Real life experience with mTOR-inhibitors after lung transplantation.

Mammalian target of rapamycin inhibitors (mTORi) are increasingly used after lung transplantation as part of a calcineurin inhibitor sparing regimen, aiming to preserve renal function. The aim of our study was to determine whether immunosuppressive therapy using mTORi in lung transplant recipients (LTR) is feasible in practice, or limited by intolerance and adverse events. Data were retrospectively assessed for all LTR transplanted between July 1991 and January 2020. Patients ever receiving mTORi (monotherapy or in combination with calcineurin inhibitor) as treatment of physicians' choice were included. 149/1184 (13%) of the LTR ever received mTORi. Main reasons to start were renal insufficiency (67%) and malignancy (21%). In 52% of the patients, mTORi was stopped due to side effects or drug toxicity after a median time of 159 days. Apart from death, main reasons for discontinuation were infection (19%) and edema (14%). Early discontinuation (<90 days) was mainly due to edema or gastrointestinal intolerance. As mTORi was stopped due to adverse events or drug intolerance in 52% of LTR, cautious consideration of advantages and disadvantages when starting mTORi is recommended.

An optimized non-destructive protocol for testing mechanical properties in decellularized rabbit trachea.

Successful tissue-engineered tracheal transplantation relies on the use of non-immunogenic constructs, which can vascularize rapidly, support epithelial growth, and retain mechanical properties to that of native trachea. Current strategies to assess mechanical properties fail to evaluate the trachea to its physiological limits, and lead to irreversible destruction of the construct. Our aim was to develop and evaluate a novel non-destructive method for biomechanical testing of tracheae in a rabbit decellularization model. To validate the performance of this method, we simultaneously analyzed quantitative and qualitative graft changes in response to decellularization, as well as in vivo biocompatibility of implanted scaffolds. Rabbit tracheae underwent two, four and eight cycles of detergent-enzymatic decellularization. Biomechanical properties were analyzed by calculating luminal volume of progressively inflated and deflated tracheae with microCT. DNA, glycosaminoglycan and collagen contents were compared to native trachea. Scaffolds were prelaminated in vivo. Native, two- and four-cycle tracheae showed equal mechanical properties. Collapsibility of eight-cycle tracheae was significantly increased from -40cm H2O (-3.9kPa). Implantation of two- and four-cycle decellularized scaffolds resulted in favorable flap-ingrowth; eight-cycle tracheae showed inadequate integration. We showed a more limited detergent-enzymatic decellularization successfully removing non-cartilaginous immunogenic matter without compromising extracellular matrix content or mechanical stability. With progressive cycles of decellularization, important loss of functional integrity was detected upon mechanical testing and in vivo implantation. This instability was not revealed by conventional quantitative nor qualitative architectural analyses. These experiments suggest that non-destructive, functional evaluation, e.g. by microCT, may serve as an important tool for mechanical screening of scaffolds before clinical implementation. STATEMENT OF SIGNIFICANCE: Decellularization is a front-running strategy to generate scaffolds for tracheal tissue-engineering. Preservation of biomechanical properties of the trachea during this process is paramount to successful clinical transplantation. In this paper, we evaluated a novel method for biomechanical testing of decellularized trachea. We detected important loss of functional integrity with progressive cycles of decellularization. This instability was not revealed by our quantitative nor qualitative analyses. These experiments suggest that the technique might serve as a performant, non-destructive tool for mechanical screening of scaffolds before clinical implementation.

Systemic lidocaine fails to improve postoperative morphine consumption, postoperative recovery and quality of life in patients undergoing posterior spinal arthrodesis. A double-blind, randomized, placebo-controlled trial.

BACKGROUND.: It is inconclusive whether the perioperative administration of systemic lidocaine provides effective postoperative analgesia and enhances recovery in major orthopaedic surgery. We hypothesised that in adolescent and adult patients undergoing posterior spinal arthrodesis, a perioperative lidocaine infusion would reduce opioid requirements during the first 24 postoperative h. METHODS.: 70 patients undergoing posterior arthrodesis were enrolled in this prospective, randomised, double-blind, placebo-controlled clinical trial. Patients received total i.v. anaesthesia with propofol and remifentanil and were randomized to an adjuvant therapy with either lidocaine [i.v.-bolus injection of 1.5 mg kg -1 at induction of anaesthesia, followed by an infusion of 1.5 mg kg -1 h -1 which was continued until six h after arrival at the post-anaesthesia care unit] or placebo (equal volumes of saline). Postoperative pain was treated with patient-controlled i.v. morphine. Primary endpoints of this study were morphine requirements in the first postoperative 24 h. RESULTS.: Systemic lidocaine did not decrease morphine requirements in the first 24 postoperative h [lidocaine-group: 48 (23) mg (mean( sd )) vs placebo-group: 51(19) mg, P = 0.22]. Likewise, groups were not different with respect to the severity of postoperative pain, morphine consumption after 48 and 72 h, incidence of postoperative nausea and vomiting, perioperative inflammation, time to recovery of intestinal function, hospital length of stay, and quality of life (assessed preoperatively and one month postoperatively using the SF-12 physical and mental composite scores). CONCLUSIONS.: In our study, systemic lidocaine had no analgesic benefits in posterior arthrodesis when added to an opioid-based anaesthetic regimen. CLINICAL TRIAL REGISTRATION.: Eudra CT 2012-005264-98.

Radiological Analysis of Unused Donor Lungs: A Tool to Improve Donor Acceptance for Transplantation?

Despite donor organ shortage, a large proportion of possible donor lungs are declined for transplantation. Criteria for accepting/declining lungs remain controversial because of the lack of adequate tools to aid in decision-making. We collected, air-inflated, and froze a large series of declined/unused donor lungs and subjected these lung specimens to CT examination. Affected target regions were scanned by using micro-CT. Lungs from 28 donors were collected. Two lungs were unused, six were declined for non-allograft-related reasons (collectively denominated nonallograft declines, n = 8), and 20 were declined because of allograft-related reasons. CT scanning demonstrated normal lung parenchyma in only four of eight nonallograft declines, while relatively normal parenchyma was found in 12 of 20 allograft-related declines. CT and micro-CT examinations confirmed the reason for decline in most lungs and revealed unexpected (unknown from clinical files or physical inspection) CT abnormalities in other lungs. CT-based measurements showed a higher mass and density in the lungs with CT alterations compared with lungs without CT abnormalities. CT could aid in the decision-making to accept or decline donor lungs which could lead to an increase in the quantity and quality of lung allografts.

Determinants of the Magnitude of Interaction Between Tacrolimus and Voriconazole/Posaconazole in Solid Organ Recipients.

Administration of azole antifungals to tacrolimus-treated solid organ recipients results in a major drug-drug interaction characterized by increased exposure to tacrolimus. The magnitude of this interaction is highly variable but cannot currently be predicted. We performed a retrospective analysis of 126 solid organ recipients (95 lung, 31 kidney) co-treated with tacrolimus and voriconazole (n = 100) or posaconazole (n = 26). Predictors of the change in tacrolimus dose-corrected trough concentrations (C/D) between baseline and tacrolimus-azole co-therapy were assessed using linear mixed modeling. Patients were genotyped for relevant polymorphisms in CYP3A4, CYP3A5, MDR1, CYP2C19, POR, and UGT1A4. Tacrolimus C/D increased by a factor 5.0 ± 2.7 (range 1.0-20.2) for voriconazole and 4.4 ± 2.6 (range 0.9-18.0) for posaconazole, suggesting that a 66% dose reduction is insufficient for the majority of patients. Change in C/D was blunted in CYP3A5 expressors (estimated effect: -43%, p = 0.017) and affected by hematocrit (+8% per %, p = 0.004), baseline C/D (-14% per 100% increase, p < 0.001), and age (+1%, p = 0.008). However, the final model explained only 22% of interindividual variability in C/D change. In conclusion, CYP3A5 genotype and several clinical variables were identified as modulators of the tacrolimus-azole interaction, but these did not permit accurate predictions in individual patients.

The role of recipient derived interleukin-17A in a murine orthotopic lung transplant model of restrictive chronic lung allograft dysfunction.

The single most important cause of late mortality after lung transplantation is chronic lung allograft dysfunction (CLAD). However, the pathological development of CLAD was not as simple as previously presumed and subclassification phenotypes, bronchiolitis obliterans syndrome (BOS) and restrictive CLAD (rCLAD), have been introduced. We want to re-investigate how CLAD manifests in the murine orthotopic lung transplant model and investigate the role of interleukin 17A (IL-17A) within this model. Orthotopic LTx was performed in CB57BL/6, IL-17 WT and IL-17 KO mice. In a first experiment, CB57BL/6 mice receiving an isograft (CB57BL/6) or allograft (BALB/C) were compared. In a second experiment IL-17 WT and IL-17 KO mice (both CB57BL/6 background) received an allograft (BALB/C). Mice received daily immunosuppression with steroids and cyclosporine and were sacrificed 10weeks after transplantation for histopathological analysis by an experienced lung pathologist. After murine orthotopic lung transplantation, the allograft histopathologically presented features of human rCLAD (i.e. overt inflammation, pleural/parenchymal fibrosis and obliterative bronchiolitis). In the IL-17A KO group, less inflammation in the bronchovascular axis (p=0.03) was observed and a non-significant trend towards less bronchovascular fibrosis, pleural/septal inflammation and fibrosis, and parenchymal inflammation and fibrosis when compared to WT mice. The major mismatch orthotopic lung transplant model resembles features of human rCLAD. IL-17A mediated immunity is involved in the inflammatory component, but had little influence on the degree of fibrosis. Further mechanistic and therapeutic studies in this mouse model are needed to fully understand the mechanisms in rCLAD.

Parametric Response Mapping of Bronchiolitis Obliterans Syndrome Progression After Lung Transplantation.

Bronchiolitis obliterans syndrome (BOS) remains a major complication after lung transplantation. Air trapping and mosaic attenuation are typical radiological features of BOS; however, quantitative evaluation remains troublesome. We evaluated parametric response mapping (PRM, voxel-to-voxel comparison of inspiratory and expiratory computed tomography [CT] scans) in lung transplant recipients diagnosed with BOS (n = 20) and time-matched stable lung transplant recipients (n = 20). Serial PRM measurements were performed prediagnosis, at time of BOS diagnosis, and postdiagnosis (Tpre , T0 , and Tpost , respectively), or at a postoperatively matched time in stable patients. PRM results were correlated with pulmonary function and confirmed by microCT analysis of end-stage explanted lung tissue. Using PRM, we observed an increase in functional small airway disease (fSAD), from Tpre to T0 (p = 0.006) and a concurrent decrease in healthy parenchyma (p = 0.02) in the BOS group. This change in PRM continued to Tpost , which was significantly different compared to the stable patients (p = 0.0002). At BOS diagnosis, the increase in fSAD was strongly associated with a decrease in forced expiratory volume in 1 s (p = 0.011). Micro-CT confirmed the presence of airway obliteration in a sample of a BOS patient identified with 67% fSAD by PRM. We demonstrated the use of PRM as an adequate output to monitor BOS progression in lung transplant recipients.

Prophylactic Azithromycin Therapy After Lung Transplantation: Post hoc Analysis of a Randomized Controlled Trial.

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.

Role of genetics in lung transplant complications.

There is increasing knowledge that patients can be predisposed to a certain disease by genetic variations in their DNA. Extensive genetic variation has been described in molecules involved in short- and long-term complications after lung transplantation (LTx), such as primary graft dysfunction (PGD), acute rejection, respiratory infection, chronic lung allograft dysfunction (CLAD), and mortality. Several of these studies could not be confirmed or were not reproduced in other cohorts. However, large multicenter prospective studies need to be performed to define the real clinical consequence and significance of genotyping the donor and receptor of a LTx. The current review presents an overview of genetic polymorphisms (SNP) investigating an association with different complications after LTx. Finally, the major drawbacks, clinical relevance, and future perspectives will be discussed.

Azithromycin and the treatment of lymphocytic airway inflammation after lung transplantation.

Lymphocytic airway inflammation is a major risk factor for chronic lung allograft dysfunction, for which there is no established treatment. We investigated whether azithromycin could control lymphocytic airway inflammation and improve allograft function. Fifteen lung transplant recipients demonstrating acute allograft dysfunction due to isolated lymphocytic airway inflammation were prospectively treated with azithromycin for at least 6 months (NCT01109160). Spirometry (FVC, FEV1 , FEF25-75 , Tiffeneau index) and FeNO were assessed before and up to 12 months after initiation of azithromycin. Radiologic features, local inflammation assessed on airway biopsy (rejection score, IL-17(+) cells/mm(2) lamina propria) and broncho-alveolar lavage fluid (total and differential cell counts, chemokine and cytokine levels); as well as systemic C-reactive protein levels were compared between baseline and after 3 months of treatment. Airflow improved and FeNO decreased to baseline levels after 1 month of azithromycin and were sustained thereafter. After 3 months of treatment, radiologic abnormalities, submucosal cellular inflammation, lavage protein levels of IL-1ß, IL-8/CXCL-8, IP-10/CXCL-10, RANTES/CCL5, MIP1-α/CCL3, MIP-1ß/CCL4, Eotaxin, PDGF-BB, total cell count, neutrophils and eosinophils, as well as plasma C-reactive protein levels all significantly decreased compared to baseline (p < 0.05). Administration of azithromycin was associated with suppression of posttransplant lymphocytic airway inflammation and clinical improvement in lung allograft function.

Body mass index in lung transplant candidates: a contra-indication to transplant or not?

BACKGROUND: According to International Society of Heart and Lung Transplantation criteria, high body mass index (BMI; ≥ 30 kg/m(2)) is a relative contraindication for lung transplantation (LT). On the other hand, low BMI may be associated with worse outcome. We investigated the influence of pre-LT BMI on survival after LT in a single-center study. METHODS: Patients were divided according to the World Health Organization criteria into 4 groups: BMI <18.5 kg/m(2) (underweight), BMI 18.5-24.9 kg/m(2) (normal weight), BMI 25-29.9 kg/m(2) (overweight), and BMI ≥ 30 kg/m(2) (obesity). An additional analysis was made per underlying disease. RESULTS: BMI was determined in a cohort of 546 LT recipients, of which 28% had BMI <18.5 kg/m(2). Underweight resulted in similar survival (P = .28) compared with the normal weight group. Significantly higher mortality was found in overweight (P = .016) and obese patients (P = .031) compared with the normal-weight group. Subanalysis of either underweight (P = .19) or obese COPD patients (P = .50) did not reveal worse survival. In patients with interstitial lung disease, obesity was associated with increased mortality (P = .031) compared with the normal-weight group. In cystic fibrosis patients, underweight was not associated with a higher mortality rate (P = .12) compared with the normal-weight group. CONCLUSIONS: Low pre-LT BMI did not influence survival rate in our cohort, independently from underlying disease.

Genetic variation in immunoglobulin G receptor affects survival after lung transplantation.

Chronic rejection remains the most important complication after lung transplantation (LTx). There is mounting evidence that both rheumatoid arthritis and chronic rejection share similar inflammatory mechanisms. As genetic variants in the FCGR2A gene that encodes the immunoglobulin gamma receptor (IgGR) have been identified in rheumatoid arthritis, we investigated the relationship between a genetic variant in the IgGR gene and chronic rejection and mortality after LTx. Recipient DNA from blood or explant lung tissue of 418 LTx recipients was evaluated for the IgGR (rs12746613) polymorphism. Multivariate analysis was carried out, correcting for several co-variants. In total, 216 patients had the CC-genotype (52%), 137 had the CT-genotype (33%) and 65 had the TT-genotype (15%). Univariate analysis demonstrated higher mortality in the TT-genotype compared with both other genotypes (p < 0.0001). Multivariate analysis showed that the TT-genotype had worse survival compared with the CC-genotype (hazard ratio [HR] = 2.26, p = 0.0002) but no significance was observed in the CT-genotype (HR = 1.32, p = 0.18). No difference was seen for chronic rejection. The TT-genotype demonstrated more respiratory infections (total, p = 0.037; per patient, p = 0.0022) compared with the other genotypes. A genetic variant in the IgGR is associated with higher mortality and more respiratory infections, although not with increased prevalence of chronic rejection, after LTx.

Pirfenidone: a potential new therapy for restrictive allograft syndrome?

This case report describes the evolution of pulmonary function findings (FVC, FEV1 and TLC) and CT features with pirfenidone treatment for restrictive allograft syndrome following lung transplantation. Furthermore, we herein report hypermetabolic activity on (18) F-FDG PET imaging in this setting, which could indicate active fibroproliferation and pleuroparenchymal remodeling. These findings may warrant further investigation.

Acute liver failure due to Varicella zoster virus infection after lung transplantation: a case report.

Most adults are Varicella zoster virus (VZV)-positive at the age of 20 years. Some, however, remain antibody-negative and may develop primary chicken pox during adulthood. We report a patient with Williams-Campbell syndrome who underwent double-lung transplantation while being VZV-negative. One year after the successful procedure, he was admitted with fulminant hepatic failure and some cutaneous vesicles in his face. Despite a rapid diagnosis of VZV infection and treatment with acyclovir, his situation deteriorated within 24 hours and while awaiting an urgent liver transplantation, he developed multiple organ failure and died.

Lymphocytic bronchiolitis after lung transplantation is associated with daily changes in air pollution.

Acute rejection represents a major problem after organ transplantation, being a recognized risk for chronic rejection and mortality. Recently, it became clear that lymphocytic bronchiolitis (LB, B-grade acute rejection) is more important than previously thought, as it predisposes to chronic rejection. We aimed to verify whether daily fluctuations of air pollution, measured as particulate matter (PM) are related to histologically proven A-grade rejection and/or LB and bronchoalveolar lavage (BAL) fluid cellularity after lung transplantation. We fitted a mixed model to examine the association between daily variations in PM(10) and A-grade rejection/LB on 1276 bronchoscopic biopsies (397 patients, 416 transplantations) taken between 2001 and 2011. A difference of 10 µg/m(3) in PM(10) 3 days before diagnosis of LB was associated with an OR of 1.15 (95% CI 1.04-1.27; p = 0.0044) but not with A-grade rejection (OR = 1.05; 95% CI 0.95-1.15; p = 0.32). Variations in PM(10) at lag day 3 correlated with neutrophils (p = 0.013), lymphocytes (p = 0.0031) and total cell count (p = 0.024) in BAL. Importantly, we only found an effect of PM10 on LB in patients not taking azithromycin. LB predisposed to chronic rejection (p < 0.0001). The risk for LB after lung transplantation increased with temporal changes in particulate air pollution, and this was associated with BAL neutrophilia and lymphocytosis. Azithromycin was protective against this PM effect.

Determinants of physical activity in daily life in candidates for lung transplantation.

BACKGROUND: Participation in daily physical activity (PA) has never been objectively assessed in candidates for lung transplantation (LTx). The main research questions were: 1) How active are LTx-candidates in daily life? 2) What are determinants of activity behavior before LTX? METHODS: Ninety-six candidates for LTx (diagnosis of COPD or interstitial lung disease; mean age 55 ± 7 years) underwent measurements of PA, pulmonary function, 6-min walking distance (6MWD), muscle force and health-status (SF-36 scale). RESULTS: Patients were markedly inactive (5% of waking hours walking, 26% standing and 69% sedentary). Backward multiple regression identified 6MWD (expressed as % of predicted value; ß = 73.0 steps, partial r(2) = 0.36, p = 0.00), a higher score on the energy/fatigue scale of the SF-36 (ß = 28.6 steps, partial r(2) = 0.09, p = 0.00) and a higher expiratory muscle force (expressed as % of predicted value; ß = 11.8 steps, partial r(2) = 0.05, p = 0.02) as determinants of daily steps. Minutes of mild to moderate (≥2 METs) activity were determined by 6MWD (expressed as % of predicted value; ß = 2.14 min, partial r(2) = 0.30, p = 0.00), inspiratory muscle force (expressed as % of predicted value; ß = 0.33 min, partial r(2) = 0.04, p = 0.05) and seasonal influences (spring/summer vs. autumn/winter: ß = 18.95 min, partial r(2) = 0.04, p = 0.05). The overall fit of the models was r(2) = 0.50 and r(2) = 0.38, respectively. CONCLUSIONS: The 6MWD was the main determinant of an inactive lifestyle in these patients. Respiratory muscle force, energy and fatigue and seasonal variations explained some additional variability in activity behavior. Patients should be encouraged to participate in interventions aimed at improving physical fitness and participation in daily physical activity before LTx.

The need for a new animal model for chronic rejection after lung transplantation.

The single most important cause of late mortality after lung transplantation is obliterative bronchiolitis (OB), clinically characterized by a decrease in lung function and morphologically by characteristic changes. Recently, new insights into its pathogenesis have been acquired: risk factors have been identified and the use of azithromycin showed a dichotomy with at least 2 different phenotypes of bronchiolitis obliterans syndrome (BOS). It is clear that a good animal model is indispensable to further dissect and unravel the pathogenesis of BOS. Many animal models have been developed to study BOS but, so far, none of these models truly mimics the human situation. Looking at the definition of BOS, a good animal model implies histological OB lesions, possibility to measure lung function, and airway inflammation. This review sought to discuss, including pros and cons, all potential animal models that have been developed to study OB/BOS. It has become clear that a new animal model is needed; recent developments using an orthotopic mouse lung transplantation model may offer the answer because it mimics the human situation. The genetic variants among this species may open new perspectives for research into the pathogenesis of OB/BOS.

Neutrophilic reversible airways dysfunction after liver transplantation: a case report.

In the present case report we have described a 46-year-old female patient who underwent a liver transplantation in 1998 for polycystic disease and developed a syndrome of increasing dyspnea, with sputum production and a progressive decline in pulmonary function [forced expiratory volume in one second (FEV(1)) (decreased from 153% predicted to 87% predicted). Further examination revealed an impressive tree in a bud pattern with diffuse peribronchiolar infiltrates on computed axial tomographic scan of the thorax. Sputum cultures remained negative. Bronchoscopic central airway biopsy specimens showed lymphocytic bronchitis; sputum induction showed 92% neutrophils. This condition was similar to the bronchiolitis obliterans syndrome after lung transplantation, although the specific neutrophilic phenotype of bronchiolitis obliterans syndrome has recently been renamed as neutrophilic reversible allograft/airway dysfunction, based on a progressive decline in FEV(1), neutrophilic airway inflammation and its response to neomacrolides. Additional azithromycin treatment resulted in complete recovery in our patient, with normalization of FEV(1) and computed axial tomographic scan of the thorax at 3 months after initiation. This case report suggests that neutrophilic reversible allograft airway dysfunction can no longer be diagnosed only after lung transplantation. Moreover, it demonstrates that this condition is not always related to allograft rejection, but rather may be induced by non-immunologic factors, which remain to be further investigated.