Endoscopic advanced imaging of the respiratory tract: exploring probe-based confocal laser endomicroscopy in emphysema.

: Probe-based confocal laser endomicroscopy (pCLE) was performed in 15 patients with emphysema and 15 healthy subjects to visualise small airways in a direct and dynamic way. Morphometry shows that the median cross-sectional area of the alveolar openings at the level of the alveolar ducts is significantly larger in emphysema (7.2×104 µm2) as compared with healthy subjects (5.2×104 µm2) (p=0.0002). Normalised autofluorescence intensity histograms show a decrease in median autofluorescence intensity (mAFI) in emphysema (p=0.001). mAFI correlates well with Tiffeneau index (r=0.66, p=0.007, 95% CI 0.21 to 0.88). Autofluorescence intensity in emphysema correlates with corresponding data of CT-based quantification. pCLE-based morphometry and autofluorescence intensity analysis in emphysema is able to detect regional changes inside the 'quiet zone'. TRIAL REGISTRATION NUMBER: Results, NCT01204970.

"White-Out" After Lung Transplantation: A Multicenter Cohort Description of Late Acute Graft Failure.

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.

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.

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.

Combined or Serial Liver and Lung Transplantation for Epithelioid Hemangioendothelioma: A Case Series.

Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor with variable biological and clinical behavior. There is increasing experience with liver transplantation (LiTx) for hepatic EHE, even in cases of extrahepatic disease localization. Until now, no cases of lung transplantation (LuTx) had been reported for pulmonary EHE. This report describes three cases of EHE with multifocal disease in patients who underwent either serial or combined LiTx and LuTx.

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.

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.

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.

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.

Once in a blue moon: Primaquine-induced methemoglobinemia - A case report.

Methemoglobinemia is a rare blood disorder that should be suspected in patients with cyanosis and low oxygen saturation of around 85%, especially when both do not improve despite supplemental oxygen. We describe the case of a 67-year-old lung transplant patient who was treated with primaquine and clindamycin because of a positive Pneumocystis jirovecii polymerase chain reaction on bronchoalveolar lavage fluid. Soon thereafter the patient developed increasing shortness of breath, central cyanosis and hypoxia, with an oxygen saturation of 86% on pulse oximetry despite supplemental oxygen. Arterial blood gas analysis showed a peculiar dark brown color and a significantly increased methemoglobin percentage. A diagnosis of methemoglobinemia due to primaquine was made. As treatment option, we preferred ascorbic acid over methylene blue because of concerns of possibly eliciting a serotonin syndrome. Our patient recovered rapidly after initiation of appropriate treatment. A high index of suspicion is crucial since this condition is potentially fatal.

A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation.

Azithromycin reduces airway inflammation and improves forced expiratory volume in 1 s (FEV1) in chronic rejection or bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTx). Azithromycin prophylaxis might prevent BOS. A double-blind randomised controlled trial of azithromycin (n = 40) or placebo (n = 43), initiated at discharge and administered three times a week for 2 yrs, was performed in 2005-2009 at the Leuven University Hospital (Leuven, Belgium). Primary end-points were BOS-free and overall survival 2 yrs after LTx; secondary end-points were acute rejection, lymphocytic bronchiolitis and pneumonitis rate, prevalence of pseudomonal airway colonisation or gastro-oesophageal reflux, and change in FEV1, airway and systemic inflammation over time. Patients developing BOS were assessed for change in FEV1 with open-label azithromycin. BOS occurred less in patients receiving azithromycin: 12.5 versus 44.2% (p = 0.0017). BOS-free survival was better with azithromycin (hazard ratio 0.27, 95% CI 0.092-0.816; p = 0.020). Overall survival, acute rejection, lymphocytic bronchiolitis, pneumonitis, colonisation and reflux were comparable between groups. Patients receiving azithromycin demonstrated better FEV1 (p = 0.028), and lower airway neutrophilia (p = 0.015) and systemic C-reactive protein levels (p = 0.050) over time. Open-label azithromycin for BOS improved FEV1 in 52.2% patients. No serious adverse events were noted. Azithromycin prophylaxis attenuates local and systemic inflammation, improves FEV1 and reduces BOS 2 yrs after LTx.

Lung transplantation for respiratory failure; Belgium amongst the world leaders.

Lung transplantation is a life-saving treatment option in carefully selected patients with end-stage lung disease. Life expectancy after this form of treatment has progressively increased with a current survival of 90% after 1 year, 70% after 5 years, and 50% after 10 years in experienced centers. Apart from a survival benefit, this treatment aims to improve the quality of life. Bilateral lung transplantation is the type of operation that is performed most frequently because of superior survival results, especially when chronic rejection develops. Single lung transplantation is now reserved for older patients with pulmonary fibrosis. Heart-lung transplantation is rarely done, only in patients with Eisenmenger's syndrome or complex congenital heart disease. Belgium is one of the world leaders in terms of number of deceased organ donors with a lung recovery rate of about 35%. With a total of 8.3 lung transplants per million population, Belgium is currently the number 1 in the world. The procedure nowadays is performed in 4 University Hospitals (UA-KUL-ULB-UCL) in the country. Between 1983 and 2009, nearly 1000 proedures were performed. The most common indication was emphysema, followed by cystic fibrosis, pulmonary fibrosis, pulmonary arterial hypertension, and Eisenmenger's syndrome. Further application of this treatment option is hampered by several problems such as donor organ shortage, primary graft dysfunction, chronic rejection presenting as bronchiolitis obliterans syndrome, and side effect of chronic immunosuppression. In the Laboratory for Experimental Thoracic Surgery and the Laboratory for Pneumology at the Katholieke Universiteit Leuven, intensive research is done by our group looking for new methods to increase the lung donor pool and to prevent and to treat chronic rejection.

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.

Plasmacytoid dendritic cells in pulmonary lymphoid follicles of patients with COPD.

Plasmacytoid dendritic cells (pDCs) are professional antigen-presenting cells with antiviral and tolerogenic capabilities. Viral infections and autoimmunity are proposed to be important mechanisms in the pathogenesis of chronic obstructive pulmonary disease (COPD). The study aimed to quantify blood dendritic cell antigen 2-positive pDCs in lungs of subjects with or without COPD by immunohistochemistry and flow cytometry, combined with the investigation of the influence of cigarette smoke extract (CSE) on the function of pDCs in vitro. pDCs were mainly located in lymphoid follicles, a finding compatible with their expression of lymphoid homing chemokine receptors CXCR3 and CXCR4. pDC accumulated in the lymphoid follicles and in lung digests of patients with mild to moderate COPD, compared with smokers without airflow limitation and patients with COPD Global Initiative for Chronic Obstructive Lung disease (GOLD) stage III-IV. Exposing maturing pDC of healthy subjects to CSE in vitro revealed an attenuation of the expression of co-stimulatory molecules and impaired interferon-α production. Maturing pDC from patients with COPD produced higher levels of tumour necrosis factor (TNF)-α and interleukin (IL)-8 compared to pDC from healthy subjects. CSE significantly impairs the antiviral function of pDCs. In COPD, a GOLD stage dependent accumulation of pDC in lymphoid follicles is present, combined with an enhanced production of TNF-α and IL-8 by maturing pDCs.

Azithromycin reduces pulmonary fibrosis in a bleomycin mouse model.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease without proper treatment. Despite intensive research, the exact underlying pathogenesis remains elusive. It is regarded as a continuous injury, resulting in inflammation, infiltration, and proliferation of fibroblasts and extracellular matrix deposition, leading to an irreversible restrictive lung function deterioration and death. In this study the effect of azithromycin, a macrolide antibiotic on bleomycin-induced pulmonary fibrosis was investigated. C57BL/6 mice were intratracheally instilled with bleomycin (0.5 mg/kg) or saline. In the bleomycin group, half of the animals received azithromycin every other day from day 1 on. Bronchoalveolar lavage and histology were performed at days 7 and 35, and pulmonary function tests on day 35. At day 35, fibrotic lesions (spindle cell proliferation/collagen I deposition) were paralleled by a restrictive lung function pattern. Alterations were found in neutrophils and macrophages (innate immunity) and in T(H)2, T(H)17, and Treg cytokines (adaptive immunity). Azithromycin significantly reduced both fibrosis and the restrictive lung function pattern. This study demonstrated a beneficial effect of azithromycin on bleomycin-induced pulmonary fibrosis. A possible mechanism could be a modulation of both innate immunity and adaptive immunity. These findings might suggest a potential role for azithromycin in the treatment of IPF.

Follicular bronchiolitis: a rare cause of bronchiolitis obliterans syndrome after lung transplantation: a case report.

This case report is the first confirmed case of follicular bronchiolitis (FB), a rare bronchiolar disorder characterized by peribronchiolar lymphoid follicles, in a series of over 400 lung transplantations performed in our center. It is to our knowledge, the first publication describing FB after lung transplantation (LTx), presenting as chronic allograft dysfunction or bronchiolitis obliterans syndrome (BOS).

Plasma C-reactive protein levels correlate with markers of airway inflammation after lung transplantation: a role for systemic inflammation in bronchiolitis obliterans syndrome?

OBJECTIVE: Plasma C-reactive protein (CRP) concentration has been associated with allograft dysfunction in cardiac and renal transplantation; data in lung transplantation (LTx), however, are lacking. We hypothesized that in Ltx, systemic inflammation may be associated with airway inflammation, which has an important role in the development of chronic allograft dysfunction or bronchiolitis obliterans syndrome after LTx. METHODS: In this retrospective, longitudinal, cohort study, plasma CRP concentration, bronchoalveolar lavage (BAL) inflammatory markers (interleukin [IL]-6 and IL-8 protein levels and cell differentials), and pulmonary function (forced expiratory volume in 1 second) were evaluated in 100 LTx recipients at discharge and at 3-, 6-, and 12-month follow-up. The Spearman rank test was used to determine a possible relationship between these parameters at each routine follow-up visit. RESULTS: Plasma CRP concentration positively correlated with BAL total cell count and neutrophilia, whereas there was a negative correlation with pulmonary function at discharge and at 3 and 6 months after LTx. A correlation between plasma CRP concentration and BAL interleukin levels was present at discharge (IL-6 and IL-8) and at 6 months (IL-8) after LTx. CONCLUSION: Systemic inflammation and IL-8-mediated neutrophilic airway inflammation seem to be associated after LTx. Therefore, systemic inflammation has a possible role in the development of bronchiolitis obliterans syndrome after LTx.