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Clinical implications of the immunomodulatory effects of macrolides on sinusitis
Clinical Implications of the Immunomodulatory Effects of Macrolides on Sinusitis Yuichi Majima, MD
This article reviews the treatment of chronic sinusitis with macrolides. Chronic sinusitis is often the result of bacterial infections that lead to chronic inflammation with thickening of the sinus mucosa and hypersecretion of mucus. In addition to their anti-infective properties, some macrolides possess immunomodulatory effects. These macrolides have been used successfully to treat diffuse panbronchiolitis, a progressive inflammatory lung disease, and may be useful for treatment of asthma, chronic bronchitis, chronic sinusitis, cystic fibrosis, and bronchiectasis. The clinical benefits of macrolides in patients with chronic sinusitis include decreased nasal secretions and postnasal drip, with improvement in nasal obstruction. In vivo and in vitro studies show that some macrolides affect neutrophil chemotaxis and infiltration, inflammatory cytokine production, mucus production, and the transportability of airway secretions. These findings indicate that macrolides are promising agents for treating chronic inflammation of the airways. Am J Med. 2004;117(9A):20S–25S. © 2004 by Elsevier Inc.
From the Department of Otorhinolaryngology, Mie University School of Medicine, Tsu, Mie, Japan. Requests for reprints should be addressed to Yuichi Majima, MD, Department of Otorhinolaryngology, Mie University School of Medicine, 2-174 Edobashi Tsu, Mie 514-8507, Japan. 20S
© 2004 by Elsevier Inc. All rights reserved.
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hronic sinusitis is a common chronic inflammatory airway disease, affecting about 13% of the population in the United States.1 Patients with chronic sinusitis have excess nasal discharge, congestion, headache, and fatigue, which significantly decrease the quality of life for these patients. Chronic sinusitis is common in patients with acquired immunodeficiency syndrome, cystic fibrosis, and asthma; its treatment thus represents an important challenge in clinical practice. Certain members of the macrolide class of drugs have anti-inflammatory as well as antimicrobial properties. These drugs may be effective in patients with chronic sinusitis or other chronic inflammatory airway diseases by decreasing the inflammation that is important in the pathogenesis of these diseases.2,3 Macrolides reduce neutrophil migration, the oxidative burst in phagocytes, cytokine expression through the inhibition of transcription factors, eosinophilic inflammation, and the expression of adhesion molecules.2– 6 These drugs inhibit expression of some of the mucin genes and inhibit biofilm formation of Pseudomonas aeruginosa, a common cause of infection in chronic inflammatory airway diseases.7 These anti-inflammatory properties of the macrolides differ based on their ring structure. The 14- and 15-member ring macrolides, such as erythromycin, clarithromycin, and roxithromycin, effectively reduce the inflammatory response in chronic inflammatory diseases of the airways, whereas the 16-member ring macrolide josamycin has little efficacy.8 Most of the clinical studies of the anti-inflammatory properties of macrolides have been in patients with diffuse panbronchiolitis (DPB). DPB is a chronic inflammatory airway disease of unknown etiology, mainly confined to East Asia, which is characterized by progressive loss of pulmonary function. Before the routine long-term use of macrolides, the prognosis was poor for these patients. Treatment with erythromycin improves pulmonary function, decreases mucus hypersecretion, and reduces respiratory infections. Most importantly, whereas the 5-year survival of patients with untreated DPB between 1980 and 1984 was 71%, the 10-year survival of patients treated with macrolides improved to 94% after 1985.9 The dramatic improvement in these patients led to clinical trials in patients with other chronic inflammatory airway diseases such as chronic sinusitis. This review summarizes the clinical benefits of macrolides for the treatment of chronic sinusitis and the current evidence 1548-2766/04/$22.00 doi:10.1016/j.amjmed.2004.07.025
A Symposium: Clinical Implications of Macrolide Treatment for Sinusitis/Majima
Figure 1. Bacterial infections initiate a cycle of inflammation in patients with chronic sinusitis. This inflammation can lead to tissue damage, mucociliary dysfunction, poor sinus ventilation, and mucus hypersecretion. LPS ⫽ lipopolysaccharide.
for their mechanisms of action in this chronic inflammatory airway disease.
CHRONIC SINUSITIS Chronic sinusitis often is a disease of unknown etiology. Patients with chronic sinusitis have sinus pain, sinus headache, nasal congestion, mucopurulent discharge, and fatigue lasting ⬎3 months. The diagnosis is confirmed radiographically. Chronic sinusitis is characterized by obstruction of the ostium of paranasal sinuses that promotes stagnation and accumulation of highly viscous mucus secretions as well as mucociliary dysfunction. The stagnant fluid is easily infected, which then leads to inflammation. The pathogenesis of chronic sinusitis involves a vicious cycle of self-mediated inflammation and bacterial reinfection.10 These bacterial infections initiate a series of events that can lead to chronic sinusitis as shown in Figure 1.11–14 The infection causes chemotaxis and infiltration of neutrophils, mononuclear cells, and T-cells to the sinuses and an excessive release of proteases from neutrophils that damage the mucosa and facilitate fluid secretion. These immune cells and the respiratory epithelium produce the proinflammatory cytokines interleukin (IL)-8, transforming growth factor (TGF)–, and tumor necrosis factor (TNF)–␣.15–17 Bacterial products such as lipopolysaccharides, the elastases produced by inflammatory cells, and other inflammatory mediators such as vasoactive amines, as well as the immune complex and arachidonic acid metabolites, cause both inflammation in the sinus mucosa and poor sinus ventilation. Inflammation in the sinuses causes swelling of the
nasal and sinus mucosa that can obstruct the sinus ostium.18,19 Poor ventilation of the sinuses reduces ciliary activity,20,21 enhances bacterial growth, increases proliferation of small capillaries,22 and causes leakage of blood components. Other effects include activation of platelets and fibroblasts as well as mucous gland hyperplasia. Glandular hyperplasia induced by growth factors such as epidermal growth factor and keratinocyte growth factor23 causes hypersecretion of mucus,24 and fibroblast activation leads to thickening of the sinus mucosa. Hypersecretion of abnormal viscoelastic mucus causes mucociliary dysfunction,25 which accelerates the accumulation of sinus secretions and leads to chronic inflammation.
CLINICAL TRIALS Most studies that show the efficacy of long-term treatment with macrolides for patients with chronic sinusitis are small and open label. Collectively, however, these studies show a clear clinical benefit of macrolide therapy in patients with chronic sinusitis. For example, in an open-label, prospective study, clarithromycin (400 mg once daily) for 8 to 12 weeks improved symptoms and rhinoscopic findings in 45 adults with chronic sinusitis, 20 of whom were refractory to surgery. The rate of improvement was related to the duration of therapy and ranged from 5% at 2 weeks to 71% at 12 weeks. After 12 weeks of therapy, more than half of patients had a reduction in quantity and viscosity of nasal secretions, postnasal drip, and nasal obstruction.26 Similar findings were reported using roxithromycin therapy.27
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Surgery can be an important treatment option for chronic sinusitis to facilitate adequate drainage and improve ventilation of the sinuses. However, some patients do not respond to this type of intervention. In patients with persistent postsurgical sinusitis, macrolide therapy was shown to reduce symptoms in these individuals who were refractory to conservative treatment. In this subgroup of patients, the addition of a nonmacrolide antibacterial drug offered no additional reduction in symptoms.28 In this study, 12 of 17 patients with persistent sinusitis even after surgery had significant improvement after 3 months of erythromycin 250 mg twice daily or clarithromycin 250 mg once daily.28 These 12 patients continued therapy and were reassessed at 12 months. After 1 year of macrolide therapy, there was significant improvement in mucociliary transit time, endoscopic nasal scoring, and symptoms of nasal congestion, runny nose and sticky secretions, and headache in these patients. Similar findings were shown in a retrospective study of patients with persistent postsurgical sinusitis who had sinus surgery ⱖ1 year before enrollment in the study. A total of 57 patients were treated with erythromycin and 92 patients did not receive erythromycin. Patients treated with erythromycin received 600 mg daily for 1 to 2 months, 400 mg daily in the next 1 to 2 months, and 200 mg daily in the last 1 to 2 months of treatment. Improvement in the symptoms of chronic sinusitis was greater in patients receiving erythromycin (88%) than in patients who did not receive erythromycin therapy (69%).29 Effects of Macrolides on Nasal Polyps Many people with chronic sinusitis have nasal polyps that increase obstruction. Although nasal polyps have an unclear etiology, a relation between inflammation and the presence of nasal polyps is well documented. Inflammatory mediators such as IL-1, IL-5, IL-6, IL-8, and RANTES are present in nasal polyps.12,30 –33 There are 2 studies that show the effectiveness of macrolide therapy in decreasing the size of nasal polyps in patients with chronic sinusitis. In the first study of 20 patients with chronic paranasal rhinosinusitis, clarithromycin 400 mg once daily for 8 to 12 weeks significantly reduced the size of nasal polyps.34 The decrease in the size of nasal polyps correlated significantly with a reduction in the concentration of IL-8 in nasal lavage from these patients. Patients who did not have a decline in the concentration of IL-8 did not have a decrease in the size of polyps. In another study of 20 patients with nasal polyps and chronic sinusitis, roxithromycin treatment at a dose of 150 mg once daily for 8 weeks was associated with a decrease in polyp size in ⬎50% of the patients.35 Macrolides effectively decreased the size of the polyps despite the presence of allergies or the extent of eosinophilic infiltration. Results from these studies suggest that IL-8, an important mediator of neutrophil accumulation in the respiratory tract, 22S
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may be related to nasal polyp shrinkage due to macrolide suppression of cytokine production in inflammatory cells in sinus epithelium.34,35 An in vitro study showed that macrolides reduce proliferation of fibroblasts from nasal polyps.36 In this study, roxithromycin suppressed the proliferation of fibroblasts in biopsies from patients with nasal polyps. Proliferation of nasal polyp fibroblasts cell lines was also inhibited when patients were treated with 300 mg/day of roxithromycin for 1 month before biopsy and the generation of cell lines. The current clinical experience of macrolides in chronic sinusitis warrants the development of larger, placebo-controlled clinical trials. Effects of Macrolides on Otitis Media (OM) with Effusion (OME) OME is often associated with chronic sinusitis and is characterized by chronic inflammation with hypersecretion of mucus by goblet cells.37 Chronic OME was shown to resolve with long-term erythromycin therapy. In a study of 16 patients with sinobronchial syndrome treated for ⬎4 months with 600 mg/day erythromycin, most patients showed an improvement in symptoms of chronic sinusitis and resolution of OM.37 However, conflicting results have been reported in children who have OME. In a double-blind, placebo-controlled study, 147 children with OME received erythromycin 50 mg/kg per day for 14 days.38 The number of children free from middle ear effusion was not different between those receiving erythromycin or placebo. In another study, clarithromycin 5– 8 mg/kg per day was administered for ⬎2 months to 55 children with OME.39 The cure rate was significantly higher (66%) for patients receiving clarithromycin compared with 16% for those in the control group. Furthermore, of the children receiving clarithromycin, children who had OME associated with chronic sinusitis had a higher cure rate. Additional studies are needed to determine the effectiveness of macrolide therapy for the treatment of OME associated with chronic sinusitis.
MECHANISMS OF ACTION Although the mechanisms of action of macrolides in chronic sinusitis are unclear, numerous in vitro studies have suggested possible mechanisms by which macrolides are effective. Similar to DPB, the inflammation in patients with chronic sinusitis is mediated by neutrophils.15,16,40 – 42 In the sinus mucosa, the predominant inflammatory cells are lymphocytes and mononuclear cells.43,44 Macrolides reduce the concentrations of proinflammatory cytokines, reduce neutrophil migration and inflammatory mediators such as neutrophil elastase, and inhibit the proliferation of fibroblasts that are important in the pathogenesis of chronic sinusitis.45– 47 In vitro studies of cultured nasal mucosa from patients with chronic rhinosinusitis show that clarithromycin is as effective as prednisolone in reducing the concentrations of Volume 117 (9A)
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Figure 2. Macrolides (M) reduce inflammation of the nasal and sinus mucosa by inhibiting the production of proinflammatory cytokines, neutrophil elastase, and the migration of neutrophils. Macrolides also have a direct inhibitory effect on mucus hypersecretion.
IL-8, IL-5, and granulocyte/macrophage colony-stimulating factor.45 Macrolides reduce the expression of proinflammatory mediators such as IL-2, IL-6, IL-8, TNF-␣, and intercellular adhesion molecule–1 through their inhibitory effects on the transcriptional activation of nuclear factor–B and activator protein–1, nuclear transcription factors that stimulate the expression of proinflammatory cytokines.48 –52 These effects have been shown in both airway epithelial cells and fibroblasts. Several clinical studies also suggest possible mechanisms for the anti-inflammatory effects of the macrolides in patients with chronic sinusitis. In a phase 4, prospective, open-label study of 25 patients with chronic sinusitis, clarithromycin treatment was associated with reduced markers of inflammation such as macrophages (CD68), elastase, IL-6, IL-8, eosinophil activity, TNF-␣, and edema.53 The reduced inflammation was associated with a 41% improvement in the clinical signs and symptoms of chronic sinusitis. A significant reduction in the concentration of IL-8 and the number of neutrophils was also correlated with improved sinus aeration in patients with chronic sinusitis treated with macrolides.40, 41 Effects of Macrolides on Mucus Hypersecretion The mechanisms for the development of mucus hypersecretion are multifactorial and include effects of cytokines, chemokines, and oxygen radicals from neutrophils on the airways as well as direct effects of macrolides. The effects of macrolides have been shown in tissue culture, in animal models, and in clinical trials. Among the studies showing direct effects of macrolides on mucus secretion, erythromycin inhibited the secretion of glucosamine, a component of mucus from human airway explants, in a concentration-dependent manner.54 Clarithromycin and erythromycin inhibited mucus secretion from human
mucoepidermoid carcinoma cells and human nasal epithelial cells.50 Penicillin, ampicillin, tetracycline, and cephalosporin did not affect mucus secretion in this model system. In animal studies to determine effects of macrolides on mucus secretion, clarithromycin and erythromycin block the infiltration of neutrophils into airway goblet cells leading to reduced mucus secretion.50,55,56 As a result of decreased infiltration of neutrophils, there is less goblet cell hyperplasia. Reduction in mucus secretion may be due not only to the decreased hyperplasia of the goblet cells, but also by the inhibition of expression of the mucin gene MUC5AC, which is found primarily in goblet cells.50 –52,55 As shown in the in vitro and animal studies, macrolides inhibit mucus secretion in patients with inflammatory airway diseases, such as chronic sinusitis. In a study of 10 patients with purulent rhinitis compared with 10 healthy controls, clarithromycin 500 mg twice daily for 2 weeks restored nasal secretions to normal, decreased secretion volume 10-fold, and increased mucociliary transportability by 30% in patients with purulent rhinitis.57 These reports suggest that macrolides have both direct inhibitory effects on epithelial secretory cells and indirect anti-inflammatory effects. Possible mechanisms by which macrolides are effective in the treatment of chronic sinusitis are shown in Figure 2.
CONCLUSION The anti-inflammatory properties of macrolides have been extensively studied in patients with DPB.2,4,5 The effectiveness of macrolides in patients with DPB has led to the study of the anti-inflammatory effects of these agents in patients with chronic sinusitis, cystic fibrosis, and chronic bronchitis. In vivo and in vitro studies suggest that erythromycin, clarithromycin, and roxithromy-
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cin are effective at modulating inflammation in chronic sinusitis, leading to clinical benefits for patients with this disease. The mechanisms of action for the anti-inflammatory properties of macrolides are still not entirely understood, but appear to be multifactorial. Further studies are needed to fully understand which molecular changes are most important for the anti-inflammatory effects of macrolides in chronic sinusitis and other chronic inflammatory airway diseases. One question is which macrolide has the best anti-inflammatory properties. The 14-member ring macrolides erythromycin, clarithromycin, and roxithromycin have good antiinflammatory properties, whereas the 16-member ring macrolide josamycin has little efficacy. The reason for this difference is not known. Large, placebo-controlled, prospective, double-blind trials are needed to further elucidate the role of macrolides in patients with chronic sinusitis. Ongoing and future trials should determine the longterm efficacy of macrolides for the treatment of chronic inflammatory airway diseases, as well as development of resistance and the duration of effects after cessation of treatment.
REFERENCES 1. Murphy MP, Fishman P, Short SO, Sullivan SD, Yueh B, Weymuller EA Jr. Health care utilization and cost among adults with chronic rhinosinusitis enrolled in a health maintenance organization. Otolaryngol Head Neck Surg. 2002; 127:367–376. 2. Culic O, Erakovic V, Parnham MJ. Anti-inflammatory effects of macrolide antibiotics. Eur J Pharmacol. 2001;429:209 – 229. 3. Rubin BK, Tamaoki J. Macrolide antibiotics as biological response modifiers. Curr Opin Investig Drugs. 2000;1:169 – 172. 4. Jaffe A, Bush A. Anti-inflammatory effects of macrolides in lung disease. Pediatr Pulmonol. 2001;31:464 –473. 5. Zalewska-Kaszubska J, Gorska D. Anti-inflammatory capabilities of macrolides. Pharmacol Res. 2001;44:451–454. 6. Anderson R, Theron AJ, Feldman C. Membrane-stabilizing, anti-inflammatory interactions of macrolides with human neutrophils. Inflammation. 1996;20:693–705. 7. Gaylor AS, Reilly JC. Therapy with macrolides in patients with cystic fibrosis. Pharmacotherapy. 2002;22:227–239. 8. Shirai T, Sato A, Chida K. Effect of 14-membered ring macrolide therapy on chronic respiratory tract infections and polymorphonuclear leukocyte activity. Intern Med. 1995;34:469 –474. 9. Kudoh S, Azuma A, Yamamoto M, Izumi T, Ando M. Improvement of survival in patients with diffuse panbronchiolitis treated with low-dose erythromycin. Am J Respir Crit Care Med. 1998;157:1829 –1832. 10. Sakakura Y, Majima Y, Harada T, Hattori M, Ukai K. Nasal mucociliary transport of chronic sinusitis in children. Arch Otolaryngol Head Neck Surg. 1992;118:1234 –1237. 11. Gwaltney JM Jr. Acute community-acquired sinusitis. Clin Infect Dis. 1996; 23:1209-1223; quiz 1224 –1225. 12. Bachert C, Wagenmann M, Rudack C, Hopken K, Hillebrandt M, Wang D, van Cauwenberge P. The role of cytokines in infectious sinusitis and nasal polyposis. Allergy. 1998;53:2–13. 24S November 8, 2004
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13. Demoly P, Crampette L, Mondain M, Enander I, Jones I, Bousquet J. Myeloperoxidase and interleukin-8 levels in chronic sinusitis. Clin Exp Allergy. 1997;27:672–675. 14. Rudack C, Stoll W, Bachert C. Cytokines in nasal polyposis, acute and chronic sinusitis. Am J Rhinol. 1998;12:383–388. 15. Takeuchi K, Yuta A, Sakakura Y. Interleukin-8 gene expression in chronic sinusitis. Am J Otolaryngol. 1995;16:98 – 102. 16. Suzuki H, Takahashi Y, Wataya H, Ikeda K, Nakabayashi S. Mechanism of neutrophil recruitment induced by IL-8 in chronic sinusitis. J Allergy Clin Immunol. 1996;98:659 –670. 17. Min YG, Lee CH, Rhee CS, Hong SK, Kwon SH. Increased expression of IL-4, IL-5, IFN-gamma, IL-6, IL-8, and TGFbeta mRNAs in maxillary mucosa of patients with chronic sinusitis. Am J Rhinol. 1999;13:339 –343. 18. Drettner B, Aust R. Pathophysiology of the paranasal sinuses. Acta Otolaryngol. 1977;82:16 –19. 19. Guo Y, Majima Y, Hattori M, Seki S, Sakakura Y. Effect of functional endoscopic sinus surgery on maxillary sinus mucosa. Arch Otolaryngol Head Neck Surg. 1997;123:1097– 1100. 20. Luk CK, Dulfano MJ. Effect of pH, viscosity and ionicstrength changes on ciliary beeting frequency of human bronchial explants. Clin Sci. 1983;64:449 –451. 21. Saida S. Ciliary activity of nasal and maxillary epithelia in man. Mie Med J. 1986;36:9 –18. 22. Yamakawa M, Liu LX, Date T, et al. Hypoxia-induced factor–1 mediates activation of cultured vascular endotherial cells by inducing multiple angiogenic factors. Circ Res. 2003;93:664 –673. 23. Kimura T, Majima Y, Guo Y, Yoshida T. The effect of growth factors on the proliferation and differentiation of human nasal gland cells. Arch Otolaryngol Head Neck Surg. 2002; 128:578 –582. 24. Tos M, Morgensen C. Mucus production in chronic maxillary sinusitis. Acta Otolaryngol. 1984;97:151–159. 25. Majima Y, Sakakura Y, Hattori M, Hirata K. Rheological properties of nasal mucus from patients with chronic sinusitis. Am J Rhinol. 1993;7:217–221. 26. Hashiba M, Baba S. Efficacy of long-term administration of clarithromycin in the treatment of intractable chronic sinusitis. Acta Otolaryngol Suppl. 1996;525:73–78. 27. Kimura N, Nishioka K, Nishizaki K, Ogawa T, Naitou Y, Masuda Y. Clinical effect of low-dose, long-term roxithromycin chemotherapy in patients with chronic sinusitis. Acta Med Okayama. 1997;51:33–37. 28. Cervin A, Kalm O, Sandkull P, Lindberg S. One-year lowdose erythromycin treatment of persistent chronic sinusitis after sinus surgery: clinical outcome and effects on mucociliary parameters and nasal nitric oxide. Otolaryngol Head Neck Surg. 2002;126:481–489. 29. Moriyama H, Yanagi K, Ohtori N, Fukami M. Evaluation of endoscopic sinus surgery for chronic sinusitis: post-operative erythromycin therapy. Rhinology. 1995;33:166 –170. 30. Allen JS, Eisma R, Leonard G, Lafreniere D, Kreutzer D. Interleukin-8 expression in human nasal polyps. Otolaryngol Head Neck Surg. 1997;117:535–541. 31. Allen JS, Eisma R, Leonard G, Kreutzer D. Interleukin-3 interleukin-5, and granulocyte-macrophage colony-stimulating factor expression in nasal polyps. Am J Otolaryngol. 1997;18:239 –246. 32. Allen JS, Eisma R, LaFreniere D, Leonard G, Kreutzer D. Characterization of the eosinophil chemokine RANTES in nasal polyps. Ann Otol Rhinol Laryngol. 1998;107:416 –420. Volume 117 (9A)
A Symposium: Clinical Implications of Macrolide Treatment for Sinusitis/Majima 33. Bachert C, Wagenmann M, Hauser U, Rudack C. IL-5 synthesis is upregulated in human nasal polyp tissue. J Allergy Clin Immunol. 1997;99:837–842. 34. Yamada T, Fujieda S, Mori S, Yamamoto H, Saito H. Macrolide treatment decreased the size of nasal polyps and IL-8 levels in nasal lavage. Am J Rhinol. 2000;14:143–148. 35. Ichimura K, Shimazaki Y, Ishibashi T, Higo R. Effect of new macrolide roxithromycin upon nasal polyps associated with chronic sinusitis. Auris Nasus Larynx. 1996;23:48 –56. 36. Nonaka M, Pawankar R, Tomiyama S, Yagi T. A macrolide antibiotic, roxithromycin, inhibits the growth of nasal polyp fibroblasts. Am J Rhinol. 1999;13:267–272. 37. Iino Y, Sugita K, Toriyama M, Kudo K. Erythromycin therapy for otitis media with effusion in sinobronchial syndrome. Arch Otolaryngol Head Neck Surg. 1993;119:648 –651. 38. Moller P, Dingsor G. Otitis media with effusion: can erythromycin reduce the need for ventilating tubes? J Laryngol Otol. 1990;104:200 –202. 39. Iino Y. Clinical efficacy of macrolide therapy for otitis media with effusion in children. Otorhinolaryngology Tokyo. 1999; 42:585–590. 40. Fujita K, Shimizu T, Majima Y, Sakakura Y. Effects of macrolides on interleukin-8 secretion from human nasal epithelial cells. Eur Arch Otorhinolaryngol. 2000;257:199 –204. 41. Suzuki H, Shimomura A, Ikeda K, Oshima T, Takasaka T. Effects of long-term low-dose macrolide administration on neutrophil recruitment and IL-8 in the nasal discharge of chronic sinusitis patients. Tohoku J Exp Med. 1997;182: 115–124. 42. Lee HS, Majima Y, Sakakura Y, Shinogi J, Kawaguchi S, Kim BW. Quantitative cytology of nasal secretions under various conditions. Laryngoscope. 1993;103:533–537. 43. Nishimoto K, Ukai K, Harada T, Shun JC, Sakakura Y. Lymphocyte subsets of maxillary mucosa in chronic inflammation. Acta Otolaryngol. 1988;106:291–298. 44. Forsgren K, Fukami M, Penttila M, Kumlien J, Stierna P. Endoscopic and Caldwell-Luc approaches in chronic maxillary sinusitis: a comparative histopathologic study on preoperative and postoperative mucosal morphology. Ann Otol Rhinol Laryngol. 1995;104:350 –357. 45. Wallwork B, Coman W, Feron F, Mackay-Sim A, Cervin A. Clarithromycin and prednisolone inhibit cytokine production in chronic rhinosinusitis. Laryngoscope. 2002;112: 1827–1830. 46. Suzuki H, Shimomura A, Ikeda K, Furukawa M, Oshima T, Takasaka T. Inhibitory effect of macrolides on interleukin-8
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secretion from cultured human nasal epithelial cells. Laryngoscope. 1997;107:1661–1666. Nonaka M, Pawankar R, Saji F, Yagi T. Effect of roxithromycin on IL-8 synthesis and proliferation of nasal polyp fibroblasts. Acta Otolaryngol Suppl. 1998;539:71–75. Abe S, Nakamura H, Inoue S, et al. Interleukin-8 gene repression by clarithromycin is mediated by the activator protein-1 binding site in human bronchial epithelial cells. Am J Respir Cell Mol Biol. 2000;22:51–60. Aoki Y, Kao PN. Erythromycin inhibits transcriptional activation of NF– kappaB, but not NFAT, through calcineurinindependent signaling in T cells. Antimicrob Agents Chemother. 1999;43:2678 –2684. Shimizu T, Shimizu S, Hattori R, Gabazza EC, Majima Y. In vivo and in vitro effects of macrolide antibiotics on mucus secretion in airway epithelial cells. Am J Respir Crit Care Med. 2003;168:581–587. Desaki M, Takizawa H, Ohtoshi T, et al. Erythromycin suppresses nuclear factor– kappaB and activator protein–1 activation in human bronchial epithelial cells. Biochem Biophys Res Commun. 2000;267:124 –128. Miyanohara T, Ushikai M, Matsune S, Ueno K, Katahira S, Kurono Y. Effects of clarithromycin on cultured human nasal epithelial cells and fibroblasts. Laryngoscope. 2000; 110:126 –131. MacLeod CM, Hamid QA, Cameron L, Tremblay C, Brisco W. Anti-inflammatory activity of clarithromycin in adults with chronically inflamed sinus mucosa. Adv Ther. 2001;18: 75–82. Goswami SK, Kivity S, Marom Z. Erythromycin inhibits respiratory glycoconjugate secretion from human airways in vitro. Am Rev Respir Dis. 1990;141:72–78. Tamaoki J, Nakata J, Takeda Y, Takemura H, Tagaya E, Konno K. Effect of macrolide antibiotics on airway goblet hypersecretion in guinea pigs [in Japanese]. Kansenshogaku Zasshi. 1996;70:591–596. Takahashi Y, Shimizu T, Sakakura Y. Effects of indomethacin, dexamethasone, and erythromycin on endotoxin-induced intraepithelial mucus production of rat nasal epithelium. Ann Otol Rhinol Laryngol. 1997;106:683–687. Rubin BK, Druce H, Ramirez OE, Palmer R. Effect of clarithromycin on nasal mucus properties in healthy subjects and in patients with purulent rhinitis. Am J Respir Crit Care Med. 1997;155:2018 –2023.
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This article reviews the treatment of chronic sinusitis with macrolides. Chronic sinusitis is often the result of bacterial infections that lead to chronic inflammation with thickening of the sinus mucosa and hypersecretion of mucus. In addition to their anti-infective properties, some macrolides possess immunomodulatory effects. These macrolides have been used successfully to treat diffuse panbronchiolitis, a progressive inflammatory lung disease, and may be useful for treatment of asthma, chronic bronchitis, chronic sinusitis, cystic fibrosis, and bronchiectasis. The clinical benefits of macrolides in patients with chronic sinusitis include decreased nasal secretions and postnasal drip, with improvement in nasal obstruction. In vivo and in vitro studies show that some macrolides affect neutrophil chemotaxis and infiltration, inflammatory cytokine production, mucus production, and the transportability of airway secretions. These findings indicate that macrolides are promising agents for treating chronic inflammation of the airways. Am J Med. 2004;117(9A):20S–25S. © 2004 by Elsevier Inc.
From the Department of Otorhinolaryngology, Mie University School of Medicine, Tsu, Mie, Japan. Requests for reprints should be addressed to Yuichi Majima, MD, Department of Otorhinolaryngology, Mie University School of Medicine, 2-174 Edobashi Tsu, Mie 514-8507, Japan. 20S
© 2004 by Elsevier Inc. All rights reserved.
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hronic sinusitis is a common chronic inflammatory airway disease, affecting about 13% of the population in the United States.1 Patients with chronic sinusitis have excess nasal discharge, congestion, headache, and fatigue, which significantly decrease the quality of life for these patients. Chronic sinusitis is common in patients with acquired immunodeficiency syndrome, cystic fibrosis, and asthma; its treatment thus represents an important challenge in clinical practice. Certain members of the macrolide class of drugs have anti-inflammatory as well as antimicrobial properties. These drugs may be effective in patients with chronic sinusitis or other chronic inflammatory airway diseases by decreasing the inflammation that is important in the pathogenesis of these diseases.2,3 Macrolides reduce neutrophil migration, the oxidative burst in phagocytes, cytokine expression through the inhibition of transcription factors, eosinophilic inflammation, and the expression of adhesion molecules.2– 6 These drugs inhibit expression of some of the mucin genes and inhibit biofilm formation of Pseudomonas aeruginosa, a common cause of infection in chronic inflammatory airway diseases.7 These anti-inflammatory properties of the macrolides differ based on their ring structure. The 14- and 15-member ring macrolides, such as erythromycin, clarithromycin, and roxithromycin, effectively reduce the inflammatory response in chronic inflammatory diseases of the airways, whereas the 16-member ring macrolide josamycin has little efficacy.8 Most of the clinical studies of the anti-inflammatory properties of macrolides have been in patients with diffuse panbronchiolitis (DPB). DPB is a chronic inflammatory airway disease of unknown etiology, mainly confined to East Asia, which is characterized by progressive loss of pulmonary function. Before the routine long-term use of macrolides, the prognosis was poor for these patients. Treatment with erythromycin improves pulmonary function, decreases mucus hypersecretion, and reduces respiratory infections. Most importantly, whereas the 5-year survival of patients with untreated DPB between 1980 and 1984 was 71%, the 10-year survival of patients treated with macrolides improved to 94% after 1985.9 The dramatic improvement in these patients led to clinical trials in patients with other chronic inflammatory airway diseases such as chronic sinusitis. This review summarizes the clinical benefits of macrolides for the treatment of chronic sinusitis and the current evidence 1548-2766/04/$22.00 doi:10.1016/j.amjmed.2004.07.025
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Figure 1. Bacterial infections initiate a cycle of inflammation in patients with chronic sinusitis. This inflammation can lead to tissue damage, mucociliary dysfunction, poor sinus ventilation, and mucus hypersecretion. LPS ⫽ lipopolysaccharide.
for their mechanisms of action in this chronic inflammatory airway disease.
CHRONIC SINUSITIS Chronic sinusitis often is a disease of unknown etiology. Patients with chronic sinusitis have sinus pain, sinus headache, nasal congestion, mucopurulent discharge, and fatigue lasting ⬎3 months. The diagnosis is confirmed radiographically. Chronic sinusitis is characterized by obstruction of the ostium of paranasal sinuses that promotes stagnation and accumulation of highly viscous mucus secretions as well as mucociliary dysfunction. The stagnant fluid is easily infected, which then leads to inflammation. The pathogenesis of chronic sinusitis involves a vicious cycle of self-mediated inflammation and bacterial reinfection.10 These bacterial infections initiate a series of events that can lead to chronic sinusitis as shown in Figure 1.11–14 The infection causes chemotaxis and infiltration of neutrophils, mononuclear cells, and T-cells to the sinuses and an excessive release of proteases from neutrophils that damage the mucosa and facilitate fluid secretion. These immune cells and the respiratory epithelium produce the proinflammatory cytokines interleukin (IL)-8, transforming growth factor (TGF)–, and tumor necrosis factor (TNF)–␣.15–17 Bacterial products such as lipopolysaccharides, the elastases produced by inflammatory cells, and other inflammatory mediators such as vasoactive amines, as well as the immune complex and arachidonic acid metabolites, cause both inflammation in the sinus mucosa and poor sinus ventilation. Inflammation in the sinuses causes swelling of the
nasal and sinus mucosa that can obstruct the sinus ostium.18,19 Poor ventilation of the sinuses reduces ciliary activity,20,21 enhances bacterial growth, increases proliferation of small capillaries,22 and causes leakage of blood components. Other effects include activation of platelets and fibroblasts as well as mucous gland hyperplasia. Glandular hyperplasia induced by growth factors such as epidermal growth factor and keratinocyte growth factor23 causes hypersecretion of mucus,24 and fibroblast activation leads to thickening of the sinus mucosa. Hypersecretion of abnormal viscoelastic mucus causes mucociliary dysfunction,25 which accelerates the accumulation of sinus secretions and leads to chronic inflammation.
CLINICAL TRIALS Most studies that show the efficacy of long-term treatment with macrolides for patients with chronic sinusitis are small and open label. Collectively, however, these studies show a clear clinical benefit of macrolide therapy in patients with chronic sinusitis. For example, in an open-label, prospective study, clarithromycin (400 mg once daily) for 8 to 12 weeks improved symptoms and rhinoscopic findings in 45 adults with chronic sinusitis, 20 of whom were refractory to surgery. The rate of improvement was related to the duration of therapy and ranged from 5% at 2 weeks to 71% at 12 weeks. After 12 weeks of therapy, more than half of patients had a reduction in quantity and viscosity of nasal secretions, postnasal drip, and nasal obstruction.26 Similar findings were reported using roxithromycin therapy.27
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Surgery can be an important treatment option for chronic sinusitis to facilitate adequate drainage and improve ventilation of the sinuses. However, some patients do not respond to this type of intervention. In patients with persistent postsurgical sinusitis, macrolide therapy was shown to reduce symptoms in these individuals who were refractory to conservative treatment. In this subgroup of patients, the addition of a nonmacrolide antibacterial drug offered no additional reduction in symptoms.28 In this study, 12 of 17 patients with persistent sinusitis even after surgery had significant improvement after 3 months of erythromycin 250 mg twice daily or clarithromycin 250 mg once daily.28 These 12 patients continued therapy and were reassessed at 12 months. After 1 year of macrolide therapy, there was significant improvement in mucociliary transit time, endoscopic nasal scoring, and symptoms of nasal congestion, runny nose and sticky secretions, and headache in these patients. Similar findings were shown in a retrospective study of patients with persistent postsurgical sinusitis who had sinus surgery ⱖ1 year before enrollment in the study. A total of 57 patients were treated with erythromycin and 92 patients did not receive erythromycin. Patients treated with erythromycin received 600 mg daily for 1 to 2 months, 400 mg daily in the next 1 to 2 months, and 200 mg daily in the last 1 to 2 months of treatment. Improvement in the symptoms of chronic sinusitis was greater in patients receiving erythromycin (88%) than in patients who did not receive erythromycin therapy (69%).29 Effects of Macrolides on Nasal Polyps Many people with chronic sinusitis have nasal polyps that increase obstruction. Although nasal polyps have an unclear etiology, a relation between inflammation and the presence of nasal polyps is well documented. Inflammatory mediators such as IL-1, IL-5, IL-6, IL-8, and RANTES are present in nasal polyps.12,30 –33 There are 2 studies that show the effectiveness of macrolide therapy in decreasing the size of nasal polyps in patients with chronic sinusitis. In the first study of 20 patients with chronic paranasal rhinosinusitis, clarithromycin 400 mg once daily for 8 to 12 weeks significantly reduced the size of nasal polyps.34 The decrease in the size of nasal polyps correlated significantly with a reduction in the concentration of IL-8 in nasal lavage from these patients. Patients who did not have a decline in the concentration of IL-8 did not have a decrease in the size of polyps. In another study of 20 patients with nasal polyps and chronic sinusitis, roxithromycin treatment at a dose of 150 mg once daily for 8 weeks was associated with a decrease in polyp size in ⬎50% of the patients.35 Macrolides effectively decreased the size of the polyps despite the presence of allergies or the extent of eosinophilic infiltration. Results from these studies suggest that IL-8, an important mediator of neutrophil accumulation in the respiratory tract, 22S
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may be related to nasal polyp shrinkage due to macrolide suppression of cytokine production in inflammatory cells in sinus epithelium.34,35 An in vitro study showed that macrolides reduce proliferation of fibroblasts from nasal polyps.36 In this study, roxithromycin suppressed the proliferation of fibroblasts in biopsies from patients with nasal polyps. Proliferation of nasal polyp fibroblasts cell lines was also inhibited when patients were treated with 300 mg/day of roxithromycin for 1 month before biopsy and the generation of cell lines. The current clinical experience of macrolides in chronic sinusitis warrants the development of larger, placebo-controlled clinical trials. Effects of Macrolides on Otitis Media (OM) with Effusion (OME) OME is often associated with chronic sinusitis and is characterized by chronic inflammation with hypersecretion of mucus by goblet cells.37 Chronic OME was shown to resolve with long-term erythromycin therapy. In a study of 16 patients with sinobronchial syndrome treated for ⬎4 months with 600 mg/day erythromycin, most patients showed an improvement in symptoms of chronic sinusitis and resolution of OM.37 However, conflicting results have been reported in children who have OME. In a double-blind, placebo-controlled study, 147 children with OME received erythromycin 50 mg/kg per day for 14 days.38 The number of children free from middle ear effusion was not different between those receiving erythromycin or placebo. In another study, clarithromycin 5– 8 mg/kg per day was administered for ⬎2 months to 55 children with OME.39 The cure rate was significantly higher (66%) for patients receiving clarithromycin compared with 16% for those in the control group. Furthermore, of the children receiving clarithromycin, children who had OME associated with chronic sinusitis had a higher cure rate. Additional studies are needed to determine the effectiveness of macrolide therapy for the treatment of OME associated with chronic sinusitis.
MECHANISMS OF ACTION Although the mechanisms of action of macrolides in chronic sinusitis are unclear, numerous in vitro studies have suggested possible mechanisms by which macrolides are effective. Similar to DPB, the inflammation in patients with chronic sinusitis is mediated by neutrophils.15,16,40 – 42 In the sinus mucosa, the predominant inflammatory cells are lymphocytes and mononuclear cells.43,44 Macrolides reduce the concentrations of proinflammatory cytokines, reduce neutrophil migration and inflammatory mediators such as neutrophil elastase, and inhibit the proliferation of fibroblasts that are important in the pathogenesis of chronic sinusitis.45– 47 In vitro studies of cultured nasal mucosa from patients with chronic rhinosinusitis show that clarithromycin is as effective as prednisolone in reducing the concentrations of Volume 117 (9A)
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Figure 2. Macrolides (M) reduce inflammation of the nasal and sinus mucosa by inhibiting the production of proinflammatory cytokines, neutrophil elastase, and the migration of neutrophils. Macrolides also have a direct inhibitory effect on mucus hypersecretion.
IL-8, IL-5, and granulocyte/macrophage colony-stimulating factor.45 Macrolides reduce the expression of proinflammatory mediators such as IL-2, IL-6, IL-8, TNF-␣, and intercellular adhesion molecule–1 through their inhibitory effects on the transcriptional activation of nuclear factor–B and activator protein–1, nuclear transcription factors that stimulate the expression of proinflammatory cytokines.48 –52 These effects have been shown in both airway epithelial cells and fibroblasts. Several clinical studies also suggest possible mechanisms for the anti-inflammatory effects of the macrolides in patients with chronic sinusitis. In a phase 4, prospective, open-label study of 25 patients with chronic sinusitis, clarithromycin treatment was associated with reduced markers of inflammation such as macrophages (CD68), elastase, IL-6, IL-8, eosinophil activity, TNF-␣, and edema.53 The reduced inflammation was associated with a 41% improvement in the clinical signs and symptoms of chronic sinusitis. A significant reduction in the concentration of IL-8 and the number of neutrophils was also correlated with improved sinus aeration in patients with chronic sinusitis treated with macrolides.40, 41 Effects of Macrolides on Mucus Hypersecretion The mechanisms for the development of mucus hypersecretion are multifactorial and include effects of cytokines, chemokines, and oxygen radicals from neutrophils on the airways as well as direct effects of macrolides. The effects of macrolides have been shown in tissue culture, in animal models, and in clinical trials. Among the studies showing direct effects of macrolides on mucus secretion, erythromycin inhibited the secretion of glucosamine, a component of mucus from human airway explants, in a concentration-dependent manner.54 Clarithromycin and erythromycin inhibited mucus secretion from human
mucoepidermoid carcinoma cells and human nasal epithelial cells.50 Penicillin, ampicillin, tetracycline, and cephalosporin did not affect mucus secretion in this model system. In animal studies to determine effects of macrolides on mucus secretion, clarithromycin and erythromycin block the infiltration of neutrophils into airway goblet cells leading to reduced mucus secretion.50,55,56 As a result of decreased infiltration of neutrophils, there is less goblet cell hyperplasia. Reduction in mucus secretion may be due not only to the decreased hyperplasia of the goblet cells, but also by the inhibition of expression of the mucin gene MUC5AC, which is found primarily in goblet cells.50 –52,55 As shown in the in vitro and animal studies, macrolides inhibit mucus secretion in patients with inflammatory airway diseases, such as chronic sinusitis. In a study of 10 patients with purulent rhinitis compared with 10 healthy controls, clarithromycin 500 mg twice daily for 2 weeks restored nasal secretions to normal, decreased secretion volume 10-fold, and increased mucociliary transportability by 30% in patients with purulent rhinitis.57 These reports suggest that macrolides have both direct inhibitory effects on epithelial secretory cells and indirect anti-inflammatory effects. Possible mechanisms by which macrolides are effective in the treatment of chronic sinusitis are shown in Figure 2.
CONCLUSION The anti-inflammatory properties of macrolides have been extensively studied in patients with DPB.2,4,5 The effectiveness of macrolides in patients with DPB has led to the study of the anti-inflammatory effects of these agents in patients with chronic sinusitis, cystic fibrosis, and chronic bronchitis. In vivo and in vitro studies suggest that erythromycin, clarithromycin, and roxithromy-
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cin are effective at modulating inflammation in chronic sinusitis, leading to clinical benefits for patients with this disease. The mechanisms of action for the anti-inflammatory properties of macrolides are still not entirely understood, but appear to be multifactorial. Further studies are needed to fully understand which molecular changes are most important for the anti-inflammatory effects of macrolides in chronic sinusitis and other chronic inflammatory airway diseases. One question is which macrolide has the best anti-inflammatory properties. The 14-member ring macrolides erythromycin, clarithromycin, and roxithromycin have good antiinflammatory properties, whereas the 16-member ring macrolide josamycin has little efficacy. The reason for this difference is not known. Large, placebo-controlled, prospective, double-blind trials are needed to further elucidate the role of macrolides in patients with chronic sinusitis. Ongoing and future trials should determine the longterm efficacy of macrolides for the treatment of chronic inflammatory airway diseases, as well as development of resistance and the duration of effects after cessation of treatment.
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A Symposium: Clinical Implications of Macrolide Treatment for Sinusitis/Majima 33. Bachert C, Wagenmann M, Hauser U, Rudack C. IL-5 synthesis is upregulated in human nasal polyp tissue. J Allergy Clin Immunol. 1997;99:837–842. 34. Yamada T, Fujieda S, Mori S, Yamamoto H, Saito H. Macrolide treatment decreased the size of nasal polyps and IL-8 levels in nasal lavage. Am J Rhinol. 2000;14:143–148. 35. Ichimura K, Shimazaki Y, Ishibashi T, Higo R. Effect of new macrolide roxithromycin upon nasal polyps associated with chronic sinusitis. Auris Nasus Larynx. 1996;23:48 –56. 36. Nonaka M, Pawankar R, Tomiyama S, Yagi T. A macrolide antibiotic, roxithromycin, inhibits the growth of nasal polyp fibroblasts. Am J Rhinol. 1999;13:267–272. 37. Iino Y, Sugita K, Toriyama M, Kudo K. Erythromycin therapy for otitis media with effusion in sinobronchial syndrome. Arch Otolaryngol Head Neck Surg. 1993;119:648 –651. 38. Moller P, Dingsor G. Otitis media with effusion: can erythromycin reduce the need for ventilating tubes? J Laryngol Otol. 1990;104:200 –202. 39. Iino Y. Clinical efficacy of macrolide therapy for otitis media with effusion in children. Otorhinolaryngology Tokyo. 1999; 42:585–590. 40. Fujita K, Shimizu T, Majima Y, Sakakura Y. Effects of macrolides on interleukin-8 secretion from human nasal epithelial cells. Eur Arch Otorhinolaryngol. 2000;257:199 –204. 41. Suzuki H, Shimomura A, Ikeda K, Oshima T, Takasaka T. Effects of long-term low-dose macrolide administration on neutrophil recruitment and IL-8 in the nasal discharge of chronic sinusitis patients. Tohoku J Exp Med. 1997;182: 115–124. 42. Lee HS, Majima Y, Sakakura Y, Shinogi J, Kawaguchi S, Kim BW. Quantitative cytology of nasal secretions under various conditions. Laryngoscope. 1993;103:533–537. 43. Nishimoto K, Ukai K, Harada T, Shun JC, Sakakura Y. Lymphocyte subsets of maxillary mucosa in chronic inflammation. Acta Otolaryngol. 1988;106:291–298. 44. Forsgren K, Fukami M, Penttila M, Kumlien J, Stierna P. Endoscopic and Caldwell-Luc approaches in chronic maxillary sinusitis: a comparative histopathologic study on preoperative and postoperative mucosal morphology. Ann Otol Rhinol Laryngol. 1995;104:350 –357. 45. Wallwork B, Coman W, Feron F, Mackay-Sim A, Cervin A. Clarithromycin and prednisolone inhibit cytokine production in chronic rhinosinusitis. Laryngoscope. 2002;112: 1827–1830. 46. Suzuki H, Shimomura A, Ikeda K, Furukawa M, Oshima T, Takasaka T. Inhibitory effect of macrolides on interleukin-8
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