Stijn Verleden

A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation

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 (n = 40) or placebo (n = 43), 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% (p = 0.0017). BOS-free survival was better with azithromycin (hazard ratio 0.27, 95% CI 0.092–0.816; p = 0.020). Overall survival, acute rejection, lymphocytic bronchiolitis, pneumonitis, colonisation and reflux were comparable between groups. Patients receiving azithromycin demonstrated better FEV1 (p = 0.028), and lower airway neutrophilia (p = 0.015) and systemic C-reactive protein levels (p = 0.050) 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.

Survival determinants in lung transplant patients with chronic allograft dysfunction.

Background. Chronic lung allograft dysfunction (CLAD) remains the leading cause of mortality after lung transplantation. Methods. In this retrospective single-center study, we aimed to identify different phenotypes of and risk factors for mortality after CLAD diagnosis using univariate and multivariate Cox proportional hazard survival regression analysis. Results. CLAD was diagnosed in 71 of 294 patients (24.2%) at 30.9±22.8 months after transplantation. Pulmonary function was obstructive in 51 (71.8%) of the CLAD patients, restrictive in 20 (28.2%) patients, of whom 17 had persistent parenchymal infiltrates on pulmonary computer tomography (CAT) scan. In univariate analysis, previous development of neutrophilic reversible allograft dysfunction (NRAD, P=0.012) and a restrictive pulmonary function (P=0.0024) were associated with a worse survival, whereas there was a strong trend for early development of CLAD and persistent parenchymal infiltrates on CAT scan (P=0.067 and 0.056, respectively). In multivariate analysis, early development of CLAD (P=0.0067), previous development of NRAD (P=0.0016), and a restrictive pulmonary function pattern (P=0.0005) or persistent parenchymal infiltrates on CAT scan (P=0.0043) remained significant. Conclusion. Although most CLAD patients develop an obstructive pulmonary function, 28% develop a restrictive pulmonary function, compatible with the recently defined restrictive allograft syndrome phenotype. Early-onset CLAD, previous development of NRAD, and the development of restrictive allograft syndrome are associated with worse survival after CLAD has been diagnosed.

Innate and Adaptive Interleukin-17–producing Lymphocytes in Chronic Inflammatory Lung Disorders

During T-cell receptor activation in a particular cytokine environment, naive CD4+ T cells may differentiate into lineages defined by their pattern of cytokine production and transcription factors: T helper type 1 (Th1), Th2, Th17, and Th22 cells; follicular helper T cells; and inducible regulatory T cells. Th17 cells have been recognized as a distinct lineage of Th cells, and associations between IL-17 and human disease have been known somewhat longer. It would be an oversimplification to restrict IL-17 to Th17 cells. Indeed, IL-17 is also expressed by other cells including IL-17-producing γδ T (γδ T-17) cells, natural killer T-17 cells, and IL-17-producing lymphoid tissue-induced cells. IL-17 was cloned in 1995 as a cytokine expressed by T cells, exerting inflammatory effects on epithelial, endothelial, and fibroblast cells. IL-17 is a solid link between innate and adaptive immunity and can exert both beneficial and deleterious effects. The discovery of IL-17 T cells has provided exciting new insights into host defense, immunoregulation, and autoimmunity. Unquestionably, data from mouse models have contributed enormously to our insight into immunological mechanisms. However, because of numerous differences between murine and human immunology, data obtained in mice are not simply interchangeable. We review IL-17 T cells exclusively in the human situation and more specifically their potential role in respiratory diseases. The advances in our understanding of IL-17 regulation offer opportunities to dissect the human IL-17 system and to reflect on the clinical presentation of lung diseases. More importantly, the IL-17 system allows us to speculate on new therapeutic opportunities. Some results have been previously reported in an abstract.

Long-term azithromycin therapy for bronchiolitis obliterans syndrome: Divide and conquer?

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 = 23/62/20/2), who were treated with azithromycin for 3.1 ± 1.9 years. Patients were evaluated 6.3 ± 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 ≥ 10% 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 = 0.025), in whom it significantly decreased to 4.2% (1.8% to 17.6%) (p = 0.041) after 3 to 6 months of azithromycin. Responders demonstrated better survival compared with non-responders (p = 0.050), with 6 and 21 patients, respectively, dying during follow-up (p = 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] = 0.12 [95% confidence interval 0.05 to 0.28], p < 0.0001; and HR = 0.98 [95% confidence interval 0.97 to 0.98], p < 0.0001, respectively) and retransplantation/death during follow-up (HR 0.10 [95% confidence interval 0.02 to 0.48], p = 0.004; and HR 0.96 [95% confidence interval 0.95 to 0.98], p < 0.0001, respectively). CONCLUSIONS Long-term azithromycin benefits pulmonary function and survival in BOS, particularly in patients with increased lavage neutrophilia.

Obliterative bronchiolitis following lung transplantation: from old to new concepts?

Lung transplantation has come of age and is now considered a valid treatment for selected patients with end‐stage lung disease. In recent years, survival rates have much improved, although the development of chronic rejection, characterized by a progressive and irreversible decline in FEV1, which is clinically defined as bronchiolitis obliterans syndrome (BOS) remains the major obstacle to long‐term survival. Extensive research efforts with special emphasis on innate immunity have recently led to new insights with the identification of at least two different phenotypes: on the one hand there is an azithromycin‐responsive phenotype (the so‐called neutrophilic reversible allograft/airways dysfunction (NRAD), on the other hand there is an azithromycin‐unresponsive phenotype (the fibroproliferative form of BOS or classical obliterative bronchiolitis). The present review intends to give the scientific evidence for these two subtypes, and to clarify the role of azithromycin in the treatment of BOS.

Medium-term outcome after lung transplantation is comparable between brain-dead and cardiac-dead donors

BACKGROUND Donation after cardiac death (DCD) to overcome the donor organ shortage is now moving into the clinical setting, but the medium-term outcome after DCD lung transplantation (LTx) remains largely unknown. METHODS In this retrospective study, DCD LTx recipients (n = 21) were compared with a cohort of donation-after-brain-death (DBD) LTx recipients (n = 154) transplanted between February 2007 and July 2010. Immediate (post)operative outcome was evaluated by assessing need for peri-operative extracorporeal membrane oxygenation (ECMO), time to extubation, hospital discharge and primary graft dysfunction (PGD) within the first 48 hours. Survival, incidence of bronchiolitis obliterans syndrome (BOS), acute rejection (AR) and inflammatory markers in blood and in bronchoalveolar lavage (BAL) were assessed and compared over a median follow-up of 327 days for DCD and 531 days for DBD, showing no statistically significant difference (NS). RESULTS There were no differences between groups with regard to patient characteristics except for a higher number of patients transplanted for obliterative bronchiolitis in the DCD group (4 of 21 vs 7 of 154; p < 0.05). In the DCD group, 2 of 21 patients died, vs 23 of 154 patients in the DBD group (NS). Actuarial survival rates at 6 months, 1 year and 3 years are 95%, 95% and 71% for the DCD group and 96%, 91% and 75% for the DBD group (NS). Three patients (14%) in the DCD group developed BOS vs 15 patients (10%) in the DBD group (NS). Survival and freedom from BOS were not different between the groups. AR, inflammatory markers and immediate (post)operative outcome also did not differ. CONCLUSIONS In our experience, both early- and medium-term outcome in DCD lung recipients is comparable to that of DBD lung recipients. Use of lungs recovered from controlled donors after cardiac death is a safe option for expansion of the donor pool.

Anti-inflammatory and immunomodulatory properties of azithromycin involved in treatment and prevention of chronic lung allograft rejection.

Chronic lung allograft rejection is the single most important cause of death in lung transplant recipients after the first postoperative year, resulting in a 5-year survival rate of approximately 50%, which is far behind that of other solid organ transplantations. Spirometry is routinely used as a clinical marker for assessing pulmonary allograft function and diagnosing chronic lung allograft rejection after lung transplantation (LTx). As such, a progressive obstructive decline in pulmonary allograft function (forced expiratory volume in 1 sec [FEV1]) in absence of all other causes (currently defined as bronchiolitis obliterans syndrome [BOS]) is considered to reflect the evolution of chronic lung allograft rejection. BOS has a 5-year prevalence of approximately 45% and is thought to be the final common endpoint of various alloimmunologic and nonalloimmunologic injuries to the pulmonary allograft, triggering different innate and adaptive immune responses. Most preventive and therapeutic strategies for this complex process have thus far been largely unsuccessful. However, the introduction of the neomacrolide antibiotic azithromycin (AZI) in the field of LTx as of 2003 made it clear that some patients with established BOS might in fact benefit from such therapy due to its various antiinflammatory and immunomodulatory properties, as summarized in this review. Particularly in patients with an increased bronchoalveolar lavage neutrophilia (i.e., 15%–20% or more), AZI treatment could result in an increase in FEV1 of at least 10%. More recently, it has become clear that prophylactic therapy with AZI actually may prevent BOS and improve FEV1 after LTx, most likely through its interactions with the innate immune system. However, one should always be aware of possible adverse effects related to AZI when implementing this drug as prophylactic or long-term treatment. Even so, AZI therapy after LTx can generally be considered as safe.

Bronchiolitis obliterans syndrome and restrictive allograft syndrome: do risk factors differ?

Background Chronic rejection is the major problem hampering long-term survival after lung transplantation. Recently, it became clear that patients may develop an obstructive (bronchiolitis obliterans syndrome [BOS]) or a restrictive lung function defect (restrictive allograft syndrome [RAS]), for which specific risk factors are unknown. Methods A retrospective analysis of our lung transplantation cohort was performed (n=380). Patients with an irreversible decline in forced expiratory volume in 1 second were identified and classified as BOS or RAS. Patient characteristics, bronchoalveolar lavage (BAL) cellularity, rates of respiratory tract infection, colonization, acute rejection, and lymphocytic bronchiolitis were compared between BOS, RAS, and stable patients. Results There were 103 patients suffering from chronic rejection, of which 79 had BOS and 24 were diagnosed with RAS. There were more patients with infection and pseudomonal colonizations in BOS and RAS compared with control (P=0.0090 and P=0.0034, respectively). More patients ever experienced acute and severe acute rejections (A≥2; both P<0.0001) and lymphocytic bronchiolitis (P=0.0006) in BOS and RAS versus control. There were more patients experiencing severe lymphocytic bronchiolitis in RAS compared with BOS (P=0.031). BAL neutrophilia in BOS and RAS were elevated at days 360, 540, and 720 versus control. BOS, but especially RAS patients, experienced more frequent episodes of increased BAL eosinophilia (≥2%; P<0.0001). Conclusion Acute rejection, lymphocytic bronchiolitis, colonization with pseudomonas, infection, and BAL eosinophilia and neutrophilia are risk factors for the later development not only of RAS but also of BOS.

Functional and computed tomographic evolution and survival of restrictive allograft syndrome after lung transplantation.

BACKGROUND Restrictive allograft syndrome (RAS) has recently been defined as a novel phenotype of chronic lung allograft dysfunction (CLAD) after lung transplantation. The goal was to describe computed tomographic (CT) changes of RAS patients and to correlate this with spirometry and survival. METHODS All 24 established RAS patients at our center were retrospectively included. CT scans from pre-CLAD, CLAD, post-CLAD and late-CLAD subjects were systematically evaluated by a blinded observer using a semi-quantitative scoring system. Changes in CT patterns were correlated with spirometry and survival. RESULTS The most prominent CT features at diagnosis of CLAD as compared with pre-CLAD were appearance of central (p = 0.020) and peripheral ground glass opacities (p = 0.052), as well as septal and non-septal lines (p = 0.020). Survival after diagnosis of CLAD was only associated with the absolute value of forced vital capacity (FVC) at diagnosis (R = 0.46 and p = 0.021), and not with any CT alterations. Evolution of CT abnormalities after diagnosis of CLAD included significant increases in (traction) bronchiectasis (p < 0.0001), central (p = 0.051) and peripheral (p = 0.0002) consolidation, architectural deformation (p = 0.0002), volume loss (p = 0.0004) and hilus retraction (p = 0.0036). The absolute FVC decrease post-CLAD diagnosis correlated with CT alterations. CONCLUSIONS In the early stages of RAS, central and peripheral ground glass opacities are the most prominent feature on CT, whereas, in later stages, bronchiectasis, traction, central and peripheral consolidation, architectural deformation, volume loss and hilus retraction are more pronounced. CT changes, however, could not predict survival, whereas FVC at diagnosis of CLAD seems to be the best predictor of survival.

Age-related differences in metabolites in the posterior cingulate cortex and hippocampus of normal ageing brain: A 1H-MRS study

OBJECTIVE To study age-related metabolic changes in N-acetylaspartate (NAA), total creatine (tCr), choline (Cho) and myo-inositol (Ins). MATERIALS AND METHODS Proton magnetic resonance spectroscopy (1H-MRS) was performed in the posterior cingulate cortex (PCC) and the left hippocampus (HC) of 90 healthy subjects (42 women and 48 men aged 18-76 years, mean±SD, 48.4±16.8 years). Both metabolite ratios and absolute metabolite concentrations were evaluated. Analysis of covariance (ANCOVA) and linear regression were used for statistical analysis. RESULTS Metabolite ratios Ins/tCr and Ins/H2O were found significantly increased with age in the PCC (P<0.05 and P≤0.001, respectively), and in the HC (P<0.01 for both). An increased tCr/H2O was only observed in the PCC (P<0.01). Following absolute quantification based on the internal water signal, significantly increased concentrations of Ins and tCr in the PCC confirmed the relative findings (P<0.01 for both). CONCLUSION Age-related increases of tCr and Ins are found in the PCC, whereas this holds only true for Ins in the HC, indicating possible gliosis in the ageing brain. No age-dependent NAA decreases were observed in the PCC nor the HC. The 1H-MRS results in these specific brain regions can be important to differentiate normal ageing from age-related pathologies such as mild cognitive impairment (MCI) and Alzheimers disease.