Mucolytics for bronchiectasis

Wilkinson, Mark and Sugumar, Karnam and Milan, Stephen and Hart, Anna and Crockett, Alan and Crossingham, Iain (2014) Mucolytics for bronchiectasis. Cochrane Database of Systematic Reviews. ISSN 1469-493X

Abstract

Abstract Background Bronchiectasis is predominantly an acquired disease process that represents the end stage of a variety of unrelated pulmonary insults. It is defined as persistent irreversible dilatation and distortion of medium-sized bronchi. It has been suggested that with widespread use of high-resolution computed tomography, more bronchiectasis diagnoses are being made. Patients diagnosed with bronchiectasis frequently have difficulty expectorating sputum. Sputum therefore is retained in the lungs and may become infected, leading to further lung damage. Mucolytic agents target hypersecretion or changed physiochemical properties of sputum to make it easier to clear. One drug, recombinant human DNase, breaks down the DNA that is released at the site of infection by neutrophils. Mucus clearance along with antimicrobial therapy remains an integral part of bronchiectasis management. Chest physiotherapy along with mucolytic agents is commonly used in practice without clear supportive evidence. Objectives To determine whether ingested or inhaled mucolytics are effective in the treatment of patients with bronchiectasis. Search methods We searched the Cochrane Airways Group Specialised Register and reference lists of relevant articles. We contacted experts in the field and drug companies. Searches were current as of June 2013. Selection criteria Randomised trials of mucolytic treatment in people with bronchiectasis but not cystic fibrosis. Data collection and analysis Data extraction was performed independently by two review authors. Study authors were contacted for confirmation. Main results Four trials (with a combined total of 528 adult participants) were included, but almost none of the data from these studies could be aggregated in a meta-analysis. One trial (with 88 participants) compared bromhexine versus placebo. Compared with placebo, high doses of bromhexine with antibiotics eased difficulty in expectoration (mean difference (MD) -0.53, 95% confidence interval (CI) -0.81 to -0.25 at 16 days); the quality of the evidence was rated as low. A reduction in sputum production was noted with bromhexine (MD -21.5%, 95% CI -38.9 to -4.1 at day 16); again the quality of the evidence was rated as low. No significant differences between bromhexine and placebo were observed with respect to reported adverse events (odds ratio (OR) 2.93; 95% CI 0.12 to 73.97), and again the quality of the evidence was rated as low. In a single small, blinded but not placebo-controlled trial of older (> 55 years) participants with stable bronchiectasis and mucus hypersecretion, erdosteine combined with physiotherapy over a 15-day period improved spirometry and sputum purulence more effectively compared with physiotherapy alone. The spirometric improvement was small (MD 200 mL in forced expiratory volume in one second (FEV1) and 300 mL in forced vital capacity (FVC)) and was apparent only at day 15, not at earlier time points. The remaining two studies (with a combined total of 410 participants) compared recombinant human DNase (RhDNase) versus placebo. These two studies were very different (one was a two-week study of 61 participants, and the other ran for 24 weeks and included 349 participants), and the opportunity for combining data from the two studies was very limited. Compared with placebo, recombinant human DNase showed no difference in FEV1 or FVC in the smaller study but showed a significant negative effect on FEV1 in the larger and longer study. For reported adverse events, no significant differences between recombinant human DNase and placebo were noted. In all of the above comparisons of recombinant human DNase versus placebo, the quality of the evidence was judged to be low. Authors' conclusions Given the harmful effects of recombinant human DNase in one trial and no evidence of benefit, this drug should be avoided in non–cystic fibrosis bronchiectasis, except in the context of clinical trials. Evidence is insufficient to permit evaluation of the routine use of other mucolytics for bronchiectasis. High doses of bromhexine coupled with antibiotics may help with sputum production and clearance, but long-term data and robust clinical outcomes are lacking. Similarly, erdosteine may be a useful adjunct to physiotherapy in stable patients with mucus hypersecretion, but robust longer-term trials are required. Generally, clinical trials in children on the use of various mucolytic agents are lacking. As the number of agents available on the market, such as RhDNase, acetylcysteine and bromhexine, is increasing, improvement of the evidence base is needed. Plain language summary Mucolytic drugs (to help make phlegm easier to cough up) for people with bronchiectasis Review question: This review considered the question of whether mucolytics may be helpful for people with bronchiectasis who do not also have cystic fibrosis. Studies of participants with cystic fibrosis were not included in this review, and we are unable to draw any conclusions on this treatment's relevance to people with cystic fibrosis. Background: Bronchiectasis is a lung condition that usually develops after a series of lung problems (such as childhood infections, problems in lung structure, tuberculosis and cystic fibrosis). A lot of mucus (phlegm) collects in the lungs, causing discomfort and the need to cough it up. The phlegm also collects bacteria, which can add to breathing difficulties. Mucolytic drugs break down phlegm, which can make it easier to cough up. Study characteristics: Four studies (with a total of 528 participants) were identified that met the inclusion criterion of comparing mucolytic treatment versus no mucolytic treatment. All studies were conducted in adults. One study considered bromhexine versus placebo, two compared RhDNase versus placebo (one for a period of two weeks and the other over a period of 24 weeks) and the fourth compared erdosteine with physiotherapy versus physiotherapy alone in elderly patients. The small number of studies available for review and their different designs meant that only descriptions of the individual studies were possible with very limited opportunities for combining the studies in single analyses. Key results: No strong evidence is available to support the use of these drugs in people with bronchiectasis (from causes other than cystic fibrosis); however it is not possible to draw any clear conclusions, as so few studies have been reported. Quality of the evidence: Details of the way patients were allocated to receive or not receive mucolytics were not clearly described in any of the four studies. This was considered carefully in the review in relation to our level of uncertainty in interpreting the results. When this is taken into account, together with the imprecision of the results, estimates of the usefulness of mucolytics as treatment were generally judged to be of low quality in relation to (non–cystic fibrosis) bronchiectasis.