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• W1749324265 abstract "Prophylactic azithromycin treatment has been demonstrated to improve freedom from bronchiolitis obliterans syndrome (BOS) 2 years after lung transplantation (LTx). In the current study, we re-evaluated the long-term effects of this prophylactic approach in view of the updated classification system for chronic lung allograft dysfunction (CLAD). A retrospective, intention-to-treat analysis of a randomized controlled trial comparing prophylactic treatment with placebo (n = 43) versus azithromycin (n = 40) after LTx was performed. Graft dysfunction (CLAD), graft loss (retransplantation, mortality), evolution of pulmonary function and functional exercise capacity were analyzed 7 years after inclusion of the last study subject. Following LTx, 22/43 (51%) patients of the placebo group and 11/40 (28%) patients of the azithromycin group ever developed CLAD (p = 0.043). CLAD-free survival was significantly longer in the azithromycin group (p = 0.024). No difference was present in proportion of obstructive versus restrictive CLAD between both groups. Graft loss was similar in both groups: 23/43 (53%) versus 16/40 (40%) patients (p = 0.27). Long-term pulmonary function and functional exercise capacity were significantly better in the azithromycin group (p < 0.05). Prophylactic azithromycin therapy reduces long-term CLAD prevalence and improves CLAD-free survival, pulmonary function, and functional exercise capacity after LTx. Prophylactic azithromycin treatment has been demonstrated to improve freedom from bronchiolitis obliterans syndrome (BOS) 2 years after lung transplantation (LTx). In the current study, we re-evaluated the long-term effects of this prophylactic approach in view of the updated classification system for chronic lung allograft dysfunction (CLAD). A retrospective, intention-to-treat analysis of a randomized controlled trial comparing prophylactic treatment with placebo (n = 43) versus azithromycin (n = 40) after LTx was performed. Graft dysfunction (CLAD), graft loss (retransplantation, mortality), evolution of pulmonary function and functional exercise capacity were analyzed 7 years after inclusion of the last study subject. Following LTx, 22/43 (51%) patients of the placebo group and 11/40 (28%) patients of the azithromycin group ever developed CLAD (p = 0.043). CLAD-free survival was significantly longer in the azithromycin group (p = 0.024). No difference was present in proportion of obstructive versus restrictive CLAD between both groups. Graft loss was similar in both groups: 23/43 (53%) versus 16/40 (40%) patients (p = 0.27). Long-term pulmonary function and functional exercise capacity were significantly better in the azithromycin group (p < 0.05). Prophylactic azithromycin therapy reduces long-term CLAD prevalence and improves CLAD-free survival, pulmonary function, and functional exercise capacity after LTx. Chronic lung allograft dysfunction (CLAD) is the principal cause of late morbidity and mortality following lung transplantation (LTx) (1.Yusen RD Edwards LB Kucheryavaya AY The registry of the International Society for Heart and Lung Transplantation: Thirty-first adult lung and heart-lung transplant report–2014 focus theme: Retransplantation.J Heart Lung Transplant. 2014; 33 (et al): 1009-1024Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar). CLAD clinically either presents as an obstructive pulmonary function decline, defined as obstructive CLAD (bronchiolitis obliterans syndrome, BOS); or as a restrictive pulmonary function defect, called restrictive CLAD (restrictive allograft syndrome, RAS) (2.Verleden GM Raghu G Meyer KC Glanville AR Corris P A new classification system for chronic lung allograft dysfunction.J Heart Lung Transplant. 2014; 33: 127-133Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar). Although BOS was generally thought to be irreversible, recent evidence suggests that about 35% of patients with supposed BOS may in fact respond to macrolides, that is, display a ≥10% improvement in forced expiratory volume in 1 s (FEV1) after 3–6 months of treatment (3.Gerhardt SG McDyer JF Girgis RE Conte JV Yang SC Orens JB Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: Results of a pilot study.Am J Respir Crit Care Med. 2003; 168: 121-125Crossref PubMed Scopus (300) Google Scholar, 4.Verleden GM Dupont LJ Azithromycin therapy for patients with bronchiolitis obliterans syndrome after lung transplantation.Transplantation. 2004; 77: 1465-1467Crossref PubMed Scopus (148) Google Scholar, 5.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; 174: 566-570Crossref PubMed Scopus (262) Google Scholar, 6.Gottlieb J Szangolies J Koehnlein T Golpon H Simon A Welte T Long-term azithromycin for bronchiolitis obliterans syndrome after lung transplantation.Transplantation. 2008; 85: 36-41Crossref PubMed Scopus (192) Google Scholar, 7.Vanaudenaerde BM Meyts I Vos R A dichotomy in bronchiolitis obliterans syndrome after lung transplantation revealed by azithromycin therapy.Eur Respir J. 2008; (et al): 832-843Crossref PubMed Scopus (142) Google Scholar, 8.Vos R Vanaudenaerde BM Ottevaere A Long-term azithromycin therapy for bronchiolitis obliterans syndrome: Divide and conquer?.J Heart Lung Transplant. 2010; 29 (et al): 1358-1368Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar). This was recently confirmed in a placebo-controlled trial in patients with BOS, in whom azithromycin was demonstrated to be superior to placebo regarding improvement in FEV1 (9.Corris PA Ryan VA Small T A randomised controlled trial of azithromycin therapy in bronchiolitis obliterans syndrome (BOS) post lung transplantation.Thorax. 2015; 70 (et al): 442-450Crossref PubMed Scopus (113) Google Scholar). Therefore, the current clinical practice guidelines recommend initiating azithromycin therapy in patients with suspected BOS (10.Meyer KC Raghu G Verleden GM An international ISHLT/ATS/ERS clinical practice guideline: Diagnosis and management of bronchiolitis obliterans syndrome.Eur Respir J. 2014; 44 (et al): 1479-1503Crossref PubMed Scopus (375) Google Scholar). So-called “responders” to azithromycin, mostly patients with elevated bronchoalveolar lavage neutrophilia, were initially classified as “neutrophilic-reversible allograft dysfunction” (NRAD), which is nowadays renamed to “azithromycin responsive allograft dysfunction” (ARAD). The latter entity is currently no longer regarded to reflect CLAD, which is by definition characterized by a persistent decline in FEV1 of at least 20% compared to the two best postoperative values and for which no specific other cause can be identified (1.Yusen RD Edwards LB Kucheryavaya AY The registry of the International Society for Heart and Lung Transplantation: Thirty-first adult lung and heart-lung transplant report–2014 focus theme: Retransplantation.J Heart Lung Transplant. 2014; 33 (et al): 1009-1024Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar,2.Verleden GM Raghu G Meyer KC Glanville AR Corris P A new classification system for chronic lung allograft dysfunction.J Heart Lung Transplant. 2014; 33: 127-133Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar). In addition, it has become clear that some patients develop a restrictive form of lung allograft dysfunction not compatible with BOS (2.Verleden GM Raghu G Meyer KC Glanville AR Corris P A new classification system for chronic lung allograft dysfunction.J Heart Lung Transplant. 2014; 33: 127-133Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar,11.Verleden SE Ruttens D Vandermeulen E Restrictive chronic lung allograft dysfunction: Where are we now?.J Heart Lung Transplant. 2015; 34 (et al): 625-630Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar,12.Sato M Waddell TK Wagnetz U Restrictive allograft syndrome (RAS): A novel form of chronic lung allograft dysfunction.J Heart Lung Transplant. 2011; 30 (et al): 735-742Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar). Hence, the term CLAD was recently introduced as an overarching term to cover different phenotypes of chronic lung allograft dysfunction (1.Yusen RD Edwards LB Kucheryavaya AY The registry of the International Society for Heart and Lung Transplantation: Thirty-first adult lung and heart-lung transplant report–2014 focus theme: Retransplantation.J Heart Lung Transplant. 2014; 33 (et al): 1009-1024Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar). The etiology of CLAD is multifactorial and treatment of established CLAD is often disappointing. Therefore, prevention may be a more effective therapeutic strategy. As such, we previously demonstrated that prophylactic azithromycin therapy, when given in addition to conventional immunosuppression, could significantly improve post-LTx outcome, both freedom from apparent BOS and allograft function (FEV1), which effects were attributable to attenuated airway and systemic inflammation (13.Vos R Vanaudenaerde BM Verleden SE A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation.Eur Respir J. 2011; 37 (et al): 164-172Crossref PubMed Scopus (201) Google Scholar). In retrospect, however, the observed effects may have been, at least partially, due to modulation/prevention of ARAD, which is driven by neutrophilic airways inflammation. Indeed, during the initial 2-year study period, 23 patients (n = 18 placebo, n = 5 azithromycin) apparently developed BOS (stage ≥1), in whom subsequently study medication was stopped and open-label azithromycin initiated. Afterwards, FEV1 significantly improved (to BOS stage 0) in 12/23 (52%) patients (including 10/18 (56%) patients receiving placebo and 2/5 (40%) patients receiving azithromycin, the latter later admitted not having taken their study medication properly) (13.Vos R Vanaudenaerde BM Verleden SE A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation.Eur Respir J. 2011; 37 (et al): 164-172Crossref PubMed Scopus (201) Google Scholar). With hindsight, these “responders” to azithromycin should now be re-classified as suffering from ARAD at that time; and would currently no longer be regarded to have been suffering from BOS. As such, true CLAD (excluding ARAD) was probably only present in the “nonresponders” at that time, being only 11/23 (48%) patients in whom no spirometric improvement was seen after initiation of open-label azithromycin treatment. Our current aim was therefore to evaluate the long-term effects of prophylactic azithromycin therapy post-LTx in view of the new classification for CLAD, including BOS and RAS. Hence, graft dysfunction (CLAD-free survival), graft loss (retransplantation, mortality), evolution of pulmonary function and functional exercise capacity were retrospectively assessed. Both original study groups (placebo vs. azithromycin) were analyzed 7 years after inclusion of the last study subject according to an intention-to-treat approach. Patients were previously included in a double-blind, randomized controlled trial of placebo (n = 43) or azithromycin (250 mg) (n = 40) (NCT01009619), initiated at discharge post-LTx and administered three times a week (inclusion from September 2005 until December 2007), as previously described (13.Vos R Vanaudenaerde BM Verleden SE A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation.Eur Respir J. 2011; 37 (et al): 164-172Crossref PubMed Scopus (201) Google Scholar). This study had sufficient sample size and power to meet its primary end point (30% reduction of BOS prevalence 2 years after LTx). As per protocol, patients diagnosed with apparent BOS during the study, were shifted from study drug to open-label “rescue” treatment with azithromycin 250 mg three times a week (continued indefinitely) and were subsequently followed up in our standardized outpatient care program. After the initial 2-year study period, study medication (placebo or azithromycin) was continued until 3 years post-LTx according to the same protocol, that is, allowing open-label “rescue” treatment for apparent BOS. Thus, study medication was blinded for the patients and their treating clinical transplant physicians during this period (GV, LD, and JY) and solely unblinded for the research fellows BMV and RV for publication of the initial study findings after the initial 2-year study period in 2010 (13.Vos R Vanaudenaerde BM Verleden SE A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation.Eur Respir J. 2011; 37 (et al): 164-172Crossref PubMed Scopus (201) Google Scholar). At 3 years post-LTx, the study was stopped and study medication (in those patients not yet given open-label azithromycin treatment) was discontinued in all patients during their subsequent outpatient visits. During later follow-up, open-label azithromycin treatment was initiated at the physicians’ discretion, mostly in case of newly diagnosed allograft dysfunction. Graft dysfunction (CLAD-free survival), graft loss (retransplantation, mortality), evolution of pulmonary function and of functional exercise capacity were retrospectively analyzed 7 years after inclusion of the last study subject (as of December 2014) according to an intention-to-treat approach comparing both original study groups (placebo vs. azithromycin). As previously described in detail (13.Vos R Vanaudenaerde BM Verleden SE A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation.Eur Respir J. 2011; 37 (et al): 164-172Crossref PubMed Scopus (201) Google Scholar), all patients received conventional triple-drug immunosuppression with methylprednisolone, a calcineurin inhibitor (cyclosporine A or tacrolimus) and a cytostatic agent (azathioprine or mycophenolate mofetil); infection prophylaxis and treatment with a proton pump inhibitor. In case of CLAD progression despite treatment with azithromycin, optimization of immunosuppressives, a tapering course of oral steroids and treatment with montelukast was administered. In selected cases, retransplantation was performed. None of the studied patients underwent total lymph node irradiation or extracorporeal photopheresis for progressive CLAD. CLAD was diagnosed as a persistent decline in FEV1 of at least 20% compared to the two best postoperative values, in absence of other causes (2.Verleden GM Raghu G Meyer KC Glanville AR Corris P A new classification system for chronic lung allograft dysfunction.J Heart Lung Transplant. 2014; 33: 127-133Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar). In that case, further differentiation into BOS or RAS was performed, using total lung capacity (TLC) and/or FEV1/FVC ratio and/or forced vital capacity (FVC) and computerized tomography (CT) scan findings (2.Verleden GM Raghu G Meyer KC Glanville AR Corris P A new classification system for chronic lung allograft dysfunction.J Heart Lung Transplant. 2014; 33: 127-133Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar). RAS was diagnosed as either a persistent decrease of >10% in TLC, >20% in FVC or increasing FEV1/FVC ratio in combination with a >20% decrease in FEV1 and with persistent infiltrates on CT scan, without any other identifiable cause. All included patients previously had provided written informed consent before randomization; both the original trial and the current analysis were approved by the institutional review board (ML3199). Statistical analyses (Graphpad Prism 4.0 software, San Diego, CA) were performed on an intention-to-treat basis, comparing patients previously assigned to prophylactic treatment with placebo or azithromycin (14.Troosters T Gosselink R Decramer M Six minute walking distance in healthy elderly subjects.Eur Respir J. 1999; 14: 270-274Crossref PubMed Scopus (704) Google Scholar). Group means were compared using unpaired, two-tailed t-test or Mann–Whitney test depending of normality distribution. Fisher’s exact or χ2 test was used to compare proportions. Two-way ANOVA test was used for analysis of lung function evolution. Kaplan–Meier survival curves and log-rank analysis was used for time-to-event analysis: freedom from CLAD and graft loss. For the end point CLAD, survival times were censored at retransplantation, death or end of follow-up as of December 1, 2014. Eighty-three patients had been randomly assigned to a placebo group (n = 43) or an azithromycin group (n = 40) (13.Vos R Vanaudenaerde BM Verleden SE A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation.Eur Respir J. 2011; 37 (et al): 164-172Crossref PubMed Scopus (201) Google Scholar). In brief, included patients were mostly female (57%) with smoking-related emphysema (51%) who underwent bilateral lung transplantation (73%). Baseline demographical characteristics, pulmonary function (FEV1), functional excercise capacity (6-minute walk test, 6MWT), postoperative variables and routine immunosuppressive management were similar in both groups (13.Vos R Vanaudenaerde BM Verleden SE A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation.Eur Respir J. 2011; 37 (et al): 164-172Crossref PubMed Scopus (201) Google Scholar) (Table S1). Severe airway complications, such as stenosis or dehiscence, were an exclusion criterion before study randomization; and were not present during later follow-up in this cohort. None of the patients were lost to follow-up and total time of follow-up was comparable in the placebo (2046 ± 152 days) and azithromycin group (2182 ± 152 days) (p = 0.33). Overall, open-label azithromycin treatment, either during the initial 2-year study period (after stopping the study drug) or in the course of later follow-up, was initiated in 55/83 (66%) patients, which was comparable in both groups: 30/43 (70%) patients of the placebo group and 25/40 (63%) patients of the azithromycin group (p = 0.49) were initiated on open-label azithromycin (Figure 1). In retrospect, initiation of open-label azithromycin in the placebo group was due to CLAD (i.e. no subsequent improvement in FEV1) in 17/30 (56%) patients, while in 11/30 (37%) patients ARAD could post hoc be diagnosed (i.e. subsequent ≥10% FEV1 improvement) and in 2/30 (7%) patients azithromycin was initiated because of recurrent infections. Of the ARAD patients in the placebo group, thus who initially demonstrated an improvement in FEV1, 5/11 (45%) patients later developed CLAD during follow-up, despite continued open-label azithromycin treatment, bringing the total number of patients in the placebo group ever developing CLAD after LTx to 22/43 (51%). In the azithromycin group, open-label azithromycin was initiated because of CLAD in 11/25 (44%) patients, ARAD in 9/25 (36%) patients and recurrent respiratory infections in 5/25 (20%) patients (p = 0.31). None of the ARAD patients in the azithromycin group later developed CLAD during follow-up, bringing the total number of patients in the azithromycin group ever developing CLAD after LTx to 11/40 (28%). CLAD prevalence following prior ARAD was remarkably higher in the placebo group (n = 5/11) compared to the azithromycin group (n = 0/9) (p = 0.038) (Figure 1), which may relate to earlier onset of ARAD in the placebo group (591 ± 154 days) compared to the azithromycin group (1477 ± 286 days) (p = 0.027). Indeed, in the placebo group 7/11 (64%) patients developed ARAD during the initial study period (thus while being treated with placebo) and 4/11 (36%) developed ARAD during later follow-up, whereas in the azithromycin group only 2/9 (22%) patients developed ARAD during the initial study period (both with study drug (=azithromycin mal compliance) and 7/9 (78%) patients developed ARAD during later follow-up (p = 0.064). A total of 13/43 (30%) patients in the placebo group never received open-label azithromycin, neither during the initial study period nor during later follow-up, which was due to patient’s death during the initial study period (n = 6) or later follow-up (n = 2) (all free from CLAD at that moment), while the remaining five patients never received azithromycin after transplantation. In the azithromycin group, 15/40 (37%) patients were never initiated on open-label azithromycin treatment: This was due to patient’s death during later follow-up (n = 5) (all free from CLAD at that moment), while the remaining 10 patients are currently alive without need for azithromycin. CLAD developed less frequently in patients of the azithromycin group compared to those of the placebo group: in the latter 22/43 patients (51%) developed CLAD versus 11/40 patients (28%) in the azithromycin group (p = 0.043). Overall, CLAD-free survival was significantly worse in the placebo group (p = 0.024) (Figure 2A), with a 75% CLAD-free survival of 1.76 years in the placebo group versus 4.06 years in the azithromycin group, or an average difference of 2.3 years favoring randomization to azithromycin. Obstructive CLAD (BOS) developed in 16/43 (37%) patients of the placebo group and in 8/40 (20%) patients of the azithromycin group (p = 0.10), whereas restrictive CLAD (RAS) developed in 6/43 (14%) patients of the placebo group and in 3/40 (7.5%) patients of the azithromycin group (p = 0.49). Thus, no difference was observed in proportion of BOS and RAS: 16/22 (73%) CLAD patients in the placebo group had developed BOS versus 8/11 (73%) in the azithromycin group; and 6/22 (27%) CLAD patients in the placebo group had developed RAS versus 3/11 (27%) in the azithromycin group, respectively. Overall, graft loss was similar between the placebo and azithromycin group (p = 0.25) (Figure 2B). Graft loss after the diagnosis of CLAD was also comparable between groups (p = 0.74) (Figure S1). Graft loss attributable to CLAD occurred in 14/43 (32%) patients in the placebo group and in 7/40 (18%) patients of the azithromycin group (p = 0.14). All-cause mortality was similar in the placebo and azithromycin group: In the placebo group 21/43 (49%) patients died during follow-up versus 14/40 (35%) patients in the azithromycin group (p = 0.27). Cause of death was comparable in both groups: In the placebo group mortality was attributable to CLAD in 12/21 (57%) patients, malignancy in 4/21 (19%), pulmonary infection in 2/21 (9%), nonpulmonary infection in 1/21 (5%), enteric ischemia in 1/21 (5%), and unknown in 1/21 (5%) patients; whereas in the azithromycin group mortality was due to CLAD in 6/14 (43%) patients, malignancy in 4/14 (28%), pulmonary infection in 1/14 (7%), and nonpulmonary infection in 3/14 (21%) patients (p = 0.54). Retransplantation for CLAD was similar in the placebo and azithromycin group: 5/43 (11%) patients in the placebo group and 3/40 (7.5%) patients in the azithromycin group underwent retransplantation (p = 0.71). Of the retransplant patients, 3/5 in the placebo group and 1/3 in the azithromycin group later died, cause of death was CLAD (n = 2) or infection (n = 1) in the placebo group and CLAD (n = 1) in the azithromycin group. Both FVC and FEV1 were on average significantly better in the azithromycin group compared to placebo during follow-up: FVC (Liters) p = 0.040 and FVC (%predicted) p < 0.0001; FEV1 (Liters) p = 0.051, and FEV1 (%predicted) p < 0.0011, respectively (Figures 3 and S2). 6MWT was on average significantly better in the azithromycin group compared to the placebo group during follow-up: 6MWT (meters) p = 0.0041 and 6MWT (% predicted) p < 0.0001, respectively (Figures 3 and S2) (14.Troosters T Gosselink R Decramer M Six minute walking distance in healthy elderly subjects.Eur Respir J. 1999; 14: 270-274Crossref PubMed Scopus (704) Google Scholar). The mean difference in 6MWT obtained during follow-up was 43.6 ± 25.3 m favoring azithromycin (526.6 ± 15.9 m in the azithromycin group vs. 483.0 ± 16.1 m in the placebo group), reflecting a minimal clinically important difference of more than 25 m (15.Holland AE Hill CJ Rasekaba T Lee A Naughton MT McDonald CF Updating the minimal important difference for Six-Minute Walk Distance in patients with chronic obstructive pulmonary disease.Arch Phys Med Rehabil. 2010; 91: 221-225Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar). QT was 370 ± 4.6 ms and QTc 435 ± 3.5 ms before the start of open-label azithromycin treatment (data available in n = 55/55 [100%] of patients); and were respectively 371 ± 4.4 ms and 422 ± 2.8 ms after a mean of 7.2 ± 0.6 months of treatment (data available in n = 53/55 [96%] of patients) (QT p = 0.54 and QTc p = 0.0051, respectively). Thus, there was no QT or QTc prolongation with azithromycin. Prevention of CLAD is an important therapeutic approach given that no real therapeutic options are available for established CLAD, except perhaps retransplantation in selected cases. Our current aim was to evaluate the long-term effects of prophylactic azithromycin therapy following LTx in view of the new classification for CLAD (2.Verleden GM Raghu G Meyer KC Glanville AR Corris P A new classification system for chronic lung allograft dysfunction.J Heart Lung Transplant. 2014; 33: 127-133Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar). We observed that prophylactic azithromycin treatment, compared to placebo, effectively reduced CLAD prevalence, improved CLAD-free survival, long-term pulmonary function and functional exercise capacity after LTx, whereas no benefit regarding graft loss was seen. Importantly, QT or QTc were not prolonged by azithromycin. As such, the current study is the first to demonstrate that CLAD onset can effectively be postponed by azithromycin, which is most likely due to its extensive anti-inflammatory and immunomodulatory properties, preventing/attenuating early posttransplant airway inflammation (16.Vos R Verleden SE Ruttens D Azithromycin and the treatment of lymphocytic airway inflammation after lung transplantation.Am J Transplant. 2014; 14 (et al): 2736-2748Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar,17.Vos R Vanaudenaerde BM Verleden SE Anti-inflammatory and immunomodulatory properties of azithromycin involved in treatment and prevention of chronic lung allograft rejection.Transplantation. 2012; 94 (et al): 101-109Crossref PubMed Scopus (75) Google Scholar). The most benefit regarding pulmonary function and functional exercise capacity is apparently obtained during the initial 2 years post-LTx, as both pulmonary function and functional exercise capacity in both groups seem to diverge in favor of azithromycin during this initial period, as originally described in this cohort (13.Vos R Vanaudenaerde BM Verleden SE A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation.Eur Respir J. 2011; 37 (et al): 164-172Crossref PubMed Scopus (201) Google Scholar), whereas during later follow-up evolution over time is quite parallel in both groups. This corroborates the recent findings that an obstructive lung function pattern early after LTx is associated with earlier development of BOS (18.Suhling H Dettmer S Rademacher J Spirometric obstructive lung function pattern early after lung transplantation.Transplantation. 2012; 93 (et al): 230-235Crossref PubMed Scopus (14) Google Scholar). As such, one could say that patients are seemingly given a functional “head-start” with prophylactic azithromycin treatment compared to the placebo-treated patients. One may even question whether “ad infinitum” continuation of azithromycin, instead of discontinuation after some years, may not even longer preserve the lung function and even further postpone CLAD onset, especially given that open-label azithromycin treatment afterwards was restarted in most patients because of novel allograft dysfunction. The difference in functional exercise capacity between groups can probably partially be explained by the better pulmonary function and lower CLAD prevalence in the azithromycin group. Indeed, in patients with CLAD, low exercise capacity has been associated with decreased inspiratory capacity, which may be secondary to air trapping and hyperinflation (increased residual volume) and/or restrictive lung disease (decreased TLC); as is seen in either BOS or RAS, respectively (19.Suhling H de Wall C Rademacher J Low exercise tolerance correlates with reduced inspiratory capacity and respiratory muscle function in recipients with advanced chronic lung allograft dysfunction.Transplantation. 2013; 95 (et al): 1045-1050Crossref PubMed Scopus (5) Google Scholar). Impaired respiratory muscle function was also shown to decrease exercise capacity in CLAD (19.Suhling H de Wall C Rademacher J Low exercise tolerance correlates with reduced inspiratory capacity and respiratory muscle function in recipients with advanced chronic lung allograft dysfunction.Transplantation. 2013; 95 (et al): 1045-1050Crossref PubMed Scopus (5) Google Scholar), yet in the current study, the worse functional exercise capacity in the placebo is probably not due an increase in steroid myopathy since we previously documented that the use of steroids during the initial 2 years after LTx was similar between both groups (13.Vos R Vanaudenaerde BM Verleden SE A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation.Eur Respir J. 2011; 37 (et al): 164-172Crossref PubMed Scopus (201) Google Scholar). Graft loss in both groups, on the other hand, was comparable, which may be due to initiation of open-label azithromycin “rescue” treatment in patients with suspected CLAD, possibly resulting in better long-term outcome in those patients. Indeed, the fact that CLAD-related death was not significantly different between both groups is actually in line with previous reports demonstrating that patients with CLAD (mainly BOS) tend to live longer when treated with azithromycin compared to CLAD/BOS patients not being treated with azithromycin (8.Vos R Vanaudenaerde BM Ottevaere A Long-term azithromycin therapy for bronchiolitis obliterans syndrome: Divide and conquer?.J Heart Lung Transplant. 2010; 29 (et al): 1358-1368Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar,20.Jain R Hachem RR Morrell MR Azithromycin is associated with increased survival in lung transplant recipients with bronchiolitis obliterans syndrome.J Heart Lung Transplant. 2010; 29 (et al): 531-537Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar). Consequently, these patients may, therefore, die because of other reasons (mainly cancer), rather than due to CLAD per se. Some considerations should be taken into account when implementing long-term prophylactic azithromycin therapy (17.Vos R Vanaudenaerde BM Verleden SE Anti-inflammatory and immunomodulatory properties of azithromycin involved in treatment and prevention of chronic lung allograft rejection.Transplantation. 2012; 94 (et al): 101-109Crossref PubMed Scopus (75) Google Scholar,21.Li H Liu D-H Chen L-L Meta-analysis of the adverse effects of long-term azithromycin use in patients with chronic lung diseases.Antimicrob Agents Chemother. 2014; 58 (et al): 511-517Crossref PubMed Scopus (49) Google Scholar). Lately, much attention was be given to possible cardiovascular events with macrolides, particularly arrhythmias, mainly in case of concomitant use of other QT-prolonging medicines or underlying structural heart disease. However, azithromycin may be considered the safest of all macrolides in this respect since serum levels in healthy volunteers are >3000 times lower than drug concentrations required for cardiomyocyte potassium channel (hERG/IKr)-blockade, action potential prolongation and QTc prolongation (22.Abo-Salem E Fowler JC Attari M Antibiotic-induced cardiac arrhythmias.Cardiovasc Ther. 2014; 32 (et al): 19-25Crossref PubMed Scopus (54) Google Scholar, 23.Giudicessi JR Ackerman MJ Azithromycin and risk of sudden cardiac death: Guilty as charged or falsely accused?.Cleve Clin J Med. 2013; 80: 539-544Crossref PubMed Scopus (30) Google Scholar, 24.Albert RK Schuller JL COPD Clinical Research Network. Macrolide antibiotics and the risk of cardiac arrhythmias.Am J Respir Crit Care Med. 2014; 189: 1173-1180Crossref PubMed Scopus (112) Google Scholar). Caution is nevertheless required for toxic accumulation of azithromycin in patients with impaired hepatic function. In our cohort, we could not detect any QT or QTc prolongation with azithromycin, nor were Torsades de Pointes detected during follow up on annual 24-h Holter monitoring; and none of our patients succumbed due to sudden cardiac death possibly related to ventricular arrhythmias. As such, our data corroborates recent evidence that this risk for arrhythmias has been overestimated and that chronic azithromycin therapy can be safely used in the majority of subjects for whom macrolides are recommended (24.Albert RK Schuller JL COPD Clinical Research Network. Macrolide antibiotics and the risk of cardiac arrhythmias.Am J Respir Crit Care Med. 2014; 189: 1173-1180Crossref PubMed Scopus (112) Google Scholar). Inevitable limitations to the current analysis are inherent to its retrospective design, single-center approach and number of included patients. Nevertheless, both sample size and follow-up time posttransplant can actually be regarded as quite considerable in view of the average transplant center volume world wide. Moreover, the current placebo group actually reflects the general LTx population, at least concerning post-Tx CLAD prevalence and CLAD-free survival (1.Yusen RD Edwards LB Kucheryavaya AY The registry of the International Society for Heart and Lung Transplantation: Thirty-first adult lung and heart-lung transplant report–2014 focus theme: Retransplantation.J Heart Lung Transplant. 2014; 33 (et al): 1009-1024Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar). There may be considerable inter observer variability in diagnosing presence and time of BOS onset (25.Kapila A Baz MA Valentine VG Bhorade SM AIRSAC investigatorsReliability of diagnostic criteria for bronchiolitis obliterans syndrome after lung transplantation: A survey.J Heart Lung Transplant. 2015; 34: 65-74Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). As for RAS this has currently not been demonstrated, yet the same finding will probably be true. However, the current patients were each individually assessed together by the authors DR, SEV, GMV, and RV; after which CLAD presence/absence, time of onset and phenotype (BOS/RAS) were decided upon in overall agreement. Moreover, more “objective” parameters such as FVC and FEV1 evolution over time demonstrated significant differences between both studied groups, which is a reflection of the higher CLAD prevalence and incidence in the placebo group. Another possible bias may be compliance. In the initial study, 2/40 (5%) patients of the azithromycin group later admitted not having taken their study medication correctly (i.e. “often forgotten,” nevertheless overall adherence was thus 95%), both of which demonstrated significant improvement in FEV1 after being switched to open-label azithromycin, compatible with ARAD (13.Vos R Vanaudenaerde BM Verleden SE A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation.Eur Respir J. 2011; 37 (et al): 164-172Crossref PubMed Scopus (201) Google Scholar). During the initial study period, as previously reported, no study drug discontinuation was present in the placebo group; and study drug discontinuation only occurred in 2/40 (5%) patients of the azithromycin group because of nausea and diarrhea (13.Vos R Vanaudenaerde BM Verleden SE A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation.Eur Respir J. 2011; 37 (et al): 164-172Crossref PubMed Scopus (201) Google Scholar). During later follow-up, however, none of the patients discontinued azithromycin treatment, nor admitted mal-compliance. This is most likely related to increasing knowledge regarding the beneficial effects of azithromycin during the recent years, because of which patients were probably more reluctant to discontinue azithromycin as they nowadays consider this as a “vital” drug, next to their immunosuppressants. In summary, our long-term follow-up data support a sustained benefit of posttransplant, prophylactic azithromycin in prolonging CLAD-free survival and preserving allograft function and exercise capacity. The authors wish to acknowledge the following persons for their complimentary support: C. Jans, C. Rosseel, M. Meelberghs (Lung Transplant Outpatient Clinic); Prof. Dr. C. Dooms, J. Foulon, F. Vandeweyer, E. Putseys (Dept. of Endoscopy); G. Celis (Dept. of Pulmonary Function); Prof. Dr. P. De Leyn, Dr. W. Coosemans, Prof. Dr. P. Nafteux Dr. H. Decaluwé, Dr. H. Van Veer (Dept. of Thoracic Surgery); Prof. Dr. M. Schetz, Prof. Dr. S. Van Cromphaut (Intensive Care Unit); Apr. Dr. A. Vranckx, Apr. Dr. T. De Rijdt (Dept. of Experimental Pharmacy). This work was supported by ClinicalTrials.gov Identifier with grant number NCT01009619; RV is supported by the Research Foundation Flanders (FWO) (KAN2014 1.5.139.14) and Klinisch Onderzoeksfonds (KOF) KULeuven. SEV is supported by the FWO (12G 8715N). GMV is supported by the FWO (G.0723.10, G.0679.12 and G.0679.12). DEVR (G.3C04.99), LJD and BMV are senior research fellows of the FWO. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation. Additional Supporting Information may be found in the online version of this article. Download .docx (.21 MB) Help with docx files Table S1: Demographics (adapted from Ref. 14). Patients’ characteristics, initial secondary outcome parameters and immunosuppressive regimen for the patients of the placebo arm (n = 43) and of the azithromycin arm (n = 40) (13). Acute rejection and lymphocytic bronchiolitis, CMV, and non-CMV pneumonitis episodes were assessed for each patient until drop-out, reaching BOS or death within 2 years after LTx, or for the other patients until 2 years after LTx. Data regarding anti-HLA antibodies (Luminex assay) are available since 2010 and not available in patients who deceased before 2010. Immunosuppressive regimen for each patient was assessed at discharge; and for the patients alive at 2 years after LTx. Data are presented either as median (interquartile range), mean (± standard deviation), or as total value (percentage). Groups were compared using unpaired, two-tailed t-test, Mann–Whitney test or χ2 test where appropriate. p < 0.05 is considered significant. COPD, chronic obstructive pulmonary disease; LTx, lung transplantation (SS, sequential single; S, single; H, heart-); CMV, cytomegalovirus; PGD, primary graft dysfunction; ICU, intensive care unit; FEV1, forced expiratory volume in one second; A ≥ 2, at least moderate acute rejection on histopathology; B ≥ 2, at least moderate lymphocytic bronchiolitis on histopathology; P. aeruginosa, Pseudomonas aeruginosa; HLA, human leucocyte antigen; DSA, donor specific antigen; CNI, calcineurin inhibitor; CsA, cyclosporine A; FK, Tacrolimus (FK506); AZA, azathioprine; MMF, mycophenolate mofetil; NA, not applicable. Download .docx (.21 MB) Help with docx files Figure S1: Kaplan–Meier curve: Freedom from graft loss (retransplantation or death) after CLAD diagnosis in the placebo (n = 43) and azithromycin (n = 40) group. No significant difference in freedom from graft loss between both study arms (p = 0.74). AZI, azithromycin; CLAD, chronic lung allograft dysfunction. Download .docx (.21 MB) Help with docx files Figure S2: (A) Forced vital capacity (FVC) in absolute values (L) comparing the placebo (n = 43) and azithromycin (n = 40) group at best FVC and 1, 2, 3, 5, and 7 years after LTx. Significant difference in FVC between both study arms (p = 0.04). (B) Forced expiratory volume in 1 s (FEV1) in absolute values (L) comparing the placebo (n = 43) and azithromycin (n = 40) group at best FVC and 1, 2, 3, 5, and 7 years after LTx. Nearly significant difference in FEV1 between both study arms (p = 0.051). (C) Six-minute walk test (6MWT) in absolute values (m) comparing the placebo (n = 43) and azithromycin (n = 40) group at discharge and 1, 2, 3, 5, and 7 years after LTx. Significant difference in 6MWT between both study arms (p = 0.0041)." @default.
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• W1749324265 title "Prophylactic Azithromycin Therapy After Lung Transplantation: Post hoc Analysis of a Randomized Controlled Trial" @default.
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