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Purpose of Review: Chronic lung allograft dysfunction (CLAD) remains a life-threatening complication following lung transplantation. Different CLAD phenotypes have recently been defined, based on the combination of pulmonary function testing and chest computed tomography (CT) scanning and spurred renewed interests in differential diagnosis, risk factors and management of CLAD., Recent Findings: Given their crucial importance in the differential diagnosis, we will discuss the latest development in assessing the pulmonary function and chest CT scan, but also their limitations in proper CLAD phenotyping, especially with regards to patients with baseline allograft dysfunction. Since no definitive treatment exists, it remains important to timely identify clinical risk factors, but also to assess the presence of specific patterns or biomarkers in tissue or in broncho alveolar lavage in relation to CLAD (phenotypes). We will provide a comprehensive overview of the latest advances in risk factors and biomarker research in CLAD. Lastly, we will also review novel preventive and curative treatment strategies for CLAD., Summary: Although this knowledge has significantly advanced the field of lung transplantation, more research is warranted because CLAD remains a life-threatening complication for all lung transplant recipients., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Bronchiolitis obliterans syndrome (BOS) after lung transplantation is characterized by fibrotic small airway remodeling, recognizable on high-resolution computed tomography (HRCT). We studied the prognostic value of key HRCT features at BOS diagnosis after lung transplantation., Methods: The presence and severity of bronchiectasis, mucous plugging, peribronchial thickening, parenchymal anomalies, and air trapping, summarized in a total severity score, were assessed using a simplified Brody II scoring system on HRCT at BOS diagnosis, in a cohort of 106 bilateral lung transplant recipients transplanted between January 2004 and January 2016. Obtained scores were subsequently evaluated regarding post-BOS graft survival, spirometric parameters, and preceding airway infections., Results: A high total Brody II severity score at BOS diagnosis (P = 0.046) and high subscores for mucous plugging (P = 0.0018), peribronchial thickening (P = 0.0004), or parenchymal involvement (P = 0.0121) are related to worse graft survival. A high total Brody II score was associated with a shorter time to BOS onset (P = 0.0058), lower forced expiratory volume in 1 s (P = 0.0006) forced vital capacity (0.0418), more preceding airway infections (P = 0.004), specifically with Pseudomonas aeruginosa (P = 0.002), and increased airway inflammation (P = 0.032)., Conclusions: HRCT findings at BOS diagnosis after lung transplantation provide additional information regarding its underlying pathophysiology and for future prognosis of graft survival., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To describe our experience with lung transplantation (LTx) from donors ≥70 years and compare short and long-term outcomes to a propensity-matched cohort of donors <70 years., Background: Although extended-criteria donors have been widely used to enlarge the donor pool, the experience with LTx from older donors (≥70 years) remains limited., Methods: All single-center bilateral LTx between 2010 and 2020 were retrospectively analyzed. Matching (1:1) was performed for the donor (type, sex, smoking history, x-ray abnormalities, partial pressure of oxygen/fraction of inspired oxygen ratio, and time on ventilator) and recipient characteristics (age, sex, LTx indication, perioperative extracorporeal life support, and cytomegalovirus mismatch). Primary graft dysfunction grade-3, 5-year patient, and chronic lung allograft dysfunction-free survival were analyzed., Results: Out of 647 bilateral LTx, 69 were performed from donors ≥70 years. The mean age in the older donor cohort was 74 years (range: 70-84 years) versus 49 years (range: 12-69 years) in the matched younger group. No significant differences were observed in the length of ventilatory support, intensive care unit, or hospital stay. Primary graft dysfunction-3 was 26% in the older group versus 29% in younger donor recipients ( P = 0.85). Reintervention rate was comparable (29% vs 16%; P = 0.10). Follow-up bronchoscopy revealed no difference in bronchial anastomotic complications ( P = 1.00). Five-year patient and chronic lung allograft dysfunction-free survivals were 73.6% versus 73.1% ( P = 0.72) and 51.5% versus 59.2% ( P = 0.41), respectively., Conclusions: LTx from selected donors ≥70 years is feasible and safe, yielding comparable short and long-term outcomes in a propensity-matched analysis with younger donors (<70 years)., Competing Interests: R.V. is supported as a senior clinical research fellow by the Research Foundation Flanders (FWO) Belgium. G.M.V. and D.V.R. are supported by the Broere Charitable Foundation. L.J.C. is supported by a KU Leuven University Chair funded by Medtronic, a post-doctoral grant from the University Hospitals Leuven (KOOR—UZ Leuven) and a research project from the Research Foundation Flanders (FWO) Belgium (G090922N). The remaining authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose of Review: New chronic lung allograft dysfunction (CLAD) consensus documents were published in 2019, defining four phenotypes; bronchiolitis obliterans syndrome, restrictive allograft syndrome, mixed and undefined. Clearly, validation of these guidelines in a real life cohort is critical., Recent Findings: Indeed, validation has been performed recently, both after bilateral lung transplantation (LTx) and after single LTx illustrating that precise phenotyping based on pulmonary function alone can be difficult. Undertaking regular chest computed tomography scanning does appear very helpful in establishing the prognosis of the patients with CLAD., Summary: Pulmonary function changes may not always identify the exact phenotype of CLAD and we provide further evidence for the important role of chest imaging at diagnosis and during the follow-up of patients with CLAD., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Chronic lung allograft dysfunction (CLAD) remains a major barrier preventing long-term survival following lung transplantation. As our clinical knowledge regarding its definition and presentation has significantly improved over the last years, adequate biomarkers to predict development of CLAD, phenotype of CLAD or prognosis post-CLAD diagnosis are definitely needed., Recent Findings: Radiological and physiological markers are gradually entering routine clinical practice. In-depth investigation of biological samples including broncho-alveolar lavage, biopsy and serum has generated potential biomarkers involved in fibrogenesis, airway injury and inflammation but none of these are universally accepted or implemented although progress has been made, specifically regarding donor-derived cell-free DNA and donor-specific antibodies., Summary: Although a lot of promising biomarkers have been put forward, a very limited number has made it to routine clinical practice. Nevertheless, a biomarker that leads to earlier detection or more adequate disease phenotyping would advance the field enormously., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Lung transplantation is an important treatment option for various end-stage lung diseases. However, survival remains limited due to graft rejection and infections. Despite that fungal infections are frequent and carry a bad prognosis, there is currently no consensus on efficacy, optimal drug, route, or duration of antifungal prophylaxis. This narrative review summarizes current strategies for antifungal prophylaxis after lung transplantation., Methods: English language articles in Embase, Pubmed, UptoDate, and bibliographies were used to assess the efficacy and safety of available antifungal agents for prophylaxis in adult lung transplant recipients., Results: Overall, there are limited high-quality data. Universal prophylaxis is more widely used and may be preferable over targeted prophylaxis. Both formulations of inhaled amphotericin B and systemic azoles are effective at reducing fungal infection rates, yet with their own specific advantages and disadvantages. The benefit of combination regimens has yet to be proven. Considering the post-transplant timing of the onset of fungal infections, postoperative prophylaxis during the first postoperative months seems indicated for most patients., Conclusions: Based on existing literature, universal antifungal prophylaxis with inhaled amphotericin B and systemic voriconazole for at least 3-6 mo after lung transplantation may be advisable, with a slight preference for amphotericin B because of its better safety profile., Competing Interests: The following authors are supported by a research fellowship: R.V. is a senior clinical research fellow of the Fund for Scientific Research Flanders (FWO). G.M.V. is supported by the Broere Charitable Foundation. The other authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: To investigate the diagnostic yield of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in lung transplant recipients., Methods: A single-center, retrospective cohort study including 234 18F-FDG PET examinations in 199 lung transplant recipients. Indication for PET referral, 18F-FDG PET diagnosis/findings and final clinical diagnosis were classified into 3 groups: malignancy, infection/inflammation not otherwise specified, and chronic lung allograft dysfunction with restrictive allograft syndrome phenotype. Sensitivity/specificity analysis was performed to determine accuracy of 18F-FDG PET in each group., Results: Sensitivity of 18F-FDG PET for malignancy was 91.4% (95% confidence interval, 82.5%-96.0%) and specificity was 82.3% (95% confidence interval, 74.5%-88.1%). Infection/inflammation not otherwise specified and restrictive allograft syndrome as indication for 18F-FDG PET comprised relatively small groups (14 and 31 cases, respectively). In addition, 18F-FDG PET revealed clinically relevant incidental findings in 15% of cases., Conclusions: Referral for 18F-FDG PET after lung transplantation mainly occurred to confirm or rule out malignancy. In this specific setting, 18F-FDG PET has a high diagnostic yield. Accuracy of 18F-FDG PET for other indications is less clear, given small sample sizes. Clinically relevant diagnoses, unrelated to the primary indication for 18F-FDG PET, are found relatively often in this immunocompromised cohort., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Lung transplantation (LTx) is increasingly used as ultimate treatment modality in end-stage interstitial lung diseases (ILDs). This review aims to give an overview of the latest evolutions in this field., Recent Findings: In the last two years, important new findings regarding LTx outcomes in specific ILD entities have been reported. More data are available on optimization of pre-LTx management of ILD patients especially with regard to pretransplant antifibrotic treatment., Summary: LTx is the only treatment option with curative intent for ILDs and is increasingly used for this indication. Several studies have now reported adequate outcomes in different ILD entities, although outcome is shown to be affected by underlying telomeropathies. As new studies could not replicate inferior survival with single compared with double LTx, both options remain acceptable. ILD specialists can beneficially impact on post-LTx outcome by optimizing pre-LTx management: corticosteroids should be avoided, antifibrotics should be initiated whenever possible and BMI and nutritional status optimized, rehabilitation and depression-screening strategies should be implemented in all LTx candidates, as these interventions may all improve postlung transplant survival.

Purpose of Review: In this article, an overview of the survival after lung transplantation will be given, with a focus on factors affecting outcome and differences in survival determined by underlying disease., Recent Findings: Lung transplantation is an established treatment modality for patients with various end-stage lung diseases. The most recent International Society for Heart and Lung Transplantation Registry reports a 1 and 5-year survival of 85 and 59%, respectively, for adult lung transplant recipients transplanted since 2010. Over the past decades, significant improvements in patient outcomes have been achieved related to changes in donor selection, organ preservation, perioperative management and better treatment of postoperative complications. However, long-term graft and patient outcomes still lag behind that of other solid organ transplantations. Chronic lung allograft dysfunction (CLAD) a condition which develops in about 50% of recipients 5 year after lung transplantation, remains the major barrier for long-term survival, although development of solid organ cancer is nowadays also an increasing cause of late mortality., Summary: Lung transplantation offers a survival benefit in well chosen patients with end-stage lung diseases. However, CLAD, side effects of immunosuppressive therapy and solid organ cancer remain important challenges impairing long-term survival. Advances in prevention and treatment of chronic rejection are critical to further improve outcome.

Purpose of Review: Chronic lung allograft dysfunction (CLAD) has been recently introduced as an umbrella-term encompassing all forms of chronic pulmonary function decline posttransplant with bronchiolitis obliterans syndrome and restrictive allograft syndrome as the most important subtypes. Differential diagnosis and management, however, remains complicated., Recent Findings: Herein, we provide an overview of the different diagnostic criteria (pulmonary function, body plethysmography and radiology) used to differentiate bronchiolitis obliterans syndrome and restrictive allograft syndrome, their advantages and disadvantages as well as potential problems in making an accurate differential diagnosis. Furthermore, we discuss recent insights in CLAD management and treatment and advances in the search for accurate biomarkers of CLAD., Summary: Careful dissection of CLAD phenotypes is of utmost importance to assess patient prognosis, but uniform diagnostic criteria are desperately needed. There is a long way ahead, but the first steps towards this goal are now taken; tailored individualized therapy will be the golden standard to treat CLAD in the future, but randomized placebo-controlled and multicentre trials are needed to identify new and powerful therapeutic agents.

Background: Differential diagnosis of phenotypes of chronic lung allograft dysfunction (CLAD) remains troublesome. We hypothesized that F-fluorodeoxyglucose positron emission tomography with computed tomography (F-FDG PET/CT) may help in differential diagnosis of CLAD phenotypes, as it showed promising results regarding diagnosis and prognosis in interstitial lung diseases., Methods: A monocentric, retrospective study was performed including all lung transplant recipients suffering from bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS) who underwent F-FDG PET/CT scan, in comparison with stable lung transplant recipients. Maximum standardized uptake value (SUVmax) was associated with pulmonary function and survival. Proof-of-concept microCT and glucose transporter-1 staining served as morphologic validation for regions with different SUVmax., Results: Maximum standardized uptake value was higher in RAS (median, 2.6; n = 29) compared with BOS (median, 1.0; n = 15) and stable patients (median, 0.59; n = 8) (P < 0.0001). In RAS, high SUVmax was associated with worse survival after F-FDG PET/CT (P = 0.0004; hazard ratio, 1.82). Forced vital capacity at F-FDG PET/CT inversely correlated with SUVmax (R = -0.40, P = 0.03). MicroCT analysis revealed extensive fibrosis in regions of high SUVmax, with an increased number of glucose transporter-1-positive cells., Conclusions: F-fluorodeoxyglucose positron emission tomography with CT may noninvasively differentiate RAS from BOS. RAS patients with areas of increased lung metabolism have worse outcome, demonstrating the potential use of F-FDG PET/CT during follow-up after lung transplantation.

Background: Solid organ transplantation is a valid treatment option for selected patients with organ failure due to an underlying telomeropathy; however, the feasibility of multiple-organ transplantation if several organs are compromised is unclear., Methods: We describe 2 patients with telomeropathy due to heterozygous telomerase RNA component or telomerase reverse transcriptase mutation, who successfully underwent serial or combined liver and lung transplantation for concurrent liver fibrosis/cirrhosis and pulmonary fibrosis., Results: Despite a challenging posttransplant course, long-term outcomes were favorable, with both patients doing fine now, respectively, 12/20 and 24 months after multiple-organ transplantation., Conclusions: To our knowledge, this is the first report of multiple solid organ transplantation in documented telomeropathy. These cases highlight current difficulties of timely diagnosis, therapeutic approach, and postoperative complications in telomeropathy patients in whom several organs are affected.

Background: Insults to the airway epithelium play a key role in constrictive bronchiolitis after lung transplantation, the typical hallmark of chronic rejection. Our hypothesis is that immunosuppressives might affect airway integrity., Methods: A biculture of human bronchial epithelial cells and lung microvascular endothelial cells was exposed to immunosuppressives (serum through levels) for 24 hours or 4 days. Cytotoxicity, transepithelial electrical resistance (TEER), and permeability was measured after exposure to monotherapies and combination therapies. Apoptosis, oxidative stress, inflammation (IL-8), real-time polymerase chain reaction for epithelial-to-mesenchymal transition and tight junction proteins were assessed in exposed cells., Results: Mycophenolate mofetil (MMF) and combination therapies including MMF, at serum trough levels and higher, are toxic for the human bronchial epithelial cells after 4-day exposure. Moreover, already after 24 hours, TEER of cells exposed to MMF decreases and permeability increases. MMF did not induce apoptosis, oxidative stress, loss of tight junctions or production of IL-8 after 24 hours, but possibly induces epithelial-to-mesenchymal transition in epithelial cells. MMF was detectable at both sides of the biculture and was also present in bronchoalveolar lavage of lung transplantation patients. Other immunosuppressives were not toxic, neither changed TEER or permeability., Conclusions: Our findings suggest that MMF is present in the airways of lung transplant patients and might affect the structural integrity of the airway, which needs further investigation and validation in the clinical setting.

Background: Donation after cardiac death (DCD) to overcome the donor organ shortage is well accepted in the clinical setting, although long-term outcome after DCD lung transplantation (LTx) remains largely unknown., Methods: In this retrospective study, DCD LTx recipients (n = 59) were compared with a cohort of donation after brain death (DBD) LTx recipients (n = 331) transplanted between February 2007 and September 2013; follow-up was until January 1, 2016. Short-term (duration of mechanical ventilation, intensive care unit stay, hospital stay, and highest primary graft dysfunction score within 72 hours) and long-term (chronic lung allograft dysfunction-free and overall survival) follow-up were compared over a median follow-up of 50.5 (±3.7) months for DCD and 66.8 (±1.5) months for DBD., Results: There were no differences between groups with regard to patient characteristics: age (P = 0.78), underlying disease (P = 0.30) and type of type of LTx (P = 0.10), except sex where more males were transplanted with a DCD donor (62.7%) vs (48.3%, P = 0.048). There was no difference in time on mechanical ventilation (P = 0.59), intensive care unit stay (P = 0.74), highest primary graft dysfunction score (P = 0.67) and hospital stay (P = 0.99). Moreover, chronic lung allograft dysfunction-free (P = 0.86) and overall survival (P = 0.15) did not differ between the DBD and DCD groups., Conclusions: In our experience, both short- and long-term outcomes in DCD lung recipients are comparable to that of DBD lung recipients. Therefore, DCD LTx can be considered a safe strategy that significantly increased our transplant activity.

Purpose of Review: Chronic lung allograft dysfunction (CLAD) was recently introduced as an overarching term covering different phenotypes of chronic allograft dysfunction, including obstructive CLAD (bronchiolitis obliterans syndrome), restrictive CLAD (restrictive allograft syndrome) and graft dysfunction due to causes not related to chronic rejection. In the present review, we will highlight the latest insights and current controversies regarding the new CLAD terminology, underlying pathophysiologic mechanisms, diagnostic approach and possible treatment options., Recent Findings: Different pathophysiological mechanisms are clearly involved in clinically distinct phenotypes of chronic rejection, as is reflected by differences in histology, allograft function and imaging. Therefore, not all CLAD patients may equally benefit from specific therapies., Summary: The recent introduction of CLAD importantly changed the clinical practice in lung transplant recipients. Given the relative low accuracy of the current diagnostic tools, future research should focus on specific biomarkers, more sensitive pulmonary function parameters and imaging techniques for timely CLAD diagnosis and phenotyping. Personalized or targeted therapeutic options for adequate prevention and treatment of CLAD are required.

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)-1β (P<0.01), IL-1Rα (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)-1α/CCL3 (P<0.001), MIP-1β/CCL4, and vascular endothelial growth factor (VEGF; P<0.05) were differentially regulated in RAS compared to stable, whereas in neutrophilic BOS IL-1β (P<0.001), IL-1Rα (P<0.01), IL-7 (P<0.05), IL-8/CXCL8 (P<0.001), MCP-3/CXCCL7 (P<0.05) and MIP-1α/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.

Background: Caveolin-1 (CAV-1), a structural protein of the cell membrane, is involved in tissue homeostasis, inflammation, oxidative stress, microbial clearance, and fibrosis., Methods: We investigated a genetic predisposition of the CAV-1 gene on survival, acute and chronic rejection, lymphocytic bronchiolitis (LB), and respiratory infection after lung transplantation (LTx)., Results: In 503 of 568 patients, the CAV-1 (rs3807989) polymorphism was successfully determined; 92 had the AA, 234 the AG, and 177 the GG genotype. Patients with the GG genotype had a decreased mortality with a adjusted hazard ratio of 0.72 (CI=0.53-0.98; P=0.034), but no association was found with chronic rejection, LB, acute rejection, or respiratory infections, although significantly less patients with the GG genotype died of infections (P=0.029). Airway neutrophilia (P=0.047) and systemic C-reactive protein (CRP, P=0.034) were decreased over time in the GG carriers compared to carriers of the A allele., Conclusion: We conclude that the GG genotype of CAV-1 is protective, associated with a decreased overall mortality but not with acute or chronic rejection, LB, and respiratory infections after LTx. The decreased mortality was linked with less infections of any kind and also lower systemic CRP, and airway neutrophils were observed, suggesting an overall decreased susceptibility for infectious complications in carriers of the GG genotype.

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.

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.

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.

Background: Vitamin D deficiency has been reported in different chronic pulmonary diseases like asthma and chronic obstructive pulmonary disease, but little is known in lung transplant recipients., Methods: Serum 25-hydroxyvitamin D (25-OHD) levels and pulmonary function (forced expiratory volume in 1 sec [FEV(1)] %predicted) were measured in 131 lung transplant patients during their yearly posttransplant check-up hospital stay, and the total number of infections and perivascular/peribronchiolar rejections were assessed from transplantation on., Results: Vitamin D deficiency (<30 ng/mL) occurred in 62 of 131 patients (47.3%), of whom 26 (19.8%) were severely deficient (<20 ng/mL). The FEV(1) was significantly lower in the deficient group compared with the group with normal levels (P=0.019). Moreover, we could find an association between FEV(1) and 25-OHD levels in univariate analysis (P=0.018), which remained significant in multivariate analysis (P=0.012). The same holds true for the association between 25-OHD levels and the peak postoperative FEV(1) (P=0.021 in multivariate analysis). We also identified significantly more patients with moderate to severe B-grade rejections in the deficient group (P=0.0038)., Conclusion: Vitamin D deficiency is present in 47% of our lung transplant patients and seems independently associated with a lower FEV(1) and more severe B-grade rejections. This study raises the potential need for additional vitamin D treatment in lung transplantation and clearly indicates the role of a randomized placebo-controlled trial with vitamin D supplementation, which is ongoing in our center.

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.

Purpose of Review: During a classical lung transplantation procedure, there is no attempt to restore the bronchial circulation, giving rise to ischemia of the mucosa with initial loss of ciliated function. This might compromise the ciliary function and the infection defense mechanisms of the airways., Recent Findings: Although initially the airways are characterized by ischemia (epithelial sloughing), later on, there seems to be a restoration of the ciliary function and up to now, there is no clear evidence that there is an increased risk of infectious episodes due to the lack of bronchial circulation, although this has not extensively been investigated., Summary: Local pulmonary defense mechanisms after lung transplantation without bronchial revascularization seem to be preserved at least in a stable condition. Whether the loss of bronchial circulation has a negative impact when complications develop (such as bronchiolitis obliterans syndrome) remains speculative.

Background: Neutrophilic airway inflammation and associated oxidative stress contribute to airway injury and the development of bronchiolitis obliterans syndrome after lung transplantation (LTx). Exhaled carbon monoxide (eCO) reflects heme oxygenase-1 activity in response to oxidative stress. We investigated whether airway neutrophilia and eCO levels are associated in stable LTx recipients., Methods: In this cross-sectional pilot study, 45 stable LTx recipients were included. During routine follow-up at the outpatient clinic, pulmonary function testings together with eCO measurements before broncho-alveolar lavage (BAL) were performed. BAL cell differentials and interleukin (IL)-8 protein levels were assessed and correlated with eCO., Results: In the studied cohort, eCO levels were increased in patients with elevated (>3%) BAL neutrophilia compared with those with normal BAL neutrophilia (P=0.025). Furthermore, eCO levels significantly correlated with BAL neutrophilia and IL-8 levels in the cohort as a whole (r=0.50; P=0.0005 for total cells, r=0.43; P=0.003 for %cells and r=0.30; P=0.045 for IL-8). This was even more obvious in the LTx recipients with increased (>3%) BAL neutrophilia (r=0.70; P=0.0007 for total cells and r=0.80; P<0.0001 for %cells). For a cutoff of 4 ppm, sensitivity, specificity, positive and negative predictive value of eCO for detecting elevated BAL neutrophilia were 84.0%, 45.0%, 65.6%, and 69.2%, respectively (P=0.049)., Conclusions: Elevated eCO levels in stable LTx recipients may reflect an increased BAL neutrophilia and could, therefore, be used as a noninvasive marker for airway inflammation after LTx.

Background: Exhaled nitric oxide (eNO) is increased in patients with bronchiolitis obliterans syndrome (BOS) after lung transplantation. However, the accuracy of eNO measurements in diagnosing BOS is unknown., Methods: Thirty-two lung-transplant patients were included. Their immunosuppressive regimen consisted of cyclosporin A (tacrolimus), azathioprine (mycophenolate mofetil), and oral but no inhaled steroids. eNO levels and spirometry were prospectively followed until 2 years after transplantation or until the patient developed BOS., Results: Thirteen patients (group A) developed BOS (607 +/- 158 days after transplantation). Their mean eNO level at that time was 24.3 +/- 13.2 parts per billion (ppb), whereas the eNO value in the stable patients at 2 years (group B) was 11.4 +/- 4.9 ppb, P=0.0054. All group A patients had an eNO of 15 or greater ppb. Seven patients of group B also had an eNO of 15 or greater ppb, resulting in a test accuracy for the diagnosis of BOS of 0.78. However, considering only those patients who had two consecutive measurements (3-6 weeks apart) of eNO 15 or greater ppb during the months preceding the diagnosis of BOS or in the whole 2-year evaluation period, only 3 of 19 patients in group B (false-positives) but 12 of 13 in group A (1 false-negative) now fulfilled that criteria, which became positive at a mean of 263 +/- 169 days before the diagnosis of BOS was met, based on the forced expiratory volume in 1 second criteria. This increased the accuracy to 0.88., Conclusion: Measurements of eNO appear to be an accurate test for the early diagnosis of BOS.

Background: Bronchiolitis obliterans syndrome (BOS) is the leading cause of late mortality after lung transplantation., Methods: We added azithromycin (AZI) (250 mg/day for 5 days, followed by 250 mg every other day) to the current immunosuppressive therapy in eight lung transplant recipients (mean age 36 years) with established BOS in an attempt to prevent further decline of the forced expiratory volume in 1 sec (FEV1)., Results: Before the administration of AZI, there was a gradual decline of the FEV1 (-34.4%+/-14.7%) compared with the patients' best postoperative values. Twelve weeks after AZI had been added, there was a significant increase in the FEV1 (+18.3%+/-14.6%, P <0.0001, analysis of variance) with an absolute increase of 328+/-305 mL. This increase persisted in three patients during 9 months of follow-up., Conclusions: AZI is a promising drug for some patients with BOS after lung transplantation. The exact mechanism of action is unknown at the present time.

Objective: To investigate the value of in situ preservation and ex vivo evaluation of lungs from a non-heart-beating donor (NHBD) prior to long-term cold storage., Summary Background Data: The use of pulmonary grafts from NHBD might alleviate the organ shortage. However, viability testing of these grafts is mandatory to transplant only those lungs with excellent function., Methods: Pigs were divided into two groups. In the control group, lungs were flushed, explanted, and stored for 4 hours (4 degrees C). In the study group, pigs were killed and left untouched for 90 minutes. Thereafter, the lungs were cooled for 150 minutes via chest drains. Graft function of the left lung in both groups was assessed in an isolated ventilation and reperfusion circuit 4 hours after death. The lung was then cooled and stored. Twenty-four hours after death, the pulmonary graft was reassessed in the same model., Results: We did not observe a statistical significant difference between the two groups in pulmonary vascular resistance, mean airway pressure, and partial oxygen tension at each time point. There was also no statistical significant difference in wet-to-dry weight ratio. Finally, no statistical difference was found within both groups comparing the assessment at 24 hours with the interim evaluation at 4 hours., Conclusions: These data demonstrate that: 1) 90 minutes of warm ischemia and 150 minutes of intrapleural cooling do not affect pulmonary graft function; and 2) NHBD lungs can be safely preserved up to 24 hours. Finally, we have demonstrated that interim ex vivo evaluation of NHBD lungs is a valid and safe method to assess graft function.

Background: Conversion after transplantation from cyclosporine to tacrolimus is often performed because of recurrent acute/chronic rejection or unacceptable side effects such as nephrotoxicity, arterial hypertension, and cosmetic disorders. Although gastrointestinal discomfort is often reported after transplantation, it is usually not considered a sufficient reason for conversion, although tacrolimus seems beneficial with regards to gastric motor activity in renal transplant patients., Methods: A lung transplantation was performed in a 41-year-old woman with alpha-1 antitrypsin deficiency emphysema. Because the patient presented severe symptoms of nausea, vomiting, and dyspepsia, without obvious endoscopic explanation, that resulted in highly variable cyclosporine trough levels, she was converted from cyclosporine to tacrolimus., Results: After conversion, dyspepsia, nausea, and vomiting resolved. Neurological complications caused by a transient high trough level of tacrolimus resolved completely upon dose reduction with tacrolimus trough levels remaining very stable afterwards., Conclusion: Tacrolimus may be the immunosuppressant of choice after solid organ transplantation in patients with problems related to gastric motor dysfunction.