Treatment of bronchiectasis

Management

The aims of bronchiectasis management are to reduce symptoms, reduce exacerbation frequency, preserve lung function and improve health related quality of life.[12,33] Patient education is of great importance as many patients have a high treatment burden with physiotherapy regimes, inhaled and oral therapy regimes and frequent hospital visits. Optimising treatment compliance, rapid recognition of exacerbations and appropriate use of complex therapies requires active patient engagement. Patients should be advised to stop smoking as smoking will accelerate lung function decline and predispose to mortality. [74] As with most other chronic illnesses, patients with bronchiectasis will be offered the annual influenza vaccination in accordance with national guidelines.[12]

 

Airway clearance

Despite limited evidence, airway clearance techniques are widely considered a key component of management.[12] There is little high quality data comparing different techniques for effectiveness. The choice is therefore largely determined by patient choice and ease of use.

 

Chest physiotherapy

Chest clearance techniques include physiotherapy regimes such as Active Cycle of Breathing Technique and Postural Drainage with or without adjuncts such as positive airway pressure devices, (e.g “Flutter” devices providing oscillatory positive pressure), or high frequency chest wall oscillation.[57] Small, but significant improvements can be seen in exercise capacity, sputum volume and HRQOL in patients who use chest physiotherapy compared with control.[75.76] The availability of a physiotherapist or other health professional experience in teaching chest clearance techniques is invaluable for patient education.

 

Inhaled hyperosmolar agents

As an adjunct to standard chest physiotherapy, nebulized hypertonic saline can alter the mucus osmolality making it easier to clear.[77] Hypertonic saline can improve FEV1 when used in combination with chest physiotherapy.[78] Recent trials of inhaled mannitol, another hyperosmolar agent, suggest it can increase sputum volume compared to placebo, although the overall significance of this to patients is not entirely clear.[79,80]

 

DNase

The experience of recombinant DNase acts as a cautionary tale in extrapolating results in cystic fibrosis to patients with non-CF bronchiectasis. Despite being effective in selected patients with CF, DNase was shown to be potentially harmful in a randomised controlled trial in NCFBE, reducing FEV1.[81] It is therefore not advised for use in this group of patients, and highlights the different pathophysiology in NCFB, compared with CF associated bronchiectasis.

 

Long Term Antibiotics

Long-term suppressive antibiotic therapy aims to reduce the bacterial load in the airways, interrupting the ‘vicious cycle’. According to the hypothesis, this should slow down disease progression and lead to improved symptoms and a reduction in exacerbation frequency.[53]

 Until recently there has been a lack of evidence to guide long term antibiotic therapy in NCFBE, but the recent publication of a number of randomised controlled trials have established clearly that long term antibiotic therapy can reduce exacerbations as well as providing other benefits.

 

Oral macrolide therapy

The BAT, BLESS and EMBRACE trails compare the effects of long term macrolide therapy (either 6 or 12 months) to placebo.[66,82,83] All these trials have shown a significant reduction in exacerbation frequency compared to placebo during the treatment period. The BAT trail showed a median exacerbation frequency of 2 in the placebo group compared with 0 in the treatment group after 12 months (P<0.001).[82] Both 12-month trails showed a reduction in FEV1 decline for the treatment group, although these were small and of doubtful clinical significance.[82,83] The main concern of macrolide therapy is a marked increase in macrolide resistance in oropharyngeal and other bacteria. The BAT trial showed macrolide resistance of 88% in the treatment group compared to 26% on placebo.[82] Azithromycin was associated with increased gastrointestinal side effects in the BAT trial, although erythromycin appeared to be better tolerated.[83] There have been other concerns regarding macrolides including an increased incidence of cardiovascular events although no cardiovascular complications were observed in these small RCT’s.[84,85]

Macrolides have anti-inflammatory effects including inhibition of inflammatory cell migration, cytokine secretion and attenuation of the production of reactive oxygen species.[86] Whether the benefit of macrolides is attributable to their antibiotic or anti-inflammatory effect is unclear.

BTS guidelines recommend consideration of long term oral antibiotics for patients with ≥ 3 exacerbations a year or those chronically colonised with Pseudomonas aeruginosa.[12] These guidelines were written before the publication of the three recent trials and given that the EMBRACE trial showed benefit in patients with one or more exacerbations per year these recommendations may change. In clinical practice, macrolides are most frequently used in patients with three or more exacerbations per year, patients with Pseudomonas aeruginosa and also in patients with less frequent exacerbations who continue to have significant impairment of quality of life despite standard treatment.

Inhaled antibiotic therapy

Nebulised or inhaled antibiotics deliver a high concentration of the drug to the airways, reducing systemic absorption and therefore theoretically are associated with fewer side effects compared with oral therapy. A 12 month randomised control trial comparing nebulized gentamicin to nebulized 0.9% saline found a significant reduction in bacterial load, associated with decreases in exacerbation frequency and improvements in quality of life.[87] This was associated with a reduction in airway and systemic inflammation.[37] A 3 month follow-up review after treatment was stopped showed all outcome measures returned to baseline suggesting that this type of therapy needs to be continued long term for sustained benefit.[87]

Pseudomonas aeruginosa colonisation is associated with a worse prognosis in most studies.[16,73] Inhaled antibiotics can suppress P.aeruginosa bacterial load and even achieved eradication of P.aeruginosa in 30% of patients treated in the nebulised gentamicin trial.[87,88] Inhaled tobramycin has been successful in treating CF patients with chronic Pseudomonas aeruginosa infection.[89] A study by Barker et al showed nebulised tobramycin also has benefits in non-CF bronchiectasis.[89]  During the study, tobramycin was given twice daily for 4 weeks. At 6 weeks the pathogen was eradicated in 35% of patients while all patients in the placebo group had persistant colonization. There were some adverse effects with bronchospasm and cough. Larger studies of Tobramycin are needed in non-CF bronchiectasis. Several newer agents are now in late phase clinical trials including dry power inhaled ciprofloxacin, nebulized liposomal ciprofloxacin and inhaled colistin which was the subject of a recent phase III trial demonstrating improved quality of life and a reduction in exacerbations in compliant patients.

 

Anti-inflammatory therapy

Bronchiectasis is thought to be predominantly a neutrophil driven disorder, and neutrophils are largely resistant to the anti-inflammatory effects of corticosteroids. There is no role for oral corticosteroids in bronchiectasis out-with the treatment of ABPA.[47] Inhaled corticosteroids are currently indicated in patients with asthma, COPD or airway hyper-reactivity. They may have some benefits in bronchiectasis. Some studies have shown that regular high dose inhaled steroids reduce 24-hour sputum volume, reduce inflammatory markers in sputum and improve quality of life.[90] However they have not shown any significant improvement in lung function, or exacerbation frequency. A Cochrane review acknowledges they have short-term benefits but concludes there is insufficient evidence to recommend their routine use.[90] Recent data in COPD shows an increase in pneumonia with the use of inhaled steroids.[91] Whether this is true in bronchiectasis is uncertain but would be a concern in a population already at high risk of serious respiratory infections.

 A large number of promising anti-inflammatory therapies specifically targeting neutrophils, such as neutrophil elastase inhibitors and CXCR2 antagonists are now entering clinical trials.[92]

 

Pseudomonas aeruginosa eradication treatment

In keeping with recommendations in cystic fibrosis, most specialist centres will attempt eradication of P. aeruginosa upon first isolation. The British Thoracic Society guidelines provides a useful algorithm for P.aeruginosa eradication.[12]

 

Pulmonary rehabilitation

Patients with bronchiectasis with significant breathlessness benefit from pulmonary rehabilitation and should be routinely referred for this service.[93]

 

Treatment of Exacerbations

An exacerbation is defined as a deterioration of usual symptoms, particularly with an increase in sputum volume and purulence.[12] A sputum sample should be obtained at the initial presentation of an exacerbation and sent for culture. While pending sputum culture results, patients should receive treatment targeted towards organisms in previous sputum samples, based on previous sensitivity results. This emphasises the importance of sending regular sputum samples while patients are clinically stable. Due to the higher bacterial loads and difficulty in achieving antibiotic penetration into biofilms, longer courses of therapy are given in bronchiectasis and most advocate 14 days for exacerbations.[12] BTS guidelines state that intravenous antibiotics may be considered in patients who fail to respond to oral therapy, or sputum culture reveals organisms to which no oral therapy is beneficial (e.g multidrug resistant pseudomonas aeruginosa) or where patients are systemically unwell.[12]