Review
The role of macrolides in asthma: current evidence and future directions

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Summary

Macrolides, such as clarithromycin and azithromycin, possess antimicrobial, immunomodulatory, and potential antiviral properties. They represent a potential therapeutic option for asthma, a chronic inflammatory disorder characterised by airway hyper-responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing. Results from clinical trials, however, have been contentious. The findings could be confounded by many factors, including the heterogeneity of asthma, treatment duration, dose, and differing outcome measures. Recent evidence suggests improved effectiveness of macrolides in patients with sub-optimally controlled severe neutrophilic asthma and in asthma exacerbations. We examine the evidence from clinical trials and discuss macrolide properties and their relevance to the pathophysiology of asthma. At present, the use of macrolides in chronic asthma or acute exacerbations is not justified. Further work, including proteomic, genomic, and microbiome studies, will advance our knowledge of asthma phenotypes, and help to identify a macrolide-responsive subgroup. Future clinical trials should target this subgroup and place emphasis on clinically relevant outcomes such as asthma exacerbations.

Introduction

In 1949, erythromycin (the first macrolide) was isolated from metabolites of the bacterium Streptomyces erythrae (now called Saccharopolyspora erythrae of the Actinobacteria phylum) in a soil sample from the Philippines.1 Macrolides are one of the most widely used antibiotic groups and have an expanding role in the treatment of a broad range of chronic respiratory diseases, including cystic fibrosis, non-cystic fibrosis bronchiectasis, and chronic obstructive pulmonary disease (COPD).2, 3, 4 Macrolides could also represent an attractive therapeutic option for asthma, which is characterised by chronic airway inflammation and bronchial hyper-responsiveness. Chronic asthma is often complicated by acute exacerbations, of which a major proportion is triggered by viral respiratory infections.5 In view of the immunomodulatory and potential antiviral properties of macrolides, they could have a beneficial effect in asthma. Furthermore, macrolides are effective against a broad range of respiratory bacterial pathogens, including the atypical bacteria Chlamydophila pneumoniae and Mycoplasma pneumoniae, both of which are implicated in chronic asthma and asthma exacerbations.6

Macrolides have a macrocyclic lactone ring of at least 12 elements whose size and features can be modified to derive agents with different properties. For example, erythromycin, clarithromycin, roxithromycin, and troleandomycin consist of a 14-membered ring, whereas azithromycin has a 15-membered ring. These subtle changes in structure give the advanced-generation macrolides, particularly azithromycin, improved bioavailability, acid stability, and half-life (40–68 h for azithromycin).7 Ketolides, such as telithromycin, are derived from erythromycin and are structurally related to macrolides; they have two bacterial ribosomal binding sites that confer better effectiveness against macrolide-resistant organisms than other macrolides.8

Whereas the scientific rationale for the use of macrolides in asthma might be persuasive, their efficacy in clinical trials has been variable, which is possibly related to many underpowered studies. A Cochrane database systematic review in 2005 was inconclusive,9 although a recent meta-analysis concluded that macrolide use for 3 weeks or more showed improvement in peak expiratory flow, clinical symptoms, quality of life, and airway hyper-reactivity.10 However, the substantial risk of antimicrobial resistance and concerns about adverse effects associated with long-term macrolide use must be considered.11, 12, 13

Although the use of macrolides in asthma is difficult to justify at present, there might be reason for cautious optimism. Asthma is widely recognised as a heterogeneous syndrome with distinct phenotypes and endotypes.14 Macrolides could be effective in certain phenotypes but not others. In a recent study, azithromycin therapy significantly reduced the rate of exacerbation in a subgroup of patients with severe neutrophilic asthma, although the mechanism of benefit was unclear.15 However, the primary endpoint in this study was the rate of severe exacerbation during the 26-week treatment period. Classically, forced expiratory volume in 1 s (FEV1) is deemed the primary outcome measurement but exacerbation frequency might be a more clinically and economically meaningful outcome.16

Key messages

  • Macrolides such as azithromycin and clarithromycin have antimicrobial, immunomodulatory, and potential antiviral properties

  • Macrolides are effective in a broad range of chronic respiratory disorders, such as cystic fibrosis, non-cystic fibrosis bronchiectasis, and diffuse panbronchiolitis, in which neutrophilic inflammation is central

  • Evidence to support the widespread use of macrolides for asthma is inadequate; however, macrolides might be effective in patients with severe neutrophilic asthma in whom symptoms are poorly controlled. Further mechanistic investigations and clinical trials are needed to validate this hypothesis

  • Long-term use of macrolides could be associated with the emergence of antimicrobial-resistant organisms and adverse cardiovascular events in at-risk populations, thus their prescription should be rationalised

  • Future clinical trials of macrolides in chronic asthma should use a range of clinically relevant outcome measures, with emphasis on frequency of asthma exacerbations

In this Review, we examine the evidence from clinical trials in chronic asthma and acute exacerbations, and discuss the scientific merits of macrolides (ie, their immunomodulatory, antiviral, and antibacterial properties) and their relevance to the pathophysiology of asthma. Finally, we discuss the potential hazards of macrolide therapy, future research, and the clinical directions of possible macrolide use in asthma.

Section snippets

Clinical trials: conflicting evidence

In the mid-20th century, oral corticosteroids were widely used as maintenance and rescue therapy, and considerably improved the management of moderate and severe asthma. However, this improvement was achieved at the cost of substantial steroid-induced side-effects,17 and forced the search for steroid-sparing agents. In 1958, Kaplan and Goldin18 reported that troleandomycin reduced sputum production and corticosteroid requirement in patients with frequent infective exacerbations, and other

Immunomodulatory properties

Macrolides have immunomodulatory effects independent of their antibacterial activity. Although these effects have been noted in clinical trials and animal studies, they are most readily studied with in-vitro cell culture systems. Here we review the immunomodulatory activities of macrolides relevant to asthma. Azithromycin is the most studied macrolide (figure). Although cell culture and animal studies are very helpful, they do not show the complexity and heterogeneity of asthma phenotypes, thus

Potential direct and indirect antiviral properties

Respiratory viruses play an integral role in asthma pathogenesis and exacerbations.101, 102 Bronchiolitis and wheezing caused by respiratory syncytial virus (RSV) bronchiolitis and lower-respiratory-tract human rhinovirus (HRV) infections in early life are strongly associated with the development of asthma in childhood;103, 104 whether this is a causal relation remains to be confirmed. Furthermore, respiratory viruses cause a substantial proportion of acute exacerbations, with HRVs accounting

Efficacy against a broad range of pathogenic respiratory bacteria

The role of bacteria in chronic and acute asthma remains undefined. The understanding of the relation between C pneumoniae and M pneumoniae and chronic and acute asthma has been hampered by many factors, including insensitive or non-specific culture and serological methods for bacterial detection. Endobronchial biopsies tend to yield more reliable results but involve invasive diagnostic procedures. However, culture-independent studies have shown the existence of a complex and diverse bacterial

Effects on mucus production

Airway mucus hypersecretion contributes to the morbidity of asthma, especially in severe disease.131 The 14-member macrolides, particularly clarithromycin, reduce mucus hypersecretion via inhibition of TNFα production, which stimulates mucin genes MUC5B and MUC5AC in airway goblet cells.132 Furthermore, clarithromycin inhibits goblet cell hyperplasia induced by interleukin 13, a process that is resistant to corticosteroid therapy.133 These effects might partly explain why patients with severe

Adverse effects

Nausea and diarrhoea are the most common macrolide-related gastrointestinal adverse effects. These effects have been noted in studies of different respiratory diseases including cystic fibrosis and asthma.10, 37, 134 Although not life-threatening, adverse symptoms invariably reduce treatment compliance and, more importantly, quality of life.

Albert and co-workers59 showed that hearing decrements were 5% more common in patients with COPD given azithromycin than in controls.59 Irreversible hearing

Scientific research

Although there is substantial published work showing the antimicrobial, antiviral, and immunomodulatory properties of macrolides, which antimicrobial and immunomodulatory properties are most important is unclear. In-vitro studies have shown the efficacy of macrolides against respiratory viral infections, including HRV, RSV, and influenza virus.139 Further in-vivo and clinical studies are needed to validate these findings, which might explain the positive effects of telithromycin in acute asthma

Conclusion

Macrolides possess antimicrobial, immunomodulatory, and potential antiviral properties, and they have been used successfully in a broad range of chronic respiratory disorders with predominantly neutrophilic inflammation. The evidence is inadequate to justify the use of macrolides in chronic asthma or acute exacerbation instead of conventional treatment or as an adjunct therapy. Asthma is a heterogeneous syndrome consisting of different phenotypes with different underlying causes and

Search strategy and selection criteria

We searched PubMed for peer-reviewed studies published in English between Jan 1, 1970, and Dec 1, 2013, and with the search terms “asthma”, “wheeze”, “asthma exacerbation”, “macrolide”, “azithromycin”, “telithromycin”, “roxithromycin”, “clarithromycin”, and “erythromycin”. We also searched the reference lists of identified articles and personal literature libraries. Articles deemed relevant were selected.

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