The role of the small airways in the clinical expression of asthma in adults

doi:10.1016/j.jaci.2011.11.017

Journal of Allergy and Clinical Immunology

Volume 129, Issue 2, February 2012, Pages 381-387.e1

https://doi.org/10.1016/j.jaci.2011.11.017 Get rights and content

Background

The clinical relevance of increased ventilation heterogeneity, a marker of small-airways disease, in asthmatic patients is unclear. Ventilation heterogeneity is an independent determinant of airway hyperresponsiveness (AHR), improves with bronchodilators and inhaled corticosteroids (ICSs), and worsens during exacerbations, but its relationship to asthma control is unknown.

Objective

We sought to determine the association between ventilation heterogeneity and current asthma control before and after ICS treatment.

Methods

Adult subjects with asthma had lung function and asthma control (5-item Asthma Control Questionnaire [ACQ-5 score] ≥1.5 = poorly controlled, ACQ-5 score ≤0.75 = well controlled) measured at baseline. A subgroup with AHR had repeat measurements after 3 months of high-dose ICS treatment. The indices of ventilation heterogeneity in the regions of the lung where gas transport occurs predominantly through convection (ventilation heterogeneity in convection-dependent airways [Scond]) and through diffusion (ventilation heterogeneity in diffusion-dependent airways [Sacin]) were derived by using the multiple-breath nitrogen washout technique.

Results

At baseline (n = 105), subjects with poorly controlled asthma had worse FEV₁, fraction of exhaled nitric oxide measured at 200 mL/s (Feno), Scond, and Sacin values. In the treatment group (n = 50) spirometric, Feno, residual volume (RV)/total lung capacity (TLC), AHR, and Scond values significantly improved. Asthma control also improved (mean ACQ-5 score, 1.3-0.7; P < .0001). The change in ACQ-5 score correlated with changes in Feno (r_s = 0.31, P = .03), Sacin (r_s = 0.32, P = .02), and Scond (r_s = 0.41, P = .003) values. The independent predictors of a change in asthma control were changes in Scond and Sacin values (model r² = 0.20, P = .005).

Conclusions

Current asthma control is associated with markers of small-airways disease. Improvements in ventilation heterogeneity with anti-inflammatory therapy are associated with improvements in symptoms. Sensitive measures of small-airway function might be useful in monitoring the response to therapy in asthmatic subjects.

Section snippets

Methods

Adult subjects were recruited from a volunteer database at the Woolcock Institute of Medical Research by advertising throughout the University of Sydney and from referrals by local respiratory physicians. Subjects were eligible if they had a physician’s diagnosis of asthma and either current symptoms, a current asthma prescription, or both.²⁴ Subjects were nonsmokers (<10 pack-year smoking history and no smoking within the last 6 months), had no chest infections or antibiotic or oral prednisone

Baseline

Baseline demographics for 105 asthmatic subjects categorized according to current asthma control are shown in Table I. Subjects in this cohort were relatively young adults (range, 24-51 years), and there were no differences in age or disease duration across asthma control categories. Treatment intensities with ICSs and LABAs were similar between the groups. The prevalence of atopy (n = 98/105) and smoking history (mean, 0.6 pack years) did not differ between the groups.

Compared with the group

Discussion

In the current study ventilation heterogeneity was worse in patients with poorly controlled asthma. Furthermore, changes in ventilation heterogeneity after a period of ICS treatment correlated with changes in asthma symptom control independently of all other measured physiologic variables. These results demonstrate that abnormal small-airway function contributes to the expression of asthma symptoms.

The novel findings from this analysis advance our understanding of the underlying causes of

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: Supported by research grants from the National Health and Medical Research Council (NHMRC) of Australia and the Cooperative Research Centre for Asthma and Airways (CRCAA). Pharmaxis Ltd provided the mannitol kits for the bronchial challenge.

: Disclosure of potential conflict of interest: C. S. Farah has received honoraria from AstraZeneca, GlaxoSmithKline, and Novartis. G. G. King has received research support from the Cooperative Research Centre for Asthma, the National Health and Medical Research Council, and GlaxoSmithKline and has provided legal consultation/expert witness testimony for GlaxoSmithKline, AstraZeneca, and Boehringer Ingelheim. C. M. Salome has received research support from the Cooperative Research Centre for Asthma and Airways, the National Health and Medical Research Council of Australia, and GlaxoSmithKline. The rest of the authors declare that they have no relevant conflicts of interest.

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Asthma and lower airway diseaseThe role of the small airways in the clinical expression of asthma in adults

Background

Objective

Methods

Results

Conclusions

Section snippets

Methods

Baseline

Discussion

J Allergy Clin Immunol

Am J Med

J Allergy Clin Immunol

Respir Med

Chest

Chest

Respir Med

Respir Med

J Allergy Clin Immunol

Chest

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

Recurrent exacerbations in severe asthma are associated with enhanced airway closure during stable episodes

Am J Respir Crit Care Med

Convection- and diffusion-dependent ventilation maldistribution in normal subjects

J Appl Physiol

Model simulations of gas mixing and ventilation distribution in the human lung

J Appl Physiol

Lung clearance index at 4 years predicts subsequent lung function in children with cystic fibrosis

Am J Respir Crit Care Med

Noninvasive assessment of airway alterations in smokers: the small airways revisited

Am J Respir Crit Care Med

Small airways function declines after allogeneic hematopoietic stem cell transplantation

Eur Respir J

Evidence of acinar airway involvement in asthma

Am J Respir Crit Care Med

Ventilation heterogeneity is a major determinant of airway hyperresponsiveness in asthma, independent of airway inflammation

Thorax

Ventilation distribution during histamine provocation

J Appl Physiol

Airway obstruction and ventilation-perfusion relationships in acute severe asthma

Am Rev Respir Dis

Nitrogen washout slope in poorly controlled asthma

Allergy

Asthma and lower airway disease
The role of the small airways in the clinical expression of asthma in adults