Key messages
- Due to a lack of robust evidence, it is unclear if mucolytics are helpful for children with chronic suppurative lung disease (CSLD). We found only one small study with design limitations.
- Larger, well-designed studies are needed to assess the benefits and potential harms of mucolytic medications in children with CSLD.
What is chronic suppurative lung disease (CSLD)?
Chronic suppurative lung diseases are conditions associated with chronic infection and inflammation of the airways with excessive mucus, leading to a daily wet cough for the children affected. They include the conditions of protracted bacterial bronchitis and bronchiectasis. If treated properly in childhood, the cycle of ongoing infection, inflammation and disruption of the airways' ability to clear mucus can be broken and so prevent and even reverse lung damage.
How is CSLD treated?
The two main aspects of treating CSLD are appropriate use of antibiotics and chest physiotherapy, which improves airway clearance. Chest physiotherapy aids in the clearing of mucus from the airways and can be manual techniques, such as percussion of the chest wall (which involves rhythmically striking the chest wall with cupped hands to loosen mucus from the walls of the airways, making it easier to cough up) and breathing and huffing exercises. Both aspects can help improve disease management, such as reducing the number of flare-ups, improving lung function and quality of life.
What did we want to find out?
Mucolytics are drugs which can help break down mucus and make it easier for children to cough up and so, potentially, may be very helpful for this condition. We wanted to find out if there was any evidence as to how helpful mucolytics are for children with CSLD, including with bronchiectasis not due to cystic fibrosis, in preventing exacerbations, improving children's lung function and improving their quality of life.
What did we do?
We searched databases and registries for studies that compared a mucolytic with a dummy treatment or no treatment in children aged 18 years and under with CSLD.
What did we find?
We found only one small study which assessed a mucolytic (inhalation of hypertonic saline) in 63 children with bronchiectasis, with results reported for 52 children.
Main results
Whilst a small single study found that using inhaled hypertonic saline before chest physiotherapy in children with CSLD might reduce the number of flare-ups and improve lung function, when compared to not using nebulised hypertonic saline before chest physiotherapy, the evidence is not certain.
We also found two ongoing studies, one using hypertonic saline and one using a mucolytic taken by mouth (erdosteine), which will potentially be included in future updates of this review.
What are the limitations of the evidence?
There are serious limitations to the evidence as the study was small and only lasted eight weeks. We also had concerns about study design; for example, people knew which treatment the children were getting. The study did not report on unwanted effects or quality of life. We did not find any studies on other mucolytics, such as oral mucolytics, studies of treatment given during a bronchiectasis flare-up, or for other diseases like protracted bacterial bronchitis, and there were no studies that took place outside of hospital. Further research is necessary to answer this important clinical question.
How up to date is this evidence?
The search was undertaken up to September 2024 and the included study was published in 2021. Thus, this review is up-to-date but limited due to being based on a single small study with design limitations.
This systematic review is limited to a single small study, which we judged to be at high risk of bias. It remains uncertain whether regular nebulised hypertonic saline during a stable state reduces exacerbations or improves lung function. Further multi-centre, well-designed RCTs of longer duration that investigate various mucolytics are required to answer this important clinical question.
Chronic suppurative lung disease (CSLD) is an umbrella term to define the spectrum of endobronchial suppurative lung disease, including bronchiectasis and protracted bacterial bronchitis (PBB), associated with chronic wet or productive cough. Research that explores new therapeutic options in children with CSLD has been identified by clinicians and patients as one of the top research priorities. Mucolytic agents work to improve mucociliary clearance and interrupt the vicious vortex of airway infection and inflammation, hence they have potential as a therapeutic option.
To assess the effects of mucolytics for reducing exacerbations, improving quality of life and other clinical outcomes in children with CSLD (including PBB and bronchiectasis), and to assess the risk of harm due to adverse events.
An Information Specialist searched the Cochrane Airways Trials Register to June 2022, and a review author searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase databases to 27 September 2024. Other review authors handsearched respiratory journals.
We included randomised controlled trials (RCTs), of both cross-over and parallel design, that compared a mucolytic with a placebo or 'no intervention' control group and included children (aged 18 years and under) with any type of CSLD (including PBB and bronchiectasis). We excluded studies with adult participants and studies in children with cystic fibrosis, empyema, pulmonary abscess or bronchopulmonary fistula.
Two authors independently reviewed titles and abstracts to assess eligibility for inclusion. The authors then assessed study quality and extracted data. They assessed the quality of the study using the Cochrane risk of bias tool (RoB 2), and used GRADE to assess the certainty of evidence. Outcomes of interest to be analysed included: i) for maintenance or stable state: rate of exacerbations, ii) for exacerbation state: time to resolution of respiratory exacerbation, iii) lung function – forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), iv) quality of life and v) adverse events. Only one study met the inclusion criteria, so we could not perform a meta-analysis. Data were continuous, so we reported outcomes as mean differences.
The sole included RCT was a cross-over study of 63 children in the total cohort, with reported data and analysis of only 52 children (26 per arm) with non-cystic fibrosis bronchiectasis. The study compared 3% hypertonic saline nebulised before chest physiotherapy with a control arm (physiotherapy alone), with each phase lasting eight weeks. Children in the hypertonic saline arm had a mean age of 9.80 (SD 2.97) years and 42.3% were male; those in the control arm had a mean age of 9.10 (SD 2.40) years and 38.4% were male.
Only results of the first arm of the cross-over study were included in this review. The RCT reported a clinically important difference between the groups for our review's primary outcome: rate of respiratory exacerbations. The mean number of exacerbations per child-year was 2.50 (SD 0.64) in the intervention group and 7.80 (SD 1.05) in the control group (mean difference (MD) −5.30, 95% CI −5.77 to −4.83; 1 study, 52 participants; very low-certainty evidence).
The RCT also reported that the percentage point improvement in mean % predicted FEV1 and FVC from baseline to week eight was better with hypertonic saline compared to control. Mean FEV1 improvement was 14.15% (SD 5.50) in the intervention group versus 5.04% (SD 5.55) in the control group (MD 9.11%, 95% CI 6.11 to 12.11; 1 study, 52 participants; very low-certainty evidence). While for FVC, the mean improvement was 13.77% (SD 5.73) compared with 7.54% (SD 4.90), respectively (MD 6.23%, 95% CI 3.33 to 9.13; 1 study, 52 participants; very low-certainty evidence). Quality of life measures were not used.
We judged the study to have a high risk of bias due to unblinding, missing data, deviation from the intended intervention and reporting bias with measurement and selection of outcome measures. The authors reported that there were no dropouts due to adverse events. No data were available regarding quality of life.
The included study assessed mucolytic use during a stable state, and we found no studies of mucolytic use during an exacerbation. We also found no studies assessing oral mucolytics, other inhaled mucolytics, use in PBB, or in settings other than hospital outpatients.
We also found two ongoing studies, one using hypertonic saline and one using an oral mucolytic agent erdosteine, which will potentially be included in future updates of this review.