The histomorphological spectrum of restrictive chronic lung allograft dysfunction and implications for prognosis.

Chronic lung allograft dysfunction continues to be the main contributor to poor long-term allograft survival after lung transplantation. The restrictive phenotype of chronic lung allograft dysfunction carries a particularly poor prognosis. Little is known about the pathogenetic mechanisms involved in restrictive chronic lung allograft dysfunction. In this study, we performed histomorphological and immunohistochemical analysis of restrictive chronic lung allograft dysfunction lungs. Explant lung tissue from 21 restrictive chronic lung allograft dysfunction patients was collected and histopathologic patterns of rejection, fibrosis and vascular changes were scored after routine histochemical stains and additional immunohistochemistry for endothelial markers and C4d. In all, 75% of cases showed evidence of acute cellular rejection; lymphocytic bronchiolitis was absent in most lungs, whereas in 55% there was obliterative bronchiolitis. Almost half of the cases showed a pattern consistent with pleuroparenchymal fibro-elastosis (n=10), and a subset showed nonspecific interstitial pneumonia (n=5) or irregular emphysema (n=5). Fibrinous alveolar exudates were frequently seen in association with fibrosis (n=6), but no diffuse alveolar damage was found. Evidence of microvascular damage was present in most cases. An emphysematous pattern of fibrosis was associated with a better survival (P=0.0030), whereas fibrinous exudates were associated with a worse survival (P=0.0007). In addition to the previously described nonspecific interstitial pneumonia and pleuroparenchymal fibro-elastosis patterns in restrictive chronic lung allograft dysfunction, we are the first to describe a pattern of fibrosis-induced subpleural/paraseptal emphysema. This pattern confers a better survival, whereas fibrinous exudates are associated with a worse survival. We believe that our findings offer a pathogenetic theory for pleuroparenchymal fibro-elastosis in restrictive chronic lung allograft dysfunction, and show that restrictive chronic lung allograft dysfunction is an increasingly heterogeneous disease with presumably different mechanisms of subpattern formation.

An association of particulate air pollution and traffic exposure with mortality after lung transplantation in Europe.

Air pollution from road traffic is a serious health risk, especially for susceptible individuals. Single-centre studies showed an association with chronic lung allograft dysfunction (CLAD) and survival after lung transplantation, but there are no large studies.13 lung transplant centres in 10 European countries created a cohort of 5707 patients. For each patient, we quantified residential particulate matter with aerodynamic diameter ≤10 µm (PM10) by land use regression models, and the traffic exposure by quantifying total road length within buffer zones around the home addresses of patients and distance to a major road or freeway.After correction for macrolide use, we found associations between air pollution variables and CLAD/mortality. Given the important interaction with macrolides, we stratified according to macrolide use. No associations were observed in 2151 patients taking macrolides. However, in 3556 patients not taking macrolides, mortality was associated with PM10 (hazard ratio 1.081, 95% CI 1.000-1.167); similarly, CLAD and mortality were associated with road lengths in buffers of 200-1000 and 100-500 m, respectively (hazard ratio 1.085- 1.130). Sensitivity analyses for various possible confounders confirmed the robustness of these associations.Long-term residential air pollution and traffic exposure were associated with CLAD and survival after lung transplantation, but only in patients not taking macrolides.

End-stage cystic fibrosis lung disease is characterised by a diverse inflammatory pattern: an immunohistochemical analysis.

BACKGROUND: Cystic fibrosis (CF) lung disease is characterised by vigorous airway inflammation eventually resulting in severe lung damage. This study aimed to describe the diversity of the inflammatory pattern in end-stage CF lungs by evaluating and quantifying which components of the innate and adaptive immunity are involved, and by assessing whether this is gender-specific. METHODS: CF explant lung tissue (n = 20) collected at time of transplantation and control tissue (n = 22) was sectioned (9 µm) and stained for neutrophils, eosinophils, mast cells, dendritic cells, macrophages, CD4 T cells, cytotoxic T cells and B cells. Quantification with special attention for immune cell location was performed. RESULTS: Neutrophils, mast cells, dendritic cells, macrophages, CD4 T and cytotoxic T cells were significantly increased in CF compared to controls and there was a disproportionate increase of neutrophils around the airways in CF. Large amounts of lymphoid follicles were found in the CF lung and they had a skewed B cell/T cell composition. Upon subdividing the CF patients into a male and female population, eosinophils, mast cells and CD4 T cells were increased specifically in CF females. In this subpopulation, lymphoid follicles had less B cells and more CD8 T cells. CONCLUSION: These data demonstrate a diverse inflammatory response in the CF lung, reflected by an increase of both myeloid and lymphoid immune cells. Inflammation in the CF lung appeared to be gender-specific in our population, as the significant increase of eosinophils, mast cells and CD4 T cells was especially notable in the female subpopulation.

Interleukin-1α induced release of interleukin-8 by human bronchial epithelial cells in vitro: assessing mechanisms and possible treatment options.

Survival after lung transplantation is hampered by chronic lung allograft dysfunction (CLAD). Persistently elevated BAL-neutrophilia is observed in some patients despite treatment with azithromycin, which may be induced by IL-1α. Our aim is to establish an in vitro model, assess mechanistic pathways and test different therapeutic strategies of IL-1α-induced release of IL-8 by human bronchial epithelial cells. Bronchial epithelial cells (16HBE) were stimulated with IL-1α with or without azithromycin or dexamethasone. IL-8 protein was analyzed in cell supernatant. Different MAP kinases (p38, JNK, ERK1/2 , Iκß) and targets known to be involved in tumor formation (PI3K, Akt) were investigated. Finally, different treatment options were tested for their potential inhibitory effect. IL-1α induced IL-8 in bronchial epithelial cells, which was dose-dependently inhibited by dexamethasone but not by azithromycin. IL-1α induced p38 and Akt phosphorylation, but activation of these MAPK was not inhibited by dexamethasone. JNK, ERK1/2 , Iκß and PI3K were not activated. None of the tested drugs reduced the IL-1α induced IL-8 production. We established an in vitro model wherein steroids inhibit the IL-1α-induced IL-8 production, while azithromycin was ineffective. Despite using this simple in vitro model, we could not identify a new treatment option for azithromycin-resistant airway neutrophilia.

Immunological diversity in phenotypes of chronic lung allograft dysfunction: a comprehensive immunohistochemical analysis.

Chronic rejection after organ transplantation is defined as a humoral- and cell-mediated immune response directed against the allograft. In lung transplantation, chronic rejection is nowadays clinically defined as a cause of chronic lung allograft dysfunction (CLAD), consisting of different clinical phenotypes including restrictive allograft syndrome (RAS) and bronchiolitis obliterans syndrome (BOS). However, the differential role of humoral and cellular immunity is not investigated up to now. Explant lungs of patients with end-stage BOS (n = 19) and RAS (n = 18) were assessed for the presence of lymphoid (B and T cells) and myeloid cells (dendritic cells, eosinophils, mast cells, neutrophils, and macrophages) and compared to nontransplant control lung biopsies (n = 21). All myeloid cells, with exception of dendritic cells, were increased in RAS versus control (neutrophils, eosinophils, and mast cells: all P < 0.05, macrophages: P < 0.001). Regarding lymphoid cells, B cells and cytotoxic T cells were increased remarkably in RAS versus control (P < 0.001) and in BOS versus control (P < 0.01). Interestingly, lymphoid follicles were restricted to RAS (P < 0.001 versus control and P < 0.05 versus BOS). Our data suggest an immunological diversity between BOS and RAS, with a more pronounced involvement of the B-cell response in RAS characterized by a structural organization of lymphoid follicles. This may impact future therapeutic approaches.

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

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

A decade of extended-criteria lung donors in a single center: was it justified?

Despite a worldwide need to expand the lung donor pool, approximately 75% of lung offers are not accepted for transplantation. We investigated the impact of liberalizing lung donor acceptance criteria during the last decade on the number of effective transplants and early and late outcomes in our center. All 514 consecutive lung transplants (LTx) performed between Jan 2000 and Oct 2011 were included. Donors were classified as matching standard criteria (SCD; n = 159) or extended criteria (ECD; n = 272) in case they fulfilled at least one of the following criteria: age >55 years, PaO2 /FiO2 at PEEP 5 cmH2 O < 300 mmHg at time of offer, presence of abnormalities on chest X-ray, smoking history, presence of aspiration, presence of chest trauma, or donation after circulatory death. Outcome parameters were primary graft dysfunction (PGD) grade at 0, 12, 24, and 48 h after LTx, time to extubation, stay in intensive care unit (ICU), early and late infection, acute rejection and bronchiolitis obliterans syndrome (BOS), and survival. Two hundred and seventy-two recipients (63.1%) received ECD lungs. PGD grade at T0 was similar between groups, while at T12 (<0.01), T24 (<0.01), and T48 (<0.05), PGD3 was observed more often in ECDs. ICU stay (P < 0.05) was longer in ECDs compared with SCDs. Time to extubation, respiratory infections, acute rejection, lymphocytic bronchiolitis, BOS, and survival were not different between groups. Accepting ECDs contributed in increasing the number of lung transplants performed in our center. Although this lung donor strategy has an impact on early postoperative outcome, liberalizing criteria did not influence long-term outcome after LTx.

CYFRA 21.1 in bronchoalveolar lavage of idiopathic pulmonary fibrosis patients.

AIM: Idiopathic pulmonary fibrosis (IPF) is one of the most aggressive forms of interstitial lung diseases, however, clinically relevant biomarkers of diagnosis or prognosis are lacking. In this study, we investigated the levels of a fragment of Cytokeratin 19 (CYFRA 21.1) in bronchoalveolar lavage (BAL) of IPF patients at time of diagnosis. We further evaluated associations between CYFRA 21.1, pulmonary function evolution, mortality, and BAL cell count. MATERIALS AND METHODS: Using the Lumipulse® G1200, CYFRA 21.1 was measured in BAL samples of 81 IPF patients and 9 controls. Based upon the median detected level (1.2 ng/mL) of CYFRA 21.1 in IPF patients, they were subdivided into an IPF CYFRA 21.1 low group (≤ 1.2 ng/mL) and IPF CYFRA 21.1 high group (> 1.2 ng/mL). RESULTS: The CYFRA 21.1 levels were significantly higher in BAL of IPF patients compared to controls (P = .0015).Worse survival was observed, but no changes in pulmonary function, for IPF patients with high CYFRA 21.1 levels versus patients with low CYFRA 21.1 levels [P = .030, HR: 0.41, (0.18-0.92)[. The CYFRA 21.1 level correlated with both neutrophils (%: R = 0.60, P < .0001; #: R = 0.47, P < .0001) and eosinophils (%: R = 0.38, P = .0005; #: R = 0.30, P < .0072). CONCLUSIONS: CYFRA 21.1 is increased in BAL of IPF patients. IPF patients with a high CYFRA 21.1 concentration have a worse survival. CYFRA 21.1 levels correlate with eosinophils and neutrophils. Further studies are warranted in using CYFRA 21.1 as a biomarker for IPF prognosis.

The site and nature of airway obstruction after lung transplantation.

RATIONALE: The chronic rejection of lung allografts is attributable to progressive small airway obstruction. OBJECTIVES: To determine precisely the site and nature of this type of airway obstruction. METHODS: Lungs from patients with rejected lung allografts treated by a second transplant (n = 7) were compared with unused donor (control) lungs (n = 7) using multidetector computed tomography (MDCT) to determine the percentage of visible airways obstructed in each airway generation, micro-computed tomography (microCT) to visualize the site of obstruction, and histology to determine the nature of this obstruction. MEASUREMENTS AND MAIN RESULTS: The number of airways visible with MDCT was not different between rejected and control lungs. However, 10 ± 7% of observed airways greater than 2 mm in diameter, 50 ± 22% of airways between 1 and 2 mm in diameter, and 73 ± 10% of airways less than 1 mm in diameter were obstructed in the rejected lungs. MicroCT confirmed that the mean lumen diameter of obstructed airways was 647 ± 317 µm but showed no difference in either total number and cross-sectional area of the terminal bronchioles or in alveolar dimensions (mean linear intercept) between groups (P > 0.05). In addition, microCT demonstrated that only segments of the airways are obstructed. Histology confirmed a constrictive form of bronchiolitis caused by expansion of microvascular-rich granulation tissue in some locations and collagen-rich scar tissue in others. CONCLUSIONS: Chronic lung allograft rejection is associated with a progressive form of constrictive bronchiolitis that targets conducting airways while sparing larger airways as well as terminal bronchioles and the alveolar surface.

Mechanistic differences between phenotypes of chronic lung allograft dysfunction after lung transplantation.

Distinct phenotypes of chronic lung allograft dysfunction (CLAD) after lung transplantation are emerging with lymphocytic bronchiolitis (LB)/azithromycin reversible allograft dysfunction (ARAD), classical or fibrotic bronchiolitis obliterans syndrome (BOS), and restrictive allograft syndrome (RAS) proposed as separate entities. We have additionally identified lung transplant recipients with prior LB, demonstrating persistent airway neutrophilia (PAN) despite azithromycin treatment. The aim of this study was to evaluate differences in the airway microenvironment in different phenotypes of CLAD. Bronchoalveolar lavage (BAL) from recipients identified as stable (control), LB/ARAD, PAN, BOS, and RAS were evaluated for differential cell counts and concentrations of IL-1α, IL-1ß, IL-6, IL-8, and TNF-α. Primary human bronchial epithelial cells were exposed to BAL supernatants from different phenotypes and their viability measured. BOS and RAS showed increased BAL neutrophilia but no change in cytokine concentrations compared with prediagnosis. In both LB/ARAD and PAN, significant increases in IL-1α, IL-1ß, and IL-8 were present. BAL IL-6 and TNF-α concentrations were increased in PAN and only this phenotype demonstrated decreased epithelial cell viability after exposure to BAL fluid. This study demonstrates clear differences in the airway microenvironment between different CLAD phenotypes. Systematic phenotyping of CLAD may help the development of more personalized approaches to treatment.

Neutrophilic reversible allograft dysfunction (NRAD) and restrictive allograft syndrome (RAS).

Lung transplantation is currently considered as an ultimate live-saving treatment for selected patients suffering from end-stage pulmonary disease. Long-term survival, however, is hampered by chronic rejection, or chronic lung allograft dysfunction (CLAD). Recently, various phenotypes within CLAD have been identified, challenging the established clinical definition of bronchiolitis obliterans syndrome (BOS). Some patients with presumed BOS, for instance, demonstrate an important improvement in forced expiratory volume in the first second of expiration (FEV1) after treatment with azithromycin. These patients are characterized by the presence of excess (≥ 15%) bronchoalveolar lavage (BAL) neutrophils, in absence of concurrent infection. This phenotype of CLAD has been redefined as neutrophilic reversible allograft dysfunction (NRAD), and these patients generally have a very good prognosis after diagnosis. Another group of patients with CLAD develop a restrictive rather than an obstructive pulmonary function defect (defined as a decline in total lung capacity of at least 10%) and demonstrate persistent interstitial and ground-glass opacities on chest computed tomographic (CT) scan. This phenotype is called restrictive allograft syndrome (RAS), and patients with RAS have a much worse prognosis after diagnosis. This review further discusses both of these CLAD phenotypes that do not fit the classical definition of BOS. Potential pathophysiological mechanisms, etiology, diagnosis, prognosis, and treatments are discussed.

Hospital-acquired infections after acute ischaemic stroke and its association with healthcare-related costs and functional outcome.

INTRODUCTION: Acute ischaemic stroke is associated with important mortality, morbidity, and healthcare-related costs. Age, pre-stroke functionality and stroke severity are important contributors to functional outcome. Stroke patients also risk developing infections during hospitalization. We sought to explore possible predictors of post-stroke infections and the relationship of post-stroke infection with healthcare-related costs and functional outcome. METHODS: This single-centre retrospective study included 530 patients treated for ischaemic stroke between January 2017 and February 2019. Antibiotics' administration was used as a proxy for post-stroke infection. Functional outcome at 90 days was assessed by the modified Rankin Scale (mRS). Total healthcare-related costs were recorded for the index hospital stay. Multivariable analysis for post-stroke infection was done with the independent factors sex, age, pre-stroke mRS, National Institutes of Health Stroke Scale (NIHSS) and diabetes mellitus. RESULTS: Twenty percent of patients had a post-stroke infection. NIHSS (OR 1.10, 95%CI 1.06-1.13, p < 0.0001) and diabetes mellitus (OR 2.18, 95%CI 1.28-3.71, p = 0.0042) were independent predictors for post-stroke infection. Mean total healthcare-related costs were 15,374 euro (SD 19,968; IQR 3,380-18,165), with a mean of 31,061 euro (SD 29,995; IQR 12,584-42,843) in patients with infection, compared to 11,406 euro (SD 13,987; IQR 3,083-12,726) in patients without (p < 0.0001). Median 90-days mRS was 5 (IQR 3-6) in patients with infection versus 1 (IQR 0-3.5) in patients without (p < 0.0001). CONCLUSIONS: In patients, admitted for acute ischaemic stroke, stroke severity and diabetes mellitus were identified as the main predictors for post-stroke infection. Hospital-acquired infections were associated with increased costs and worse functional outcome.

Prediction of Functional Outcome After Acute Ischemic Stroke: Comparison of the CT-DRAGON Score and a Reduced Features Set.

Background and Purpose: The CT-DRAGON score was developed to predict long-term functional outcome after acute stroke in the anterior circulation treated by thrombolysis. Its implementation in clinical practice may be hampered by its plethora of variables. The current study was designed to develop and evaluate an alternative score, as a reduced set of features, derived from the original CT-DRAGON score. Methods: This single-center retrospective study included 564 patients treated for stroke, in the anterior and the posterior circulation. At 90 days, favorable [modified Rankin Scale score (mRS) of 0-2] and miserable outcome (mRS of 5-6) were predicted by the CT-DRAGON in 427 patients. Bootstrap forests selected the most relevant parameters of the CT-DRAGON, in order to develop a reduced set of features. Discrimination, calibration and misclassification of both models were tested. Results: The area under the receiver operating characteristic curve (AUROC) for the CT-DRAGON was 0.78 (95% CI 0.74-0.81) for favorable and 0.78 (95% CI 0.72-0.83) for miserable outcome. Misclassification was 29% for favorable and 13.5% for miserable outcome, with a 100% specificity for the latter. National Institutes of Health Stroke Scale (NIHSS), pre-stroke mRS and age were identified as the strongest contributors to favorable and miserable outcome and named the reduced features set. While CT-DRAGON was only available in 323 patients (57%), the reduced features set could be calculated in 515 patients (91%) (p < 0.001). Misclassification was 25.8% for favorable and 14.4% for miserable outcome, with a 97% specificity for miserable outcome. The reduced features set had better discriminative power than CT-DRAGON for both outcomes (both p < 0.005), with an AUROC of 0.82 (95% CI 0.79-0.86) and 0.83 (95% CI 0.77-0.87) for favorable and miserable outcome, respectively. Conclusions: The CT-DRAGON score revealed acceptable discrimination in our cohort of both anterior and posterior circulation strokes, receiving all treatment modalities. The reduced features set could be measured in a larger cohort and with better discrimination. However, the reduced features set needs further validation in a prospective, multicentre study. Clinical Trial Registration: http://www.clinicaltrials.gov. Identifiers: NCT03355690, NCT04092543.

The Effect of Immunosuppression on Airway Integrity.

BACKGROUND: Insults to the airway epithelium play a key role in constrictive bronchiolitis after lung transplantation, the typical hallmark of chronic rejection. Our hypothesis is that immunosuppressives might affect airway integrity. METHODS: A biculture of human bronchial epithelial cells and lung microvascular endothelial cells was exposed to immunosuppressives (serum through levels) for 24 hours or 4 days. Cytotoxicity, transepithelial electrical resistance (TEER), and permeability was measured after exposure to monotherapies and combination therapies. Apoptosis, oxidative stress, inflammation (IL-8), real-time polymerase chain reaction for epithelial-to-mesenchymal transition and tight junction proteins were assessed in exposed cells. RESULTS: Mycophenolate mofetil (MMF) and combination therapies including MMF, at serum trough levels and higher, are toxic for the human bronchial epithelial cells after 4-day exposure. Moreover, already after 24 hours, TEER of cells exposed to MMF decreases and permeability increases. MMF did not induce apoptosis, oxidative stress, loss of tight junctions or production of IL-8 after 24 hours, but possibly induces epithelial-to-mesenchymal transition in epithelial cells. MMF was detectable at both sides of the biculture and was also present in bronchoalveolar lavage of lung transplantation patients. Other immunosuppressives were not toxic, neither changed TEER or permeability. CONCLUSIONS: Our findings suggest that MMF is present in the airways of lung transplant patients and might affect the structural integrity of the airway, which needs further investigation and validation in the clinical setting.

High-dose vitamin D after lung transplantation: A randomized trial.

BACKGROUND: Vitamin D may have innate immunomodulatory functions with potentially beneficial therapeutic effects in lung transplant recipients. METHODS: This was a single-center, double blind, randomized, placebo-controlled, prevention trial of once-monthly oral vitamin D (cholecalciferol; 100,000 IU, n = 44) vs placebo (n = 43) during 2 years in adult lung transplant recipients enrolled from October 2010 to August 2013. Primary outcome was prevalence of chronic lung allograft dysfunction (CLAD) 3 years after transplantation. Secondary outcomes included overall survival, prevalence of acute rejection, lymphocytic bronchiolitis and infection, lung function, pulmonary and systemic inflammation, and bone mineral density. RESULTS: All included patients underwent bilateral lung transplantation and were mostly middle-aged men with prior smoking-related emphysema. Levels of 25-hydroxy vitamin D after 1 year (p < .001) and 2 years (p < .001) were significantly higher in the vitamin D group compared with the placebo group. No difference was observed for CLAD prevalence (p = 0.7) or CLAD-free survival between both groups (p = 0.7). Secondary outcomes were overall comparable between both groups (all p > 0.05). CONCLUSIONS: Once-monthly oral vitamin D supplementation after lung transplantation fails to demonstrate a significant difference in CLAD prevalence, innate immunomodulatory, or a beneficial clinical effect compared with placebo.

Predictors of survival in restrictive chronic lung allograft dysfunction after lung transplantation.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is the main factor limiting long-term survival after lung transplantation. Besides bronchiolitis obliterans syndrome, a restrictive phenotype of CLAD (rCLAD) exists, which is associated with poor prognosis after diagnosis. However, survival determinants for rCLAD remain to be elucidated. Our aim in this study was to establish parameters predicting survival in patients with rCLAD. METHODS: All patients diagnosed with rCLAD in 2 lung transplant centers were assessed in a retrospective manner. Various clinical parameters [demography, pulmonary function, bronchoalveolar lavage (BAL), histopathology, radiology and blood differentials] at rCLAD diagnosis were correlated with graft survival using unadjusted and adjusted analysis. RESULTS: A total of 53 patients with rCLAD were included with a median graft survival after diagnosis of 1.1 years. Univariate analysis demonstrated that lower-lobe-dominant or diffuse infiltrates on chest computed tomography, presence of an identifiable trigger before rCLAD onset, lymphocytic bronchiolitis, increased BAL neutrophilia, increased BAL eosinophilia and increased blood eosinophils were associated with inferior graft survival after rCLAD diagnosis. Multivariate analysis confirmed the association of location of infiltrates and blood eosinophilia on graft survival. CONCLUSION: In this study we have identified parameters associated with graft survival after rCLAD diagnosis that may be useful to predict prognosis.

Humoral immunity in phenotypes of chronic lung allograft dysfunction: A broncho-alveolar lavage fluid analysis.

BACKGROUND: Recently, antibody mediated rejection (AMR) has been associated with a higher incidence of chronic lung allograft dysfunction (CLAD) and mortality after lung transplantation (LTx). We investigated markers related to AMR and matrix remodeling in CLAD, with special attention for its two phenotypes being bronchiolitis obliterans syndrome (BOS) and restrictive CLAD (rCLAD). METHODS: Immunoglobulins (IgA, IgE, IgG1-IgG4, total IgG and IgM) and complement (C4d and C1q) were quantified in lung lavage samples at the moment of BOS (n=15) or RAS (n=16) diagnosis; and were compared to stable transplant patients who served as control (n=14). Also, airway remodeling and metalloproteinases (MMPs) were investigated via zymography and gelatin degradation. The presence of DSA was additionally assessed in blood. RESULTS: Total IgG, IgG1-IgG4 and IgM were increased in rCLAD versus control (p<0.001) and BOS patients (p<0.01). IgA and IgE were increased in rCLAD compared to control (respectively p<0.05 and p<0.01), but not to BOS. Total IgG and IgE were increased in BOS versus control (respectively p<0.01 and p<0.05). Complement proteins were exclusively present in rCLAD and correlated positively with immunoglobulins. Additionally, in blood, DSA were more present in rCLAD (p=0.041). MMP-9 levels increased in RAS and BOS versus control (p<0.001) and MMP-9 induced gelatin degradation was only increased in BOS compared to control (p<0.01). CONCLUSION: We demonstrated increased levels of immunoglobulins and complement proteins dominantly present in rCLAD. This leads to the belief that antibodies and AMR might play a more important role in rCLAD compared to BOS. Therefore, anti B-cell therapy could offer beneficial therapeutic effects in patients diagnosed with rCLAD, which needs further research.

Interleukin-17 receptor polymorphism predisposes to primary graft dysfunction after lung transplantation.

BACKGROUND: Primary graft dysfunction (PGD), with an incidence of 11% to 57%, is a major cause of morbidity and mortality within the first 30 days after lung transplantation (LTx). In this study, we postulate that recipient genetic variants in interleukin-17 and -23 receptor genes (IL-17R and IL-23R, respectively) may predispose LTx recipients to an increased risk for developing PGD. METHODS: Seven genetic variants of IL-17R and IL-23R were successfully genotyped in 431 lung transplant recipients. Our primary end-point was PGD and secondary end-points were time to extubation, intensive care unit (ICU) stay, bronchoalveolar lavage neutrophilia and serum C-reactive protein. RESULTS: The AA genotype of the rs882643 genetic variant of IL-17R was associated with higher PGD grades at 0 hour (adjusted p = 0.042), 12 hours (adjusted p = 0.013) and 48 hours (adjusted p = 0.0092) after LTx. The GG genotype of the rs2241049 genetic variant of IL-17R was associated with higher PGD grades at 48 hours (adjusted p = 0.0067) after LTx. For both genetic variants, no association was found with extubation time, ICU stay, post-operative BAL neutrophilia, serum CRP, chronic lung allograft dysfunction (CLAD) or graft loss. CONCLUSION: Both genetic variants of IL-17R (rs882643 and rs2241049) were associated with PGD. This confirms a genetic predisposition toward PGD and suggests a role of IL-17 in driving neutrophilia in PGD.

Restrictive chronic lung allograft dysfunction: Where are we now?

Chronic lung allograft dysfunction (CLAD) remains a frequent and troublesome complication after lung transplantation. Apart from bronchiolitis obliterans syndrome (BOS), a restrictive phenotype of CLAD (rCLAD) has recently been recognized, which occurs in approximately 30% of CLAD patients. The main characteristics of rCLAD include a restrictive pulmonary function pattern with a persistent decline in lung function (FEV1, FVC and TLC), persistent parenchymal infiltrates and (sub)pleural thickening on chest CT scan, as well as pleuroparenchymal fibroelastosis and obliterative bronchiolitis on histopathologic examination. Once diagnosed, median survival is only 6 to 18 months compared with 3 to 5 years with BOS. In this perspective we review the historic evidence for rCLAD and describe the different diagnostic criteria and prognosis. Furthermore, we elaborate on the typical radiologic and histopathologic presentations of rCLAD and highlight risk factors and mechanisms. Last, we summarize some opportunities for further research including the urgent need for adequate therapy. In this perspective we not only assess the current knowledge, but also clarify the existing gaps in understanding this increasingly recognized complication after lung transplantation.