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We would like to congratulate Ward and colleagues1 on their very important study which showed that significant changes in airway basement membrane thickness in asthma were not observed until after 3 months of treatment with high dose inhaled corticosteroids (ICS), by which time maximum improvement in lung function and airway inflammation had already occurred.
The authors remind us that current guidelines advocate titration of ICS dosages against symptoms and spirometric data, and express their concern that, under these guidelines, ICS treatment would have been stepped down at 3 months, before the maximal benefit in airway hyperresponsiveness (AHR) and airway remodelling had been achieved. However, we have shown in a long term study of inhaled budesonide2 that AHR continued to improve over an 18 month period even while the ICS dose was being down-titrated. In this study AHR improved by a mean of 3.1 doubling doses after 4 months of high dose budesonide treatment, with a further 1.6 doubling dose improvement over 14 months of ICS dose reduction.
Ward and colleagues used high dose ICS (equivalent to 3000 μg/day beclomethasone), and commented that the changes they observed may well have been achieved with much lower doses. However, in the 2 year study by Sont and colleagues which tested the addition of AHR to the usual treatment algorithm,3 patients receiving approximately 300 μg/day ICS did not show the reductions in basement membrane thickness and exacerbations which were seen in the intervention group. The latter group started with approximately 1100 μg/day, reducing to 700 μg/day. In our double blind study2 patients who commenced treatment with budesonide 1600 μg/day ultimately achieved the same improvement in AHR as those starting with 3200 μg/day. However, the higher starting dose resulted in more rapid normalisation of airway responsiveness and a significantly reduced rate of exacerbations in patients who achieved normal airway responsiveness.
Further studies are needed to establish the optimal dosing regimen required for long term achievement of optimal asthma control and reversal of remodelling. It appears that initial ICS doses may need to be somewhat higher than those required to achieve clinical improvement alone, but the dosage may be able to be down-titrated without loss of benefit. As Ward and colleagues have shown, short term studies will primarily reflect anti-inflammatory effects, but it is important that guidelines concerning ICS dosages should also take into account long term studies which reflect changes in remodelling.
We would like to thank Dr Reddel and colleagues for their encouraging and constructive communication regarding our study.1 An implication of our findings was that titration of inhaled corticosteroid (ICS) medication “simply” against symptoms and basic spirometric values, as specified in current international guidelines, may be inadequate, leading to reduction of ICS before optimal benefit in terms of airway remodelling and bronchial hyperreactivity (BHR).1 We feel that our data are complementary to those of Sont et al2 who found that modulation of ICS against BHR led to fewer exacerbations, greater improvement in forced expiratory volume in 1 second (FEV1) and, in a subgroup who agreed to participate, a significant reduction in reticular basement membrane thickening compared with a group treated using current guidelines.
Understandably, but unfortunately, the 2 year study by Sont et al was restricted to two biopsy episodes and inflammatory and remodelling changes could have occurred at any time during the 2 years between bronchoscopies. It was of interest that patients in the two treatment groups were not different in terms of inflammatory cell changes. Overall, the scarce pathophysiological data that are available indicate that long term modulation of at least a component of BHR might involve changes in airway remodelling,1,2 with earlier changes in BHR being more related to cellular inflammation.
Our experience is that adequately powered bronchoscopic studies3 are particularly demanding, and we do not advocate routine direct assessment of airway remodelling.1 The use of BHR testing, or other physiological measurements that may reflect airway remodelling,4 is perhaps more practicable in contributing to the assessment of asthma control. However, in a survey of the British Thoracic Society Directory of Laboratories, the majority of the 68% of centres that responded did not perform BHR assessment, and the median number of tests per year in the 58 of the 139 responders that did was 25 (range 1–480).4 In addition, even when standardised methodology is adopted for academic multicentre studies, there is considerable variability even when using “identical” BHR equipment.5
Asthma guidelines have to be firmly placed in the real world and it is incumbent on clinical researchers to respond to this, as well as concerns regarding potential for overtreatment.6 Further work is required and, in particular, we agree with Reddel and colleagues that further studies are needed to establish the optimal dosing regimen required for long term achievement of optimal asthma control and reversal of remodelling.7 The results of such work may have future significance for the refinement of evidence based guidelines relating to the initiation and duration of asthma treatments.