Prediction of treatment-response to inhaled corticosteroids by mannitol-challenge test in COPD. A proof of concept

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Abstract

Background

There are no predictors known that can identify COPD patients who will respond to treatment with ICS.

Method

We investigated 30 patients (median age 65 (range 44–83, 12 females) with mild to moderately severe COPD. All patients had post bronchodilator FEV1/forced vital capacity ratio of less than 70% and a reversibility of less than 12% and 200 ml from baseline. We wanted to determine if airway responsiveness (AHR) to histamine and mannitol could predict who would respond to a 3-month course of ICS.

Results

At baseline, all patients had AHR to histamine, but only 7 (23%) patients to mannitol. After 3 months of treatment with ICS, there was no significant change in spirometry or the quality of life when analysing all individuals together. However, FEV1% predicted improved from 67% (IQR12) to 79% (IQR16) in mannitol positive patients; whereas it was unchanged in the mannitol negative patients. The difference in the mean change of FEV1% predicted between the two groups was 12 (IQR13.5) and this was highly significant (p=0.001). The improvement in quality of life (SGRQ 30 (IQR10.5) to 21 (IQR12; p=0.01) was only significant in the patients positive to mannitol.

Conclusion

We propose that AHR to mannitol could predict ICS-responsiveness in mild to moderately severe COPD patients.

Introduction

The role of inhaled corticosteroids (ICS) in patients with COPD is still under debate. Based on current guidelines [1], a subgroup of patients, with severe airway obstruction and/or frequent exacerbations, seem to benefit. Currently there is no reliable predictor for a steroid response in COPD patients [2]. Airway hyperresponsiveness (AHR) is often present in patients with COPD [3]. There are two categories of bronchial provocation tests used to identify AHR direct and indirect: the direct test involves challenge with a pharmacological agent such as histamine and methacholine that acts directly on receptors on bronchial smooth muscle to cause contraction. The indirect test such as exercise or mannitol cause the airways to narrow by release of mediators from inflammatory cells [4], [5], [6]. Indirect challenge like mannitol appear to be more specific for identifying active asthma and for predicting an exacerbation of asthma [7]. In the Lung Health Study AHR to histamine was found in more than 62% of men and 87% of women with COPD [3], [8]. The reason for this high prevalence of AHR in COPD is not known. It may simply relate to the airway calibre at baseline serving to amplify the narrowing induced by a pharmacological agent [9]. It may also reflect specific characteristics such as the current airway inflammation or the genetically determined autonomic nervous system [10]. In a Dutch cohort study, increased AHR to histamine predicted mortality from COPD especially in smokers [11]. Airway hyperresponsiveness to ‘indirect’ stimuli such as adenosine-monophosphate (AMP), eucapnic hyperventilation or mannitol has been less intensively investigated in COPD: In contrast to asthma, patients with chronic bronchitis do not have AHR to eucapnic hyperventilation [12], [13] most likely due to their inability to achieve the high rate of ventilation required for a positive test. In COPD, AHR to AMP is more severe in current smokers than non-smokers [14]. However, there is also some evidence that AHR to AMP is associated with increased numbers of mucosal CD8+ cells and eosinophils in the sputum and/or mediated by mast cell stimulation [15], [16]. Mannitol is another stimulus that acts indirectly. It is thought to cause airway narrowing by increasing the osmolarity of the airway surface, an event that causes the release of mediators from different inflammatory cells in the airways such as mast cells and/or eosinophils [6]. In a very recent publication by Perng et al. [17], sputum eosinophils were more frequently found in COPD patients with reversibility to a short-acting bronchodilator than those without reversibility. Thus, patients with a combination of asthma and COPD, might benefit from a therapy with inhaled corticosteroids. We therefore wanted to know if AHR to mannitol predicts the response to ICS in COPD patients who do not have a significant reversibility of their airflow limitation in response to a beta-2-adrenoceptor agonist.

Section snippets

Subjects

Thirty mild to moderately severe COPD patients were recruited. All patients were current or ex-smokers for at least 10 years, had post bronchodilator FEV1/forced vital capacity ratio of less than 70% and a reversibility of less than 12% and 200 ml from baseline after inhaling 0.2 mg salbutamol [1]. Patients with a history of asthma, upper respiratory tract infection in the last 4 weeks or those taking oral steroids in the last 3 months or inhaling corticosteroids in the last month were excluded.

Results

The patients' characteristics are summarized in Table 1. At baseline, seven out of 30 patients (23%) had AHR to mannitol and all had a positive response to histamine. There were no significant differences between the characteristics of the mannitol positive and negative patients at baseline. Allergies to house dust mite were found only in three patients (one with AHR to mannitol and two without AHR). After 3 months of treatment with ICS, there were no significant change in spirometry or quality

Discussion

The results suggest that subjects with COPD, who have a positive response to mannitol, are likely to have an improvement in FEV1 in response to 3 months of treatment with ICS in addition to an improvement in AHR to mannitol. Five of the 7 subjects responsive to mannitol had a marked improvement in FEV1. Four had a reduction in PD15 in keeping with those reported for people with asthma [23]. The seven subjects would not have been identified on the basis of their response to histamine as all had

Acknowledgements

The use application for mannitol described in this study is covered by United States Patent no. 5817 028 and internationally by PCT/AU95/000086. The patent is owned by Central Sydney Area Health Service, NSW, Australia and is licensed to Pharmaxis Ltd, French's Forrest, NSW, Australia.

The study was supported financially by a grant from Boehringer Ingelheim (Switzerland) GmbH. The inhaled Budesonide was given by Novartis Pharma AG, Switzerland. The mannitol tests were provided by Pharmaxis Ltd.

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