155: Clinical benefit of chronic low dose azythromycin treatment in patients with bronchiolitis obliterans (original) (raw)
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Long-term azithromycin therapy for bronchiolitis obliterans syndrome: Divide and conquer?
The Journal of Heart and Lung Transplantation, 2010
BACKGROUND: Azithromycin may reverse or halt the decline of pulmonary function (FEV 1 ) in bronchiolitis obliterans syndrome (BOS). In this study we investigated the effects of long-term azithromycin treatment in lung transplant recipients with BOS. METHODS: A retrospective, observational, cohort study was performed on 107 patients with BOS (Stages 0p/1/2/3, n ϭ 23/62/20/2), who were treated with azithromycin for 3.1 Ϯ 1.9 years. Patients were evaluated 6.3 Ϯ 3.8 years after transplantation and assessed for evolution of FEV 1 , bronchoalveolar lavage neutrophilia and overall survival after initiation of azithromycin. Survival curves were analyzed using the log-rank test. Cox proportional hazard survival regression analysis was performed to estimate hazard ratios of clinical variables predicting outcome. RESULTS: FEV 1 increased Ն10% after 3 to 6 months of treatment in 40% of patients, of whom 33% later redeveloped BOS. FEV 1 further declined in 78% and stabilized in 22% of the remaining non-responders. Pre-treatment neutrophilia was higher in responders: 29.3% (9.3% to 69.7%) vs 11.5% (2.9% to 43.8%) (p ϭ 0.025), in whom it significantly decreased to 4.2% (1.8% to 17.6%) (p ϭ 0.041) after 3 to 6 months of azithromycin. Responders demonstrated better survival compared with non-responders (p ϭ 0.050), with 6 and 21 patients, respectively, dying during follow-up (p ϭ 0.027). Multivariate analysis identified initial azithromycin response and earlier post-transplant initiation of azithromycin to be protective for both BOS progression/relapse (hazard ratio [HR] ϭ 0.12 [95% confidence interval 0.05 to 0.28], p Ͻ 0.0001; and HR ϭ 0.98 [95% confidence interval 0.97 to 0.98], p Ͻ 0.0001, respectively) and retransplantation/death during follow-up (HR 0.10 [95% confidence interval 0.02 to 0.48], p ϭ 0.004; and HR 0.96 [95% confidence interval 0.95 to 0.98], p Ͻ 0.0001, respectively). CONCLUSIONS: Long-term azithromycin benefits pulmonary function and survival in BOS, particularly in patients with increased lavage neutrophilia.
European Respiratory Journal, 2005
Bronchiolitis obliterans (BO) is a serious noninfectious pulmonary complication following allogeneic bone marrow transplantation (BMT). Azithromycin, a macrolide antibiotic, may have a beneficial effect in BO through its anti-inflammatory effect. The aim of the current study was to investigate the potential effect of azithromycin on pulmonary function tests (PFTs) in BO complicating BMT.
Early Detection of Airway Involvement in Obliterative Bronchiolitis after Lung Transplantation
American Journal of Respiratory and Critical Care Medicine, 2000
As defined by the International Society for Heart and Lung Transplantation, the diagnosis of posttransplant obliterative bronchiolitis (OB) is based on histopathologic features and/or spirometric staging criteria, using FEV 1 to determine the extent of disease. However, this last parameter reflects an advanced bronchiolar process. The present study investigated whether physiologic parameters reflecting smaller airways dysfunction on one hand, and neutrophils in bronchoalveolar lavage fluid (BALF) on the other hand, could be useful for the earlier detection of bronchiolitis obliterans syndrome (BOS). We analyzed data obtained both from 765 pulmonary function test results and from 467 BALF specimens from 45 patients who survived at least 1 yr after surgery (n ϭ 47, including two retransplantations). Of the transplant procedures, 22 were associated with BOS and 25 were not. The mean delay from transplantation to the diagnosis of BOS was 578 d (range: 122 to 2,619 d). The threshold values of the following parameters were studied: decline in the forced expiratory flow rate at 25% to 75% of FVC (FEF 25-75) to р 70% of the predicted value and of baseline values, increase in the slope of the nitrogen washout curve (⌬ N 2) Ͼ 3%, and alveolar neutrophilia у 20% of the total BALF cell count. Agreement on the diagnosis of BOS (using the decline in FEV 1) was equally good for each of the four markers (kappa coefficient Ͼ 0.65, p Ͻ 10 Ϫ 5). In the OB group, mean delays after the threshold was reached for each of these parameters were 110 d (p ϭ 0.09), 173 d (p ϭ 0.03), 150 d (p ϭ 0.003), and 131 d (p ϭ 0.1), respectively, before the FEV 1 criteria were fulfilled. At the chosen threshold values, the decline in FEF 25-75 , increase in ⌬ N 2 , and development of a substantial alveolar neutrophilia all occurred significantly before a decline in FEV 1 in posttransplant OB.
Prognostic Value of Bronchiolitis Obliterans Syndrome Stage 0-p in Single-Lung Transplant Recipients
American Journal of Respiratory and Critical Care Medicine, 2005
Early diagnosis of bronchiolitis obliterans syndrome (BOS) is critical in understanding pathogenesis and devising therapeutic trials. Although potential-BOS stage (BOS 0-p), encompassing early changes in FEV(1) and forced expiratory flow, midexpiratory phase (FEF(25-75%)), has been proposed, there is a paucity of data validating its utility in single-lung transplantation. The aim of this study was to define the predictive ability of BOS 0-p in single-lung transplantation. We retrospectively analyzed spirometric data for 197 single-lung recipients. Sensitivity, specificity, and positive predictive value of BOS 0-p were examined over time using Kaplan-Meier methodology. BOS 0-p FEV(1) was associated with higher sensitivity, specificity, and positive predictive value than the FEF(25-75%) criterion over different time periods investigated. The probability of testing positive for BOS 0-p FEV(1) in patients with BOS (sensitivity) was 71% at 2 years before the onset of BOS. The probability of being free from development of BOS 0-p FEV(1) in patients free of BOS at follow-up (specificity) was 93% within the last year. Of patients who met the BOS 0-p FEV(1) criterion, 81% developed BOS or died within 3 years. The specificity and positive predictive value curves for the BOS 0-p FEV(1) were significantly different between patients with underlying restrictive versus obstructive physiology (p = 0.05 and 0.01, respectively). The FEV(1) criterion for BOS 0-p provides useful predictive information regarding the risk of development of BOS or death in single-lung recipients. The predictive value of this criterion is higher in patients with underlying restriction and is superior to the FEF(25-75%) criterion.
European Respiratory Journal, 2011
Azithromycin reduces airway inflammation and improves forced expiratory volume in 1 s (FEV1) in chronic rejection or bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTx). Azithromycin prophylaxis might prevent BOS. A double-blind randomised controlled trial of azithromycin (n540) or placebo (n543), initiated at discharge and administered three times a week for 2 yrs, was performed in 2005-2009 at the Leuven University Hospital (Leuven, Belgium). Primary end-points were BOS-free and overall survival 2 yrs after LTx; secondary end-points were acute rejection, lymphocytic bronchiolitis and pneumonitis rate, prevalence of pseudomonal airway colonisation or gastro-oesophageal reflux, and change in FEV1, airway and systemic inflammation over time. Patients developing BOS were assessed for change in FEV1 with open-label azithromycin. BOS occurred less in patients receiving azithromycin: 12.5 versus 44.2% (p50.0017). BOS-free survival was better with azithromycin (hazard ratio 0.27, 95% CI 0.092-0.816; p50.020). Overall survival, acute rejection, lymphocytic bronchiolitis, pneumonitis, colonisation and reflux were comparable between groups. Patients receiving azithromycin demonstrated better FEV1 (p50.028), and lower airway neutrophilia (p50.015) and systemic C-reactive protein levels (p50.050) over time. Open-label azithromycin for BOS improved FEV1 in 52.2% patients. No serious adverse events were noted. Azithromycin prophylaxis attenuates local and systemic inflammation, improves FEV1 and reduces BOS 2 yrs after LTx.
Association of Minimal Rejection in Lung Transplant Recipients with Obliterative Bronchiolitis
American Journal of Respiratory and Critical Care Medicine, 2004
The clinical significance of minimal acute rejection (grade A 1) in lung transplant recipients is unknown. We prospectively analyzed 1,159 transbronchial lung biopsies in 184 patients. Two hundred seventy-nine biopsies in 128 participants confirmed A 1 histology at a mean postoperative day of 229 Ϯ 340. Sixty four of 255 surveillance A 1 lesions progressed to high-grade acute rejection by 3 months of follow-up, whereas 40 developed new lymphocytic bronchiolitis. Twenty-four A 1 biopsies were symptomatic, with only two cases progressing to high-grade rejection after steroid therapy. Seventy-eight of 184 patients experienced multiple (у 2) A 1 biopsies in the first 12 months after transplant. Bronchiolitis obliterans syndrome developed in 68% of patients with multiple A 1 lesions at a mean of 599 Ϯ 435 days, compared with 43% of patients with one or less A 1 lesions at a mean of 819 Ϯ 526 (p ϭ 0.022). Eighteen patients experienced multiple A 1 biopsies after transplant in the absence of high-grade rejection episodes yet also developed earlier obliterative bronchiolitis (456 Ϯ 245 days, p ϭ 0.020). We conclude that for A 1 transbronchial lung biopsies, the conventional treatment of observation only is now challenged even in patients who are asymptomatic. Patients who experience multiple A 1 lesions develop an earlier onset of obliterative bronchiolitis and may warrant alternative immunosuppressive strategies.