29 points — moderate (Р ≤ 0.50), with ΣPC ≥ 30 points — high (Р > 0.50), inclu–ding with ΣPC ≥ 42 points — very high (Р > 0.90) (Table 2).
The assessment of the effectiveness of predicting BHR according to model 1 showed that the indicator of sensitivity was 88.2 %, specificity — 95.7 %, diagnostic efficiency — 92.5 %. The AUC = 0.951 (95% confidence interval 0.833–0.994) at p < 0.001. At the stage of highly specialized medical care for CF patients, model 2 was created, which included a total PC score of the following indicators: spirometric data of inhalation tests with increasing concentrations of HS and the level of nitrogen monoxide in the exhaled air condensate (FeNO). The logistic regression model based on the sum of PC scores of 4 parameters was adequate: χ2 = 35.79 (p < 0.001), the significance of regression coefficients B0 and B1 was p = 0.003 and p = 0.007. Graphically, model 2 is presented in Fig. 2.
The critical value of the PC sum, calculated from 4 clinical indicators of inhalation tests, was determined to be 12 points or higher for assessing the probability of BHR. With the minimum number of points (ΣPC = 0), the probabi–lity of BHR is Р = 0.027, with the maximum (ΣPC = 35) Р = 0.999. Classification into risk groups is as follows: if ΣPC ≤ 7 points, then the risk is low (Р ≤ 0.25), with 8 ≤ ΣPC ≤ 11 points — moderate (Р ≤ 0.50), with ΣPC ≥ 12 points — high (Р >0.50), including when ΣPC ≥ 19 points is very high (Р > 0.90) –(Table 2). This model has indicators of sensiti–vity of 76.5 %, specificity of 95.7 %, diagnostic efficiency of 87.5 %. The AUC = 0.954 (0.837–0.995) at p < 0.001.

Discussion

The results of foreign studies and our own experience show that approximately half of patients with CF have BHR to HS, which is characterized by airway obstruction, shortness of breath, wheezing, and cough [4, 7]. It has been found that BHR complicates the course of the bronchopulmonary process — it leads to the intensification of the infectious process and the formation of a vicious circle (obstruction-infection-inflammation with damage to lung tissues). A clinical manifestation of a vicious circle is a progressive decrease in the functional parameters of breathing [3]. For a long time, BHR was considered the leading pathophysiological mechanism in the development of bronchial asthma, however, today BHR plays an important role in the deve–lopment of bronchial obstruction syndrome in patients with CF [4, 13]. The determinants of BHR in CF differ that of bronchial asthma and are not yet fully understood.
The analysis of the research results showed that the most significant prognostic predictors for the formation of BHR in patients with CF are the presence of ABPA, the appea–rance of dry whistling rales in the lungs during auscultation, a decrease in FEV1 by 7 % or more from the baseline after inhalation of 3% NaCl solution and by 10 % or more after inhalation of 7% NaCl solution, an increase in the level of FeNO by 8 % or more from the baseline. At the same time, the presence of ABPA, as well as a decrease in FEV1 by 7 % or more from the baseline after inhalation of a 3% NaCl solution can be an independent criterion for BHR. It has been proven that in patients with CF, the growth of Aspergillus fumigatus in the lumen of the bronchi causes an immediate immunoglobulin E-mediated hypersensitivity reaction with subsequent inflammation of the bronchi, destruction of the airways and fibrosis (bronchiectasis), which is accompanied by obstruction of the airways, shortness of breath and dry wheezing [11]. The diagnostic value of FeNO level is that it can show the presence and degree of inflammation in the respiratory tract. Children with CF have been shown to have significantly lower FeNO levels, which correlates with decreased lung function in these patients. This suggests that a low FeNO may be a marker of more severe lung damage [16]. An increase in the level of FeNO in patients with CF after HS inhalation may indicate an increase in the number of inflammatory cells in the respiratory tract, which causes a change in their reactivity [4].
Two prognostic scales, which are convenient for use in practical medicine, have been created, which allow predicting the development of BHR syndrome in children with CF, and can be used at different stages of providing medical care. Model 1 considers the clinical and anamnestic data, genetic predictors, as well as clinical symptoms during inhalation tests with increasing concentrations of HS. It is recommended for use at the outpatient stage of providing medical care and in young children in whom it is not possible to conduct spirometry and assess indicators of external breathing function. At low and moderate risk, it is recommended to conduct a spirometric test according to the developed protocol for greater verification. At high risk, it is unequivocally recommended to prescribe bronchodilator therapy before inhalation of HS for the entire treatment period, while the choice of bronchodilator depends on the age of the patient: for children under 4 years of age — only combined drugs (ipratropium bromide with fenoterol hydrobromide), for older children — depending on clinical effectiveness (short- or long-acting beta-agonists, combination drugs).
Model 2, which includes an assessment of total PC score for spirometric data of inhalation tests with increasing concentrations of HS, the level of nitrogen monoxide in the exhaled air condensate, is recommended to be used at the stage of highly specialized medical care for patients with CF. At medium and high risk, the unequivocal prescription of a bronchodilator is recommended. In the presence of such a predictor as a decrease in FEF25 by 6 % or more from the baseline when using a 3% NaCl solution, it is recommended to prescribe combined bronchodilators. Research shows that bronchodilators can increase mucociliary transport, reduce inflammatory damage to the airways, increase exercise tolerance, and reduce dyspnea in CF patients [4]. Based on Cochrane reviews, it was concluded that both short- and long-acting beta-agonists may be useful for CF patients with BHR [15, 17].

Conclusions

1. Predicting the tolerability of inhalation therapy in children with cystic fibrosis at the beginning of treatment is of practical importance for the timely prevention of undesi–rable phenomena and the achievement of a positive therapeutic effect.
2. Two mathematical models for predicting the tolerabi–lity of inhalation therapy at various stages of providing me–dical care to patients with cystic fibrosis have been deve–loped, which calculate (with high probability) the risk of developing bronchial hyperreactivity syndrome, for a personalized selection of HS and the choice of preventive broncholytic therapy as needed.
Prospects for further research are to assess the effectiveness of the personalized prescription of drugs for inhalation therapy in children with CF, based on the proposed prognostic scales.
 
Received 04.02.2023
Revised 09.02.2023
Accepted 14.02.2023

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