Personalised anti-inflammatory therapy for bronchiectasis and cystic fibrosis: selecting patients for controlled trials of neutrophil elastase inhibition.

ABSTRACT

BACKGROUND: Neutrophil elastase (NE) has been linked to lung neutrophil dysfunction in bronchiectasis and cystic fibrosis (CF), making NE inhibition a potential therapeutic target. NE inhibitor trials have given mixed result perhaps because not all patients have elevated airway NE activity. METHODS: We tested whether a single baseline sputum NE measurement or a combination of clinical parameters could enrich patient populations with elevated NE activity for "personalised medicine". Intra- and interindividual variations of total and active NE levels in induced sputum from patients with CF or bronchiectasis were monitored over 14 days. Patients with established CF and bronchiectasis (n=5 per group) were recruited. NE was measured using three different methods: one total and two active NE assays. Subsequently, we analysed the association between clinical parameters and NE from a large bronchiectasis cohort study (n=381). RESULTS: All three assays showed a high degree of day-to-day variability (0-233% over 14 days). There were strong correlations found between all assays (p<0.0001). Despite high day-to-day variability, patients could be stratified into "high" or "low" groups based on moderate cut-off levels. In the bronchiectasis cohort study, factors most associated with high sputum NE levels were Pseudomonas aeruginosa infection (ß-estimate 11.5, 95% CI -6.0-29.0), sputum colour (ß-estimate 10.4, 95% CI 4.3-16.6), Medical Research Council dyspnoea score (ß-estimate 6.4, 95% CI 1.4-11.4) and exacerbation history (ß-estimate 3.4, 95% CI 1.4-5.3). Collectively, P. aeruginosa infection, sputum colour and exacerbation frequency provided the greatest specificity for "high" NE (98.7%, 95% CI 7.0-99.6%). CONCLUSION: These results show that patients with bronchiectasis and CF can be effectively divided into "high" or "low" groups, based on sputum NE assays or clinical inclusion criteria.