Effect of inhaled corticosteroids on small airways in asthma: Investigation using impulse oscillometry

doi:10.1016/j.pupt.2009.01.005

Pulmonary Pharmacology & Therapeutics

Volume 22, Issue 4, August 2009, Pages 326-332

https://doi.org/10.1016/j.pupt.2009.01.005 Get rights and content

Abstract

Background

Small airways appear to have an important role in asthma. Hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP) has ultrafine particles and accordingly greater deposition in the small airways than chlorofluorocarbon (CFC)-BDP. Impulse oscillometry systems (IOS), a new and non-invasive measure of pulmonary function, can examine the resistance of total (R5), large (R20), and small airways (R5–R20) separately, and low-frequency reactance area (AX), also considered a measure of small airways dysfunction.

Methods

Mild-to-moderate asthmatics who were inhaled corticosteroid naïve were randomized to receive 200 mcg HFA-BDP bid (n = 26) or 400 mcg CFC-BDP bid (n = 12) for 12 weeks in an open-label manner. Following baseline measurements, IOS and spirometry were repeated every 4 weeks, and methacholine challenge to separately assess airway sensitivity and airway reactivity and lung volumes at 12 weeks.

Results

Moderate correlations were found between R5–R20 or AX and spirometry and lung volume indices of small airways, and between R20 and peak expiratory flow at baseline. The two groups did not significantly differ in baseline clinical or functional parameters. At 12 weeks, all IOS indices improved in the HFA-BDP group, whereas all but R5–R20 improved with CFC-BDP. R5–R20 and AX progressively improved with HFA-BDP; these changes achieved statistical significance at 12 weeks versus the CFC-BDP group. Other IOS and spirometry indices failed to show such trends. HFA-BDP significantly attenuated methacholine airway sensitivity; the degree of this attenuation strongly correlated with R5–R20 and AX baseline values, and with improvement of AX with treatment.

Conclusion

HFA-BDP is an effective treatment of small airways in asthma. Prolonged treatment provides a progressive effect over time, which is associated with an attenuation of airway responsiveness.

Introduction

Asthma is characterized by chronic airway inflammation and associated airway hyperresponsiveness. Inflammation extends from large to small airways [1], [2], [3], [4], [5], being more intense in the latter [2], [3]. Patients with nocturnal asthma exhibit a significant influx of eosinophils to the small but not the large airways in the early morning, in association with a fall in FEV₁[2], [6]. Air trapping, a high-resolution computed tomography (HRCT) index of small airway disease, significantly correlates with the severity of asthma and airway hypersensitivity [7]. Small airways may thus be an important therapeutic target [8].

Inhaled corticosteroids (ICSs) are highly effective anti-inflammatory medications in asthma. However, some patients continue to have persistent symptoms despite high-dose ICS treatment. This may be attributed, at least in part, to poor delivery of ICS to the small airways leading to insufficient control of inflammation. Reformulation of beclomethasone dipropionate (BDP) with hydrofluoroalkane-134a (HFA) allows delivery of aerosol with much finer particles (mass median aerodynamic diameter (MMAD) of 1.1 μm) than those of conventional chlorofluorocarbon-11/12 (CFC)-BDP (3.5 μm), and this results in particles being deposited further into the lung periphery [9].

The effect of HFA-formulations of ICS on small airways in asthma has been investigated in several small studies [10], [11], [12], [13], [14]. The addition of 320 μg HFA-BDP daily for 12 weeks had greater benefits on closing volume, closing capacity, and mid-forced expiratory flow (FEF_25–75%) than the addition of 330 μg CFC-fluticasone (MMAD 2.4 μm) daily [10]. Moreover, 4 weeks' treatment with 200 μg HFA-BDP daily resulted in greater improvement of air trapping on HRCT assessed after methacholine inhalation than 200 μg CFC-BDP daily [11]. Furthermore, 680 μg HFA-flunisolide (MMAD 1.2 μm) daily for 6 weeks attenuated eosinophilic inflammation of large and small airways as assessed by endobronchial and transbronchial biopsies [12]. However, the differential and progressive effects of ICS on large and small airways remain poorly known, in part because of methodological limitations of previous studies. The invasiveness of biopsy and the radiation exposure associated with CT preclude repeated measurements over time. Dose–response studies of ICS have indicated that small airways may require longer-term treatment to obtain maximal effect [13], but evidence is lacking [14].

The impulse oscillometry system (IOS) is a non-invasive, effort-independent and thus repeatable measure to assess airway function [15]. IOS has a potential to examine respiratory resistance (R) and respiratory reactance (X) of large and small airways separately [15], and it is more sensitive to therapeutic intervention than spirometry [16]. Here we compared HFA-BDP and CFC-BDP in terms of the progressive effect of 12 weeks' treatment on pulmonary function in asthmatic patients as assessed by IOS. Spirometry, lung volumes, and the two components of airway responsiveness, airway sensitivity and reactivity, were also examined.

Section snippets

Subjects

We consecutively enrolled 48 ICS-naïve adults with mild-to-moderate asthma, who were referred to our asthma clinic of Kyoto University. Asthma was diagnosed according to the American Thoracic Society criteria [17]. The patients were lifetime nonsmokers or had smoked <5 pack-years and had quit for >12 months. None had a history or abnormal chest X-ray findings suggestive of concomitant respiratory disease.

This study was approved by the Ethics Committee at our institution, and written informed

Results

Eight patients (four assigned to receive HFA-BDP) were lost to follow-up before the end of the 12-week treatment period, and two patients had asthma exacerbations requiring oral corticosteroids due to respiratory infection, both of whom were allocated to receive HFA-BDP. Therefore, 38 patients were included in the final analysis.

Discussion

This is the first study, to our knowledge, that compared ultrafine and medium-sized aerosol formulations of ICS in terms of differential effects over time on IOS indices of large and small airways in asthma. Compared to CFC-BDP (medium-sized particles), HFA-BDP (ultrafine particles) provided greater improvement in R5–R20 and AX, IOS indices considered to reflect small airway disease. The difference between groups first reached statistical significance at 12 weeks. The decrease in AX was

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A longitudinal retrospective chart review was conducted on 55 C-SCD (161 IOS observations) and 35 non-SCD asthmatic children (C-Asthma) (58 observations), primarily to investigate the association between BMI and airway resistance in C-SCD and C-Asthma. We conducted generalized linear mixed models (GLMM), adjusted for pharmacotherapies, to demonstrate the influence of BMI on total (R₅), central (R₂₀), and peripheral (R_5-20) airway resistance and reactance (X₅, resonant frequency (Fres)). We further compared age, BMI, and IOS indices between C-SCD and C-Asthma using the Mann-Whitney test.
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BMI significantly influenced total and central airway resistance in C-SCD. While higher airway resistances reflected increased OAD in C-SCD than asthmatics, higher Fres perhaps indicated progressive pulmonary involvement in C-SCD.
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The objective of this review is to provide new advances in our understanding of the clinical importance of establishing peripheral airway impairment (PAI) by impulse oscillometry (IOS) and targeted therapy, which could result in better asthma outcomes. Data sources include PubMed and Google search, limited to English language and human disease, with key words IOS and asthma. Key findings include PAI being consistently associated with uncontrolled asthma across ethnicities, using IOS reference equations factoring Hispanic and White reference algorithms. It is noted that PAI is common even in patients considered well-controlled by asthma guidelines. In a large longitudinal analysis (Assessment of Small Airways Involved in Asthma or ATLANTIS study), a composite of R5-R20, AX, and X5 ordinal scores were independently predictive of asthma control and exacerbation in a multivariate analysis, but forced expiratory volume in 1 second was not significantly predictive of morbidities. However, combining forced expiratory volume in 1 second less than 80% with PAI resulted in greater odds of identifying uncontrolled asthma and exacerbations, than either alone. Applying an external validation method in children with asthma offers the clinician the IOS reference equations best fit for their own specific population. Several clinical phenotypes can also identify PAI with high probability, useful when IOS is not available. Poor asthma outcomes for obese patients with asthma are associated with dysanapsis and PAI, not obesity alone. Extrafine inhaled corticosteroids achieve better asthma control and improve peripheral airway function with fewer exacerbations at lower dosages than nonextrafine inhaled corticosteroid aerosols. In conclusion, these data support the benefit of adding IOS to spirometry in future asthma guidelines and suggest the potential benefit from targeted therapy.
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Effect of inhaled corticosteroids on small airways in asthma: Investigation using impulse oscillometry

Abstract

Background

Methods

Results

Conclusion

Introduction

Section snippets

Subjects

Results

Discussion

J Allergy Clin Immunol

J Allergy Clin Immunol

Clin Chest Med

J Allergy Clin Immunol

Lancet

J Allergy Clin Immunol

Chest

Chest

Chest

Respir Med

Chest

Pulm Pharmacol Ther

Respir Med

Chest

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

The structure of large and small airways in nonfatal and fatal asthma

Am Rev Respir Dis

Alveolar tissue inflammation in asthma

Am J Respir Crit Care Med