Chest
Volume 125, Issue 2, Supplement, February 2004, Pages 70S-78S
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Immunomodulatory Activity and Effectiveness of Macrolides in Chronic Airway Disease

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The use of troleandomycin as adjunctive therapy for the treatment of patients with corticosteroid-dependent asthma first suggested an immunomodulatory effect of the macrolide antibiotics. This led to studies of the macrolides in other chronic airway diseases, such as diffuse panbronchiolitis (DPB), a disease occurring primarily in East Asia. The use of macrolides for the therapy of patients with DPB has led to dramatic improvements in pulmonary function and prolonged survival. Similar benefits have been documented in Japanese studies of bronchiectasis, chronic bronchitis, and sinobronchial syndrome. Clinical and pathologic similarities between DPB and cystic fibrosis (CF) led to the investigation of macrolides for the treatment of CF. Data now suggest that persons with CF will benefit from macrolide therapy. In vitro and in vivo studies suggest that macrolides may inhibit the pulmonary influx of neutrophils, inhibit the release of proinflammatory cytokines, protect the epithelium from bioactive phospholipids, and improve the transportability of airway secretions. The immunomodulatory effects of the macrolides also may be beneficial for the treatment of other chronic inflammatory conditions.

Section snippets

The Steroid-Sparing Effects of Macrolides

A number of studies91011121314 have shown an improvement in the clinical symptoms of corticosteroid-dependent patients with asthma and a reduction in corticosteroid dosage with concomitant TAO therapy. Pharmacokinetic studies1516 have suggested that the beneficial effects of TAO therapy may be due, in part, to the inhibition of steroid metabolism. TAO was shown to significantly prolong the serum half-life of methylprednisolone. However, in reported studies, some steroid-dependent patients were

The Effects of Macrolides on Mucus Secretion

Macrolide antibiotics also appear to be mucoregulatory, that is, they are able to decrease mucus hypersecretion in persons with airway disease without suppressing baseline physiologic secretion. In a double-blind, placebo-controlled, 8-week trial of 31 patients with chronic bronchitis, bronchiectasis, or DPB, low-dose clarithromycin (100 mg twice daily) profoundly decreased the expectorated sputum volume from 51 to 24 g per day (p < 0.001).19 Treatment with clarithromycin also increased the

The Effects of Macrolides on DPB

DPB is a chronic inflammatory pulmonary disease that is well-recognized in Japan and Korea, and is less commonly diagnosed in the West.242526 Although upper airway symptoms, including chronic sinusitis, usually begin in late childhood, DPB is usually diagnosed between the second and fifth decades of life, and is characterized by chronic, progressive, obstructive, and inflammatory sinobronchial disease. The clinical diagnostic criteria of DPB are given in Table 1.2 These criteria include airflow

Clinical Studies

Kudoh and colleagues27 were the first to demonstrate that low-dose erythromycin ameliorated the signs and symptoms of DPB. Therapy often will improve the appearance of chest radiographs and normalize pulmonary function. A large number of studies352728 have confirmed the effectiveness of long-term macrolide therapy for the treatment of DPB. These are summarized here.

In a retrospective analysis of 498 Japanese patients with DPB,2 a significant improvement in survival was associated with treatment

The Effects of Macrolides in CF

Based on the similarities between DPB and CF, macrolide antibiotics have now been studied as immunomodulatory medications for the treatment of CF.4142 In a pilot study,43 daily azithromycin was given for > 3 months (and up to a year) to 7 children aged 6 to 17 years with CF and P aeruginosa infection. During the study, no concomitant therapy with steroids, dornase alfa, or IV Ig was administered to these subjects. Excluding the first 2 months of treatment from their analysis, the authors

Conclusion

In nearly all reports, patients with DPB or CF who have received macrolide antibiotics have responded with dramatic improvements in pulmonary function. The treatment of DPB is the most striking example of the benefits of macrolides. Before the introduction of macrolide therapy, the 10-year survival rate was reported to be 12 to 50%,2 but since the introduction of macrolide therapy the 10-year survival rate is now > 90%. It is probable that patients with CF may realize similar benefits with

CME Questions

The American College of Chest Physicians designates this continuing medical education activity for 1 credit hour in category 1 of the Physician's Recognition Award of the American Medical Association. To obtain credit, please complete the question form at http://www.chestnet.org. Credit can be obtained ONLY through our online process.

  • 1.

    Diagnostic criteria for DPB include all of the following except:

    • A.

      FEV1 < 70% and Pao2 < 80 mm Hg

    • B.

      Elevated titers of cold hemagglutinin × ≥ 64

    • C.

      Bilateral

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    Learning objectives:

    • 1.

      To be aware of the diagnostic criteria for DPB.

    • 2.

      To understand the clinical evidence for the efficacy of macrolides for the treatment of DPB and CF.

    • 3.

      To understand the potential immunomodulatory effects of macrolides for the treatment of chronic diseases of the airways.

    • 4.

      To understand the effects of macrolides on mucus secretion.

    • 5.

      To realize the immunomodulatory effects of macrolides are independent of their antimicrobial effects.

    • 6.

      To realize the clinical utility of these drugs for the treatment of chronic inflammatory conditions.

    Neither Dr. Rubin, nor the department(s) with which he is affiliated, has received something of value (ie, any item, payment, or service valued in excess of $750.00) from a commercial or other party related directly or indirectly to the subject of this submission. He has received research grants and honoraria, and is a consultant for Abbott Laboratories. He has also received research grants from Zambon Pharmaceuticals. Neither Dr. Henke, nor the department(s) with which he is affiliated, has received something of value (ie, any item, payment, or service valued in excess of $750.00) from a commercial or other party related directly or indirectly to the subject of this submission. This article will be presenting information about immunomodulatory uses of macrolide antibiotics that is considered research and is not yet approved for any purpose.

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