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Graft failure represents a leading cause of mortality after organ transplantation. Acute late-onset graft failure has not been widely reported. The authors describe the demographics, CT imaging-pathology findings, and treatment of patients presenting with the latter. A retrospective review was performed of lung transplant recipients at two large-volume centers. Acute late-onset graft failure was defined as sudden onset of bilateral infiltrates with an oxygenation index <200 without identifiable cause or concurrent extrapulmonary organ failure. Laboratory, bronchoalveolar lavage (BAL), radiology, and histology results were assessed. Between 2005 and 2016, 21 patients were identified. Median survival was 19 (IQR 13-36) days post onset. Twelve patients (57%) required intensive care support at onset, 12 (57%) required mechanical ventilation, and 6 (29%) were placed on extracorporeal life support. Blood and BAL analysis revealed elevated neutrophilia, with CT demonstrating diffuse ground-glass opacities. Transbronchial biopsy samples revealed acute fibrinoid organizing pneumonia (AFOP), organizing pneumonia, and diffuse alveolar damage (DAD). Assessment of explanted lungs confirmed AFOP and DAD but also identified obliterative bronchiolitis. Patients surviving to discharge without redo transplantation (n = 2) subsequently developed restrictive allograft syndrome. This study describes acute late-onset graft failure in lung allograft recipients, without known cause, which is associated with a dismal prognosis., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

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., (Copyright © 2016 Elsevier B.V. All rights reserved.)

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 (T pre , T 0 , and T post , 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 T pre to T 0 (p = 0.006) and a concurrent decrease in healthy parenchyma (p = 0.02) in the BOS group. This change in PRM continued to T post , 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., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

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., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Almost all animal models for chronic rejection (CR) after lung transplantation (LTx) fail to resemble the human situation. It was our attempt to develop a representative model of CR in mice. Orthotopic LTx was performed in allografts receiving daily immunosuppression with steroids and cyclosporine. Controls included isografts and mice only undergoing thoracotomy (SHAM). Allografts were sacrificed 2, 4, 6, 8, 10 or 12 weeks after LTx. Pulmonary function was measured repeatedly in the 12w allografts, isografts and SHAM mice. Histologically, all allografts demonstrated acute rejection (AR) around the blood vessels and airways two weeks after LTx. This decreased to 50-75% up to 10 weeks and was absent after 12 weeks. Obliterative bronchiolitis (OB) lesions were observed in 25-50% of the mice from 4-12 weeks. Isografts and lungs of SHAM mice were normal after 12 weeks. Pulmonary function measurements showed a decline in FEV(0.1), TLC and compliance in the allografts postoperatively (2 weeks) with a slow recovery over time. After this initial decline, lung function of allografts increased more than in isografts and SHAM mice indicating that pulmonary function measurement is not a good tool to diagnose CR in a mouse. We conclude that a true model for CR, with clear OB lesions in about one third of the animals, but without a decline in lung function, is possible. This model is an important step forward in the development of an ideal model for CR which will open new perspectives in unraveling CR pathogenesis and exploring new treatment options.

Post-infectious bronchiolitis obliterans (PIBO) forms a chronic obstructive lung disease in children following a severe viral respiratory infection. Subsequent dysanaptic lung growth, with differential development of the alveolar compartment over the airway compartment, was clinically described, but remains elusive. We therefore performed a detailed 3D airway characterization in PIBO compared to bronchiolitis obliterans syndrome (BOS) after lung transplantation and discarded donor lungs. Explant lungs from matched adult patients who underwent lung transplantation for end-stage PIBO (n=5), redo lung transplantation patients with end-stage BOS (n=5), and discarded donor lungs (n=5) were included. Lungs were air-inflated and frozen in fumes of liquid nitrogen. Ex vivo computed tomography (CT) scans (resolution 700 µm) were obtained and used for radiologic scoring and semi-automated 3D airway segmentation. Next, frozen lungs were sampled on matched locations (n=4/lung) and scanned with microCT (resolution 10 µm). Radiologic scoring indicated more airway wall thickening (p=0.079), bronchial dilatation (p=0.087), and pleural thickening (p=0.071) in PIBO vs BOS. The number of airways per generation was similar between groups (p=0.53), but airway diameters were increased in PIBO (generation 6-11) and in BOS lungs (generation 7-10) compared to controls, without differences between PIBO and BOS. Significantly more airways ended in BO lesions in BOS vs PIBO (p=0.016, mean 25.60% vs 12.60%), although the size of the BO lesions was increased in PIBO vs BOS (p=0.032, median 27.23mm³ vs 5.01mm³). Subsequent micro CT assessment revealed a significant lower number of terminal bronchioles (TB) in PIBO (p=0.0009, PIBO: mean 3131 TB/lung, BOS: 8360 TB/lung, controls: 10342 TB/lung), although diameters of TB were similar across groups (p=0.37). In addition, alveolar spaces tended to be larger in PIBO (p=0.070). 3D micro CT analysis confirmed that in BOS, BO lesions are only segmental with preserved TBs, while in PIBO, the airway is completely lost following the obstruction. PIBO lungs displayed a more than two-fold decrease in TB compared to BOS, with fewer but larger BO lesions and non-reopening of airways distal from BO. Our findings provide potential pathophysiologic evidence of dysanaptic lung growth in PIBO. [ABSTRACT FROM AUTHOR]