1. < review conference>
The role of macrolides in asthma: current evidence and future directions Ernie H C Wong, James D Porter, Michael R Edwards, Sebastian L Johnston Lancet Respir Med 2014,2:
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2. Contents Introduction Clinical trials: conflicting evidence
Immunomodulatory properties
Potential direct and indirect antiviral properties
Efficacy against a broad range of pathogenic respiratory bacteria
Effects on mucus production
Potential hazards of long-term macrolide treatment
Future directions
Conclusion

3. Introduction
Macrolides (Erythromycin, Clarithromycin, Azithromycin, etc.)
one of the most widely used antibiotic groups
treatment of a broad range of chronic respiratory diseases (Bronchiectasis, COPD)
an attractive therapeutic option for asthma
Chronic asthma and macrolides
acute exacerbations mainly by viral respiratory infections
In view of the antibacterial, immunomodulatory, and potential antiviral properties of macrolides, they could have a beneficial effect in chronic asthma and asthma exacerbation

4. Introduction
Asthma is widely recognized as a heterogeneous syndrome with distinct phenotypes and endotypes, and macrolides could be effective in certain phenotypes but not others
In this Review, we examine the evidence from clinical trials, and discuss the scientific merits of macrolides and their relevance to the pathophysiology of asthma
we discuss the potential hazards of macrolide therapy, future research, and the clinical directions of possible macrolide use in asthma

5. Clinical trials: conflicting evidence
Summary of randomised controlled trials of macrolides in chronic asthma

6. Clinical trials: conflicting evidence
Asthma phenotype
The heterogeneity of asthma causes varying response to treatment, and macrolide might not be efficacious across all
Neutrophilic asthma is more responsive to macrolide therapy than other asthma subtypes
Brusselle and co-workers reported that azithromycin treatment significantly reduced exacerbation rates in patients with severe neutrophilic asthma compared with placebo
Simpson and co-workers showed that clarithromycin therapy significantly reduced sputum concentrations of IL-8 and neutrophil numbers in patients with severe asthma (a subgroup with noneosinophilic asthma)

7. Clinical trials: conflicting evidence
Chronic atypical bacterial infection
Many studies have investigated whether chronic C. pneumoniae or M. pneumoniae infection has improved response to macrolide, but the results are inconsistent
Kraft and co-workers reported that clarithromycin significantly increased FEV1 in patients with asthma, with evidence of C. pneumoniae or M. pneumoniae infection
Sutherland and co-workers showed a significant improvement in airway hyper-responsiveness with clarithromycin therapy in the PCR-negative group

8. Clinical trials: conflicting evidence
Disease severity and symptom control
Macrolides seem to be effective in patients with severe neutrophilic asthma whose symptoms are poorly controlled
smokers with neutrophilic asthma did not significantly improve with macrolide therapy

9. Clinical trials: conflicting evidence
Treatment regimen, duration, and follow-up period
Azithromycin once-daily regimen would seem the most suitable in asthma
Duration is unclear, but needed up to 3 months to show a significant effect
Prolonged treatment with macrolides could be needed to achieve full beneficial effects, but must be balanced with the risk of promoting antibiotic resistance and potential adverse events

10. Clinical trials: conflicting evidence
Outcome measures
Lung function: a meta-analysis concluded macrolide therapy was not associated with improvement FEV1 but peak expiratory flow was significantly improved
Asthma symptoms (ACQ, AQLQ) : most studies showed an improvement in asthma symptoms with macrolide Tx
Acute exacerbation: only 3 of 14 RCT investigated the efficacy of long-term macrolide Tx in reducing exacerbation frequency
Biomarker: several clinical trials have shown that macrolides significantly reduce sputum eosinophil and neutrophil counts and pro-inflammatory cytokine
eosinophil, neutrophil count, pro-inflammatory cytokine 유의하게 감소시켰다고 보고 하였습니다.

11. Clinical trials: conflicting evidence
Acute exacerbation
Summary of randomised controlled trials of macrolides in acute exacerbations

12. Immunomodulatory properties
Inhibition of pro-inflammatory pathways
In lung epithelial cells, azithromycin can inhibit activation of pro-inflammatory transcription factors such as NF-κB and AP1, and thus modulate genes (thymic stromal lymphopoietin; TSLP)
NF-κB lead to the release of pro-inflammatory cytokines such as TNFα, IL-1β and IL-8, which results in recruitment and stimulation of macrophages, dendritic cells, and neutrophils
TSLP primes developing dendritic cells to be strong inducers of Th2 cells, and leads to eosinophilic airway inflammation, mucous hyperplasia, and airway hyper-responsiveness

13. Immunomodulatory properties
Modulation of macrophages and monocyte function and phenotype
Macrophages could have a role in airway inflammation, hyper-responsiveness, remodeling, and corticosteroid resistance
Azithromycin might promote the M2 macrophages (by Th2 cytokine secretion or IL-10)
Azithromycin enhanced phagocytosis of apoptotic bronchial epithelial cells and reduced expression of IL-8 and TNFα
Reductions in peripheral blood mononuclear cells were greater with azithromycin than prednisolone, and azithromycin enhanced prednisolone-mediated reductions in proliferation  supports dual therapy (macrolide+steroid)

14. Immunomodulatory properties
Antineutrophilic inflammation effects
Macrolides reduced production of pro-inflammatory cytokines, including IL-8, TNFα, IL-1β, CXCL5, CCL22, CCL5, and RANTES
Downregulation of pro-inflammatory cytokine production, including IL-8 and CXCL1, followed by increased neutrophil apoptosis and reduced superoxide production for azithromycin
Macrolides possess membrane-stabilizing activity, preventing pro-oxidative effects of several bioactive phospholipids
The effects on neutrophilic inflammation could explain the positive clinical outcomes of macrolide therapy in neutrophilic asthma

15. Immunomodulatory properties
Potential inhibition of Th2 immune response
Th2 responses are important in allergic asthma pathogenesis
Azithromycin and clarithromycin increase apoptosis in stimulated T cells by reduced expression of BCL-XL, an anti-apoptotic protein
azithromycin reduced Th0 and Th2 cell proliferation, and IL-5 production in Th2 cells

16. Potential direct and indirect antiviral properties
Respiratory viruses play an integral role in asthma pathogenesis and exacerbations
Respiratory syncytial virus(RSV) bronchiolitis and lower-respiratory-tract human rhinovirus(HRV) infections are strongly are associated with the development of asthma in childhood
respiratory viruses cause a substantial proportion of acute exacerbations (HRVs: about 60% of virus-induced exacerbations)
some macrolides could have antiviral properties
Erythromycin, clarithromycin, and bafilomycin A1 reduced the production of intercellular adhesion molecule-1 with reduced HRV titer
Azithromycin augmented HRV-induced type I and III IFNs and reduced virus replication; not Erythromycin and telithromycin

17. Potential direct and indirect antiviral properties
Macrolides could also dampen HRV induced inflammation by reducing the production of pro-inflammatory transcription factors such as NF-κB and cytokines (IL-1β, IL-6, IL-8, and TNFα)
The efficacy of macrolides against respiratory viral infections in clinical trials is contentious
In a HRV-16 infection study in healthy individuals, clarithromycin had no effect on symptom severity or nasal neutrophilic inflammation
Clarithromycin therapy for 3 weeks significantly reduced length of hospital stay, duration of oxygen requirement, and recurrence of wheeze in infants with RSV bronchiolitis

18. Efficacy against a broad range of pathogenic respiratory bacteria
The role of bacteria (C. pneumoniae, M. pneumoniae) in chronic and acute asthma remains undefined
The lung microbiome seems to differ in health and disease
Pathogenic bacteria such as Haemophilus spp are more frequently identified in patients with asthma than in healthy controls, in addition to greater bacterial burden and diversity
Interactions might exist between bacteria, allergens, and viruses, contributing to the pathogenesis and persistence of asthma
Viral infection could perturb the lung microbiome and increase the risk of secondary bacterial infection

19. Efficacy against a broad range of pathogenic respiratory bacteria
Macrolides are broad-range, bacteriostatic drugs that are effective against respiratory pathogens and inhibit bacterial protein synthesis
Azithromycin has a particularly high tissue retention rate compared with other macrolides, and a resistance to pH changes (d/t accumulating in macrophage and lymphocyte vesicles)  enables transport of azithromycin to the site of infection by host chemotaxis, but also facilitates antibacterial action on phagocytosis
Macrolides inhibit the production of virulence factors, biofilm formation, and quorum sensing in P aeruginosa infection
These properties are important in the treatment of conditions such as cystic fibrosis and diffuse panbronchiolitis, but the role of P. aeruginosa in asthma remains to be investigated

20. Immunomodulatory properties

21. Effects on mucus production
Airway mucus hypersecretion contributes to the morbidity of asthma, especially in severe disease
Macrolides, particularly clarithromycin, reduce mucus hypersecretion via inhibition of TNFα production, which stimulates mucin genes (MUC5B, MUC5AC) in airway goblet cells

22. Potential hazards of long-term macrolide treatment
Adverse effects
Nausea and diarrhea are the most common macrolide related gastrointestinal adverse effects
Hearing decrements were 5% more common in patients with COPD given azithromycin than in controls : In asthma, a meta-analysis did not show any significant hearing loss in those given azithromycin
liver injury with a high morbidity and mortality rate, but the incidence is rare
QT-interval prolongation, resulting usually in only mild delays in ventricular repolarization, which are asymptomatic ; however, it might amplify the risk of torsades de pointes (risk factor: age, cardiac comorbidities, and female sex)

23. Potential hazards of long-term macrolide treatment
Emergence of macrolide-resistant species
The widespread use of macrolides in chronic respiratory disorders has led to the emergence of macrolide-resistant species not only on an individual but also on a population scale

24. Future directions Scientific research
In-vitro studies have shown the efficacy of macrolides against HRV, RSV, and influenza virus  Further in-vivo and clinical studies are needed to validate these findings, which might explain the positive effects of telithromycin in acute asthma exacerbations
The role of bacteria in chronic asthma and acute exacerbations needs to be better defined
In a recent study, a significant outgrowth of H influenzae was noted from the baseline microbiome after HRV infection in patients with COPD
Genomic and proteomic investigations will add to our rapidly evolving knowledge of asthma phenotypes and endotypes

25. Future directions Clinical trials
Further trials should investigate whether certain subgroups respond better than others
Patients with sub-optimally controlled severe neutrophilic asthma seem to benefit most from macrolide therapy
The optimal macrolide drug, dose, regimen, and treatment duration remain uncertain
Novel macrolides are designed with a specific range of properties for the treatment of asthma
Novel macrolides with better immunomodulatory properties and no antimicrobial effect could also be used (solithromycin)

26. Future directions
Clinical trials

27. 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, which might explain the conflicting results from clinical trials
Macrolides seem to be most effective in patients with severe neutrophilic asthma

28. Conclusion
Future clinical trials should measure an array of clinically relevant outcomes (ie, exacerbation frequency combined with symptom score, lung function, and biomarkers)
Studies are needed of the benefit of macrolide therapy in acute asthma exacerbation, given the paucity of large clinical trials
Similar to other novel agents in the treatment of severe asthma, macrolides might not be effective in all patients with asthma.
These studies are the initial steps towards phenotype-targeted therapy in severe asthma