Developing drug therapies in bronchiectasis.

INTRODUCTION: Bronchiectasis is a chronic respiratory condition characterised by cough, sputum production and recurrent chest infections. There are multiple aetiologies; but in up to 50% of patients, the aetiology is unknown. The treatment is largely symptomatic with regular chest physiotherapy and antibiotics for infective exacerbations. Research is being directed towards breaking the 'vicious circle' of bronchiectasis with therapies directed at improving mucociliary clearance, treating chronic infection and reducing inflammation in the airways. AREAS COVERED: This review highlights the current status of bronchiectasis research, summarising reported and ongoing studies of potential therapeutic agents not yet assessed in large trials or licensed for treatment. A literature review was performed using the PubMed database and upcoming trials were sought on the ClinicalTrials.gov website. The article is limited to studies in preclinical to Phase II clinical trials. The trials highlighted in this article offer insight into potential therapeutic agents for the future and help highlight areas in need of further targeted research. EXPERT OPINION: There are promising new anti-infective and anti-inflammatory therapies for more advanced bronchiectasis. That being said, Phase III studies are still needed to investigate these agents further, as well as at what stage therapy should be implemented.

A prospective cohort study of the use of domiciliary intravenous antibiotics in bronchiectasis.

BACKGROUND: We introduced domiciliary intravenous (IV) antibiotic therapy in patients with bronchiectasis to promote patient-centred domiciliary treatment instead of hospital inpatient treatment. AIM: To assess the efficacy and safety of domiciliary IV antibiotic therapy in patients with non-cystic fibrosis bronchiectasis. METHODS: In this prospective study conducted over 5 years, we assessed patients' eligibility for receiving domiciliary treatment. All patients received 14 days of IV antibiotic therapy and were monitored at baseline/day 7/day 14. We assessed the treatment outcome, morbidity, mortality and 30-day readmission rates. RESULTS: A total of 116 patients received 196 courses of IV antibiotics. Eighty courses were delivered as inpatient treatment, 32 as early supported discharge (ESD) and 84 as domiciliary therapy. There was significant clinical and quality of life improvement in all groups, with resolution of infection in 76% in the inpatient group, 80% in the ESD group and 80% in the domiciliary group. Morbidity was recorded in 13.8% in the inpatient group, 9.4% in the ESD group and 14.2% in the domiciliary IV group. No mortality was recorded in either group. Thirty-day readmission rates were 13.8% in the inpatient group, 12.5% in the ESD group and 14.2% in the domiciliary group. Total bed days saved was 1443. CONCLUSION: Domiciliary IV antibiotic therapy in bronchiectasis is clinically effective and was safe in our cohort of patients.

Atorvastatin as a stable treatment in bronchiectasis: a randomised controlled trial.

BACKGROUND: Bronchiectasis is characterised by chronic cough, sputum production, and recurrent chest infections. Pathogenesis is poorly understood, but excess neutrophilic airway inflammation is seen. Accumulating evidence suggests that statins have pleiotropic effects; therefore, these drugs could be a potential anti-inflammatory treatment for patients with bronchiectasis. We did a proof-of-concept randomised controlled trial to establish if atorvastatin could reduce cough in patients with bronchiectasis. METHODS: Patients aged 18-79 years were recruited from a secondary-care clinic in Edinburgh, UK. Participants had clinically significant bronchiectasis (ie, cough and sputum production when clinically stable) confirmed by chest CT and two or more chest infections in the preceding year. Individuals were randomly allocated to receive either high-dose atorvastatin (80 mg) or a placebo, given orally once a day for 6 months. Sequence generation was done with a block randomisation of four. Random allocation was masked to study investigators and patients. The primary endpoint was reduction in cough from baseline to 6 months, measured by the Leicester Cough Questionnaire (LCQ) score, with a lower score indicating a more severe cough (minimum clinically important difference, 1·3 units). Analysis was done by intention-to-treat. The trial is registered with ClinicalTrials.gov, number NCT01299181. FINDINGS: Between June 23, 2011, and Jan 30, 2011, 82 patients were screened for inclusion in the study and 22 were excluded before randomisation. 30 individuals were assigned atorvastatin and 30 were allocated placebo. The change from baseline to 6 months in LCQ score differed between groups, with a mean change of 1·5 units in patients allocated atorvastatin versus -0·7 units in those assigned placebo (mean difference 2·2, 95% CI 0·5-3·9; p=0·01). 12 (40%) of 30 patients in the atorvastatin group improved by 1·3 units or more on the LCQ compared with five (17%) of 30 in the placebo group (difference 23%, 95% CI 1-45; p=0·04). Ten (33%) patients assigned atorvastatin had an adverse event versus three (10%) allocated placebo (difference 23%, 95% CI 3-43; p=0·02). No serious adverse events were recorded. INTERPRETATION: 6 months of atorvastatin improved cough on a quality-of-life scale in patients with bronchiectasis. Multicentre studies are now needed to assess whether long-term statin treatment can reduce exacerbations. FUNDING: Chief Scientist's Office.

Bronchiectasis: an update on current pharmacotherapy and future perspectives.

INTRODUCTION: Bronchiectasis is a common condition and is likely to be underestimated, as bronchiectasis is now a recognised problem complicating other chronic lung diseases such as severe asthma, severe chronic obstructive pulmonary disease and advanced pulmonary fibrosis. In more advanced bronchiectasis, there is a vicious cycle of excess neutrophilic airways inflammation and chronic infection of the airways. This leads to the clinical syndrome, including a chronic productive cough and recurrent chest infections. AREAS COVERED: This review provides an overview of the current pharmacotherapy options available and the potential future perspectives for treatment in adult patients with idiopathic or post-infection bronchiectasis. A PUBMED search for all Phase III and above trials on current therapies focusing on optimising airway dilatation and treatments to break the vicious cycle of infection and inflammation were sought. These therapies include antibiotics, anti-inflammatory and mucoactive therapies alongside chest physiotherapy. Landmark Phase II studies were also included. EXPERT OPINION: Current practice has predominantly been based on treatment advised from national guidelines that are mainly grade D expert opinion. Randomised controlled trials are greatly needed to improve practice of evidence-based medicine.

Particle traps prevent adverse vascular and prothrombotic effects of diesel engine exhaust inhalation in men.

BACKGROUND: In controlled human exposure studies, diesel engine exhaust inhalation impairs vascular function and enhances thrombus formation. The aim of the present study was to establish whether an exhaust particle trap could prevent these adverse cardiovascular effects in men. METHODS AND RESULTS: Nineteen healthy volunteers (mean age, 25±3 years) were exposed to filtered air and diesel exhaust in the presence or absence of a particle trap for 1 hour in a randomized, double-blind, 3-way crossover trial. Bilateral forearm blood flow and plasma fibrinolytic factors were assessed with venous occlusion plethysmography and blood sampling during intra-arterial infusion of acetylcholine, bradykinin, sodium nitroprusside, and verapamil. Ex vivo thrombus formation was determined with the use of the Badimon chamber. Compared with filtered air, diesel exhaust inhalation was associated with reduced vasodilatation and increased ex vivo thrombus formation under both low- and high-shear conditions. The particle trap markedly reduced diesel exhaust particulate number (from 150 000 to 300 000/cm(3) to 30 to 300/cm(3); P<0.001) and mass (320±10 to 7.2±2.0 µg/m(3); P<0.001), and was associated with increased vasodilatation, reduced thrombus formation, and an increase in tissue-type plasminogen activator release. CONCLUSIONS: Exhaust particle traps are a highly efficient method of reducing particle emissions from diesel engines. With a range of surrogate measures, the use of a particle trap prevents several adverse cardiovascular effects of exhaust inhalation in men. Given these beneficial effects on biomarkers of cardiovascular health, the widespread use of particle traps on diesel-powered vehicles may have substantial public health benefits and reduce the burden of cardiovascular disease.