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Many older patients with cystic fibrosis (CF) describe a component of their condition as “asthma” despite a lack of objective bronchial lability. We undertook a therapeutic trial of the leukotriene antagonist montelukast sodium in one such patient and observed a marked improvement in symptoms and peak expiratory flow rate (PEFR). Subsequently we performed an open label study in adult patients attending the Hull Adult Cystic Fibrosis Clinic.
Eleven patients (eight male) of mean (range) age 25.9 (16–44) years with stable CF and no pulmonary infective exacerbations for at least four weeks entered a two week observation period during which they recorded a daily symptom score on a scale of 1–10 and twice daily PEFR. Each patient was also asked to define a desirable and achievable individual outcome from the new therapy. After the observation period patients received montelukast sodium 10 mg nightly (Singulair; Merck Sharp & Dohme, Herts, UK) for a further two weeks.
All patients finished the study without adverse events. There was a significant augmentation in subjective symptoms score, with most pronounced improvement in exercise tolerance. Morning PEFR and PEFR variability were significantly improved (table 1). There was a positive correlation (Spearman's correlation coefficient (r S ) = 0.834) between the improvement in the day to day morning PEFR variability and percentage change in forced expiratory volume in one second (FEV1) following montelukast (p=0.01). Eight patients achieved their objective aims. Five of these patients had a positive immunological response toAspergillus fumigatus and FEV1of less than 65% of predicted.
Montelukast is a specific LTD4 receptor antagonist which has been shown to reduce symptoms and improve lung function in several large randomised controlled trials in asthma. Leukotrienes have been found in the sputum of patients with CF.1-3 Cysteinyl leukotrienes were also shown to correlate with the severity of pulmonary disease in CF.4 Our study suggests that LTD4 may have a clinically important role in the pathophysiology of CF. That the patients who benefited the most had positive Aspergillus serology provides further evidence as to a possible mechanism. Two thirds of adults with CF develop an immune response toAspergillus, usually by the IgE, mast cell, eosinophil system.5 It has been hypothesised that injured respiratory epithelium in CF allows access of aeroallergens and the presence of Aspergillus fumigatus in the mucus may stimulate the immunological response by activating local immune cells including T helper 2 (Th2) cells.6
In most patients with CF, however, as in our small study population, there is insufficient bronchial lability to meet the diagnostic criteria for asthma. These patients also do not meet the diagnostic criteria for allergic bronchopulmonary aspergillosis. We believe that colonisation of the CF airway byAspergillus stimulates Th2 inflammation and thus leukotriene synthesis. Such a Th2 mediated immune response is also characteristic of asthma.7 The confirmation of this hypothesis in randomised studies of leukotriene antagonists may have important implications for the treatment of this large subgroup of patients with CF.
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