Publications by authors named "Dirk E Van Raemdonck"

114 Publications

Lung transplantation for acute respiratory distress syndrome: A multicenter experience.

Am J Transplant 2021 Jul 13. Epub 2021 Jul 13.

Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria.

Acute respiratory distress syndrome (ARDS) is a rapidly progressive lung disease with a high mortality rate. Although lung transplantation (LTx) is a well-established treatment for a variety of chronic pulmonary diseases, LTx for acute lung failure (due to ARDS) remains controversial. We reviewed posttransplant outcome of ARDS patients from three high-volume European transplant centers. Demographics and clinical data were collected and analyzed. Viral infection was the main reason for ARDS (n = 7/13, 53.8%). All patients were admitted to ICU and required mechanical ventilation, 11/13 were supported with ECMO at the time of listing. They were granted a median LAS of 76 (IQR 50-85) and waited for a median of 3 days (IQR 1.5-14). Postoperatively, median length of mechanical ventilation was 33 days (IQR 17-52.5), median length of ICU and hospital stay were 39 days (IQR 19.5-58.5) and 54 days (IQR 43.5-127). Prolongation of peripheral postoperative ECMO was required in 7/13 (53.8%) patients with a median duration of 2 days (IQR 2-7). 30-day mortality was 7.7%, 1 and 5-year survival rates were calculated as 71.6% and 54.2%, respectively. Given the lack of alternative treatment options, the herein presented results support the concept of offering live-saving LTx to carefully selected ARDS patients.
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http://dx.doi.org/10.1111/ajt.16759DOI Listing
July 2021

Connective Tissue Growth Factor Is Overexpressed in Explant Lung Tissue and Broncho-Alveolar Lavage in Transplant-Related Pulmonary Fibrosis.

Front Immunol 2021 25;12:661761. Epub 2021 May 25.

Department of Chronic Diseases and Metabolism, Katholieke Universiteit, Leuven, Belgium.

Background: Connective tissue growth factor (CTGF) is an important mediator in several fibrotic diseases, including lung fibrosis. We investigated CTGF-expression in chronic lung allograft dysfunction (CLAD) and pulmonary graft-versus-host disease (GVHD).

Materials And Methods: CTGF expression was assessed by quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry in end-stage CLAD explant lung tissue (bronchiolitis obliterans syndrome (BOS), n=20; restrictive allograft syndrome (RAS), n=20), pulmonary GHVD (n=9). Unused donor lungs served as control group (n=20). Next, 60 matched lung transplant recipients (BOS, n=20; RAS, n=20; stable lung transplant recipients, n=20) were included for analysis of CTGF protein levels in plasma and broncho-alveolar lavage (BAL) fluid at 3 months post-transplant, 1 year post-transplant, at CLAD diagnosis or 2 years post-transplant in stable patients.

Results: qPCR revealed an overall significant difference in the relative content of CTGF mRNA in BOS, RAS and pulmonary GVHD vs. controls (p=0.014). Immunohistochemistry showed a significant higher percentage and intensity of CTGF-positive respiratory epithelial cells in BOS, RAS and pulmonary GVHD patients vs. controls (p<0.0001). BAL CTGF protein levels were significantly higher at 3 months post-transplant in future RAS vs. stable or BOS (p=0.028). At CLAD diagnosis, BAL protein content was significantly increased in RAS patients vs. stable (p=0.0007) and BOS patients (p=0.042). CTGF plasma values were similar in BOS, RAS, and stable patients (p=0.74).

Conclusions: Lung CTGF-expression is increased in end-stage CLAD and pulmonary GVHD; and higher CTGF-levels are present in BAL of RAS patients at CLAD diagnosis. Our results suggest a potential role for CTGF in CLAD, especially RAS, and pulmonary GVHD.
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http://dx.doi.org/10.3389/fimmu.2021.661761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187127PMC
May 2021

Once daily tacrolimus conversion in lung transplantation: A prospective study on safety and medication adherence.

J Heart Lung Transplant 2021 Jun 27;40(6):467-477. Epub 2021 Feb 27.

Department of Respiratory Diseases, Lung Transplantation Group, UZ Leuven, Campus Gasthuisberg, Leuven, Belgium; Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department CHROMETA, KU Leuven, Leuven, Belgium.

Background: Lung transplantation (LTx) requires a calcineurin inhibitor-based immunosuppressive regimen. A once daily (QD) tacrolimus regimen was developed to increase medication adherence. However, data concerning its safety and efficacy in LTx are lacking.

Methods: In this prospective study, stable LTx patients were consecutively converted from twice daily (BID) tacrolimus to QD tacrolimus on a 1 mg:1 mg basis. Trough level (C), renal function, cholesterol, fasting glucose, potassium and lung function were monitored six months before and up to one year after conversion. Adherence and its barriers were assessed by self-reported questionnaires (Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS) and Identification of Medication Adherence Barriers questionnaire (IMAB)) and blood-based assays (mean C and coefficient of variation (CV)).

Results: We included 372 patients, in whom we observed a decrease in tacrolimus C of 18.5% (p < 0.0001) post-conversion, requiring subsequent daily dose adaptations in both cystic fibrosis (CF) (n = 72) and non-CF patients (n = 300). We observed a small decrease in eGFR one year post-conversion (p = 0.024). No significant changes in blood creatinine, potassium, fasting glucose, cholesterol or rate of lung function decline were observed. In a subgroup of 166 patients, significantly fewer patients missed doses (8.4% vs. 19.3%, p = 0.016) or had irregular intake post-conversion (19.3% vs. 32.5%, p = 0.019). Mean C and CV, as well as the total number of barriers, also decreased significantly post-conversion.

Conclusions: In LTx, conversion from BID to QD tacrolimus (1 mg:1 mg) requires close monitoring of tacrolimus C. QD tacrolimus after transplantation is safe with respect to renal function, metabolic parameters and allograft function and improves LTx recipient adherence.
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http://dx.doi.org/10.1016/j.healun.2021.02.017DOI Listing
June 2021

A novel experimental porcine model to assess the impact of differential pulmonary blood flow on ischemia-reperfusion injury after unilateral lung transplantation.

Intensive Care Med Exp 2021 Feb 5;9(1). Epub 2021 Feb 5.

Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium.

Background: Primary graft dysfunction (PGD) remains a major obstacle after lung transplantation. Ischemia-reperfusion injury is a known contributor to the development of PGD following lung transplantation. We developed a novel approach to assess the impact of increased pulmonary blood flow in a large porcine single-left lung transplantation model.

Materials: Twelve porcine left lung transplants were divided in two groups (n = 6, in low- (LF) and high-flow (HF) group). Donor lungs were stored for 24 h on ice, followed by left lung transplantation. In the HF group, recipient animals were observed for 6 h after reperfusion with partially clamping right pulmonary artery to achieve a higher flow (target flow 40-60% of total cardiac output) to the transplanted lung compared to the LF group, where the right pulmonary artery was not clamped.

Results: Survival at 6 h was 100% in both groups. Histological, functional and biological assessment did not significantly differ between both groups during the first 6 h of reperfusion. injury was also present in the right native lung and showed signs compatible with the pathophysiological hallmarks of ischemia-reperfusion injury.

Conclusions: Partial clamping native pulmonary artery in large animal lung transplantation setting to study the impact of low versus high pulmonary flow on the development of ischemia reperfusion is feasible. In our study, differential blood flow had no effect on IRI. However, our findings might impact future studies with extracorporeal devices and represent a specific intra-operative problem during bilateral sequential single-lung transplantation.
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http://dx.doi.org/10.1186/s40635-021-00371-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862464PMC
February 2021

Distinct Airway Involvement in Subtypes of End-Stage Fibrotic Pulmonary Sarcoidosis.

Chest 2021 Jan 10. Epub 2021 Jan 10.

BREATHE, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium.

Background: Sarcoidosis is a systemic granulomatous disease that in most patients affects the lung. Pulmonary fibrotic sarcoidosis is clinically, radiologically, and pathologically a heterogeneous condition. Although substantial indirect evidence suggests small airways involvement, direct evidence currently is lacking.

Research Question: What is the role of the (small) airways in fibrotic sarcoidosis?

Study Design And Methods: Airway morphologic features were investigated in seven explant lungs with end-stage fibrotic sarcoidosis using a combination of CT scanning (large airways), micro-CT scanning (small airways), and histologic examination and compared with seven unused donor lungs as controls with specific attention focused on different radiologically defined sarcoidosis subtypes.

Results: Patients with central bronchial distortion (n = 3), diffuse bronchiectasis (n = 3), and usual interstitial pneumonia pattern (n = 1) were identified based on CT scan, showing a decrease and narrowing of large airways, a similar airway number and increased airway diameter of more distal airways, or an increase in airway number and airway diameter, respectively, compared with control participants. The number of terminal bronchioles per milliliter and the total number of terminal bronchioles were decreased in all forms of fibrotic sarcoidosis. Interestingly, the number of terminal bronchioles was correlated inversely with the degree of fibrosis. Furthermore, we identified granulomatous remodeling as a cause of small airways loss using serial micro-CT scanning and histologic examination.

Interpretation: The large airways are involved differentially in subtypes of sarcoidosis, but the terminal bronchioles universally are lost. This suggests that small airways loss forms an important aspect in the pathophysiologic features of fibrotic pulmonary sarcoidosis.
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http://dx.doi.org/10.1016/j.chest.2021.01.003DOI Listing
January 2021

Successful double-lung transplantation from a donor previously infected with SARS-CoV-2.

Lancet Respir Med 2021 03 1;9(3):315-318. Epub 2020 Dec 1.

Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium; Department of Chronic Diseases and Metabolism, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Lung Transplant Unit, KU Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1016/S2213-2600(20)30524-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831530PMC
March 2021

Flow-controlled ventilation during EVLP improves oxygenation and preserves alveolar recruitment.

Intensive Care Med Exp 2020 Nov 25;8(1):70. Epub 2020 Nov 25.

Unit of Anesthesiology and Algology, Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Leuven, Belgium.

Background: Ex vivo lung perfusion (EVLP) is a widespread accepted platform for preservation and evaluation of donor lungs prior to lung transplantation (LTx). Standard lungs are ventilated using volume-controlled ventilation (VCV). We investigated the effects of flow-controlled ventilation (FCV) in a large animal EVLP model. Fourteen porcine lungs were mounted on EVLP after a warm ischemic interval of 2 h and randomized in two groups (n = 7/group). In VCV, 7 grafts were conventionally ventilated and in FCV, 7 grafts were ventilated by flow-controlled ventilation. EVLP physiologic parameters (compliance, pulmonary vascular resistance and oxygenation) were recorded hourly. After 6 h of EVLP, broncho-alveolar lavage (BAL) was performed and biopsies for wet-to-dry weight (W/D) ratio and histology were taken. The left lung was inflated, frozen in liquid nitrogen vapors and scanned with computed tomography (CT) to assess regional distribution of Hounsfield units (HU).

Results: All lungs endured 6 h of EVLP. Oxygenation was better in FCV compared to VCV (p = 0.01) and the decrease in lung compliance was less in FCV (p = 0.03). W/D ratio, pathology and BAL samples did not differ between both groups (p = 0.16, p = 0.55 and p = 0.62). Overall, CT densities tended to be less pronounced in FCV (p = 0.05). Distribution of CT densities revealed a higher proportion of well-aerated lung parts in FCV compared to VCV (p = 0.01).

Conclusions: FCV in pulmonary grafts mounted on EVLP is feasible and leads to improved oxygenation and alveolar recruitment. This ventilation strategy might prolong EVLP over time, with less risk for volutrauma and atelectrauma.
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http://dx.doi.org/10.1186/s40635-020-00360-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686942PMC
November 2020

Peripheral Blood Eosinophilia Is Associated with Poor Outcome Post-Lung Transplantation.

Cells 2020 11 20;9(11). Epub 2020 Nov 20.

Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, B-3000 Leuven, Belgium.

Eosinophils play a role in many chronic lung diseases. In lung transplantation (LTx), increased eosinophils in bronchoalveolar lavage (BAL) was associated with worse outcomes. However, the effect of peripheral blood eosinophilia after LTx has not been investigated thoroughly. A retrospective study was performed including all LTx patients between 2011-2016. Chronic lung allograft dysfunction (CLAD)-free and graft survival were compared between patients with high and low blood eosinophils using an 8% threshold ever during follow-up. A total of 102 patients (27.1%) had high blood eosinophils (≥8%) (45 before CLAD and 17 after, 40 had no CLAD) and 274 (72.9%) had low eosinophils (<8%). Patients with high blood eosinophils demonstrated worse graft survival ( = 0.0001) and CLAD-free survival ( = 0.003) compared to low eosinophils. Patients with both high blood and high BAL (≥2%) eosinophils ever during follow-up had the worst outcomes. Within the high blood eosinophil group, 23.5% had RAS compared to 3% in the group with low eosinophils ( < 0.0001). After multivariate analysis, the association between high blood eosinophils and graft and CLAD-free survival remained significant ( = 0.036, = 0.013) independent of high BAL eosinophils and infection at peak blood eosinophilia, among others. LTx recipients with ever ≥8% blood eosinophils demonstrate inferior graft and CLAD-free survival, specifically RAS, which requires further prospective research.
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http://dx.doi.org/10.3390/cells9112516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699939PMC
November 2020

Free Airway C4d after Lung Transplantation - A Quantitative Analysis of Bronchoalveolar Lavage Fluid.

Transpl Immunol 2021 02 17;64:101352. Epub 2020 Nov 17.

Department of Chronic Diseases, Metabolism & Ageing (CHROMETA), Laboratory of Respiratory Diseases & Thoracic Surgery (BREATHE), UZ/KU Leuven, Leuven, Belgium. Electronic address:

In recent years, the utility of vascular complement factor 4d (C4d) deposition as diagnostic tool for antibody mediated rejection (AMR) after lung transplantation, has become a controversial issue. We aimed to pinpoint the problematic nature of C4d as biomarker with a simple experiment. We quantified C4d in broncho-alveolar lavage (BAL) of lung transplant patients with diverse post-transplant complications in 3 different settings of clinically clear cases of: 1/ chronic lung allograft dysfunction (CLAD); 2/ acute complications acute rejection (AR), lymphocytic bronchiolitis (LB), antibody-mediated rejection (AMR) and respiratory infection (INF); 3/ patients with parallel C4d immunostaining and Anti-HLA. All groups were compared to BAL of stable patients. C4d was measured via standard ELISA. C4d was increased in CLAD, predominantly in RAS (p = 0.0026) but not in BOS (p = 0.89). C4d was increased in all acute events, AR (p = 0.0025), LB (p < 0.0001), AMR (p = 0.0034), infections (p < 0.0001). In patients with parallel C4d immunostaining and serum HLA antibodies, C4d was increased in C4d-/HLA- (p = 0.0011); C4d-/HLA+ (p = 0.013); HLA+/C4d + (p = 0.0081). A correlation of systemic C-reactive protein (CRP) with C4d was found in all patients (r = 0.49; p < 0.0001). We hypothesize that free C4d in BAL may only be representative of a general immune response in the transplanted lung.
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http://dx.doi.org/10.1016/j.trim.2020.101352DOI Listing
February 2021

Small airway loss in the physiologically ageing lung: a cross-sectional study in unused donor lungs.

Lancet Respir Med 2021 02 5;9(2):167-174. Epub 2020 Oct 5.

Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic diseases, Metabolism and Aging (CHROMETA), KU Leuven, Leuven, Belgium.

Background: Physiological lung ageing is associated with a gradual decline in dynamic lung volumes and a progressive increase in residual volume due to diminished elastic recoil of the lung, loss of alveolar tissue, and lower chest wall compliance. However, the effects of ageing on the small airways (ie, airways <2·0 mm in diameter) remain largely unknown. By using a combination of ex-vivo conventional CT (resolution 1 mm), whole lung micro-CT (resolution 150 μm), and micro-CT of extracted cores (resolution 10 μm), we aimed to provide a multiresolution assessment of the small airways in lung ageing in a large cohort of never smokers.

Methods: For this cross-sectional study, we included donor lungs collected from 32 deceased never-smoking donors (age range 16-83 years). Ex-vivo CT and whole lung high-resolution CT (micro-CT) were used to determine total airway numbers, stratified by airway diameter. Micro-CT was used to assess the number, length, and diameter of terminal bronchioles (ie, the last generation of conducting airways); mean linear intercept; and surface density in four lung tissue cores from each lung, extracted using a uniform sampling approach. Regression β coefficients are calculated using linear regression and polynomial models.

Findings: Ex-vivo CT analysis showed an age-dependent decrease in the number of airways of diameter 2·0 mm to less than 2·5 mm (β coefficient per decade -0·119, 95% CI -0·193 to -0·045; R=0·29) and especially in airways smaller than 2·0 mm in diameter (-0·158, -0·233 to -0·084; R=0·47), between 30 and 80 years of age, but not of the larger (≥2·5 mm) diameter airways (-0·00781, -0·04409 to 0·02848; R=0·0007). In micro-CT analysis of small airways, the total number of terminal bronchioles per lung increased until the age of 30 years, after which an almost linear decline in the number of terminal bronchioles was observed (β coefficient per decade -2035, 95% CI -2818 to -1252; R=0·55), accompanied by a non-significant increase in alveolar airspace size (6·44, -0·57 to 13·45, R=0·10). Moreover, this decrease in terminal bronchioles was associated with the age-related decline of pulmonary function predicted by healthy reference values.

Interpretation: Loss of terminal bronchioles is an important structural component of age-related decline in pulmonary function of healthy, non-smoking individuals.

Funding: Research Foundation-Flanders, KU Leuven, Parker B Francis Foundation, UGent, Canadian Institutes for Health.
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http://dx.doi.org/10.1016/S2213-2600(20)30324-6DOI Listing
February 2021

Diagnostic Yield of 18F-FDG PET After Lung Transplantation: A Single-center, Retrospective Cohort Study.

Transplantation 2021 07;105(7):1603-1609

Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium.

Background: To investigate the diagnostic yield of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in lung transplant recipients.

Methods: A single-center, retrospective cohort study including 234 18F-FDG PET examinations in 199 lung transplant recipients. Indication for PET referral, 18F-FDG PET diagnosis/findings and final clinical diagnosis were classified into 3 groups: malignancy, infection/inflammation not otherwise specified, and chronic lung allograft dysfunction with restrictive allograft syndrome phenotype. Sensitivity/specificity analysis was performed to determine accuracy of 18F-FDG PET in each group.

Results: Sensitivity of 18F-FDG PET for malignancy was 91.4% (95% confidence interval, 82.5%-96.0%) and specificity was 82.3% (95% confidence interval, 74.5%-88.1%). Infection/inflammation not otherwise specified and restrictive allograft syndrome as indication for 18F-FDG PET comprised relatively small groups (14 and 31 cases, respectively). In addition, 18F-FDG PET revealed clinically relevant incidental findings in 15% of cases.

Conclusions: Referral for 18F-FDG PET after lung transplantation mainly occurred to confirm or rule out malignancy. In this specific setting, 18F-FDG PET has a high diagnostic yield. Accuracy of 18F-FDG PET for other indications is less clear, given small sample sizes. Clinically relevant diagnoses, unrelated to the primary indication for 18F-FDG PET, are found relatively often in this immunocompromised cohort.
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http://dx.doi.org/10.1097/TP.0000000000003456DOI Listing
July 2021

Intracerebral abscess due to Cutibacterium acnes after lung transplantation.

Transpl Infect Dis 2021 Feb 14;23(1):e13398. Epub 2020 Jul 14.

Department of Respiratory Disease, University Hospital Gasthuisberg, UZ Leuven, Leuven, Belgium.

Cutibacterium (C) acnes, a Gram-positive bacterium that is part of the commensal flora, is increasingly noticed as an opportunistic pathogen in serious infections in both immunocompromised and immunocompetent patients. The indolent character and often difficult identification because of its slow growth contribute to delayed diagnosis or underdiagnosis. This report highlights a unique case of a lung transplant recipient with a C acnes intracerebral abscess, and we recommend including this organism in such differential diagnosis. A 66-year-old woman, 2 years after bilateral lung transplantation for chronic obstructive pulmonary disease, presented with frontal headache, without other complaints, and with normal neurological examination. Magnetic resonance imaging showed an extensive lesion in the right frontal lobe with extensive perilesional edema. Given the broad differential diagnosis, stereotactic brain biopsy was performed and culture became positive for C acnes. She was treated with intravenous ceftriaxone for 8 weeks and per oral clindamycin for 6 months, as well as corticosteroids in tapered dose. There was a rapid favorable clinical and radiographic evolution.
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http://dx.doi.org/10.1111/tid.13398DOI Listing
February 2021

Successful eradication improves outcomes after lung transplantation: a retrospective cohort analysis.

Eur Respir J 2020 10 1;56(4). Epub 2020 Oct 1.

Dept of Respiratory Medicine, University Hospitals Leuven, Leuven, Belgium

Long-term survival after lung transplantation (LTx) is hampered by development of chronic lung allograft dysfunction (CLAD). is an established risk factor for CLAD. Therefore, we investigated the effect of eradication on CLAD-free and graft survival.Patients who underwent first LTx between July, 1991, and February, 2016, and were free from CLAD, were retrospectively classified according to presence in respiratory samples between September, 2011, and September, 2016. -positive patients were subsequently stratified according to success of eradication following targeted antibiotic treatment. CLAD-free and graft survival were compared between -positive and -negative patients; and between patients with or without successful eradication. In addition, pulmonary function was assessed during the first year following isolation in both groups.CLAD-free survival of -negative patients (n=443) was longer compared with -positive patients (n=95) (p=0.045). Graft survival of -negative patients (n=443, 82%) was better compared with -positive patients (n=95, 18%) (p<0.0001). Similarly, -eradicated patients demonstrated longer CLAD-free and graft survival compared with patients with persistent Pulmonary function was higher in successfully -eradicated patients compared with unsuccessfully eradicated patients (p=0.035). eradication after LTx improves CLAD-free and graft survival and maintains pulmonary function. Therefore, early detection and eradication should be pursued.
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http://dx.doi.org/10.1183/13993003.01720-2020DOI Listing
October 2020

Survival in adult lung transplantation: where are we in 2020?

Curr Opin Organ Transplant 2020 06;25(3):268-273

Lung Transplantation Unit, Department of Respiratory Diseases, University Hospital Gasthuisberg.

Purpose Of Review: In this article, an overview of the survival after lung transplantation will be given, with a focus on factors affecting outcome and differences in survival determined by underlying disease.

Recent Findings: Lung transplantation is an established treatment modality for patients with various end-stage lung diseases. The most recent International Society for Heart and Lung Transplantation Registry reports a 1 and 5-year survival of 85 and 59%, respectively, for adult lung transplant recipients transplanted since 2010. Over the past decades, significant improvements in patient outcomes have been achieved related to changes in donor selection, organ preservation, perioperative management and better treatment of postoperative complications. However, long-term graft and patient outcomes still lag behind that of other solid organ transplantations. Chronic lung allograft dysfunction (CLAD) a condition which develops in about 50% of recipients 5 year after lung transplantation, remains the major barrier for long-term survival, although development of solid organ cancer is nowadays also an increasing cause of late mortality.

Summary: Lung transplantation offers a survival benefit in well chosen patients with end-stage lung diseases. However, CLAD, side effects of immunosuppressive therapy and solid organ cancer remain important challenges impairing long-term survival. Advances in prevention and treatment of chronic rejection are critical to further improve outcome.
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http://dx.doi.org/10.1097/MOT.0000000000000753DOI Listing
June 2020

Early protein expression profile in bronchoalveolar lavage fluid and clinical outcomes in primary graft dysfunction after lung transplantation.

Eur J Cardiothorac Surg 2020 08;58(2):379-388

Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium.

Objectives: Primary graft dysfunction (PGD) remains a major post-transplant complication and is associated with increased morbidity and mortality. Mechanisms evoking PGD are not completely clear, but inflammation plays a central role. We investigated the association between PGD and inflammatory proteins present in immediate postoperative bronchoalveolar lavage.

Methods: All double-lung recipients transplanted at our institution from 2002 to 2018 were included in our study. We retrospectively selected 80 consecutive lung transplant recipients with different PGD grades (n = 20 for each PGD grades 0-1 to 2-3). In bronchoalveolar lavage performed within the first 24 h after donor aortic cross-clamping following lung transplantation, concentrations of 30 cytokines, chemokines and growth factors were assessed by enzyme-linked immunosorbent assay (ELISA) and correlated with donor and recipient demographics and outcomes. For analysis, 2 groups were defined: 'mild' PGD (grade 0-1) and 'severe' PGD (grades 2-3).

Results: Significant differences between mild and severe PGD were found in 8 biomarkers [interleukin (IL)-6, IL-10, IL-13, eotaxin, granulocyte colony-stimulating factor, interferon γ, macrophage inflammatory protein 1α, surfactant protein D (SP-D); P < 0.05]. Increased IL-10 and IL-13, but none of the other proteins, were associated with short-term outcome (longer time to extubation; P = 0.005 and P < 0.0001; increased intensive care unit stay; P = 0.012 and P < 0.0001; and hospital stay; P = 0.041 and P = 0.002). There were no significant differences in donor and recipient characteristics between the groups.

Conclusions: Expression profiles of key inflammatory mediators in bronchoalveolar lavage fluid differed significantly between lung transplant recipients with severe versus mild PGD and correlated with clinical outcome variables. Further research should focus on the early mechanisms leading to PGD.
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http://dx.doi.org/10.1093/ejcts/ezaa043DOI Listing
August 2020

Optimizing future lung transplant outcomes: asking the right questions for an alternative truth.

Ther Adv Respir Dis 2020 Jan-Dec;14:1753466619897879

Department of Respiratory Medicine, Lung Transplant Unit, University Hospitals Leuven, Leuven, Belgium and Department of Chronic Diseases, Metabolism & Ageing (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1177/1753466619897879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082867PMC
June 2021

Small airways pathology in idiopathic pulmonary fibrosis: a retrospective cohort study.

Lancet Respir Med 2020 06 13;8(6):573-584. Epub 2020 Feb 13.

University of British Columbia, Department of Pathology and Center for Heart and Lung Innovation at St Paul's Hospital, Vancouver, BC, Canada. Electronic address:

Background: The observation that patients with idiopathic pulmonary fibrosis (IPF) can have higher than normal expiratory flow rates at low lung volumes led to the conclusion that the airways are spared in IPF. This study aimed to re-examine the hypothesis that airways are spared in IPF using a multiresolution imaging protocol that combines multidetector CT (MDCT), with micro-CT and histology.

Methods: This was a retrospective cohort study comparing explanted lungs from patients with severe IPF treated by lung transplantation with a cohort of unused donor (control) lungs. The donor control lungs had no known lung disease, comorbidities, or structural lung injury, and were deemed appropriate for transplantation on review of the clinical files. The diagnosis of IPF in the lungs from patients was established by a multidisciplinary consensus committee according to existing guidelines, and was confirmed by video-assisted thoracic surgical biopsy or by pathological examination of the contralateral lung. The control and IPF groups were matched for age, sex, height, and bodyweight. Samples of lung tissue were compared using the multiresolution imaging approach: a cascade of clinical MDCT, micro-CT, and histological imaging. We did two experiments: in experiment 1, all the lungs were randomly sampled; in experiment 2, samples were selected from regions of minimal and established fibrosis. The patients and donors were recruited from the Katholieke Universiteit Leuven (Leuven, Belgium) and the University of Pennsylvania Hospital (Philadelphia, PA, USA). The study took place at the Katholieke Universiteit Leuven, and the University of British Columbia (Vancouver, BC, Canada).

Findings: Between Oct 5, 2009, and July 22, 2016, explanted lungs from patients with severe IPF (n=11), were compared with a cohort of unused donor (control) lungs (n=10), providing 240 samples of lung tissue for comparison using the multiresolution imaging approach. The MDCT specimen scans show that the number of visible airways located between the ninth generation (control 69 [SD 22] versus patients with IPF 105 [33], p=0·0023) and 14th generation (control 9 [6] versus patients with IPF 49 [28], p<0·0001) of airway branching are increased in patients with IPF, which we show by micro-CT is due to thickening of their walls and distortion of their lumens. The micro-CT analysis showed that compared with healthy (control) lung anatomy (mean 5·6 terminal bronchioles per mL [SD 1·6]), minimal fibrosis in IPF tissue was associated with a 57% loss of the terminal bronchioles (mean 2·4 terminal bronchioles per mL [SD 1·0]; p<0·0001), the appearance of fibroblastic foci, and infiltration of the tissue by inflammatory immune cells capable of forming lymphoid follicles. Established fibrosis in IPF tissue had a similar reduction (66%) in the number of terminal bronchioles (mean 1·9 terminal bronchioles per mL [SD 1·4]; p<0·0001) and was dominated by increased airspace size, Ashcroft fibrosis score, and volume fractions of tissue and collagen.

Interpretation: Small airways disease is a feature of IPF, with significant loss of terminal bronchioles occuring within regions of minimal fibrosis. On the basis of these findings, we postulate that the small airways could become a potential therapeutic target in IPF.

Funding: Katholieke Universiteit Leuven, US National Institutes of Health, BC Lung Association, and Genentech.
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http://dx.doi.org/10.1016/S2213-2600(19)30356-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292784PMC
June 2020

Histopathologic and radiologic assessment of nontransplanted donor lungs.

Am J Transplant 2020 06 11;20(6):1712-1719. Epub 2020 Feb 11.

Lung Transplant Unit, Department of Chronic Diseases, Metabolism and Ageing, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium.

Donor organ shortage results in significant waiting list mortality. Donor lung assessment is currently based on donors' history, gas exchange, chest X-ray, bronchoscopy findings, and ultimately in situ inspection but remains subjective. We correlated histopathology and radiology in nontransplanted donor lungs with the clinical indications to decline the offered organ. Sixty-two donor lungs, not used for transplantation (2010-2019), were procured, air-inflated, frozen, scanned with computed tomography, systematically sampled, and histologically and radiologically assessed. Thirty-nine (63%) lungs were declined for allograft-related reasons. In 13/39 (33%) lungs, histology could not confirm the reason for decline, in an additional 8/39 (21%) lungs, histologic abnormalities were only considered mild. In 16/39 (41%) lungs, radiology could not confirm the reason for decline. Twenty-three (37%) donor lungs were not transplanted due to extrapulmonary causes, of which three (13%) lungs displayed severe histologic abnormalities (pneumonia, n = 2; emphysema, n = 1), in addition to mild emphysema in 9 (39%) lungs and minor bronchopneumonia in 1 (4%). Radiology revealed ground-glass opacities in 8/23 (35%) and emphysema in 4/23 (17%) lungs. Histopathologic and radiologic assessment of nontransplanted donor lungs revealed substantial discrepancy with the clinical reason for decline. Optimization of donor lung assessment is necessary to improve current organ acceptance rates.
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http://dx.doi.org/10.1111/ajt.15790DOI Listing
June 2020

Total lymphoid irradiation in progressive bronchiolitis obliterans syndrome after lung transplantation: a single-center experience and review of literature.

Transpl Int 2020 02 19;33(2):216-228. Epub 2019 Nov 19.

Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium.

Limited results about treatment with total lymphoid irradiation (TLI) in lung transplant (LTx) recipients suffering from progressive bronchiolitis obliterans syndrome (BOS) have been reported. We performed a retrospective analysis of all LTx recipients undergoing TLI for progressive BOS in our center, focusing on long-term outcomes regarding overall survival and lung allograft function. Treatment with TLI (2004-2017, n = 20, 1 BOS stage 1, 6 BOS stage 2, and 13 BOS stage 3) resulted in significant attenuation of the FEV -decline in the majority of patients, mainly in those with a rapid decline (P = 0.0005). This allowed bridging to redo-transplantation in five patients. However, three patients progressed from BOS to RAS following prior TLI. Overall patient survival was 44% at 2 years post-TLI and 38% after 17 years. Generally, TLI was well tolerated, with limited side effects and no serious adverse events. TLI may attenuate the decline in FEV of LTx recipients with rapid progressive BOS and could thus help to bridge selected patients to redo-transplantation.
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http://dx.doi.org/10.1111/tri.13544DOI Listing
February 2020

Mortality after lung transplantation: a single-centre cohort analysis.

Transpl Int 2020 02 18;33(2):130-141. Epub 2019 Nov 18.

Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium.

Detailed data on postoperative death in lung transplant (LTx) recipients are lacking. Therefore, we investigated all deaths after LTx in a large, single-centre, 25-year follow-up cohort. Prevalence, time, place and cause of death (COD) were retrospectively analysed for all patients undergoing primary LTx between July 1991 and December 2015 in our centre. Over subsequent years, postoperative survival significantly improved, with proportionally more patients surviving to 1-year post-LTx (P < 0.0001). A total of 347 (38.9%) LTx recipients died, of which 53.6% expired within 3 years post-LTx [median time to death 910 (236-2447) days]. Autopsy was performed in 34.8% of deaths. COD included CLAD in 27.1% (BOS 63.8% vs. RAS 36.2%); infection (26.5%); malignancy (15.6%); postoperative complication (11.2%); cardiovascular disease (4.6%) or other causes (6.9%). In 8.1%, no clear COD could be determined. COD significantly differed between the various LTx indications (P = 0.047). With longer follow-up, infection becomes a less prevalent COD, but CLAD and malignancies a more important COD. The majority of patients died on the intensive care unit (40.6%) or hospital ward (29.1%), but place of death varied depending on the underlying COD. The current study provides insights into the postoperative deaths of LTx recipients.
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http://dx.doi.org/10.1111/tri.13540DOI Listing
February 2020

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

Eur Respir J 2019 11 7;54(5). Epub 2019 Nov 7.

Leuven Lung Transplant Group, Dept of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium

Introduction: Circulating 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.

Methods: Tissue 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 ELISA. Anti-HLA class I and II IgG gDSAs were identified using Luminex single antigen beads and compared with DSAs found in serum samples.

Results: Overall, 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% 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 gDSA (p=0.0008), but not in sDSA sDSA (p=0.33). In RAS, total IgG levels correlated with fibrosis (r= -0.39; p=0.02).

Conclusions: This study underlines the potential of gDSA assessment as complementary information to sDSA findings. The relevance and applications of gDSAs need further investigation.
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http://dx.doi.org/10.1183/13993003.00847-2019DOI Listing
November 2019

Myeloid-Derived Suppressor Cells in Lung Transplantation.

Front Immunol 2019 26;10:900. Epub 2019 Apr 26.

Lung Transplant Unit, Lab of Respiratory Diseases, Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium.

Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of immune cells from the myeloid lineage. MDSCs expand in pathological situations, such as chronic infection, cancer, autoimmunity, and allograft rejection. As chronic lung allograft dysfunction (CLAD) limits long-term survival after lung transplantation (LTx), MDSCs may play a role in its pathophysiology. We assessed phenotype and frequency of MDSCs in peripheral blood from lung transplant recipients and its relationship to post-transplant complications and immunosuppression. Granulocytic (G)-MDSC were identified and quantified by flow cytometry of blood from 4 control subjects and 20 lung transplant patients (stable = 6, infection = 5; CLAD = 9). G-MDSC functionality was assessed by their capability to block CD4 and CD8 T cell proliferation. More G-MDSC could be assessed using EDTA tubes compared to heparin tubes ( = 0.004). G-MDSC were increased in stable lung transplant recipients vs. non-transplant controls (52.1% vs. 9.4%; = 0.0095). The infection or CLAD groups had lower G-MDSCs vs. stable recipients (28.2% = 0.041 and 33.0%; = 0.088, respectively), but were not different among CLAD phenotypes. G-MDSC tended to correlate with cyclosporine A and tacrolimus levels ( = 0.18; = 0.17). CD4 and CD8 cells proliferation decreased by 50 and 80% if co-cultured with MDSCs (1:6 and 1:2 MDSC:T-cell ratio, respectively). In conclusion, circulating MDSCs are measurable, functional and have a G-MDSC phenotype in lung transplant patients. Their frequency is increased in stable patients, decreased during post-transplant complications, and related to level of immunosuppression. This study may pave the way for further investigations of MDSC in the context of lung transplantation.
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http://dx.doi.org/10.3389/fimmu.2019.00900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497753PMC
September 2020

Prone Positioning During Ex Vivo Lung Perfusion Influences Regional Edema Accumulation.

J Surg Res 2019 07 19;239:300-308. Epub 2019 Mar 19.

Leuven Lung Transplant Unit, Katholieke Universiteit Leuven, Leuven, Belgium.

Background: Ex vivo lung perfusion (EVLP) is developed to increase the quantity and quality of suitable grafts for lung transplantation. Standardly, lungs are mounted supine with the risk of fluid accumulation in the dorsal regions. Therefore, we investigated the impact of experimental prone position on graft function during EVLP.

Materials And Methods: Porcine lungs were mounted on a normothermic EVLP for 6 h in supine [S], (n = 7) or prone position [P], (n = 7). Physiology during EVLP was recorded. After EVLP, biopsies were assessed for wet-to-dry weight (W/D) ratios and pathology, broncho-alveolar lavage was measured, and the left lung was computed tomography (CT) scanned.

Results: Physiological parameters were similar between both groups, despite a higher pulmonary vascular resistance in [P] (P = 0.0002). In [S], W/D ratios and CT density of dorsal areas were higher compared to ventral (P = 0.0017 and P = 0.053, respectively). In [P], W/D and CT density between ventral and dorsal regions were similar, meaning that pulmonary edema was distributed more homogeneously throughout the lung. Histology and cytokine levels in perfusate and broncho-alveolar lavage did not differ between both groups.

Conclusions: Prone positioning during EVLP is feasible and leads to more homogenous distribution of interstitial fluid. Supine position resulted in more concentrated edema accumulation in lower dependent regions.
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http://dx.doi.org/10.1016/j.jss.2019.02.003DOI Listing
July 2019

The pleural mesothelium and transforming growth factor-β pathways in restrictive allograft syndrome: A pre-clinical investigation.

J Heart Lung Transplant 2019 05 6;38(5):570-579. Epub 2019 Feb 6.

Leuven Lung Transplant Group, Department of Chronic Diseases, Metabolism & Ageing, KU Leuven, Leuven, Belgium. Electronic address:

Background: Chronic lung allograft dysfunction (CLAD) hampers long-term survival after lung transplantation. Common fibrosis-related mechanisms in idiopathic pulmonary fibrosis and CLAD instigated the consideration of investigating the differential regulation of pleural mesothelium and transforming growth factor-β (TGF-β) in restrictive allograft syndrome (RAS).

Methods: TGF-β was assessed in bronchoalveolar lavage (BAL) fluid using enzyme-linked immunoassay and via immune staining of explant biopsies. To assess the role of the pleura, explanted bronchiolitis obliterans syndrome (BOS) and RAS lungs were compared using computed tomography scans, calretinin stainings, Western blot, and quantititative real-time PCR. Last, a pleural mesothelial cell line was used to assess mesothelial-to-mesenchymal transition and its inhibition.

Results: TGF-β was increased in BAL of RAS patients (p = 0.035), and was present in the (sub)pleural area of biopsies. Explanted RAS lungs demonstrated an increased volume fraction of pleura (p = 0.0004), a higher proportion of calretinin-positive stainings (p = 0.0032), and decreased E-cadherin (p = 0.019) and increased α-smooth muscle actin (p = 0.0089) mRNA expression and protein levels in isolated pleural tissue. Moreover, TGF-β stimulation of pleural mesothelial cells led to a phenotypical switch to mesenchymal cells, accompanied with an increased migratory capacity. Interleukin-1α was able to accentuate TGF-β‒induced mesothelial-to-mesenchymal transition. None of the tested drugs could inhibit mesothelial-to-mesenchymal transition at the used concentrations.

Conclusions: Our results support an interplay between TGF-β and the pleural mesothelium in the pathophysiology of RAS.
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http://dx.doi.org/10.1016/j.healun.2019.02.001DOI Listing
May 2019

Montelukast in chronic lung allograft dysfunction after lung transplantation.

J Heart Lung Transplant 2019 05 6;38(5):516-527. Epub 2018 Dec 6.

Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium; Department of Chronic Diseases, Metabolism & Ageing, Division of Respiratory Diseases, KU Leuven, Leuven, Belgium.

Background: Chronic lung allograft dysfunction (CLAD) is a major cause of post‒lung transplant mortality, with limited medical treatment options. In this study we assessed the association of montelukast treatment with pulmonary function and outcome in lung transplant recipients with progressive CLAD.

Methods: We performed a retrospective study of all lung transplant recipients transplanted between July 1991 and December 2016 at our center and who were treated for at least 3 months with montelukast for progressive CLAD, despite at least 3 months of prior azithromycin therapy. Main outcome parameters included evolution of pulmonary function and progression-free and overall survival.

Results: A total of 153 patients with CLAD (115 with bronchiolitis obliterans syndrome and 38 with restrictive allograft syndrome) were included, of whom 46% had a forced expiratory volume in 1 second (FEV) measure of between 66% and 80%, 31% an FEV between 51% and 65%, and 23% an FEV ≤50% of best post-operative FEV at start of montelukast. Montelukast was associated with attenuation in rate of FEV decline after 3 and 6 months, respectively (both p < 0.0001). Patients in whom FEV improved or stabilized after 3 months of montelukast (81%) had significantly better progression-free (p < 0.0001) and overall (p = 0.0002) survival after CLAD onset, as compared to those with further decline of FEV (hazard ratio [HR] 2.816, 95% confidence interval [CI] 1.450 to 5.467, p = 0.0022 for overall survival after CLAD onset in risk-adjusted multivariate analysis).

Conclusions: Montelukast was associated with a significant attenuation in rate of FEV decline in a substantial proportion of patients with established CLAD, which correlated with better outcome. Further study is required regarding use of montelkast.
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http://dx.doi.org/10.1016/j.healun.2018.11.014DOI Listing
May 2019

Role of 18F-FDG PET/CT in Restrictive Allograft Syndrome After Lung Transplantation.

Transplantation 2019 04;103(4):823-831

Leuven Lung Transplant Unit, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium.

Background: Differential diagnosis of phenotypes of chronic lung allograft dysfunction (CLAD) remains troublesome. We hypothesized that F-fluorodeoxyglucose positron emission tomography with computed tomography (F-FDG PET/CT) may help in differential diagnosis of CLAD phenotypes, as it showed promising results regarding diagnosis and prognosis in interstitial lung diseases.

Methods: A monocentric, retrospective study was performed including all lung transplant recipients suffering from bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS) who underwent F-FDG PET/CT scan, in comparison with stable lung transplant recipients. Maximum standardized uptake value (SUVmax) was associated with pulmonary function and survival. Proof-of-concept microCT and glucose transporter-1 staining served as morphologic validation for regions with different SUVmax.

Results: Maximum standardized uptake value was higher in RAS (median, 2.6; n = 29) compared with BOS (median, 1.0; n = 15) and stable patients (median, 0.59; n = 8) (P < 0.0001). In RAS, high SUVmax was associated with worse survival after F-FDG PET/CT (P = 0.0004; hazard ratio, 1.82). Forced vital capacity at F-FDG PET/CT inversely correlated with SUVmax (R = -0.40, P = 0.03). MicroCT analysis revealed extensive fibrosis in regions of high SUVmax, with an increased number of glucose transporter-1-positive cells.

Conclusions: F-fluorodeoxyglucose positron emission tomography with CT may noninvasively differentiate RAS from BOS. RAS patients with areas of increased lung metabolism have worse outcome, demonstrating the potential use of F-FDG PET/CT during follow-up after lung transplantation.
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http://dx.doi.org/10.1097/TP.0000000000002393DOI Listing
April 2019

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

Am J Transplant 2018 12 17;18(12):3045-3059. Epub 2018 Aug 17.

Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium.

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.
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http://dx.doi.org/10.1111/ajt.15019DOI Listing
December 2018

Montelukast for bronchiolitis obliterans syndrome after lung transplantation: A randomized controlled trial.

PLoS One 2018 6;13(4):e0193564. Epub 2018 Apr 6.

KULeuven and UZ Leuven, Dept. of Clinical and Experimental Medicine, Division of Respiratory Diseases, Lung Transplant Unit, Leuven, Belgium.

Bronchiolitis obliterans syndrome (BOS) remains the major problem which precludes long-term survival after lung transplantation. Previously, an open label pilot study from our group demonstrated a possible beneficial effect of montelukast in progressive BOS patients with low airway neutrophilia (<15%), and already on azithromycin treatment, in whom the further decline in pulmonary function was attenuated. This was, however, a non-randomized and non-placebo controlled trial. The study design is a single center, prospective, interventional, randomized, double blind, placebo-controlled trial, with a two arm parallel group design and an allocation ratio of 1:1. Randomization to additional montelukast (10 mg/day, n = 15) or placebo (n = 15) was performed from 2010 to 2014 at the University Hospitals Leuven (Leuven, Belgium) in all consecutive patients with late-onset (>2years posttransplant) BOS ≥1. Primary end-point was freedom from graft loss 1 year after randomization; secondary end-points were acute rejection, lymphocytic bronchiolitis, respiratory infection rate; and change in FEV1, airway and systemic inflammation during the study period. Graft loss at 1 y and 2y was similar in both groups (respectively p = 0. 981 and p = 0.230). Montelukast had no effect on lung function decline in the overall cohort. However, in a post-hoc subanalysis of BOS stage 1 patients, montelukast attenuated further decline of FEV1 during the study period, both in absolute (L) (p = 0.008) and % predicted value (p = 0.0180). A linear mixed model confirmed this association. Acute rejection, lymphocytic bronchiolitis, respiratory infections, systemic and airway inflammation were comparable between groups over the study period. This randomized controlled trial showed no additional survival benefit with montelukast compared to placebo, although the study was underpowered. The administration of montelukast was associated with an attenuation of the rate of FEV1 decline, however, only in recipients with late-onset BOS stage 1.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193564PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889063PMC
July 2018

Multiple Solid Organ Transplantation in Telomeropathy: Case Series and Literature Review.

Transplantation 2018 10;102(10):1747-1755

Department of Respiratory Diseases, University Hospitals Leuven.

Background: Solid organ transplantation is a valid treatment option for selected patients with organ failure due to an underlying telomeropathy; however, the feasibility of multiple-organ transplantation if several organs are compromised is unclear.

Methods: We describe 2 patients with telomeropathy due to heterozygous telomerase RNA component or telomerase reverse transcriptase mutation, who successfully underwent serial or combined liver and lung transplantation for concurrent liver fibrosis/cirrhosis and pulmonary fibrosis.

Results: Despite a challenging posttransplant course, long-term outcomes were favorable, with both patients doing fine now, respectively, 12/20 and 24 months after multiple-organ transplantation.

Conclusions: To our knowledge, this is the first report of multiple solid organ transplantation in documented telomeropathy. These cases highlight current difficulties of timely diagnosis, therapeutic approach, and postoperative complications in telomeropathy patients in whom several organs are affected.
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http://dx.doi.org/10.1097/TP.0000000000002198DOI Listing
October 2018

Immediate post-operative broncho-alveolar lavage IL-6 and IL-8 are associated with early outcomes after lung transplantation.

Clin Transplant 2018 Apr 23;32(4):e13219. Epub 2018 Feb 23.

Leuven Lung transplant unit, Department of chronic diseases, metabolism and ageing, KU Leuven, Leuven, Belgium.

Introduction: Previous studies demonstrated that increased cytokine and chemokine levels, either shortly before or after lung transplantation, were associated with post-transplant outcome. However, small patient cohorts were mostly used, focusing on 1 molecule and 1 outcome. In a large single-center cohort, we investigated the predictive value of immediate post-operative broncho-alveolar lavage (BAL) expression of IL-6 and IL-8 on multiple key outcomes, including PGD, CLAD, graft survival, as well as several secondary outcomes.

Material And Methods: All patients undergoing a first lung transplant in whom routine bronchoscopy with BAL was performed during the first 48 hours post-transplantation were included. IL-6 and IL-8 protein levels were measured in BAL via ELISA.

Results: A total of 336 patients were included. High IL-6 levels measured within 24 hours of transplantation were associated with longer time on ICU and time to hospital discharge; and increased prevalence of PGD grade 3. Increased IL-8 levels, measured within 24 hours, were associated with PGD3, more ECMO use, higher donor paO , younger donor age, but not with other short-or long-term outcome. IL-6 and IL-8 measured between 24 and 48 hours of transplantation were not associated with any outcome parameters.

Conclusion: Recipient BAL IL-6 and IL-8 within 24 hours post-transplant were associated with an increased incidence of PGD3.
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http://dx.doi.org/10.1111/ctr.13219DOI Listing
April 2018
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