© 2004 American Thoracic Society
Azithromycin and Bronchiolitis ObliteransTo the Editor:We read with interest the recent report on the pilot study by Gerhardt and colleagues (1). They investigated the effect of azithromycin on bronchiolitis obliterans syndrome after lung transplantation. Because they administered azithromycin for antiinflammatory long-term drug therapy, they found that azithromycin was effective for bronchiolitis obliterans syndrome after lung transplantation. An antiinflammatory action of macrolides has been detected in diffuse panbronchiolitis (2). Inflammatory cells and cytokines/chemokines seem to play an important role in the flu-like reaction to bronchoscopy. We measured the plasma interleukin-6 (IL-6) and soluble CD14 levels in patients who underwent bronchoscopy with or without administration of azithromycin. In patients who were not administered azithromycin, there was a significant increase of IL-6 at 4 hours after bronchoscopy (15.477 ± 28.896 vs. 44.763 ± 69.315, p < 0.001, n = 30), soluble CD14 on the day after bronchoscopy (4.534 ± 1.411 vs. 5.575 ± 2.769, p < 0.05, n = 30), and neutrophils and monocytes at 4 hours and the day after bronchoscopy (monocytes: 349 ± 133 vs. 475 ± 142, p < 0.05, n = 12; vs. 451 ± 147, n = 12, p < 0.05). In contrast, the increase of these parameters, with the exception of neutrophils, was suppressed in patients who were treated with azithromycin (IL-6: 10.750 ± 9.321 vs. 17.410 ± 13.446, p > 0.05, n = 10; soluble CD14: 4.396 ± 1.232 vs. 4.522 ± 1.288, p > 0.05, n = 10; monocytes: 341 ± 120 vs. 385 ± 215, p > 0.05, n = 8; vs. 328 ± 165, p > 0.05, n = 8). CD14 is localized on the surface of monocytes and acts as a receptor for lipopolysaccharide (3). Soluble CD14 is increased in several allergic diseases, infectious diseases, autoimmune diseases, and in bronchiolitis obliterans syndrome after lung transplantation (4). It also seems to be a marker that indicates the activation of monocytes. Conversely, Cercek and colleagues (5) reported that in the Azithromycin in Acute Coronary Syndrome trial, the antimicrobial effect of azithromycin did not prevent recurrent thrombus in the coronary arteries, because they administered azithromycin by the regimen for short-term antichlamydia therapy. The extent to which activated monocytes are involved in coronary artery thrombosis is uncertain. However, the findings of Gerhardt and colleagues (1) and our own data suggest that activated monocytes/macrophages are heavily involved in bronchial events. The antiinflammatory effect of azithromycin, especially on monocytes/macrophages, may help to prevent for both bronchial events and coronary events in which activated monocytes have a role.
First Department of Internal Medicine Kansai Medical University Osaka, Japan FOOTNOTES Conflict of Interest Statement: S.K., S.N., M.M., K.Y., and S.F. have no declared conflict of interest. REFERENCES
From the Authors: We would like to thank Dr. Nomura and colleagues for their interest in our recent article (1). Our study documented improved lung function in lung transplant recipients diagnosed with bronchiolitis obliterans syndrome (BOS) after treatment with maintenance oral azithromycin. However, the pathophysiologic mechanism(s) leading to this improvement in FEV1 remain unclear. One hypothesis is that azithromycin exerts antiinflammatory effects that may partially account for our clinical observations. Dr. Nomura and colleagues' findings support this hypothesis. They report observing increases in levels of interleukin (IL)-6, soluble CD14, neutrophils, and monocytes in patients who had undergone bronchoscopy. They also report that when patients were pretreated with azithromycin before bronchoscopy, the measured levels of IL-6, soluble CD14, and peripheral blood monocytes counts were attenuated. Interestingly, they did not observe changes in peripheral neutrophilia; however, they did not report assessing bronchoalveolar lavage (BAL) fluid for neutrophils. BAL neutrophilia has been shown to be increased in patients with BOS and may correlate with disease severity (2). In preliminary in vitro studies from our center, we have observed inhibition of IL-8 production from LPS-stimulated monocytes when exposed to azithromycin. IL-8 levels in BAL fluid have also been shown to be increased in patients with BOS and IL-8 is a potent inducer of neutrophil chemotaxis (3, 4). Currently, we are investigating whether chronic azithromycin therapy alters BAL neutrophilia in patients with BOS. Although azithromycin therapy may exert antiinflammatory effects that potentially improve BOS, the specific mechanism(s) remain unclear. We agree with Dr. Nomura and colleagues that the Azithromycin in Acute Coronary Syndrome trial may have been a negative study because the subjects were only treated with azithromycin for 5 days (5). Our study subjects were treated for an average of 14 weeks. However, Dr. Nomura and colleagues report treating their patients with a one-time dose of azithromycin before bronchoscopy, and yet detected changes in several inflammatory markers. It is clear that further studies are needed to clarify the potential mechanisms and outcomes in patients treated with azithromycin for BOS and other inflammatory processes.
The Johns Hopkins University School of Medicine Baltimore, Maryland FOOTNOTES Conflict of Interest Statement: S.G.G., J.F.M., R.J.C., and J.B.O. have no declared conflict of interest. REFERENCES
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