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Ventilation heterogeneity is a major determinant of airway hyperresponsiveness in asthma, independent of airway inflammation
  1. Sue R Downie1,
  2. Cheryl M Salome1,
  3. Sylvia Verbanck2,
  4. Bruce Thompson3,
  5. Norbert Berend1,4,
  6. Gregory G King1,4
  1. 1Woolcock Institute of Medical Research, Camperdown, Sydney, Australia
  2. 2Respiratory Division, Academic Hospital, Vrije Universiteit Brussels, 1090 Brussels, Belgium
  3. 3Department of Allergy, Immunology, and Respiratory Medicine, The Alfred Hospital and Monash University, Melbourne, Australia
  4. 4Department of Respiratory Medicine, Royal North Shore Hospital, Sydney, Australia
  1. Correspondence to:
    MsSue Downie
    Woolcock Institute of Medical Research, P O Box M77, Camperdown, NSW 2050, Australia; sued{at}


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.

  • 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
  • FeNO, 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
  • Sacin, ventilation heterogeneity in acinar lung zone
  • Scond, ventilation heterogeneity in conducting airways
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  • Published Online First 20 February 2007

  • This project was funded by the Cooperative Research Centre for Asthma.

  • Competing interests: The authors have the following potential conflicts of interest to declare: Cheryl M Salome states that her research group has received support from Boehringer Ingelheim, GlaxoSmithKline and AstraZeneca but these do not pose any conflict of interest for this paper. Norbert Berend serves on advisory boards for GlaxoSmithKline, Boehringer Ingelheim and AstraZeneca, and The Woolcock Institute of Medical Research of which he is the Director receives research grants from GlaxoSmithKline. Gregory King has received travel sponsorship from GlaxoSmithKline to attend the ATS ASM 2003 (approximately $A9000) and a GlaxoSmithKline meeting in 2003 (approximately $A10 000), travel sponsorship from AstraZeneca to attend ATS ASM 2004 (approximately $A10 000) and two AstraZeneca scientific meetings (approximate combined value $A20 000), an honorarium paid to his research institute from GlaxoSmithKline to speak at a sponsored conference in South East Asia ($A3000) in 2005, a travel grant from AstraZeneca to attend the ATS 2005 ($A6000) and a travel grant from GlaxoSmithKline to attend the ATS 2006 ($A5000). A proportion of Dr King’s research work is conducted at the Woolcock Institute of Medical Research which receives unrestricted grants from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim and Vita Medical for such work. The Woolcock Institute of Medical Research also has a consultancy agreement with Pfizer, Boehringer Ingelheim, AstraZeneca and GlaxoSmithKline for which Dr King provides consultancy services related to asthma and COPD. His research group receives a proportion of the grants and monies that arise from those companies as part of specific and general allocations of those funds for research purposes across all research groups of the Woolcock Institute of Medical Research. Dr King does not own any stocks, equity or patents that pose a conflict of interest.

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