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

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) (p < 0.01 all comparisons). Likelihood ratio tests revealed a significant association of overall survival with cfDNA (p = 0.0083), CXCL10 (p = 0.0146), and the interaction of cfDNA and CXCL10 (p = 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

Effects of long-acting bronchodilators and placebo on histamine-induced asthma symptoms and mild bronchusobstruction

SummaryStudy objectiveAccurate perception of airway caliber remains an important issue in asthma management. The way bronchodilation is perceived is partly related to the perception of the efficacy of bronchodilators in relieving complaints. In the present study, we compared the effects of salmeterol, formoterol and placebo on relief of histamine-induced asthma symptoms and mild bronchusobstruction.MethodsIn this randomized controlled, double blind study, 30 asthmatics were challenged with histamine until forced expiratory volume in 1s (FEV1) fell with ⩾20%. Subjects received salmeterol, formoterol or placebo after the histamine provocation. Pulmonary function (FEV1) and asthma symptoms (Asthma Symptom Checklist, Borg Dyspnea Scale) were assessed 5 and 20min later.ResultsFEV1 improved significantly more in the salmeterol and formoterol group than in the placebo group (P<0.001, P<0.001 and P<0.05, respectively). Salmeterol and formoterol were not different with regard to the pulmonary function recovery. No significant differences were found between the effects of salmeterol, formoterol and placebo on any of the symptom responses at the different time points.ConclusionsWe conclude that after a histamine-induced mild bronchusobstruction, a similar asthma symptom recovery occurred when inhaling salmeterol, formoterol or placebo, despite better recovery of pulmonary function in the active drug conditions

Broncho-alveolar lavage fluid recovery correlates with airway neutrophilia in lung transplant patients

SummaryBroncho-alveolar lavage (BAL) is important to assess airway inflammation. There is debate about the volume instilled, but the variation of BAL fluid recovery (BFR) has received little attention. We investigated the association between BFR and rejection/infection status after lung transplantation (LTx).We combined clinical findings, FEV1, transbronchial biopsies and BAL analysis (BFR, interleukin-8 (IL8), cell counts, microbiology) of 115 samples/LTx patients. The patients were divided into 4 groups: stable (subdivided in colonized and non-colonized), acute rejection (AR), Bronchiolitis Obliterans Syndrome (BOS) and infection.BFR was significantly lower in AR, BOS and infection, and correlated with the severity of AR and BOS. A 10ml decrease of BFR was associated with a FEV1 decrease of 4.4% and a %neutrophils and IL8 increase of 9.6% and 9.7pg/ml, respectively. Colonized stable patients had no significant differences in airway inflammation, FEV1 and BFR compared to the non-colonized stable patients.We conclude that a low BFR is an indicator of lung rejection or infection. BFR variation is related to airway obstruction and neutrophilic inflammation, which can cause an increased compliance of the airway wall, making it more collapsible. Airway colonization in stable patients had no effect on airway inflammatory parameters, BFR and FEV1

Thin-section Computed Tomography findings before and after azithromycin treatment of neutrophilic reversible lung allograft dysfunction

Recently a novel subgroup of bronchiolitis obliterans syndrome (BOS) has been described in patients after lung transplantation with high neutrophil counts in broncho-alveolar lavage and recovery of lung functional decline with azithromycin treatment. We aimed to describe the thin-section computed tomography (CT) findings of these neutrophilic reversible allograft dysfunction (NRAD) patients before and after azithromycin.status: publishe

The Belgian trial with azithromycin for acute COPD exacerbations requiring hospitalization: an investigator-initiated study protocol for a multicenter, randomized, double-blind, placebo-controlled trial

Background: Long-term use of macrolide antibiotics is effective to prevent exacerbations in chronic obstructive pulmonary disease (COPD). As risks and side effects of long-term intervention outweigh the benefits in the general COPD population, the optimal dose, duration of treatment, and target population are yet to be defined. Hospitalization for an acute exacerbation (AE) of COPD may offer a targeted risk group and an obvious risk period for studying macrolide interventions. Methods/design: Patients with COPD, hospitalized for an AE, who have a smoking history of > 10 pack-years and had > 1 exacerbation in the previous year will be enrolled in a multicenter, randomized, double-blind, placebo-controlled trial (NCT02135354). On top of a standardized treatment of systemic corticosteroids and antibiotics, subjects will be randomized to receive either azithromycin or placebo during 3 months, at an uploading dose of 500 mg once a day for 3 days, followed by a maintenance dose of 250 mg once every 2 days. The primary endpoint is the time-to-treatment failure during the treatment phase (ie, from the moment of randomization until the end of intervention). Treatment failure is a novel composite endpoint defined as either death, the admission to intensive care or the requirement of additional systemic steroids or new antibiotics for respiratory reasons, or the diagnosis of a new AE after discharge. Discussion: We investigate whether azithromycin initiated at the onset of a severe exacerbation, with a limited duration and at a low dose, might be effective and safe in the highest risk period during and immediately after the acute event. If proven effective and safe, this targeted approach may improve the treatment of severe AEs and redirect the preventive use of azithromycin in COPD to a temporary intervention in the subgroup with the highest unmet needs

Myeloid-Derived Suppressor Cells in Lung Transplantation

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 n = 6, infection n = 5; CLAD n = 9). G-MDSC functionality was assessed in vitro by their capability to block CD4 and CD8 T cell proliferation. More G-MDSC could be assessed using EDTA tubes compared to heparin tubes (p = 0.004). G-MDSC were increased in stable lung transplant recipients vs. non-transplant controls (52.1% vs. 9.4%; p = 0.0095). The infection or CLAD groups had lower G-MDSCs vs. stable recipients (28.2%p = 0.041 and 33.0%; p = 0.088, respectively), but were not different among CLAD phenotypes. G-MDSC tended to correlate with cyclosporine A and tacrolimus levels (r2 = 0.18; r2 = 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

Chronic lung allograft dysfunction: Definition, diagnostic criteria, and approaches to treatment―A consensus report from the Pulmonary Council of the ISHLT

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Chronic Rejection Pathology after Orthotopic Lung Transplantation in Mice: The Development of a Murine BOS Model and Its Drawbacks

Almost all animal models for chronic rejection (CR) after lung transplantation (LTx) fail to resemble the human situation. It was our attempt to develop a representative model of CR in mice. Orthotopic LTx was performed in allografts receiving daily immunosuppression with steroids and cyclosporine. Controls included isografts and mice only undergoing thoracotomy (SHAM). Allografts were sacrificed 2, 4, 6, 8, 10 or 12 weeks after LTx. Pulmonary function was measured repeatedly in the 12w allografts, isografts and SHAM mice. Histologically, all allografts demonstrated acute rejection (AR) around the blood vessels and airways two weeks after LTx. This decreased to 50–75% up to 10 weeks and was absent after 12 weeks. Obliterative bronchiolitis (OB) lesions were observed in 25–50% of the mice from 4–12 weeks. Isografts and lungs of SHAM mice were normal after 12 weeks. Pulmonary function measurements showed a decline in FEV0.1, TLC and compliance in the allografts postoperatively (2 weeks) with a slow recovery over time. After this initial decline, lung function of allografts increased more than in isografts and SHAM mice indicating that pulmonary function measurement is not a good tool to diagnose CR in a mouse. We conclude that a true model for CR, with clear OB lesions in about one third of the animals, but without a decline in lung function, is possible. This model is an important step forward in the development of an ideal model for CR which will open new perspectives in unraveling CR pathogenesis and exploring new treatment options

Impact of donor lung quality on post-transplant recipient outcome in the Lung Allocation Score era in Eurotransplant - a historical prospective study

The aim of this study was to investigate whether there is an impact of donation rates on the quality of lungs used for transplantation and whether donor lung quality affects post-transplant outcome in the current LAS era. All consecutive adult LTx performed in Eurotransplant (ET) between January 2012 and December 2016 were included (N=3053). Donors used for LTx in countries with high donation rate were younger (42% vs. 33% ≤ 45 years, p<0.0001), were less often smokers (35% vs. 46%, p<0.0001), had more often clear chest X-rays (82% vs. 72%, p<0.0001), had better donor oxygenation ratio's (20% vs. 26% with PaO /FiO ≤ 300 mmHg, p<0.0001) and had better lung donor score values (LDS) (28% vs. 17% with LDS=6, p<0.0001) compared to donors used for LTx in countries with low donation rate. Survival rates for the groups LDS =6 and ≥7 at 5 years were 69.7% and 60.9% (p=0.007). Lung donor quality significantly impacts on long-term patient survival. Countries with a low donation rate are more oriented to using donor lungs with a lesser quality compared to countries with a high donation rate. Instead of further stretching donor eligibility criteria, the full potential of the donor pool should be realized