Annelore Sacreas

High-dose vitamin D after lung transplantation: A randomized trial

BACKGROUND Vitamin D may have innate immunomodulatory functions with potentially beneficial therapeutic effects in lung transplant recipients. METHODS This was a single-center, double blind, randomized, placebo-controlled, prevention trial of once-monthly oral vitamin D (cholecalciferol; 100,000 IU, n = 44) vs placebo (n = 43) during 2 years in adult lung transplant recipients enrolled from October 2010 to August 2013. Primary outcome was prevalence of chronic lung allograft dysfunction (CLAD) 3 years after transplantation. Secondary outcomes included overall survival, prevalence of acute rejection, lymphocytic bronchiolitis and infection, lung function, pulmonary and systemic inflammation, and bone mineral density. RESULTS All included patients underwent bilateral lung transplantation and were mostly middle-aged men with prior smoking-related emphysema. Levels of 25-hydroxy vitamin D after 1 year (p < .001) and 2 years (p < .001) were significantly higher in the vitamin D group compared with the placebo group. No difference was observed for CLAD prevalence (p = 0.7) or CLAD-free survival between both groups (p = 0.7). Secondary outcomes were overall comparable between both groups (all p > 0.05). CONCLUSIONS Once-monthly oral vitamin D supplementation after lung transplantation fails to demonstrate a significant difference in CLAD prevalence, innate immunomodulatory, or a beneficial clinical effect compared with placebo.

Interleukin-1α induced release of interleukin-8 by human bronchial epithelial cells in vitro: assessing mechanisms and possible treatment options

Survival after lung transplantation is hampered by chronic lung allograft dysfunction (CLAD). Persistently elevated BAL‐neutrophilia is observed in some patients despite treatment with azithromycin, which may be induced by IL‐1α. Our aim is to establish an in vitro model, assess mechanistic pathways and test different therapeutic strategies of IL‐1α‐induced release of IL‐8 by human bronchial epithelial cells. Bronchial epithelial cells (16HBE) were stimulated with IL‐1α with or without azithromycin or dexamethasone. IL‐8 protein was analyzed in cell supernatant. Different MAP kinases (p38, JNK, ERK1/2, Iκβ) and targets known to be involved in tumor formation (PI3K, Akt) were investigated. Finally, different treatment options were tested for their potential inhibitory effect. IL‐1α induced IL‐8 in bronchial epithelial cells, which was dose‐dependently inhibited by dexamethasone but not by azithromycin. IL‐1α induced p38 and Akt phosphorylation, but activation of these MAPK was not inhibited by dexamethasone. JNK, ERK1/2, Iκβ and PI3K were not activated. None of the tested drugs reduced the IL‐1α induced IL‐8 production. We established an in vitro model wherein steroids inhibit the IL‐1α‐induced IL‐8 production, while azithromycin was ineffective. Despite using this simple in vitro model, we could not identify a new treatment option for azithromycin‐resistant airway neutrophilia.

The common rejection module in chronic rejection post lung transplantation

Rationale Recent studies suggest that similar injury mechanisms are in place across different solid organ transplants, resulting in the identification of a common rejection module (CRM), consisting of 11 genes that are overexpressed during acute and, to a lesser extent, chronic allograft rejection. Objectives We wanted to evaluate the usefulness of the CRM module in identifying acute rejection (AR) and different phenotypes of chronic lung transplant rejection (CLAD), i.e., bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), using transbronchial brushings, broncho-alveolar lavage (BAL) samples, and explant tissue. Methods Gene expression measurements for the 11 CRM genes (CD6, TAP1, CXCL10, CXCL9, INPP5D, ISG20, LCK, NKG7, PSMB9, RUNX3, and BASP1) were performed via qRT-PCR in 14 transbronchial brushings (AR, n = 4; no AR, n = 10), 32 BAL samples (stable, n = 13; AR, n = 8; BOS, n = 9; RAS, n = 10), and 44 tissue specimens (unused donor lungs, n = 15; BOS, n = 13; RAS, n = 16). A geometric mean score was calculated to quantitate overall burden of immune injury and a new computational model was built for the most significant genes in lung transplant injury. Results Acute rejection showed a significant difference in almost every gene analysed, validating previous observations from microarray analysis. RAS tissue demonstrated a higher geometric mean score (6.35) compared to donor tissue (4.09, p = 0.018). Analysis of individual CRM genes showed an increased expression of ISG20, CXCL10 and CXCL9 in RAS. In BAL samples, no differences were detected in gene expression or geometric mean scores between the various groups (stable, 5.15; AR, 5.81; BOS, 5.62; RAS, 7.31). A newly modelled 2-gene tissue CRM score did not demonstrate any difference between BOS and RAS (p>0.05). However, the model was able to discriminate RAS from BOS tissue (AUC = 0.75, 95% CI = 0.55–0.94, p = 0.025). Conclusion Transcriptional tissue analysis for CRM genes in CLAD can identify acute rejection and distinguish RAS from BOS. The immune activation in RAS seems similar to acute rejection after kidney/liver/heart transplantation.

Validation of a post-transplant chronic lung allograft dysfunction classification system

BACKGROUND Long-term survival after lung transplantation (LTx) is hampered by chronic lung allograft dysfunction (CLAD). Our study evaluated the prevalence and prognostic importance of obstructive and restrictive CLAD phenotypes, with or without an identifiable underlying cause, to validate the recently proposed classification system for CLAD. METHODS Data for patients who underwent LTx between 2004 and 2015 with a minimal survival of 180 days post-LTx were retrospectively collected. Double LTx patients with CLAD (defined as a persistent forced expiratory volume in 1 second decline of ≥ 20% compared with baseline) were subsequently classified according to obstructive (forced expiratory volume in 1 second /forced vital capacity [FVC] < 70%, total lung capacity > 90%, and FVC > 80%) or restrictive (total lung capacity ≤ 90% or FVC ≤ 80%) pulmonary function and to the presence of an unknown (bronchiolitis obliterans syndrome [BOS]/restrictive allograft syndrome [RAS]) or known (non-BOS/non-RAS) underlying cause. RESULTS After a median of 3.2 years, CLAD developed in 39% of double LTx patients (n = 219), of which 20% (n = 43) had an identifiable cause. Survival was worse in patients with restrictive CLAD (26%) compared with obstructive CLAD (64%; p < 0.0001). Non-BOS patients suffered from inferior survival compared with BOS patients (p = 0.0016), whereas there was no significant difference in survival between RAS and non-RAS (p = 0.17). Patients who evolved from an obstructive (BOS) to a restrictive (RAS) phenotype (10%) experienced better survival than RAS patients and a worse outcome compared with BOS patients (p < 0.0001). CONCLUSIONS Given the differences in outcome, accurate diagnosis of CLAD phenotypes is important, because this helps to inform patients about their prognosis, to reveal underlying pathogenesis, to identify homogenous patient populations for clinical trials, and to guide future therapeutic approaches.

Pirfenidone in restrictive allograft syndrome after lung transplantation: A case series

Pirfenidone may attenuate the decline of pulmonary function in restrictive allograft syndrome (RAS) after lung transplantation. We retrospectively assessed all lung transplant recipients with RAS who were treated with pirfenidone for at least 3 months (n = 11) in our lung transplant center and report on their long‐term outcomes following initiation of pirfenidone. Main outcome parameters included evolution of pulmonary function and overall survival. Pirfenidone appears to attenuate the decline in forced vital capacity and forced expiratory volume in 1 second. Notably, 3 patients were bridged to redo‐transplantation with pirfenidone for 11 (5‐12) months and are currently alive, while 3 other patients demonstrate long‐term stabilization of pulmonary function after 26.6 (range 18.4‐46.6) months of treatment. Median overall 3‐year survival after RAS diagnosis was 54.5%. Subjective intolerance, mainly anorexia and nausea, necessitating pirfenidone dose de‐escalation in 55% of patients, as well as calcineurin dose increase requirements with about 20% are important complications during pirfenidone treatment after lung transplantation. Our findings provide further evidence that pirfenidone appears to be safe and may attenuate the rate of decline in lung function in patients with RAS, but the actual clinical benefit cannot be assessed in the context of this study design and requires further investigation in a larger randomized trial.

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.