Predictors of Airway Hyperresponsiveness Differ Between Old and Young Patients With Asthma

doi:10.1378/chest.10-1839

Chest

Volume 139, Issue 6, June 2011, Pages 1395-1401

https://doi.org/10.1378/chest.10-1839 Get rights and content

Background

Age-related increases in morbidity and mortality due to asthma may be due to changes in pathophysiology as patients with asthma get older. There is limited knowledge about the effects of age on the predictors of airway hyperresponsiveness (AHR), a key feature of asthma. The aim of this study was to determine if the pathophysiologic predictors of AHR, including inflammation, ventilation heterogeneity, and airway closure, differed between young and old patients with asthma.

Methods

Sixty-one young (18-46 years) and 43 old (50-80 years) patients with asthma had lung function, lung volumes, fraction of exhaled nitric oxide, ventilation heterogeneity, and airway responsiveness to methacholine measured. Airway response to methacholine was measured by the dose-response slope, as the percent fall in FEV₁ per micromole of methacholine. Indices of ventilation heterogeneity were calculated for convection-dependent and diffusion-dependent airways.

Results

In young patients with asthma, the independent predictors of AHR were convection-dependent ventilation heterogeneity, exhaled nitric oxide, and % predicted FEV₁/FVC (model r² = 0.51, P < .0001). In old patients with asthma, the independent predictors of airway responsiveness were % predicted residual volume, diffusion-dependent ventilation heterogeneity, and % predicted FEV₁ (model r² = 0.57, P < .0001).

Conclusions

In old patients with asthma, AHR is predicted by gas trapping and ventilation heterogeneity in peripheral, diffusion-dependent airways. In the young, it is predicted by ventilation heterogeneity in less peripheral conducting airways and by inflammation. These findings suggest that there are differences in the pathophysiologic determinants of AHR between young and old patients with asthma.

Section snippets

Subjects

Subjects were recruited by advertising throughout The University of Sydney and from the volunteer database at the Woolcock Institute of Medical Research. Inclusion criteria were physician diagnosis of asthma plus current symptoms of asthma requiring regular treatment. Subjects were excluded if they had smoked within the last 6 months, had a smoking history ≥ 10 pack-years, had any major respiratory disease other than asthma, had a respiratory tract infection, or used oral prednisone in the

Subjects

One hundred four subjects with asthma participated in the study. Table 1 shows the characteristics of subjects in the young and old groups. The prevalence of AHR was lower in the old group (49%) than in the young group (70%, P = .03). Compared with young patients with asthma, the old patients with asthma had longer disease duration, more airflow obstruction, less severe AHR, and lower Feno. Diffusion-dependent ventilation heterogeneity (Sacin) was worse in the old group than in the young group,

Discussion

In this study of young (18-46 years) and old (≥ 50 years) adults with asthma, we found differences in the pathophysiologic determinants of AHR. The presence of significant interactions between age group and key predictor variables implied that there were significant qualitative differences between age groups in their relationship with AHR, which made it essential to analyze the two groups separately. In old patients with asthma, AHR was predicted by gas trapping (% predicted RV), Sacin, and

Acknowledgments

Author contributions: Ms Hardaker and Dr Salome had access to the data and take responsibility for the integrity of the data and the accuracy of the data analysis.

Ms Hardaker: contributed to the implementation, statistical analysis, interpretation, and writing.

Dr Downie: contributed to the design, implementation, interpretation, and writing.

Ms Kermode: contributed to the implementation, interpretation, and writing.

Dr Farah: contributed to the implementation, interpretation, and writing.

Dr Brown:

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Between June 30, 2014, and March 3, 2017, we recruited and evaluated 773 participants with asthma and 99 control participants. All physiological measures contributed to the clinical SAD model with the structural equation modelling analysis. The prevalence of SAD in asthma was dependent on the measure used; we found the lowest prevalence of SAD associated with acinar airway ventilation heterogeneity (S_acin), an outcome determined by multiple breath nitrogen washout that reflects ventilation heterogeneity in the most peripheral, pre-acinar or acinar airways. Impulse oscillometry and spirometry results, which were used to assess dysfunction of small-sized to mid-sized airways, contributed most to the clinical SAD score and differed between the two SAD groups. Participants in clinical SAD group 1 (n=452) had milder SAD than group 2 and comparable multiple breath nitrogen washout S_acin to control participants. Participants in clinical SAD group 2 (n=312) had abnormal physiological SAD results relative to group 1, particularly their impulse oscillometry and spirometry measurements, and group 2 participants also had more severe asthma (with regard to asthma control, treatments, exacerbations, and quality of life) than group 1. Clinical SAD scores were higher (indicating more severe SAD) in group 2 than group 1, and we found that these scores were related to asthma control, severity, and exacerbations. We found no correlation between clinical SAD and CT SAD scores.
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Even within asthma, different mechanisms contribute to severity of hyperresponsiveness. In older patients, this is predicted by air trapping and ventilation heterogeneity in the most distal small airways (Sacin), whereas ventilation heterogeneity in the more proximal small airways (Scond) and inflammation predicts the severity of hyperresponsiveness in younger individuals with asthma.54 Of interest, exhaled bronchial nitric oxide (NO), a parameter of large airway inflammation (usually related to eosinophilia) improved by ICS treatment in younger patients with asthma in conjunction with Scond.
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Funding/Support: This study was funded by the National Health and Medical Research Council of Australia and the Asthma Foundation of New South Wales.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).

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Chest

Original ResearchAsthmaPredictors of Airway Hyperresponsiveness Differ Between Old and Young Patients With Asthma

Background

Methods

Results

Conclusions

Section snippets

Subjects

Subjects

Discussion

Acknowledgments

Mech Ageing Dev

J Allergy Clin Immunol

Chest

Respir Med

Chest

J Allergy Clin Immunol

J Allergy Clin Immunol

Chest

Impact of patient-related factors on asthma control

J Asthma

Asthma in Australia 2008

Spirometric reference values from a sample of the general U.S. population

Am J Respir Crit Care Med

Elasticity of human lungs in relation to age

J Appl Physiol

Lung function growth and its relation to airway hyperresponsiveness and recent wheeze. Results from a longitudinal population study

Am J Respir Crit Care Med

Predictive markers of asthma exacerbation during stepwise dose reduction of inhaled corticosteroids

Am J Respir Crit Care Med

Correlation between exhaled nitric oxide, sputum eosinophils, and methacholine responsiveness in patients with mild asthma

Thorax

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

Thorax

Increased airway closure is a determinant of airway hyperresponsiveness

Eur Respir J

Original Research
Asthma
Predictors of Airway Hyperresponsiveness Differ Between Old and Young Patients With Asthma