Small airway function in children with mild to moderate asthmatic symptoms

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Abstract

Background

Clinical significance of small airway obstruction in mild pediatric asthma is unclear.

Objective

To evaluate small airway properties in children with mild to moderate asthmatic symptoms and the association of small airway function with asthma control and exercise-induced bronchoconstriction (EIB).

Methods

Children (5-10 years old) with recurrent wheezing (n = 42) or persistent troublesome cough (n = 16) and healthy controls (n = 19) performed impulse oscillometry (IOS), spirometry, and a multiple-breath nitrogen washout (MBNW) test. Exhaled nitric oxide (NO) was measured at multiple flow rates to determine alveolar NO concentration (Calv). Asthma control was evaluated with the Childhood Asthma Control Test (C-ACT), short-acting β2-agonist (SABA) use within the past month, and asthma exacerbations within the past year.

Results

IOS, spirometry, and exhaled NO indexes that are related to small airway function differed between children with recurrent wheezing and healthy controls, whereas only forced expiratory flow at 25% to 75% of the forced vital capacity was associated with persistent cough. The MBNW indexes showed no difference between the groups. Among symptomatic children, conducting airway ventilation inhomogeneity and Calv were associated with asthma exacerbations (P = .03 and P = .002, respectively), and lung clearance index and Calv were associated with EIB (P = .04 and P = .004, respectively). None of the proposed small airway indexes was associated with the C-ACT score or SABA use.

Conclusion

Subtle changes were observed in the proposed small airway indexes of IOS, spirometry, and exhaled NO among children with mild to moderate recurrent wheezing. Small airway dysfunction, expressed as ventilation inhomogeneity indexes and Calv, was also associated with asthma exacerbations and EIB.

Introduction

Bronchial biopsies and postmortem studies have demonstrated the involvement of small airway inflammation in asthma,[1], [2] supported by clinical studies on the association between small airway dysfunction and clinical expression of asthma.[3], [4] In children, abnormalities in the proposed small airway indexes have been related to uncontrolled or severe asthma,[5], [6], [7] but their potential to distinguish milder disease changes remains debated.[8], [9] It is plausible to hypothesize small airways to be involved to some extent in most patients with asthma,10 even in children. Early involvement of small airways has also been recognized as a risk factor for future chronic obstructive pulmonary disease.11 Furthermore, with the emergence of small-particle aerosols that reach the lung periphery, accurate measures for small airways are necessitated to identify and follow up patients who might benefit from this treatment. However, conventional lung function measures, such as forced expiratory volume in 1 second (FEV1), mainly reflect large airways, and no gold standard measures for small airways exist. Potential methods for assessing small airway properties include impulse oscillometry (IOS), spirometry, multiple-breath washout (MBW) tests, and extended exhaled nitric oxide (NO) analysis.

IOS measures respiratory resistance and reactance by analyzing responses to pulse signals of different frequencies. High-frequency resistance values, such as resistance at 20 Hz (R20), are considered to reflect large airway resistive properties, whereas lower frequencies, such as resistance at 5 Hz (R5), reflect the whole respiratory system.12 Small airway obstruction is thought to result in frequency dependence of resistance and thus increased difference between R5 and R20 (R5-20).5 Negative reactance values reflect the capacitive properties of the lung periphery, and thus reactance at 5 Hz (X5) and area under the reactance curve (AX) are considered to reflect small airway function.[5], [12]

During forced expiration, small airway obstruction is postulated to contribute to airflow limitation during the middle and end phases of the forced vital capacity (FVC). This results in diminished midexpiratory flow rates, without significant effects on FEV1, which mainly reflects large airway function at the initial part of forced expiration.13 Midexpiratory flow rates can be evaluated by calculating the forced expiratory flow between 25% and 75% of the FVC (FEF25%-75%), which is considered to reflect the medium- and small airway function.

MBW measures ventilation distribution homogeneity by analyzing the washout pattern of an inert marker gas. Lung clearance index (LCI) is postulated to reflect the overall ventilation inhomogeneity secondary to small airway disease.14 The washout pattern over several breaths aims to separate convection-dependent ventilation inhomogeneity in the small conducting airways (Scond) and diffusion-convection-dependent inhomogeneity in the acinar structures (Sacin).14

Airway inflammation enhances production of NO in the bronchial epithelium.15 At low flow rates, such as 50 mL/s, the fractional exhaled NO (Feno) mainly reflects NO from the central airways.16 With increasing flow rates, contribution of proximal airways decreases and Feno represents alveolar NO.16 Applications with multiple exhalation flow rates have been created to separate alveolar NO concentration (Calv) from bronchial NO flux (Jno).15

Our primary aim was to investigate whether small airway dysfunction is present in young children with mild to moderate asthmatic symptoms by using different indicators of small airway involvement: IOS, spirometry, multiple-breath nitrogen washout (MBNW) test, and extended Feno measurement. The secondary aim was to evaluate the association of these measurements with asthma control and exercise-induced bronchoconstriction (EIB). Finally, considering their proposed association with small airway function, we hypothesized that the small airway indexes of the compared methods would be associated with each other.

Section snippets

Methods

The study was approved by Helsinki University Hospital (IAS16 ASA04 0116) and Helsinki University Hospital Research Ethics Committee (390/13/03/03/2015). Parents of all participating children provided written consent, and depending on literacy, the children contributed an oral or written consent.

Results

Baseline characteristics of the healthy and symptomatic children are presented in Table 2. The healthy and symptomatic groups significantly differed regarding only parental smoking. Of the symptomatic children, 14 (24%) used continuous and 8 (14%) used intermittent asthma-control medication; use of these medications ceased 4 weeks or more before the diagnostic lung function measurements.

Discussion

Despite the increasing clinical and research interest toward small airways, their role in pediatric asthma is poorly understood. We found subtle but significant differences between 5- to 10-year-old children with mild to moderate asthmatic symptoms and healthy controls regarding IOS, spirometry, and Feno indexes related to small airway function, which suggests that small airway dysfunction is present even in mild asthma at this age group. Most of these differences were observed only in children

Acknowledgments

We express our gratitude for the skillful work of Research Nurse Anssi Koivuselkä in performing the lung function measurements and Professor Seppo Sarna for his statistical consultation.

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    Disclosures: Authors have nothing to disclose.

    Funding Sources: The study was funded by the Emil Aaltonen Foundation, Foundation for Pediatric Research, Ida Montin's Foundation, The Finnish Allergy Research Foundation, The Finnish Medical Foundation, The Research Foundation of the Pulmonary Diseases, and Väinö and Laina Kivi's Foundation.

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