Macrolides have long been recognised to exert immunomodulary and anti-inflammatory actions. They are able to suppress the “cytokine storm” of inflammation and to confer an additional clinical benefit through their immunomodulatory properties. A search of electronic journal articles was performed using combinations of the following keywords: macrolides, COPD, asthma, bronchitis, bronchiolitis obliterans, cystic fibrosis, immunomodulation, anti-inflammatory effect, diabetes, side effects and systemic diseases. Macrolide effects are time- and dose-dependent, and the mechanisms underlying these effects remain incompletely understood. Both in vitro and in vivo studies have provided ample evidence of their immunomodulary and anti-inflammatory actions. Importantly, this class of antibiotics is efficacious with respect to controlling exacerbations of underlying respiratory problems, such as cystic fibrosis, asthma, bronchiectasis, panbrochiolitis and cryptogenic organising pneumonia. Macrolides have also been reported to reduce airway hyper-responsiveness and improve pulmonary function. This review provides an overview on the properties of macrolides (erythromycin, clarithromycin, roxithromycin, azithromycin), their efficacy in various respiratory diseases and their adverse effects.

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Macrolides: from in vitro anti-inflammatory and immunomodulatory properties to clinical practice in respiratory diseases

Advanced macrolides, such as azithromycin (AZM) or clarithromycin (CLM), are antibiotics with immunomodulatory properties. Here we have sought to evaluate their in vitro influence on the activation of CD4+ T-cells. Isolated CD4+ T-cells were stimulated with agonistic anti-CD3/anti-CD28 monoclonal antibodies in the presence of 0.6 mg/L, 2.5 mg/L, 10 mg/L or 40 mg/L AZM or CLM. Cell proliferation, cytokine level in supernatants and cell viability was assessed. Intracellular signaling pathways were evaluated using reporter cell lines, FACS analysis, immunoblotting and in vitro kinase assays. AZM inhibited cell proliferation rate and cytokine secretion of CD4+ T-cells in a dose-dependent manner. Similarly, high concentrations of CLM (40 mg/L) also suppressed these T-cell functions. Analysis of molecular signaling pathways revealed that exposure to AZM reduced the phosphorylation of the S6 ribosomal protein, a downstream target of mTOR. This effect was also observed at 40 mg/L CLM. In vitro kinase studies using recombinant mTOR showed that AZM inhibited mTOR activity. In contrast to rapamycin, this inhibition was independent of FKBP12. We show for the first time that AZM and to a lesser extent CLM act as immunosuppressive agents on CD4+ T-cells by inhibiting mTOR activity. Our results might have implications for the clinical use of macrolides.

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Azithromycin suppresses CD4 + T-cell activation by direct modulation of mTOR activity

BACKGROUND: Lung transplant (LTx) recipients have low long-term survival and a high incidence of bronchiolitis obliterans syndrome (BOS). However, few long-term, multicenter, and precise estimates of BOS-free survival (a composite outcome of death or BOS) incidence exist. METHODS: This retrospective cohort study of primary LTx recipients (1994–2011) reported to the International Society of Heart and Lung Transplantation Thoracic Transplant Registry assessed outcomes through 2012. For the composite primary outcome of BOS-free survival, we used Kaplan-Meier survival and Cox proportional hazards regression, censoring for loss to follow-up, end of study, and re-LTx. Although standard Thoracic Transplant Registry analyses censor at the last consecutive annual complete BOS status report, our analyses allowed for partially missing BOS data. RESULTS: Due to BOS reporting standards, 99.1% of the cohort received LTx in North America. During 79,896 person-years of follow-up, single LTx (6,599 of 15,268 [43%]) and bilateral LTx (8,699 of 15,268 [57%]) recipients had a median BOS-free survival of 3.16 years (95% confidence interval [CI], 2.99–3.30 years) and 3.58 years (95% CI, 3.53–3.72 years), respectively. Almost 90% of the single and bilateral LTx recipients developed the composite outcome within 10 years of transplantation. Standard Registry analyses “overestimated” median BOS-free survival by 0.42 years and “underestimated” the median survival after BOS by about a half-year for both single and bilateral LTx (p < 0.05). CONCLUSIONS: Most LTx recipients die or develop BOS within 4 years, and very few remain alive and free from BOS at 10 years post-LTx. Less inclusive Thoracic Transplant Registry analytic methods tend to overestimate BOS-free survival. The Registry would benefit from improved international reporting of BOS and other chronic lung allograft dysfunction (CLAD) events.

Bronchiolitis obliterans syndrome-free survival after lung transplantation: An International Society for Heart and Lung Transplantation Thoracic Transplant Registry analysis.

Non-tuberculous mycobacteria (NTM) are important pathogens in lung transplant recipients This study describes the spectrum of NTM respiratory tract infections and examines the association of NTM infections with lung transplant complicationsData from 208 recipients transplanted from November 1990 to November 2005 were analyzed Follow-up data were available to November 2010 Lung infection was defined by bronchoalveolar lavage, sputum, or blood cultures in the appropriate clinical setting All identified NTM respiratory tract infections were tabulated The cohort of patients with NTM lung infections (NTM+) were compared to the cohort without infection (NTM-) Univariate and multivariate analysis was performed to determine characteristics associated with NTM infection Survival analyses for overall survival and development of bronchiolitis obliterans syndrome (BOS) were also performedIn total, 52 isolates of NTM lung infection were identified in 30 patients The isolates included Mycobacterium abscessus (46%), Mycobacterium avium complex (MAC) (36%), Mycobacterium gordonae (9%), Mycobacterium chelonae (7%), and Mycobacterium fortuitum (2%), with multiple NTM isolates seen on 3 different occasions The overall incidence was 14%, whereas cumulative incidences at 1, 3, and 5 years after lung transplantation were 11%, 15%, and 20%, respectively Comparisons between the NTM+ and NTM- cohorts revealed that NTM+ patients were more likely to be African-American and have cytomegalovirus mismatch Although no difference was seen in survival, the NTM+ cohort was more likely to develop BOS (80% vs 58%, P = 002) NTM+ infection, however, was not independently associated with development of BOS by multivariate analysisWith nearly 20 years of follow-up, 14% of lung recipients develop NTM respiratory tract infections, with M abscessus and MAC more commonly identified M gordonae was considered responsible for nearly 10% of NTM infections Although survival of patients with NTM infections is similar, a striking difference in BOS rates is present in the NTM+ and NTM- groups

Analysis of pulmonary non-tuberculous mycobacterial infections after lung transplantation.

Macrolides are drugs that have antimicrobial effects, especially against intracellular pathogens. Various studies have shown that macrolides might also have anti-inflammatory effects. Macrolides inhibit the production of interleukins and can reduce pulmonary neutrophilic inflammation. Clinical trials have demonstrated beneficial effects of macrolides in various chronic lung diseases. The objective of this study was to review recent data in the medical literature on the anti-inflammatory effects of macrolides in childhood lung diseases by searching the Medline (PubMed) database. We used the following search terms: "macrolide and cystic fibrosis"; "macrolide and asthma"; "macrolide and bronchiolitis obliterans"; and "macrolide and acute bronchiolitis". We selected articles published in international scientific journals between 2001 and 2012. Clinical studies and in vitro evidence have confirmed the anti-inflammatory effect of macrolides in respiratory diseases. Some clinical trials have shown the benefits of the administration of macrolides in patients with cystic fibrosis, although the risk of bacterial resistance should be considered in the analysis of those benefits. Such benefits are controversial in other respiratory diseases, and the routine use of macrolides is not recommended. Further controlled clinical trials are required in order to assess the efficacy of macrolides as anti-inflammatory drugs, so that the benefits in the treatment of each specific clinical condition can be better established.

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Anti-inflammatory effects of macrolides in childhood lung diseases

Background: Bronchiolitis obliterans syndrome (BOS) is the major limitation to long-term survival following lung transplantation and strategies to reduce its incidence have remained elusive. Macrolides may stabilize lung function in patients with established BOS. Their role, however, in prevention of BOS remains unexamined.

Premal Patel

Papers

Clarithromycin for prevention of bronchiolitis obliterans syndrome in lung allograft recipients.