scholarly journals MiR-21 in Lung Transplant Recipients With Chronic Lung Allograft Dysfunction

2022 ◽  
Vol 35 ◽  
Author(s):  
Naofumi Miyahara ◽  
Alberto Benazzo ◽  
Felicitas Oberndorfer ◽  
Akinori Iwasaki ◽  
Viktoria Laszlo ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Bronchiolitis Obliterans Syndrome ◽  
Micro Rna ◽  
Serum Samples ◽  
Mesenchymal Transition ◽  
Chronic Lung Allograft Dysfunction ◽  
Allograft Dysfunction ◽  
Notch Intracellular Domain ◽  
Restrictive Allograft Syndrome ◽  
Lung Transplant Recipients

Background: Micro-RNA-21 (miR-21) is a post-translational regulator involved in epithelial-to-mesenchymal transition (EMT). Since EMT is thought to contribute to chronic lung allograft dysfunction (CLAD), we aimed to characterize miR-21 expression and distinct EMT markers in CLAD.Methods: Expression of miR-21, vimentin, Notch intracellular domain (NICD) and SMAD 2/3 was investigated in explanted CLAD lungs of patients who underwent retransplantation. Circulating miR-21 was determined in collected serum samples of CLAD and matched stable recipients.Results: The frequency of miR-21 expression was higher in restrictive allograft syndrome (RAS) than in bronchiolitis obliterans syndrome (BOS) specimens (86 vs 30%, p = 0.01); Vimentin, NICD and p-SMAD 2/3 were positive in 17 (100%), 12 (71%), and 7 (42%) BOS patients and in 7 (100%), 4 (57%) and 4 (57%) RAS cases, respectively. All four markers were negative in control tissue from donor lungs. RAS patients showed a significant increase in serum concentration of miR-21 over time as compared to stable recipients (p = 0.040).Conclusion: To the best of our knowledge this is the first study highlighting the role miR-21 in CLAD. Further studies are necessary to investigate the involvement of miR-21 in the pathogenesis of CLAD and its potential as a therapeutic target.

scholarly journals Intragraft donor-specific anti-HLA antibodies in phenotypes of chronic lung allograft dysfunction

2019 ◽  
Vol 54 (5) ◽  
pp. 1900847 ◽  
Author(s):  
Annelore Sacreas ◽  
Jean-Luc Taupin ◽  
Marie-Paule Emonds ◽  
Liesbeth Daniëls ◽  
Dirk E. Van Raemdonck ◽  
...  
Keyword(s):  
Human Leukocyte ◽  
Hla Class I ◽  
Bronchiolitis Obliterans Syndrome ◽  
Clinical Findings ◽  
Micro Computed Tomography ◽  
Serum Samples ◽  
Chronic Lung Allograft Dysfunction ◽  
Leukocyte Antigen ◽  
Allograft Dysfunction ◽  
Restrictive Allograft Syndrome

IntroductionCirculating anti-human leukocyte antigen (HLA) serum donor-specific antibodies (sDSAs) increase the risk of chronic lung allograft dysfunction (CLAD) and mortality. Discrepancies between serological and pathological/clinical findings are common. Therefore, we aimed to assess the presence of tissue-bound graft DSAs (gDSAs) in CLAD explant tissue compared with sDSAs.MethodsTissue cores, obtained from explant lungs of unused donors (n=10) and patients with bronchiolitis obliterans syndrome (BOS; n=18) and restrictive allograft syndrome (RAS; n=18), were scanned with micro-computed tomography before elution of antibodies. Total IgG levels were measured via ELISA. Anti-HLA class I and II IgG gDSAs were identified using Luminex single antigen beads and compared with DSAs found in serum samples.ResultsOverall, mean fluorescence intensity was higher in RAS eluates compared with BOS and controls (p<0.0001). In BOS, two patients were sDSA+/gDSA+ and two patients were sDSA−/gDSA+. In RAS, four patients were sDSA+/gDSA+, one patient was sDSA+/gDSA− and five patients were sDSA−/gDSA+. Serum and graft results combined, DSAs were more prevalent in RAS compared with BOS (56% versus 22%; p=0.04). There was spatial variability in gDSA detection in one BOS patient and three RAS patients, who were all sDSA−. Total graft IgG levels were higher in RAS than BOS (p<0.0001) and in gDSA+versus gDSA− (p=0.0008), but not in sDSA+versus sDSA− (p=0.33). In RAS, total IgG levels correlated with fibrosis (r= −0.39; p=0.02).ConclusionsThis study underlines the potential of gDSA assessment as complementary information to sDSA findings. The relevance and applications of gDSAs need further investigation.

scholarly journals Lung Ultrasound to Phenotype Chronic Lung Allograft Dysfunction in Lung Transplant Recipients. A Prospective Observational Study

2021 ◽  
Vol 10 (5) ◽  
pp. 1078
Author(s):  
Jesper Rømhild Davidsen ◽  
Christian B. Laursen ◽  
Mikkel Højlund ◽  
Thomas Kromann Lund ◽  
Klaus Nielsen Jeschke ◽  
...  
Keyword(s):  
Lung Transplant ◽  
Lung Ultrasound ◽  
Bronchiolitis Obliterans Syndrome ◽  
High Resolution Computed Tomography ◽  
Chronic Lung Allograft Dysfunction ◽  
Pleural Thickening ◽  
Allograft Dysfunction ◽  
Restrictive Allograft Syndrome ◽  
Transplantation Center ◽  
Lung Transplant Recipients

Background: Bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS) are two distinct phenotypes of chronic lung allograft dysfunction (CLAD) in lung transplant (LTx) recipients. Contrary to BOS, RAS can radiologically present with a pleuroparenchymal fibroelastosis (PPFE) pattern. This study investigates lung ultrasound (LUS) to identify potential surrogate markers of PPFE in order to distinguish CLAD phenotype RAS from BOS. Methods: A prospective cohort study performed at a National Lung Transplantation Center during June 2016 to December 2017. Patients were examined with LUS and high-resolution computed tomography of the thorax (HRCT). Results: Twenty-five CLAD patients (72% males, median age of 54 years) were included, corresponding to 19/6 BOS/RAS patients. LUS-identified pleural thickening was more pronounced in RAS vs. BOS patients (5.6 vs. 2.9 mm) compatible with PPFE on HRCT. LUS-identified pleural thickening as an indicator of PPFE in RAS patients’ upper lobes showed a sensitivity of 100% (95% CI; 54–100%), specificity of 100% (95% CI; 82–100%), PPV of 100% (95% CI; 54–100%), and NPV of 100% (95% CI; 82–100%). Conclusion: Apical pleural thickening detected by LUS and compatible with PPFE on HRCT separates RAS from BOS in patients with CLAD. We propose LUS as a supplementary tool for initial CLAD phenotyping.

scholarly journals Twelve-month effects of everolimus on renal and lung function in lung transplantation: differences in chronic lung allograft dysfunction phenotypes

2021 ◽  
Vol 12 ◽  
pp. 204062232199344
Author(s):  
Filippo Patrucco ◽  
Elias Allara ◽  
Massimo Boffini ◽  
Mauro Rinaldi ◽  
Cristina Costa ◽  
...  
Keyword(s):  
Renal Function ◽  
Lung Function ◽  
Lung Transplant ◽  
Bronchiolitis Obliterans Syndrome ◽  
Forced Expiratory Volume ◽  
Chronic Lung Allograft Dysfunction ◽  
Allograft Dysfunction ◽  
Transplant Patients ◽  
Restrictive Allograft Syndrome ◽  
Trend Data

Background: Chronic lung allograft dysfunction (CLAD), a complication affecting the survival of lung transplanted patients, includes two clinical phenotypes: bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). Everolimus is used in CLAD because of its antiproliferative mechanism. In lung transplant patients treated with everolimus, the clinical course of renal and lung function has not yet been assessed systematically in CLAD, BOS and RAS patients for more than 6 months. Methods: We retrospectively evaluated the 12-month follow-up of renal and lung function of lung-transplanted patients switched to everolimus and evaluated the reduction in immunosuppressant dosage (ISD) and mortality. Subgroups were based on indication for everolimus treatment: CLAD and non-CLAD patients, BOS and RAS among CLAD patients. Results: We included 26 patients, 17 with CLAD (10 BOS, seven RAS). After 1 year from the everolimus switch, we observed renal function improvement (serum creatinine −17%, estimated glomerular filtration rate +24%) and stable pulmonary function [forced expiratory volume in the first second (FEV1) −0.5%, forced vital capacity (FVC) +0.05%]. RAS patients had progressive functional loss, whereas BOS patients had FEV1 improvement and FVC stability. All-cause mortality was higher in the CLAD versus non-CLAD group (41% versus 11%), without differences between BOS and RAS patients ( p > 0.05). All patients had significant and persistent ISD reduction. Conclusion: Lung transplant patients treated with everolimus had improvements in renal function and reduced ISD. We observed sustained improvements in lung function for CLAD related to BOS subgroup results, whereas RAS confirmed the 1-year worsening functional trend. Data seem to suggest one more piece of the puzzle in CLAD phenotyping.

Chronic Lung Allograft Dysfunction: Evolving Concepts and Therapies

2018 ◽  
Vol 39 (02) ◽  
pp. 155-171 ◽  
Author(s):  
Ariss DerHovanessian ◽  
W. Wallace ◽  
Joseph Lynch ◽  
John Belperio ◽  
S. Weigt
Keyword(s):  
Lung Transplantation ◽  
Therapeutic Option ◽  
Bronchiolitis Obliterans Syndrome ◽  
Term Survival ◽  
Chronic Lung Allograft Dysfunction ◽  
Allograft Dysfunction ◽  
Restrictive Allograft Syndrome ◽  
Technical Advances ◽  
End Stage

AbstractLung transplantation has become an established therapeutic option for a variety of end-stage lung diseases. Technical advances in graft procurement, implantation, perioperative care, immunosuppression, and posttransplant medical management have led to significant improvements in 1-year survival, but outcomes after the first year have improved minimally over the last two decades. The main limitation to better long-term survival after lung transplantation is chronic lung allograft dysfunction (CLAD). CLAD also impairs quality of life and increases the costs of medical care. Our understanding of CLAD manifestations, risk factors, and mechanisms is rapidly evolving. Recognition of different CLAD phenotypes (e.g., bronchiolitis obliterans syndrome and restrictive allograft syndrome) and the unique pathogenic mechanisms will be important for developing novel therapies. In addition to alloimmune-mediated rejection, we now recognize the importance of alloimmune-independent mechanisms of injury to the allograft. CLAD is the consequence of dysregulated repair of allograft injury. Unfortunately, currently available therapies for CLAD are usually not effective. However, the advances in knowledge, reviewed in this manuscript, should lead to novel strategies for CLAD prevention and treatment, as well as improvement in long-term outcomes after lung transplantation. We provide an overview of the evolving terminology related to CLAD, its varying clinical phenotypes and their diagnosis, natural history, pathogenesis, and potential treatments.

scholarly journals Potential novel biomarkers for chronic lung allograft dysfunction and azithromycin responsive allograft dysfunction

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Cecilia Veraar ◽  
Jonathan Kliman ◽  
Alberto Benazzo ◽  
Felicitas Oberndorfer ◽  
Maria Laggner ◽  
...  
Keyword(s):  
Bronchial Epithelium ◽  
Activin A ◽  
Bronchiolitis Obliterans Syndrome ◽  
Serum Concentrations ◽  
Lipocalin 2 ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Chronic Lung Allograft Dysfunction ◽  
Allograft Dysfunction ◽  
Restrictive Allograft Syndrome

AbstractChronic Lung Allograft Dysfunction (CLAD), manifesting as Bronchiolitis Obliterans Syndrome (BOS) or Restrictive Allograft Syndrome (RAS), is the main reason for adverse long-term outcome after Lung Transplantation (LTX). Until now, no specific biomarkers exist to differentiate between CLAD phenotypes. Therefore, we sought to find suitable cytokines to distinguish between BOS, RAS and Azithromycin Responsive Allograft Dysfunction (ARAD); and reveal potential similarities or differences to end-stage fibrotic diseases. We observed significantly increased Lipocalin-2 serum concentrations in RAS compared to BOS patients. In addition, in RAS patients immunohistochemistry revealed Lipocalin-2 expression in bronchial epithelium and alveolar walls. Patients with ARAD showed significantly lower Activin-A serum concentrations compared to Stable-LTX and BOS patients. Further, increased serum concentrations of Lipocalin-2 and Activin-A were predictors of worse freedom-from-CLAD in Stable-LTX patients. These biomarkers serve as promising serum biomarkers for CLAD prediction and seem suitable for implementation in clinical practice.

scholarly journals Lung Transplantation: CT Assessment of Chronic Lung Allograft Dysfunction (CLAD)

Diagnostics ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 817
Author(s):  
Anne-Laure Brun ◽  
Marie-Laure Chabi ◽  
Clément Picard ◽  
François Mellot ◽  
Philippe A. Grenier
Keyword(s):  
Lung Transplantation ◽  
Functional Decline ◽  
Bronchiolitis Obliterans Syndrome ◽  
The Other ◽  
Imaging Features ◽  
Chronic Lung Allograft Dysfunction ◽  
Allograft Dysfunction ◽  
Restrictive Allograft Syndrome ◽  
Mixed Phenotype

Chronic lung allograft rejection remains one of the major causes of morbi-mortality after lung transplantation. The term Chronic Lung Allograft Dysfunction (CLAD) has been proposed to describe the different processes that lead to a significant and persistent deterioration in lung function without identifiable causes. The two main phenotypes of CLAD are Bronchiolitis Obliterans Syndrome (BOS) and Restrictive Allograft Syndrome (RAS), each of them characterized by particular functional and imaging features. These entities can be associated (mixed phenotype) or switched from one to the other. If CLAD remains a clinical diagnosis based on spirometry, computed tomography (CT) scan plays an important role in the diagnosis and follow-up of CLAD patients, to exclude identifiable causes of functional decline when CLAD is first suspected, to detect early abnormalities that can precede the diagnosis of CLAD (particularly RAS), to differentiate between the obstructive and restrictive phenotypes, and to detect exacerbations and evolution from one phenotype to the other. Recognition of early signs of rejection is crucial for better understanding of physiopathologic pathways and optimal management of patients.

scholarly journals Linking clinical phenotypes of chronic lung allograft dysfunction to changes in lung structure

2015 ◽  
Vol 46 (5) ◽  
pp. 1430-1439 ◽  
Author(s):  
Stijn E. Verleden ◽  
Dragoş M. Vasilescu ◽  
John E. McDonough ◽  
David Ruttens ◽  
Robin Vos ◽  
...  
Keyword(s):  
Connective Tissue ◽  
Bronchiolitis Obliterans Syndrome ◽  
Fibrous Connective Tissue ◽  
Micro Ct ◽  
Lung Weight ◽  
Major Barrier ◽  
Chronic Lung Allograft Dysfunction ◽  
Allograft Dysfunction ◽  
Restrictive Allograft Syndrome ◽  
Microscopic Features

Chronic lung allograft dysfunction (CLAD) remains the major barrier to long-term success after lung transplantation. This report compares gross and microscopic features of lungs removed from patients receiving a redo-transplant as treatment for CLAD.Lungs donated by patients with either the bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS) phenotype of CLAD and appropriate control lungs (eight per group) were air-inflated, frozen solid and kept frozen while a multi-detector computed tomography (MDCT) was obtained. The lung was then cut into 2-cm thick transverse slices and sampled for micro-CT and histopathology.The MDCT showed reduced lung volume with increased lung weight and density in RAS versus BOS and control (p<0.05). Although pre-terminal bronchioles were obstructed in both phenotypes, RAS lungs showed a reduction of pre-terminal bronchioles (p<0.01). Micro-CT and matched histopathology showed that RAS was associated with reduced numbers of terminal bronchioles/lung compared to BOS and controls (p<0.01), with expansion of the interstitial compartment and obliteration of the alveolar airspaces by fibrous connective tissue.RAS is associated with greater destruction of both pre-terminal and terminal bronchioles. Additionally, the interstitial compartments are expanded and alveolar airspaces are obliterated by accumulation of fibrous connective tissue.

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