ASTHMA

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

Sue R Downie¹, Cheryl M Salome¹, Sylvia Verbanck², Bruce Thompson³, Norbert Berend^1,4, Gregory G King^1,4

¹ Woolcock Institute of Medical Research, Camperdown, Sydney, Australia
² Respiratory Division, Academic Hospital, Vrije Universiteit Brussels, 1090 Brussels, Belgium
³ Department of Allergy, Immunology, and Respiratory Medicine, The Alfred Hospital and Monash University, Melbourne, Australia
⁴ Department of Respiratory Medicine, Royal North Shore Hospital, Sydney, Australia

Correspondence to:
MsSue Downie
Woolcock Institute of Medical Research, P O Box M77, Camperdown, NSW 2050, Australia; sued{at}woolcock.org.au

Background: Airway hyperresponsiveness is the ability of airways to narrow excessively in response to inhaled stimuli and is a key feature of asthma. Airway inflammation and ventilation heterogeneity have been separately shown to be associated with airway hyperresponsiveness. A study was undertaken to establish whether ventilation heterogeneity is associated with airway hyperresponsiveness independently of airway inflammation in subjects with asthma and to determine the effect of inhaled corticosteroids on this relationship.

Methods: Airway inflammation was measured in 40 subjects with asthma by exhaled nitric oxide, ventilation heterogeneity by multiple breath nitrogen washout and airway hyperresponsiveness by methacholine challenge. In 18 of these subjects with uncontrolled symptoms, measurements were repeated after 3 months of treatment with inhaled beclomethasone dipropionate.

Results: At baseline, airway hyperresponsiveness was independently predicted by airway inflammation (partial r² = 0.20, p<0.001) and ventilation heterogeneity (partial r² = 0.39, p<0.001). Inhaled corticosteroid treatment decreased airway inflammation (p = 0.002), ventilation heterogeneity (p = 0.009) and airway hyperresponsiveness (p<0.001). After treatment, ventilation heterogeneity was the sole predictor of airway hyperresponsiveness (r² = 0.64, p<0.001).

Conclusions: Baseline ventilation heterogeneity is a strong predictor of airway hyperresponsiveness, independent of airway inflammation in subjects with asthma. Its persistent relationship with airway hyperresponsiveness following anti-inflammatory treatment suggests that it is an important independent determinant of airway hyperresponsiveness. Normalisation of ventilation heterogeneity is therefore a potential goal of treatment that may lead to improved long-term outcomes.

Abbreviations: AHR, airway hyperresponsiveness; CEV, cumulative expired volume; CFC-BDP, chlorofluorocarbon beclomethasone dipropionate; DRR, dose response ratio; FEV₁, forced expiratory volume in 1 s; FRC, functional residual capacity; FE_NO, fraction of nitric oxide in exhaled breath; FVC, forced vital capacity; HFA-BDP, hydrofluoroalkane beclomethasone dipropionate; ICS, inhaled corticosteroid; LCI, lung clearance index; MBNW, multiple breath nitrogen washout; ROC, receiver operator characteristics; S_acin, ventilation heterogeneity in acinar lung zone; S_cond, ventilation heterogeneity in conducting airways

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