Treatment of bronchiectasis in adults

Antibiotics

Antibiotics are used to treat acute exacerbations, to prevent exacerbations, or to reduce the bacterial burden. In general, the outcome of treatment with antibiotics depends on the severity of the disease. In mild to moderate bronchiectasis the infection can be completely eradicated, whereas in severe disease the bronchial tree remains chronically colonised. Antibiotics with a high penetrance (macrolides, azalides, and quinolones) are recommended in severe cases because high concentrations of bacteria are located intraluminally in association with mucus, and because thickening and scarring of the bronchial wall may reduce local bioavailability. Pseudomonas aeruginosa is inherently resistant to most antibiotics at concentrations that are achieved in vivo. The organism is susceptible to (oral) quinolones,2 but after one or two courses resistance may develop. Patients who are clinically unwell or do not respond to oral antibiotics should be admitted to hospital and given intravenous antibiotics.

Patients who relapse quickly might need prophylactic antibiotics. Three strategies have been described—a high oral dose for a prolonged period (at least four weeks), aerosolised antibiotics (for example, during alternate months), or regular pulsed courses of intravenous antibiotics (for example, two to three week courses with one or two months in between). Prolonged use of oral antibiotics for purulent bronchiectasis was investigated in a recent meta-analysis. It identified six trials that included 302 patients.5 The results of five studies were positive in terms of parameters pertaining to sputum, such as volume or purulence. However, no positive effects were seen on rates of exacerbation, lung function, or death. This contradicts the findings of a recent controlled study that investigated 500 mg of azithromycin given twice a week for six months in 30 patients.6 Pulmonary function tests did not change, but azithromycin significantly decreased the incidence of exacerbations compared with usual care (5 v 16). Inhalation of nebulised antibiotics might be a better route of administration because of its favourable benefit-risk ratio. Gentamicin 40 mg inhaled twice daily for three days improved sputum production, sputum neutrophil activity, airway obstruction, exercise capacity, and nocturnal desaturation compared with placebo.7 Tobramycin 300 mg inhaled twice daily for four weeks eradicated P auruginosa in 35% of patients and improved the medical condition of 62%.8 Ceftazidime 1 g and tobramycin 100 mg inhaled twice daily over 12 months decreased the number of hospital admissions and inpatient days.9

Flu vaccinations reduced the number of flu related exacerbations in chronic obstructive pulmonary disease,^w5 so vaccination might have a beneficial effect in bronchiectasis. However, randomised controlled trials of vaccination in patients with bronchiectasis are lacking.

Mucolytics

Mucolytics target hypersecretion or the physiochemical characteristics of sputum seen in bronchiectasis. They aim to improve tracheobronchial clearance. In one study, oral bromhexine (30 mg three times daily) was added to an antibiotic during acute infective exacerbations. It improved expectoration, the quantity and quality of sputum, and auscultatory findings.10 In another study, nebulised recombinant human DNase I (2.5 mg once or twice a day for two weeks) was given to patients with stable bronchiectasis. The study found no improvements in spirometry, quality of life, dyspnoea, safety, or ciliary transportability of the sputum.11 In a large placebo controlled study, 349 patients with idiopathic bronchiectasis in a stable condition inhaled 2.5 mg recombinant human DNase I for 24 weeks. Pulmonary exacerbations were more frequent and the decline in FEV₁ (forced expiratory volume in one second) was greater in patients who received DNase than in controls. These results contrast greatly with the positive effects of this drug in cystic fibrosis.12

Inhaled mannitol may improve impaired mucociliary clearance by inducing an influx of fluid into the airways, and thereby changing the mucous rheology. One study found that mucociliary clearance was doubled in the central and intermediate lung regions of 11 patients with bronchiectasis directly after inhaling 300 mg mannitol.^w6 A follow-up study showed that these effects lasted for at least 24 hours.^w7 Inhalation of 400 mg mannitol once daily for 12 days improved the tenacity and hydration of sputum, as well as health status.^w8 Mannitol is therefore a promising new drug, especially as it is easier and more hygienic to inhale a dry powder than to use a nebuliser. Large randomised controlled studies are needed, however, to establish its efficacy and tolerability during long term administration.13

Anti-inflammatory agents

Inhaled corticosteroids may reduce inflammation and improve airway obstruction, as they do in asthma. To date, three randomised controlled studies have investigated this hypothesis.^w9-w11 Inhaled fluticasone decreased the density of leucocytes and concentrations of the inflammatory mediators interleukin 1β, interleukin 8, and leukotriene B4 in sputum.^w11 However, a systematic review found no significant improvements in lung function.14 Recently, a large study was published in which 86 patients inhaled fluticasone 500 µg twice daily or placebo for 12 months.15 Twenty four hour sputum volume improved significantly in patients treated with fluticasone, but no change was seen in the frequency of exacerbations, the purulence of sputum, or lung function. Systemic corticosteroids may be better at penetrating the bronchial wall and therefore be more effective, but data from randomised controlled trials are available only for bronchiectasis associated with cystic fibrosis.16

Leukotriene receptor antagonists are a new class of drugs that is effective in the treatment of asthma. These drugs may be of benefit in bronchiectasis because they inhibit neutrophil mediated inflammation. To date, no randomised controlled trials of these agents have been published, however.17

Non-steroidal anti-inflammatory drugs may also be of use because they inhibit neutrophil function and the release of neutrophil elastase. In a non-controlled open study, eight patients with stable bronchiectasis received 25 mg oral indometacin three times daily for four weeks.^w12 Indometacin had a pronounced effect on two of the three neutrophil functions studied—neutrophil chemotaxis and fibronectin degradation were inhibited by more than 50%. However, lung inflammation, sputum volume, and sputum quality did not change. Interestingly, high dose ibuprofen taken consistently for four years significantly slowed the progression of lung disease in patients with cystic fibrosis.^w13 Ibuprofen has not yet been investigated in non-cystic fibrosis bronchiectasis.

Macrolides suppress inflammation—independent of their antimicrobial actions—in airway diseases like asthma, chronic obstructive pulmonary disease, cystic fibrosis, and diffuse panbronchiolitis. Indeed, macrolides improved clinical status and lung function in a few small studies of bronchiectasis.^w14-w18 In addition, a randomised placebo controlled trial in children showed that three months of treatment with clarithromycin decreased the total number of leucocytes, proportion of neutrophils, and the concentration of interleukin 8 in bronchoalveolar lavage fluid.^w18 Because bacterial growth was not eliminated the authors suggested that direct anti-inflammatory effects of clarithromycin were responsible. This contradicts a randomised placebo controlled study in adults, however, which showed that eight weeks of low dose erythromycin did not reduce the number of leucocytes or the concentrations of interleukin 1α, interleukin 8, tumour necrosis factor α, or leukotriene B4 in sputum.^w15

Bronchodilators

The mechanisms of expiratory airflow obstruction in non-cystic fibrosis bronchiectasis are not clear, but may include excessive production of mucus, distortion of the bronchial wall, and constriction of smooth muscle. Increased bronchial hyper-reactivity and some reversibility of the airflow obstruction with an inhaled bronchodilator are common. As bronchiectasis may coexist with asthma or chronic obstructive pulmonary disease, some studies have a high degree of uncertainty as to whether airway obstruction is due to asthma, chronic obstructive pulmonary disease, or bronchiectasis (or a combination). Nevertheless, as many patients show signs of airway obstruction and hyper-responsiveness, they often receive bronchodilators.

One small Malaysian study gives some information about the reversibility of airway obstruction in bronchiectasis. It included 24 patients with confirmed bronchiectasis but no signs of an acute exacerbation. The study compared 400 µg fenoterol, followed by 5 mg fenoterol 30 minutes later, with 40 µg ipratropium, followed by 500 µg ipratropium.^w19 FEV₁ increased more than 15% in response to one or both bronchodilators in 11 patients—five responded to both, three to fenoterol alone, and three to ipratropium alone. This small study suggests a significant response to bronchodilators in a subset of patients.

Cochrane reviews found no randomised controlled trials on short acting β2 adrenergic agonists,18 long acting β2 adrenergic agonists,19 anticholinergic therapy,20 or oral methylxanthines21 in patients with non-cystic fibrosis bronchiectasis. Good quality studies are therefore urgently needed in this field.

Bronchopulmonary hygiene physical therapy

Bronchopulmonary hygiene physical therapy is a form of chest physical therapy that aims to remove lung secretions in patients with acute and chronic airway diseases. Many active and passive techniques are available (table 2⇑), and the technique chosen varies between institutes and physical therapists.^{w20 w21} The evidence in support of these techniques is variable and the literature is conflicting.^w20 Two systematic reviews found insufficient evidence to support or refute this form of therapy.22 23

Exercise training

The role of pulmonary rehabilitation and inspiratory muscle training has been investigated in only one randomised controlled trial. It compared an eight week training programme of pulmonary rehabilitation alone, pulmonary rehabilitation plus inspiratory muscle training, and a control group.^w22 The authors concluded that pulmonary rehabilitation does improve exercise tolerance. Simultaneous inspiratory muscle training offered no additional benefit.

Surgery

If the area of bronchiectasis is localised and the patient's symptoms are debilitating or life threatening, surgical resection has long been thought to be of benefit. This assumption was based on several non-randomised controlled studies of uncertain value. A Cochrane review updated in 2002 found no randomised clinical trials—just case series or case-control studies.24 The largest case-control study included pneumonectomy in 190 cases, lobectomy in 202 cases, bilobectomy in 23 cases, and lobectomy combined with segmental resection in 72 cases.25 Overall mortality was 3.5%, and 71% of patients had no symptoms during follow-up (four months to 10 years). The authors therefore concluded that surgery was preferable to conventional medical treatment.