Mucolytics for bronchiectasis.
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.


OBJECTIVE
To determine whether ingested or inhaled mucolytics are effective in the treatment of patients with bronchiectasis.


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.


METHODS
Randomised trials of mucolytic treatment in people with bronchiectasis but not cystic fibrosis.


METHODS
Data extraction was performed independently by two review authors. Study authors were contacted for confirmation.


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.


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.
University Hospitals of Morecambe Bay NHS Foundation Trust, Lancaster, UK.
Mark
M
Wilkinson
Karnam
K
Sugumar
Stephen J
SJ
Milan
Anna
A
Hart
Alan
A
Crockett
Iain
I
Crossingham
D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D001964:Bromhexine / Q000627:therapeutic use; D001987:Bronchiectasis / Q000628:therapy*; D003851:Deoxyribonucleases / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005100:Expectorants / Q000627:therapeutic use*; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D011994:Recombinant Proteins / Q000627:therapeutic use; D013864:Thioglycolates / Q000627:therapeutic use; D013876:Thiophenes / Q000627:therapeutic use
D000900:Anti-Bacterial Agents; D005100:Expectorants; D011994:Recombinant Proteins; D013864:Thioglycolates; D013876:Thiophenes; C048498:erdosteine; D003851:Deoxyribonucleases; D001964:Bromhexine