Publications by authors named "Bart M Vanaudenaerde"

133 Publications

Interalveolar Pores Increase in Aging and Severe Airway Obstruction.

Am J Respir Crit Care Med 2021 Jul 9. Epub 2021 Jul 9.

Katholieke Universiteit Leuven and Universitair Ziekenhuis Gasthuisberg, Lung Transplant Unit, Leuven, Belgium;

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http://dx.doi.org/10.1164/rccm.202102-0530LEDOI 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

The transition from normal lung anatomy to minimal and established fibrosis in idiopathic pulmonary fibrosis (IPF).

EBioMedicine 2021 Apr 13;66:103325. Epub 2021 Apr 13.

Center for Heart Lung Innovation, The University of British Columbia, Vancouver, Canada.

Background: The transition from normal lung anatomy to minimal and established fibrosis is an important feature of the pathology of idiopathic pulmonary fibrosis (IPF). The purpose of this report is to examine the molecular and cellular mechanisms associated with this transition.

Methods: Pre-operative thoracic Multidetector Computed Tomography (MDCT) scans of patients with severe IPF (n = 9) were used to identify regions of minimal(n = 27) and established fibrosis(n = 27). MDCT, Micro-CT, quantitative histology, and next-generation sequencing were used to compare 24 samples from donor controls (n = 4) to minimal and established fibrosis samples.

Findings: The present results extended earlier reports about the transition from normal lung anatomy to minimal and established fibrosis by showing that there are activations of TGFBI, T cell co-stimulatory genes, and the down-regulation of inhibitory immune-checkpoint genes compared to controls. The expression patterns of these genes indicated activation of a field immune response, which is further supported by the increased infiltration of inflammatory immune cells dominated by lymphocytes that are capable of forming lymphoid follicles. Moreover, fibrosis pathways, mucin secretion, surfactant, TLRs, and cytokine storm-related genes also participate in the transitions from normal lung anatomy to minimal and established fibrosis.

Interpretation: The transition from normal lung anatomy to minimal and established fibrosis is associated with genes that are involved in the tissue repair processes, the activation of immune responses as well as the increased infiltration of CD4, CD8, B cell lymphocytes, and macrophages. These molecular and cellular events correlate with the development of structural abnormality of IPF and probably contribute to its pathogenesis.
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http://dx.doi.org/10.1016/j.ebiom.2021.103325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054143PMC
April 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

Genome-wide CRISPR screening identifies TMEM106B as a proviral host factor for SARS-CoV-2.

Nat Genet 2021 04 8;53(4):435-444. Epub 2021 Mar 8.

KU Leuven Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute, Leuven, Belgium.

The ongoing COVID-19 pandemic has caused a global economic and health crisis. To identify host factors essential for coronavirus infection, we performed genome-wide functional genetic screens with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human coronavirus 229E. These screens uncovered virus-specific as well as shared host factors, including TMEM41B and PI3K type 3. We discovered that SARS-CoV-2 requires the lysosomal protein TMEM106B to infect human cell lines and primary lung cells. TMEM106B overexpression enhanced SARS-CoV-2 infection as well as pseudovirus infection, suggesting a role in viral entry. Furthermore, single-cell RNA-sequencing of airway cells from patients with COVID-19 demonstrated that TMEM106B expression correlates with SARS-CoV-2 infection. The present study uncovered a collection of coronavirus host factors that may be exploited to develop drugs against SARS-CoV-2 infection or future zoonotic coronavirus outbreaks.
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http://dx.doi.org/10.1038/s41588-021-00805-2DOI Listing
April 2021

Profibrotic epithelial TGF-β1 signaling involves NOX4-mitochondria cross talk and redox-mediated activation of the tyrosine kinase FYN.

Am J Physiol Lung Cell Mol Physiol 2021 03 16;320(3):L356-L367. Epub 2020 Dec 16.

Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, Vermont.

Idiopathic pulmonary fibrosis (IPF) is characterized by a disturbed redox balance and increased production of reactive oxygen species (ROS), which is believed to contribute to epithelial injury and fibrotic lung scarring. The main pulmonary sources of ROS include mitochondria and NADPH oxidases (NOXs), of which the NOX4 isoform has been implicated in IPF. Non-receptor SRC tyrosine kinases (SFK) are important for cellular homeostasis and are often dysregulated in lung diseases. SFK activation by the profibrotic transforming growth factor-β (TGF-β) is thought to contribute to pulmonary fibrosis, but the relevant SFK isoform and its relationship to NOX4 and/or mitochondrial ROS in the context of profibrotic TGF-β signaling is not known. Here, we demonstrate that TGF-β1 can rapidly activate the SRC kinase FYN in human bronchial epithelial cells, which subsequently induces mitochondrial ROS (mtROS) production, genetic damage shown by the DNA damage marker γH2AX, and increased expression of profibrotic genes. Moreover, TGF-β1-induced activation of FYN involves initial activation of NOX4 and direct cysteine oxidation of FYN, and both FYN and mtROS contribute to TGF-β-induced induction of NOX4. expression in lung tissues of IPF patients is positively correlated with disease severity, although expression is down-regulated in IPF and does not correlate with disease severity. Collectively, our findings highlight a critical role for FYN in TGF-β1-induced mtROS production, DNA damage response, and induction of profibrotic genes in bronchial epithelial cells, and suggest that altered expression and activation of NOX4 and FYN may contribute to the pathogenesis of pulmonary fibrosis.
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http://dx.doi.org/10.1152/ajplung.00444.2019DOI Listing
March 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

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

Pathology of Idiopathic Pulmonary Fibrosis Assessed by a Combination of Microcomputed Tomography, Histology, and Immunohistochemistry.

Am J Pathol 2020 12 11;190(12):2427-2435. Epub 2020 Sep 11.

Centre for Heart and Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.

Idiopathic pulmonary fibrosis (IPF) is a fibrotic disease with the histology of usual interstitial pneumonia (UIP). Although the pathologist's visual inspection is central in histologic assessments, three-dimensional microcomputed tomography (microCT) assessment may complement the pathologist's scoring. We examined associations between the histopathologic features of UIP and IPF in explanted lungs and quantitative microCT measurements, including alveolar surface density, total lung volume taken up by tissue (%), and terminal bronchiolar number. Sixty frozen samples from 10 air-inflated explanted lungs with severe IPF and 36 samples from 6 donor control lungs were scanned with microCT and processed for histologic analysis. An experienced pathologist scored three major UIP criteria (patchy fibrosis, honeycomb, and fibroblastic foci), five additional pathologic changes, and immunohistochemical staining for CD68-, CD4-, CD8-, and CD79a-positive cells, graded on a 0 to 3+ scale. The alveolar surface density and terminal bronchiolar number decreased and the tissue percentage increased in lungs with IPF compared with controls. In lungs with IPF, lower alveolar surface density and higher tissue percentage were correlated with greater scores of patchy fibrosis, fibroblastic foci, honeycomb, CD79a-positive cells, and lymphoid follicles. A decreased number of terminal bronchioles was correlated with honeycomb score but not with the other scores. The three-dimensional microCT measurements reflect the pathological UIP and IPF criteria and suggest that the reduction in the terminal bronchioles may be associated with honeycomb cyst formation.
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http://dx.doi.org/10.1016/j.ajpath.2020.09.001DOI Listing
December 2020

Pathological Comparisons of Paraseptal and Centrilobular Emphysema in Chronic Obstructive Pulmonary Disease.

Am J Respir Crit Care Med 2020 09;202(6):803-811

Centre for Heart and Lung Innovation, St. Paul's Hospital, and.

Although centrilobular emphysema (CLE) and paraseptal emphysema (PSE) are commonly identified on multidetector computed tomography (MDCT), little is known about the pathology associated with PSE compared with that of CLE. To assess the pathological differences between PSE and CLE in chronic obstructive pulmonary disease (COPD). Air-inflated frozen lung specimens ( = 6) obtained from patients with severe COPD treated by lung transplantation were scanned with MDCT. Frozen tissue cores were taken from central ( = 8) and peripheral ( = 8) regions of each lung, scanned with micro-computed tomography (microCT), and processed for histology. The core locations were registered to the MDCT, and a percentage of PSE or CLE was assigned by radiologists to each of the regions. MicroCT scans were used to measure number and structural change of terminal bronchioles. Furthermore, microCT-based volume fractions of CLE and PSE allowed classifying cores into mild emphysema, CLE-dominant, and PSE-dominant. The percentages of PSE measured on MDCT and microCT were positively associated ( = 0.015). The number of terminal bronchioles per milliliter of lung and cross-sectional lumen area were significantly lower and wall area percentage was significantly higher in CLE-dominant regions compared with mild emphysema and PSE-dominant regions (all  < 0.05), whereas no difference was found between PSE-dominant and mild emphysema samples (all  > 0.5). Immunohistochemistry showed significantly higher infiltration of neutrophils ( = 0.002), but not of macrophages, CD4, CD8, or B cells, in PSE compared with CLE regions. The terminal bronchioles are relatively preserved, whereas neutrophilic inflammation is increased in PSE-dominant regions compared with CLE-dominant regions in patients with COPD.
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http://dx.doi.org/10.1164/rccm.201912-2327OCDOI Listing
September 2020

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

Late-onset "acute fibrinous and organising pneumonia" impairs long-term lung allograft function and survival.

Eur Respir J 2020 09 3;56(3). Epub 2020 Sep 3.

Dept of Chronic Diseases, Metabolism and Ageing, BREATHE, KU Leuven, Leuven, Belgium

Acute fibrinous and organising pneumonia (AFOP) after lung transplantation is associated with a rapid decline in pulmonary function. However, the relation with chronic lung allograft dysfunction (CLAD) remains unclear. We investigated the association between detection of AFOP in lung allograft biopsies with clinically important endpoints.We reviewed lung allograft biopsies from 468 patients who underwent lung transplantation at the University Hospitals Leuven (2011-2017). AFOP was categorised as early new-onset (≤90 days post-transplant) or late new-onset (>90 days post-transplant); and associated with CLAD-free survival, graft survival, donor-specific antibodies, airway and blood eosinophilia.Early and late AFOP was detected in 24 (5%) and 30 (6%) patients, respectively. CLAD-free survival was significantly lower in patients with late AFOP (median survival 2.42 years; p<0.0001) compared with patients with early or without AFOP and specifically associated with development of restrictive allograft syndrome (OR 28.57, 95% CI 11.34-67.88; p<0.0001). Similarly, graft survival was significantly lower in patients with late AFOP (median survival 4.39 years; p<0.0001) compared with patients with early AFOP or without AFOP. Late AFOP was furthermore associated with detection of circulating donor-specific antibodies (OR 4.75, 95% CI 2.17-10.60; p=0.0004) compared with patients with early or without AFOP, and elevated airway and blood eosinophilia (p=0.043 and p=0.045, respectively) compared with early AFOP patients.Late new-onset AFOP is associated with a worse prognosis and high risk of CLAD development, specifically restrictive allograft syndrome. Our findings indicate that late new-onset AFOP might play a role in the early pathogenesis of restrictive allograft syndrome.
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http://dx.doi.org/10.1183/13993003.02292-2019DOI Listing
September 2020

Comprehensive stereological assessment of the human lung using multiresolution computed tomography.

J Appl Physiol (1985) 2020 06 16;128(6):1604-1616. Epub 2020 Apr 16.

Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada.

The application of stereology to lung casts and two-dimensional microscopy images is the gold standard for quantification of the human lung anatomy. However, these techniques are labor intensive, involving fixation, embedding, and histological sectioning of samples and thus have prevented comprehensive studies. Our objective was to demonstrate the application of stereology to volumetric multiresolution computed tomography (CT) to efficiently and extensively quantify the human lung anatomy. Nontransplantable donor lungs from individuals with no evidence of respiratory disease ( = 13) were air inflated, frozen at 10 cmHO, and scanned using CT. Systematic uniform random samples were taken, scanned using micro-CT, and assessed using stereology. The application of stereology to volumetric CT imaging enabled comprehensive quantification of total lung volume, volume fractions of alveolar, alveolar duct, and tissue, mean linear intercept, alveolar surface area, alveolar surface area density, septal wall thickness, alveolar number, number-weighted mean alveolar volume, and the number and morphometry of terminal and transitional bronchioles. With the use of this data set, we found that women and men have the same number of terminal bronchioles (last generation of conducting airways), but men have longer terminal bronchioles, a smaller wall area percentage, and larger lungs due to a greater number of alveoli per acinus. The application of stereology to multiresolution CT imaging enables comprehensive analysis of the human lung parenchyma that identifies differences between men and women. The reported data set of normal donor lungs aged 25-77 yr provides reference data for future studies of chronic lung disease to determine exact changes in tissue pathology. Stereology has been the gold standard to quantify the three-dimensional lung anatomy using two-dimensional microscopy images. However, such techniques are labor intensive. This study provides a method that applies stereology to volumetric computed tomography images of frozen whole human lungs and systematic uniform random samples. The method yielded a comprehensive data set on the small airways and parenchymal lung structures, highlighting morphometric sex differences and providing a reference data set for future pathological studies.
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http://dx.doi.org/10.1152/japplphysiol.00803.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311688PMC
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

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

Identification and characterization of chronic lung allograft dysfunction patients with mixed phenotype: A single-center study.

Clin Transplant 2020 02 28;34(2):e13781. Epub 2020 Jan 28.

Lung Transplant Unit, Department of Chronic diseases, Metabolism and Aging, KU Leuven, Leuven, Belgium.

Rationale: Patients can change chronic lung allograft dysfunction (CLAD) phenotype, especially from BOS to mixed phenotype. Our aim was to further characterize these patients.

Method: Mixed CLAD was defined as a restrictive physiology with persistent CT opacities, after initial bronchiolitis obliterans syndrome (BOS) diagnosis. The incidence, prognosis, pulmonary function, radiology, pathology, and airway inflammation were compared between patients with restrictive allograft syndrome (RAS) and mixed CLAD.

Result: A total of 268 (44%) patients developed CLAD of which 47 (18%) were diagnosed with RAS "ab initio," 215 (80%) with BOS, and 6 (2%) an undefined phenotype. Twenty-five patients developed a mixed CLAD phenotype (24 BOS to mixed and 1 RAS to mixed). Survival after mixed phenotype diagnosis was comparable (P = .39) to RAS. More emphysema patients developed a mixed phenotype (P = .020) compared to RAS ab initio, while mixed CLAD patients had a lower FEV (P < .0001) and FEV /FVC (P = .0002) at diagnosis compared to RAS ab initio. CT scans in patients with the mixed phenotype demonstrated apical predominance of the opacities (P = .0034) with pleuroparenchymal fibroelastosis on histopathology.

Conclusion: We further characterized patients with a mixed phenotype of CLAD. Although the survival after diagnosis was comparable to RAS ab initio patients, there was a difference in demography, pulmonary function, radiology, and pathology.
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http://dx.doi.org/10.1111/ctr.13781DOI Listing
February 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

Transcriptional regulatory model of fibrosis progression in the human lung.

JCI Insight 2019 11 14;4(22). Epub 2019 Nov 14.

Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.

To develop a systems biology model of fibrosis progression within the human lung we performed RNA sequencing and microRNA analysis on 95 samples obtained from 10 idiopathic pulmonary fibrosis (IPF) and 6 control lungs. Extent of fibrosis in each sample was assessed by microCT-measured alveolar surface density (ASD) and confirmed by histology. Regulatory gene expression networks were identified using linear mixed-effect models and dynamic regulatory events miner (DREM). Differential gene expression analysis identified a core set of genes increased or decreased before fibrosis was histologically evident that continued to change with advanced fibrosis. DREM generated a systems biology model (www.sb.cs.cmu.edu/IPFReg) that identified progressively divergent gene expression tracks with microRNAs and transcription factors that specifically regulate mild or advanced fibrosis. We confirmed model predictions by demonstrating that expression of POU2AF1, previously unassociated with lung fibrosis but proposed by the model as regulator, is increased in B lymphocytes in IPF lungs and that POU2AF1-knockout mice were protected from bleomycin-induced lung fibrosis. Our results reveal distinct regulation of gene expression changes in IPF tissue that remained structurally normal compared with moderate or advanced fibrosis and suggest distinct regulatory mechanisms for each stage.
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http://dx.doi.org/10.1172/jci.insight.131597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948862PMC
November 2019

Airway morphometry in COPD with bronchiectasis: a view on all airway generations.

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

Laboratory of Pneumology, Dept of Chronic Diseases, Metabolism and Aging (CHROMETA), KU Leuven, Leuven, Belgium

The pathophysiological processes underlying bronchiectasis in chronic obstructive pulmonary disease (COPD) are not understood. In COPD, both small and large airways are progressively lost. It is currently not known to what extent the different airway generations of patients with COPD and bronchiectasis are involved.COPD explant lungs with bronchiectasis were compared to COPD explant lungs without bronchiectasis and unused donor lungs as controls. In order to investigate all airway generations, a multimodal imaging approach using different resolutions was conducted. Per group, five lungs were frozen (n=15) and underwent computed tomography (CT) imaging for large airway evaluation, with four tissue cores per lung imaged for measurements of the terminal bronchioles. Two additional lungs per group (n=6) were air-dried for lobar microCT images that allow airway segmentation and three-dimensional quantification of the complete airway tree.COPD lungs with bronchiectasis had significantly more airways compared to COPD lungs without bronchiectasis (p<0.001), with large airway numbers similar to control lungs. This difference was present in both upper and lower lobes. Lack of tapering was present (p=0.010) and larger diameters were demonstrated in lower lobes with bronchiectasis (p=0.010). MicroCT analysis of tissue cores showed similar reductions of tissue percentage, surface density and number of terminal bronchioles in both COPD groups compared to control lungs.Although terminal bronchioles were equally reduced in COPD lungs with and without bronchiectasis, significantly more large and small airways were found in COPD lungs with bronchiectasis.
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http://dx.doi.org/10.1183/13993003.02166-2018DOI Listing
November 2019

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

Cell-Free DNA and CXCL10 Derived from Bronchoalveolar Lavage Predict Lung Transplant Survival.

J Clin Med 2019 Feb 13;8(2). Epub 2019 Feb 13.

Department of Surgery, University of California San Francisco, San Francisco, CA 94143, USA.

Standard methods for detecting chronic lung allograft dysfunction (CLAD) and rejection have poor sensitivity and specificity and have conventionally required bronchoscopies and biopsies. Plasma cell-free DNA (cfDNA) has been shown to be increased in various types of allograft injury in transplant recipients and CXCL10 has been reported to be increased in the lung tissue of patients undergoing CLAD. This study used a novel cfDNA and CXCL10 assay to evaluate the noninvasive assessment of CLAD phenotype and prediction of survival from bronchoalveolar lavage (BAL) fluid. A total of 60 BAL samples (20 with bronchiolitis obliterans (BOS), 20 with restrictive allograft syndrome (RAS), and 20 with stable allografts (STA)) were collected from 60 unique lung transplant patients; cfDNA and CXCL10 were measured by the ELISA-based KIT assay. Median cfDNA was significantly higher in BOS patients (6739 genomic equivalents (GE)/mL) versus STA (2920 GE/mL) and RAS (4174 GE/mL) ( < 0.01 all comparisons). Likelihood ratio tests revealed a significant association of overall survival with cfDNA ( = 0.0083), CXCL10 ( = 0.0146), and the interaction of cfDNA and CXCL10 ( = 0.023) based on multivariate Cox proportional hazards regression. Dichotomizing patients based on the median cfDNA level controlled for the mean level of CXCL10 revealed an over two-fold longer median overall survival time in patients with low levels of cfDNA. The KIT assay could predict allograft survival with superior performance compared with traditional biomarkers. These data support the pursuit of larger prospective studies to evaluate the predictive performance of cfDNA and CXCL10 prior to lung allograft failure.
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http://dx.doi.org/10.3390/jcm8020241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406976PMC
February 2019

Phenotypical diversity of airway morphology in chronic lung graft vs. host disease after stem cell transplantation.

Mod Pathol 2019 06 5;32(6):817-829. Epub 2019 Feb 5.

Lung Transplant Unit, Department of Chronic diseases, Metabolism and Aging, KU Leuven, Leuven, Belgium.

Pulmonary graft vs. host disease is a diverse and underestimated complication following allogenic hematopoietic stem cell transplantation. We aimed to compare the airway architecture with chronic lung allograft dysfunction post lung transplantation. Inflated explant lungs from graft vs. host disease patients were compared with lungs with chronic lung allograft dysfunction following lung transplantation, and control lungs using a combination of CT, microCT, and histology (n = 6 per group) and pathology in the (small) airways was further quantified and analyzed. Following allogenic hematopoietic stem cell transplantation, three patients presented as bronchiolitis obliterans syndrome and three patients showed interstitial changes and restriction. The CT analysis demonstrated a strong similarity between bronchiolitis obliterans syndrome after lung transplantation and post allogenic hematopoietic stem cell transplantation, evidenced by severe ( > 50%) airway obstruction from generation 9, with 70.8% of the airways ending in obstruction. Further analysis indicated that the airways either collapsed or accumulated matrix along a segment of the airway. In patients with restriction and interstitial changes following allogenic hematopoietic stem cell transplantation, the degree of airway obstruction was lower compared with bronchiolitis obliterans syndrome post allogenic hematopoietic stem cell transplantation, but similar to restrictive allograft syndrome post lung transplantation, showing a lower proportion of airway obstruction (20-35%), decreased number of terminal bronchioles per lung (p < 0.01), and parenchymal fibrosis. We observed similarities in the airway and parenchymal morphometric changes in lung graft vs. host disease and with chronic lung allograft dysfunction following lung transplantation, suggesting similar pathophysiological mechanisms.
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http://dx.doi.org/10.1038/s41379-019-0203-2DOI Listing
June 2019
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