Airway inflammation, basement membrane thickening and bronchial hyperresponsiveness in asthma

Abstract

Background: There are few data in asthma relating airway physiology, inflammation and remodelling and the relative effects of inhaled corticosteroid (ICS) treatment on these parameters. A study of the relationships between spirometric indices, airway inflammation, airway remodelling, and bronchial hyperreactivity (BHR) before and after treatment with high dose inhaled fluticasone propionate (FP 750 µg bd) was performed in a group of patients with relatively mild but symptomatic asthma. Methods: A double blind, randomised, placebo controlled, parallel group study of inhaled FP was performed in 35 asthmatic patients. Bronchoalveolar lavage (BAL) and airway biopsy studies were carried out at baseline and after 3 and 12 months of treatment. Twenty two normal healthy non-asthmatic subjects acted as controls. Results: BAL fluid eosinophils, mast cells, and epithelial cells were significantly higher in asthmatic patients than in controls at baseline (p<0.01). Subepithelial reticular basement membrane (rbm) thickness was variable, but overall was increased in asthmatic patients compared with controls (p<0.01). Multiple regression analysis explained 40% of the variability in BHR, 21% related to rbm thickness, 11% to BAL epithelial cells, and 8% to BAL eosinophils. The longitudinal data corroborated the cross sectional model. Forced expiratory volume in 1 second improved after 3 months of treatment with FP with no further improvement at 12 months. PD 20 improved throughout the study. BAL inflammatory cells decreased following 3 months of treatment with no further improvement at 12 months (p<0.05 v placebo). Rbm thickness decreased in the FP group, but only after 12 months of treatment (mean change -1.9, 95% CI -3 to -0.7 µm; p<0.01 v baseline, p<0.05 v placebo). A third of the improvement in BHR with FP was associated with early changes in inflammation, but the more progressive and larger improvement was associated with the later improvement in airway remodelling. Conclusion: Physiology, airway inflammation and remodelling in asthma are interrelated and improve with ICS. Changes are not temporally concordant, with prolonged treatment necessary for maximal benefit in remodelling and PD 20 . Determining the appropriate dose of inhaled steroids only by reference to symptoms and lung function, as specified in current international guidelines, and even against indices of inflammation may be over simplistic. The results of this study support the need for early and long term intervention with ICS, even in patients with relatively mild asthma.

Evaluation of Airway Wall Thickness Via High-Resolution Computed Tomography in Mild Intermittent Asthma

“…13 A considerable overlap between asthmatic and healthy subjects was indicated to support the view that this aspect of airway remodeling does not necessarily discriminate individual asthmatic subjects from healthy subjects, whereas airway remodeling is generally present in asthmatic subjects as a group, which may be related to physiological change and can be positively affected by long-term therapy with inhaled corticosteroids. 25,33 A major limitation of our study is the small sample size, which limits the generalizability of our findings by making them arguable in terms of statistical power, whereas the study inclusion criteria are in accordance with the good control of external effects, and international guidelines were well followed. Hence, our study has merit and is relevant from a clinical point of view as it suggests that even mild intermittent asthma may induce structural changes in the small airways.…”

Remodelage bronchique dans l’asthme

“…Si on estime que ces changements précèdent le diagnostic clinique, les interventions thérapeutiques de type anti-inflammatoire n'interviendront peut-être jamais assez tôt pour être efficaces [2]. Les résultats des traitements par des fortes doses de CSI sont contradictoires : pour certains, elles entraînent une diminution de l'hyperactivité bronchique attribuée pour les deux tiers à une diminution du remodelage, et un tiers à la diminution de l'inflammation [32]. En revanche, d'autres études n'ont pas permis de conclure à un effet des CSI sur le remodelage bronchique [33].…”

Improvement in asthma endpoints when aiming for total control: salmeterol/fluticasone propionate versus fluticasone propionate alone

“…Although not studied in the GOAL study, a number of studies have shown that long-term treatment with ICS leads to a reduction in airway inflammation and hyper-responsiveness, and a reversal in airway remodelling. [11][12][13] In the study by Ward et al, although a reduction in inflammatory cell counts was seen after three months of treatment with fluticasone propionate, improvements in airway remodelling were not seen until 12 months of treatment. 11 The effects of ICS therapy in airway remodelling are a source of controversy and this issue requires further research.…”

“…[11][12][13] In the study by Ward et al, although a reduction in inflammatory cell counts was seen after three months of treatment with fluticasone propionate, improvements in airway remodelling were not seen until 12 months of treatment. 11 The effects of ICS therapy in airway remodelling are a source of controversy and this issue requires further research.The GOAL study used a stable dosing treatment strategy, following an initial titration period. Further support for a longer-term stable dosing approach has been suggested by the CONCEPT study, in which patients who stepped-up their treatment and were stable initially on salmeterol/fluticasone propionate (50/250 mcg twice daily) had substantially better long-term outcomes than patients randomised to adjusted dosing with formoterol/budesonide (6/200 mcg), which allowed patients to reduce their treatment to once daily.…”