Should macrolides be used for chronic asthma?

Main point: Studies do not show that macrolides are better than placebo for most outcomes. There may be a benefit on symptom scales and lung function but the latter depends on how this is measured. The evidence was very low quality so we can't rule out the possibility of other benefits or harms.

Background

Asthma is a chronic disease in which inflammation of the airways leads to coughing, wheezing and breathing problems. There are probably different reasons for this inflammation and why it persists, and these may require different treatments. Infection in the lungs may be one cause, and macrolides are a type of antibiotic that may be used long-term as a way of improving symptoms for these people.

How we answered the question

We looked for studies on adults or children with asthma who were either given a macrolide or placebo for at least four weeks to see if it improved their symptoms and made it less likely for them to have an asthma attack, often referred to as an 'exacerbation'. We carried out our most recent search for studies in April 2015. After finding all of the relevant studies, we pulled out information about asthma attacks requiring hospital admission, asthma attacks that needed to be treated with oral steroids, symptom scales, asthma control, quality of life, several measures of lung function, the need for rescue inhalers, serious side effects and measures of asthma activity in blood and sputum.

What we found

We found 23 studies, including 16 new ones that had been published since the last search was done in 2007. Overall, just over 1500 people received either macrolide or placebo. There were a lot of problems in the way studies were described and how well they reported data, which made us consider the evidence to be very low quality, undermining our confidence in most of the results. The studies were quite different from each other, for example in the severity of people's asthma, the type of macrolide they were given and the length of the treatment period.

Our review did not show that macrolides were better than placebo for most of the important outcomes we looked at. However, they may have some benefits on symptom scales and lung function, and we cannot rule out the possibility that they are helpful for some people or that they cause harm. There were no reports of serious side effects of macrolides, but 16 studies didn't say whether or not any occurred.

Authors' conclusions: 

Existing evidence does not show macrolides to be better than placebo for the majority of clinical outcomes. However, they may have a benefit on symptom scales and some measures of lung function, and we cannot rule out the possibility of other benefits or harms because the evidence is of very low quality due to heterogeneity among patients and interventions, imprecision and reporting biases.

The review highlights the need for researchers to report clinically relevant outcomes accurately and completely using guideline definitions of exacerbations and validated scales. The possible benefit of macrolides in patients with non-eosinophilic asthma based on subgroup analyses in two of the included studies may require further investigation.

Read the full abstract...
Background: 

Asthma is a chronic disease in which inflammation of the airways causes symptomatic coughing, wheezing, and difficult breathing. The inflammation may have different underlying causes, including a reaction to infection in the lungs. Macrolides are antibiotics with antimicrobial and antiinflammatory activities that have been used long-term to control asthma symptoms.

Objectives: 

To assess the effects of macrolides for managing chronic asthma.

Search strategy: 

We searched the Cochrane Airways Group Specialised Register up to April 2015. We also manually searched bibliographies of previously published reviews and conference proceedings and contacted study authors. We included records published in any language in the search.

Selection criteria: 

Randomised controlled clinical trials involving both children and adults with chronic asthma treated with macrolides versus placebo for more than four weeks .

Data collection and analysis: 

Two reviewers independently examined all records identified in the searches then reviewed the full text of all potentially relevant articles before extracting data in duplicate from all included studies.

Main results: 

Twenty-three studies met the inclusion criteria, randomising a total of 1513 participants to receive macrolide or placebo. The quality of evidence was generally very low due to incomplete reporting of study methodology and clinical data, suspected publication bias, indirectness of study populations, risk of bias and imprecision (because of small numbers of patients and events). Most of the included studies reported data from patients with persistent or severe asthma, but inclusion criteria, interventions and outcomes were highly variable.

Macrolides were not found to be better than placebo for the majority of clinical outcomes including exacerbations requiring hospital admission (odds ratio (OR) 0.98, 95% confidence interval (CI) 0.13 to 7.23; participants = 143; studies = 2; I2 = 0%) or at least treatment with oral steroids (OR 0.82, 95% CI 0.43 to 1.57; participants = 290; studies = 5; I2 = 0%). The evidence on asthma control (standardised mean difference (SMD) -0.05, 95% CI -0.26 to 0.15), quality of life (mean difference (MD) 0.06, 95% CI -0.12 to 0.24) and rescue medication use (MD -0.26, 95% CI -0.65 to 0.12) was all of very low quality and did not show a benefit of macrolide treatment. There was some evidence that macrolides led to some improvement on symptom scales (SMD -0.35, 95% CI -0.67 to 0.02), and in lung function (forced expiratory volume in one second (FEV1): MD 0.08, 95% CI 0.02 to 0.14), although not on all the measures we assessed. Measures of bronchial hyperresponsiveness were too varied to pool, but most studies showed no clear benefit of macrolide over placebo. Two studies recruiting people taking regular oral corticosteroids suggested macrolides may have a steroid-sparing effect in this population. Macrolides were well tolerated with respect to severe adverse events, although less than half of the studies reported the outcome (OR 0.80, 95% CI 0.24 to 2.68; participants = 434; studies = 7; I2 = 0%). Reporting of specific side effects was too patchy across studies to analyse meaningfully. As already reported in the previous versions of the systematic review, biomarkers of asthma activity, such as sputum and serum level of eosinophil cationic protein (ECP) or sputum and serum eosinophils, were lower in patients treated with macrolides, but this was not associated with clinical benefits.

Two within-study subgroup analyses showed a possible benefit of macrolides for non-eosinophilic asthma, but it was not possible to investigate this further using the data available for this review.

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