Wskaźniki nieswoistej reaktywności oskrzeli u pacjentów z ciężką postacią astmy – określenie fenotypu u dzieci w wieku szkolnym

Mykola Garas, Serhii Sazhyn, Gennadii Lekhkun, Roman Goncharuk, Nataliya Gorenko

Higher State Educational Establishment «Bukovinian State Medical University», Chernivtsi, Ukraine 

ABSTRACT

Introduction: Severe asthma phenotype is characterized by peculiarities of inflammatory process in the airways and consequently hypersensitivity and bronchial lability.

The aim: The study aims at determining the diagnostic value of bronchial lability indices in identifying severe bronchial asthma phenotype compared to the moderate variant of disease in schoolchildren.

Materials and methods: We formed two clinical groups of observation, the first clinical group included 57 children with severe asthma phenotype, the second clinical group included 65 patients with moderate disease course. Bronchial lability was determined by evaluating their response to dosed physical activity (bronchospasm index) and short-acting β2-agonist inhalation (200 mcg of salbutamol – bronchodilation index).

Results: Despite the lack of probable differences in average bronchospasm index in children of comparison groups, patients with severe bronchial asthma tended to more pronounced bronchospasm after dosed physical activity. Pronounced bronchospasm after physical activity (bronchospasm index >20%) is characteristic for children with severe disease persistence. Significantly higher bronchodilation index and severe bronchodilation reaction (bronchodilation index >25%) was determined in children of the first clinical group. Statistical analysis showed that all bronchial lability indices at these distribution points in confirming severe bronchial asthma proved to be highly specific, but low-sensitive with insufficient likelihood ratio.

Conclusions: So, the use of bronchial lability indices for screening of severe asthma phenotype is justified only in combination with other parameters reflecting the characteristic phenomena of disease because of the large proportion of false negative results and insufficient likelihood ratio.

Wiad Lek 2018, 71, 8, -1540

Introduction

Bronchial asthma is a chronic respiratory disease characterized by reversible airway obstruction and increased airway irritability usually associated with inflammation of tissues of airway muscles, congestion or constriction of airway small muscles [1]. Asthma is an inflammatory disorder characterized by airway obstruction, airway hyperresponsiveness, and airway inflammation, all of which are variable among patients and variable in time within any specific patient. Understanding the mechanism that underlies this observed variability, and using that understanding to advance the science of asthma and the care of asthmatic patients, is an essential purpose of developing phenotypes [2]. Asthma is a heterogeneous disease for which a strong genetic basis is firmly established. Although the generally accepted definition includes three domains of symptoms (variable airway obstruction, airway hyperresponsiveness, and airway inflammation), there is general agreement that, rather than being a single disease entity, asthma consists of related, overlapping syndromes [3].

Asthma severity is assessed retrospectively from the level of treatment required to control symptoms and exacerbations. So, asthma severity has often been based on prescribed treatment step. Severity is often also used to describe the intensity of asthma symptoms, the magnitude of airflow limitation, or the nature of an exacerbation [4].

Along with the fact that the main goal of bronchial asthma treatment is achieving and maintaining control over the disease symptoms, one aspect of insufficient control over the disease is its phenotypic heterogeneity [5]. However, some authors [5, 6] single out a separate “severe asthma” phenotype in children’s age among age-specific, clinical and pathophysiological bronchial asthma subtypes.

Severe asthma affects less than 10% of patients with asthma and is associated with substantial morbidity and mortality and a large fraction of the health care costs among patients with asthma [7, 8]. Severe asthma in children is a complicated and heterogeneous disorder that is extremely challenging to treat [9]. Although patients with “severe” asthma tend to be characterized by ongoing symptoms and airway inflammation despite treatment with high doses of inhaled and systemic corticosteroids, there is increasing recognition of marked phenotypic heterogeneity within affected patients [10]; severe asthma is characterized by the need for treatment with high doses of inhaled corticosteroids and includes several clinical and pathophysiological phenotypes [11].

Children with severe asthma may fall into 2 categories, difficult-to treat asthma or severe therapy-resistant asthma. Difficult-to-treat asthma is defined as poor control due to an incorrect diagnosis or comorbidities, or poor adherence due to adverse psychological or environmental factors [12]. Severe therapy-resistant asthma affects a small proportion of children with asthma and is characterized by persistent symptoms, acute severe exacerbations, and/or fixed airflow obstruction despite treatment with high-dose steroid therapy, and after modifiable factors such as poor adherence and persistent allergen exposure has been addressed [13].

Actually, severe asthma phenotype is characterized by some molecular peculiarities of inflammatory process in the airways and consequently hypersensitivity and bronchial lability, the study of which will help in the development of targeted individualized therapeutic program for children that are resistant to therapy [14].

The aim

The study aims at determining the diagnostic value of bronchial lability indices in identifying severe bronchial asthma phenotype compared to the moderate variant of disease in schoolchildren.

Materials and methods

According to the regulated criteria [15] we formed two clinical groups of observation. The first, or basic, clinical group (I) included 57 children with severe persistent bronchial asthma phenotype. The second (II) clinical group of comparison included 65 patients with moderate persistent disease course. The groups of comparison were analyzed by the main clinical characteristics. In patients of the first clinical group the average disease duration reached 8,0±0,48 years, in the group of comparison it was 6,2±0,52 years (p<0,05). The average age of children with severe bronchial asthma phenotype was 12,6±0,43 years, in schoolchildren of the second clinical group it was 12,4±0,45 years (p<0,05), there were 59,6% of boys in the first clinical group, 63% (Pφ>0,05) – among the pupils with moderate course of the disease, in both groups rural residents dominated (61,4% and 50,8% in the first and second clinical group respectively, p>0,05). All observations are performed due to the bioethics principles.

Bronchial lability was determined according to recommendations [16-19] by evaluating their response to dosed physical activity and short-acting β2-agonist inhalation (200 mcg of salbutamol) followed by calculating bronchial lability index as a sum of components – bronchospasm index:

bronchospasm index = ((pre-exercise FEV1 – post-exercise FEV1) / pre-exercise FEV1) x 100%

and bronchodilation index:

bronchodilation index = ((FEV1 after inhalation salbutamol – initial FEV1) / initial FEV1) x 100%

Bronchial motor salbutamol test with value higher than 12% was thought to be positive [19]. In the study of bronchial lability in some patients an increase in FEV1 after dosed physical activity was observed as well as the decrease in this index after salbutamol inhalation, which were recorded as negative values of bronchospasm indices and bronchodilation (bronchospasm and bronchodilation indices). Thus, in children of the first clinical group negative values of bronchospasm index were detected in 16,3% of cases, and negative results of bronchodilation index occurred in 12,5% of cases. In the comparison group the given phenomenon occurred in 18,1% and 7,9% of patients respectively. The appearance of these negative values of spirometric indices was reflected in the following way: in 5,4% of cases in the first clinical group and in 7,9% of cases in the comparison group the bronchial lability index (bronchial lability index) also had negative values. As such bronchial response to dosed physical activity and bronchial β2-agonist inhalation can not be considered typical, such children were not involved into the analysis of bronchial tree lability.

Statistical analysis of the data was performed according to the position of biostatistics. To evaluate the diagnostic value of tests we measured their sensitivity, specificity, predictive value of positive and negative results defining their confidence intervals (95% CI) and ratio of test results plausibility. The assessment of the event implementation risk was held taking into consideration the probability values of relative risk, odds ratios and after-test probabilities, as well as their confidence intervals values [20, 21].

Results and discussion

Table I represents the bronchial lability indices in children of groups of comparison in response to the dosed physical activity (bronchospasm index) and salbutamol inhalation (bronchodilation index), and the average values of integrative bronchial lability index.

Despite the lack of probable differences in average bronchospasm index in children of comparison groups, patients with severe bronchial asthma tended to more pronounced bronchospasm after dosed physical activity. Thus, the values of this index that exceeded 10% were observed in 34,1% of children with severe bronchial asthma and in 28,5% of patients in the comparison group (Pφ>0,05). Pronounced bronchospasm after physical activity (bronchospasm index >20%) is characteristic for children with severe disease persistence. Thus, the value of bronchospasm index, which exceeded 20%, were observed in 14,6% of cases in schoolchildren of the first clinical group and in patients with moderate bronchial asthma – in 9,5% of cases (Pφ>0,05). It should be noted that in children of clinical groups of comparison minor bronchospasm was observed equally often after physical activity. Thus, less than 5% bronchospasm index occurred in 46,4% of patients of the first clinical group and in 45,2% of children in the comparison group (Pφ>0,05).

Along with significantly higher bronchodilation index in children of the first clinical group, it was determined that severe bronchodilation reaction (bronchodilation index >25%) was observed in 16,7% of patients of the first clinical group and in 6,1% of children of the comparison group (Pφ>0,05).

It is noted that in patients with severe bronchial asthma bronchial lability index values higher than 30% were observed in 19,0% of cases, and in representatives of the second clinical group – in 10,2% of cases (Pφ>0,05).

Excessive bronchial lability is a characteristic feature for children with bronchial asthma, particularly pronounced reaction to various bronchospasmodic and bronchodilation stimuli; it seemed reasonable to identify and assess the diagnostic value of indices that characterize airways lability, namely bronchospasm and bronchodilation indices and integrated bronchial lability index (table II).

All bronchial lability indices at these distribution points in confirming severe bronchial asthma proved to be highly specific, but low-sensitive with insufficient likelihood ratio within 2,1-2,5 for positive test results and 0,7-0,9 – for their negative results. Taking into consideration the above mentioned, we can assume that their independent use for screening of severe bronchial asthma is unjustified. At the same time, when the values of indices exceeded these distribution points, after-test likelihood of severe asthma detection using bronchospasm index increased by 18%, increased by 21% when calculating bronchodilation index and by 29% when calculating bronchial lability index.

Table III contains risk indices of severe bronchial asthma with consideration of bronchial lability indices. It is noted that pronounced increase in bronchial patency after salbutamol inhalation (bronchodilation index >15%) indicated the greatest risk of severe bronchial asthma.

Conclusions

1. Children with severe bronchial asthma phenotype are characterized by significantly greater bronchial lability mainly due to likely distinct dilatation reaction to β2-agonist inhalation.

2. The use of bronchial lability indices for screening of severe bronchial asthma phenotype is justified only in combination with other parameters reflecting the characteristic phenomena of disease because of the large proportion of false negative results and insufficient likelihood ratio.

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Authors’ contributions:

According to the order of the Authorship.

Conflict of interest:

The Authors declare no conflict of interest.

CORRESPONDING AUTHOR

Mykola Garas

49a, Avangardna str., flat 31, 58023, Chernivtsi, Ukraine

tel: +380954491324

e-mail: garas.mykola@bsmu.edu.ua

Received: 19.07.2018

Accepted: 01.10.2018

Table I. Bronchial lability indices in schoolchildren of clinical groups (M±m)

Clinical groups

Number of children

Bronchospasm index,

%

Bronchodilation index,

%

Bronchial lability index, %

Children with severe bronchial asthma

42

8,9±1,49

13,9±1,80

22,8±2,36

Children with moderate bronchial asthma

49

8,0±1,32

9,1±1,18

15,9±1,74

Р

>0,05

<0,05

<0,05

Table II. Diagnostic value of bronchial lability indices in severe bronchial asthma verification, %

Bronchial lability indices

Sensitivity

Specificity

Predictive

value of positive results

Predictive value of negative results

Bronchospasm index > 22%

15

93

67

53

Bronchodilation index > 15%

38

85

64

65

Bronchial lability index > 30%

24

89

67

57

Table III.Bronchial lability indices as risk symptoms of severe persistent bronchial asthma

Bronchial lability indices

Absolute risk

Odds ratio

(95% CI)

Relative risk (95% CI)

Bronchospasm index > 22%

0,19

2,2 (0,5-9,5)

1,4 (0,4-5,3)

Bronchodilation index > 15%

0,29

3,4 (1,3-8,6)

1,8 (0,9-3,8)

Bronchial lability index > 30%

0,23

2,6 (0,8-8,4)

1,5 (0,6-4,1)