David Ruttens

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.

Restrictive chronic lung allograft dysfunction: Where are we now?

Chronic lung allograft dysfunction (CLAD) remains a frequent and troublesome complication after lung transplantation. Apart from bronchiolitis obliterans syndrome (BOS), a restrictive phenotype of CLAD (rCLAD) has recently been recognized, which occurs in approximately 30% of CLAD patients. The main characteristics of rCLAD include a restrictive pulmonary function pattern with a persistent decline in lung function (FEV1, FVC and TLC), persistent parenchymal infiltrates and (sub)pleural thickening on chest CT scan, as well as pleuroparenchymal fibroelastosis and obliterative bronchiolitis on histopathologic examination. Once diagnosed, median survival is only 6 to 18 months compared with 3 to 5 years with BOS. In this perspective we review the historic evidence for rCLAD and describe the different diagnostic criteria and prognosis. Furthermore, we elaborate on the typical radiologic and histopathologic presentations of rCLAD and highlight risk factors and mechanisms. Last, we summarize some opportunities for further research including the urgent need for adequate therapy. In this perspective we not only assess the current knowledge, but also clarify the existing gaps in understanding this increasingly recognized complication after lung transplantation.

The site and nature of airway obstruction after lung transplantation.

RATIONALE The chronic rejection of lung allografts is attributable to progressive small airway obstruction. OBJECTIVES To determine precisely the site and nature of this type of airway obstruction. METHODS Lungs from patients with rejected lung allografts treated by a second transplant (n = 7) were compared with unused donor (control) lungs (n = 7) using multidetector computed tomography (MDCT) to determine the percentage of visible airways obstructed in each airway generation, micro-computed tomography (microCT) to visualize the site of obstruction, and histology to determine the nature of this obstruction. MEASUREMENTS AND MAIN RESULTS The number of airways visible with MDCT was not different between rejected and control lungs. However, 10 ± 7% of observed airways greater than 2 mm in diameter, 50 ± 22% of airways between 1 and 2 mm in diameter, and 73 ± 10% of airways less than 1 mm in diameter were obstructed in the rejected lungs. MicroCT confirmed that the mean lumen diameter of obstructed airways was 647 ± 317 μm but showed no difference in either total number and cross-sectional area of the terminal bronchioles or in alveolar dimensions (mean linear intercept) between groups (P > 0.05). In addition, microCT demonstrated that only segments of the airways are obstructed. Histology confirmed a constrictive form of bronchiolitis caused by expansion of microvascular-rich granulation tissue in some locations and collagen-rich scar tissue in others. CONCLUSIONS Chronic lung allograft rejection is associated with a progressive form of constrictive bronchiolitis that targets conducting airways while sparing larger airways as well as terminal bronchioles and the alveolar surface.

Neutrophilic Reversible Allograft Dysfunction (NRAD) and Restrictive Allograft Syndrome (RAS)

Lung transplantation is currently considered as an ultimate live-saving treatment for selected patients suffering from end-stage pulmonary disease. Long-term survival, however, is hampered by chronic rejection, or chronic lung allograft dysfunction (CLAD). Recently, various phenotypes within CLAD have been identified, challenging the established clinical definition of bronchiolitis obliterans syndrome (BOS). Some patients with presumed BOS, for instance, demonstrate an important improvement in forced expiratory volume in the first second of expiration (FEV1) after treatment with azithromycin. These patients are characterized by the presence of excess (≥ 15%) bronchoalveolar lavage (BAL) neutrophils, in absence of concurrent infection. This phenotype of CLAD has been redefined as neutrophilic reversible allograft dysfunction (NRAD), and these patients generally have a very good prognosis after diagnosis. Another group of patients with CLAD develop a restrictive rather than an obstructive pulmonary function defect (defined as a decline in total lung capacity of at least 10%) and demonstrate persistent interstitial and ground-glass opacities on chest computed tomographic (CT) scan. This phenotype is called restrictive allograft syndrome (RAS), and patients with RAS have a much worse prognosis after diagnosis. This review further discusses both of these CLAD phenotypes that do not fit the classical definition of BOS. Potential pathophysiological mechanisms, etiology, diagnosis, prognosis, and treatments are discussed.

A decade of extended-criteria lung donors in a single center: was it justified?

Despite a worldwide need to expand the lung donor pool, approximately 75% of lung offers are not accepted for transplantation. We investigated the impact of liberalizing lung donor acceptance criteria during the last decade on the number of effective transplants and early and late outcomes in our center. All 514 consecutive lung transplants (LTx) performed between Jan 2000 and Oct 2011 were included. Donors were classified as matching standard criteria (SCD; n = 159) or extended criteria (ECD; n = 272) in case they fulfilled at least one of the following criteria: age >55 years, PaO2/FiO2 at PEEP 5 cmH2O < 300 mmHg at time of offer, presence of abnormalities on chest X‐ray, smoking history, presence of aspiration, presence of chest trauma, or donation after circulatory death. Outcome parameters were primary graft dysfunction (PGD) grade at 0, 12, 24, and 48 h after LTx, time to extubation, stay in intensive care unit (ICU), early and late infection, acute rejection and bronchiolitis obliterans syndrome (BOS), and survival. Two hundred and seventy‐two recipients (63.1%) received ECD lungs. PGD grade at T0 was similar between groups, while at T12 (<0.01), T24 (<0.01), and T48 (<0.05), PGD3 was observed more often in ECDs. ICU stay (P < 0.05) was longer in ECDs compared with SCDs. Time to extubation, respiratory infections, acute rejection, lymphocytic bronchiolitis, BOS, and survival were not different between groups. Accepting ECDs contributed in increasing the number of lung transplants performed in our center. Although this lung donor strategy has an impact on early postoperative outcome, liberalizing criteria did not influence long‐term outcome after LTx.

Differential cytokine, chemokine and growth factor expression in phenotypes of chronic lung allograft dysfunction.

Background Chronic lung allograft dysfunction is a heterogeneous entity limiting long-term survival after lung transplantation. Different clinical phenotypes (bronchiolitis obliterans syndrome [BOS]-neutrophilic BOS-restrictive allograft syndrome [RAS]) have been identified but the mechanisms remain elusive. Methods In this study, we measured 34 different cytokines, chemokines, and growth factors in bronchoalveolar lavage fluid of 20 stable patients, 20 patients suffering from non-neutrophilic BOS, 17 from neutrophilic BOS, and 20 from RAS using classic enzyme-linked immunosorbent assay and multiplex technology. Results Total cell count and % neutrophils were elevated in neutrophilic BOS and RAS compared to stable and non-neutrophilic BOS patients, whereas also the % eosinophils was elevated at diagnosis of RAS. Levels of interleukin (IL)-1&bgr; (P<0.01), IL-1R&agr; (P<0.001), IL-6 (P<0.001), IL-8/CXCL8 (P<0.001), IP-10/CXCL10 (P<0.05), MCP-1/CCL2 (P<0.05), macrophage inflammatory protein (MIP)-1&agr;/CCL3 (P<0.001), MIP-1&bgr;/CCL4, and vascular endothelial growth factor (VEGF; P<0.05) were differentially regulated in RAS compared to stable, whereas in neutrophilic BOS IL-1&bgr; (P<0.001), IL-1R&agr; (P<0.01), IL-7 (P<0.05), IL-8/CXCL8 (P<0.001), MCP-3/CXCCL7 (P<0.05) and MIP-1&agr;/CCL-3 (P<0.05) were significantly upregulated compared to stable patients. We could not detect any differences between non-neutrophilic BOS and stable patients. Interestingly, bronchoalveolar lavage IL-6, interferon gamma-induced protein (IP)-10/CXCL10 and interferon-inducible T-cell alpha chemoattractant/chemokine (C-X-C motif) ligand 11 (ITAC/CXCL10) were associated with survival after diagnosis in RAS patients. Conclusion There were major differences in cytokine and chemokine expression in our different study groups. Especially IL-6, but also IP-10/CXCL10, and VEGF may be interesting mediators in RAS.

Elevated bronchoalveolar lavage eosinophilia correlates with poor outcome after lung transplantation.

Background Eosinophils are involved in the pathophysiology of many respiratory diseases, but the exact role of eosinophilia in lung transplantation has not been thoroughly investigated. Methods We performed a retrospective analysis of our transplanted patients between 2001 and 2011, with a minimum follow-up of 1 year. Using a cutoff of ≥2% eosinophilia in bronchoalveolar lavage (BAL) fluid, chronic lung allograft dysfunction (CLAD)–free survival and overall survival was compared between 66 patients demonstrating at least one BAL with eosinophils ≥2% and 253 control patients (never BAL ≥2%). Results Patients with increased BAL eosinophilia demonstrated worse CLAD-free and overall survival (both P<0.0001) compared with controls. Eosinophilic BAL predisposed to development of bronchiolitis obliterans syndrome but particularly to restrictive allograft syndrome (P<0.0001). After correction for covariates, the association between eosinophilic BAL and CLAD but equally death remained significant (P=0.0047 and 0.0011). Blood eosinophil and C-reactive protein levels were also elevated at the time of eosinophilic BAL. Conclusion BAL eosinophilia ≥2% is associated with poor outcome in our lung transplant patients as demonstrated by worse CLAD-free and overall survival. Interestingly, increased BAL eosinophilia may be specifically associated with the development of restrictive allograft syndrome, which needs further prospective investigation.

Pregnancy after heart and lung transplantation

Patients awaiting transplantation should be counseled regarding posttransplant contraception and the potential adverse outcomes associated with posttransplant conception. Pregnancy should be avoided for at least 1-2 years post transplant to minimize the risks to allograft function and fetal well-being. Transplant patients, particularly lung transplant recipients, have an increased risk of maternal and neonatal pregnancy-related complications, including prematurity and low birth weight, postpartum graft loss, and long-term morbidity and mortality compared to other solid-organ recipients. Therefore, careful monitoring by a specialized transplant team is crucial. Maintenance of immunosuppression is recommended, except for mycophenolate and mammalian target of rapamycin inhibitors (mTORi), which should be replaced before conception. Immunosuppressants must be regularly monitored and dosing adjusted to avoid graft rejection. Monitoring during labor is mandatory and epidural anesthesia recommended. Vaginal delivery should be standard and cesarean delivery only performed for obstetric reasons. Breastfeeding poses risks of neonatal exposure to immunosuppressants and is generally contraindicated.