Study of Azithromycin for Lymphocytic Bronchiolitis/Bronchitis After Lung Transplantation (AZI002)

A Prospective, Open-label Study of Azithromycin for Lymphocytic Bronchiolitis/Bronchitis After Lung Transplantation

This study investigates the role of azithromycin treatment for lymphocytic bronchitis/bronchiolitis after lung transplantation.

Lymphocytic bronchitis/bronchiolitis is one of the major risk factors for development of chronic rejection/BOS after lung transplantation. There is currently no established treatment available for this condition. There is now mounting evidence that IL-17 producing lymphocytes (TH17) not only participate in chronic allograft rejection/BOS, but are also present within the airway wall during lymphocytic bronchiolitis and that IL-17 mRNA-levels in bronchoalveolar lavage fluid of these patients are upregulated. As such, TH17 may account for the increased BAL neutrophilia seen in these patients, as IL-17 may be responsible for driving IL-8 secretion (a neutrophil-attracting chemokine) from various cell types in the airways. Since azithromycin has previously been shown to reduce both IL-17 induced IL-8 production by human airway smooth muscle cells 'in vitro' and bronchoalveolar IL-8/neutrophil levels in LTx recipients with established BOS, we believe that azithromycin has great potential for treating lymphocytic bronchi(oli)tis by attenuating this TH17/IL-17/IL-8-mediated airway inflammation, possibly even halting the subsequent development of chronic rejection/BOS after lung transplantation. In this study, histologic, spirometric, bronchoalveolar an radiologic features will be investigated in patients treated with confirmed lymphocytic bronchitis/bronchiolitis treated with azithromycin.

azithromycin, lymphocytic bronchitis or bronchiolitis, lung transplantation, acute allograft rejection, chronic allograft rejection, bronchiolitis obliterans syndrome

Add-on of study-drug (azithromycin) to 'standard of care': 250 mg daily for 5 days, followed by 250 mg every other day until the end of the study-period (6 months treatment).

Add-on of study-drug (azithromycin) to 'standard of care' at diagnosis of lymphocytic bronchi(oli)tis. Study-drug regime: 250 mg daily for 5 days, followed by 250 mg every other day until the end of the study-period (6 months treatment).

Evolution of bronchoalveolar cellularity and protein levels (IL-8, IL-17) after 3 months of treatment

Evolution of radiologic features (e.g. tree-in-bud, consolidation, bronchiectasis, air trapping, etc.) on chest X-ray or HRCT after 3 months of treatment

Inclusion Criteria: Signed informed consent Adult (age at least 18 years old at moment of transplantation) Able to take oral medication Histologic diagnosis of lymphocytic bronchiolitis or bronchitis ('grade B') without concurrent acute cellular allograft rejection 'grade A' ≥2 Exclusion Criteria: Severe suture problems (e.g. airway stenosis) requiring lasering or stenting

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Vanaudenaerde BM, Wuyts WA, Geudens N, Dupont LJ, Schoofs K, Smeets S, Van Raemdonck DE, Verleden GM. Macrolides inhibit IL17-induced IL8 and 8-isoprostane release from human airway smooth muscle cells. Am J Transplant. 2007 Jan;7(1):76-82. doi: 10.1111/j.1600-6143.2006.01586.x. Epub 2006 Oct 25.

Vanaudenaerde BM, Dupont LJ, Wuyts WA, Verbeken EK, Meyts I, Bullens DM, Dilissen E, Luyts L, Van Raemdonck DE, Verleden GM. The role of interleukin-17 during acute rejection after lung transplantation. Eur Respir J. 2006 Apr;27(4):779-87. doi: 10.1183/09031936.06.00019405.

Verleden GM, Vanaudenaerde BM, Dupont LJ, Van Raemdonck DE. Azithromycin reduces airway neutrophilia and interleukin-8 in patients with bronchiolitis obliterans syndrome. Am J Respir Crit Care Med. 2006 Sep 1;174(5):566-70. doi: 10.1164/rccm.200601-071OC. Epub 2006 Jun 1.