Survival outcomes following urgent lung transplantation in France and the USA.

INTRODUCTION: Lung graft allocation can be based on a score (Lung Allocation Score) as in the USA or sequential proposals combined with a discrete priority model as in France. We aimed to analyse the impact of allocation policy on the outcome of urgent lung transplantation (LT). METHODS: US United Network for Organ Sharing (UNOS) and French Cristal databases were retrospectively reviewed to analyse LT performed between 2007 and 2017. We analysed the mortality risk of urgent LT by fitting Cox models and adjusted Restricted Mean Survival Time. We then compared the outcome after urgent LT in the UNOS and Cristal groups using a propensity score matching. RESULTS: After exclusion of patients with chronic obstructive pulmonary disease/emphysema and redo LT, 3775 and 12 561 patients underwent urgent LT and non-urgent LT in the USA while 600 and 2071 patients underwent urgent LT and non-urgent LT in France. In univariate analysis, urgent LT was associated with an HR for death of 1.24 (95% CI 1.05 to 1.48) in the Cristal group and 1.12 (95% CI 1.05 to 1.19) in the UNOS group. In multivariate analysis, the effect of urgent LT was attenuated and no longer statistically significant in the Cristal database (HR 1.1 (95% CI 0.91 to 1.33)) while it remained constant and statistically significant in the UNOS database (HR 1.12 (95% CI 1.05 to 1.2)). Survival comparison of urgent LT patients between the two countries was significantly different in favour of the UNOS group (1-year survival rates 84.1% (80.9%-87.3%) vs 75.4% (71.8%-79.1%) and 3-year survival rates 66.3% (61.9%-71.1%) vs 62.7% (58.5%-67.1%), respectively). CONCLUSION: Urgent LT is associated with adverse outcome in the USA and in France with a better prognosis in the US score-based system taking post-transplant survival into account. This difference between two healthcare systems is multifactorial.

Tablets or oral suspension for posaconazole in lung transplant recipients? Consequences for trough concentrations of tacrolimus and everolimus.

AIMS: A new formulation of posaconazole (PCZ), delayed-release tablets (PCZ-tab), increases PCZ bioavailability and plasma trough concentrations (Cmin ) over those achieved with an oral suspension (PCZ-susp). PCZ is an inhibitor of cytochrome P450 3A4 and P-glycoprotein. We therefore investigated the impact of PCZ-tab treatment on blood Cmin and doses of tacrolimus (TAC) and everolimus (EVR). METHODS: Eighteen lung transplant patients receiving TAC (n = 13) or TAC + EVR (n = 5) between June 2015 and March 2016 were retrospectively included. Ten of these patients received both PCZ-tab and PCZ-susp (i.e. switched patients); the other 8 received only PCZ-tab. Plasma Cmin of PCZ (n = 64), blood Cmin of TAC (n = 299) and EVR (n = 80) were determined during routine therapeutic drug monitoring by liquid chromatography-tandem mass spectrometry. RESULTS: PCZ Cmin on PCZ-tab treatment (n = 48) was 2.5 times higher than that on PCZ-susp therapy (n = 16), for both PCZ patients (P < .0001) and for switched patients (P = .003). PCZ initiation, regardless of galenic form, increased TAC and EVR Cmin adjusted for dose (D), 3-fold and 3.5-fold, respectively (P < .0001 for both). PCZ-tab treatment was associated with a higher TAC Cmin /D (PCZ-tab vs PCZ-susp: 0.004 ± 0.004 L-1 vs 0.009 ± 0.006 L-1 , P < .0001) and lower TAC daily dose than PCZ-susp (PCZ-tab vs PCZ-susp: 1.08 ± 0.92 vs 2.32 ± 1.62 mg d-1 , P < .0001). EVR Cmin /D was higher and EVR dose tended to be lower on PCZ-tab than on PCZ-susp. CONCLUSION: The greater PCZ exposure achieved during PCZ-tab treatment increased drug-drug interactions with TAC and EVR, resulting in greater exposure, potentially exposing patients to higher risks of adverse effects.

Blood CD9+ B cell, a biomarker of bronchiolitis obliterans syndrome after lung transplantation.

Bronchiolitis obliterans syndrome is the main limitation for long-term survival after lung transplantation. Some specific B cell populations are associated with long-term graft acceptance. We aimed to monitor the B cell profile during early development of bronchiolitis obliterans syndrome after lung transplantation. The B cell longitudinal profile was analyzed in peripheral blood mononuclear cells from patients with bronchiolitis obliterans syndrome and patients who remained stable over 3 years of follow-up. CD24hi CD38hi transitional B cells were increased in stable patients only, and reached a peak 24 months after transplantation, whereas they remained unchanged in patients who developed a bronchiolitis obliterans syndrome. These CD24hi CD38hi transitional B cells specifically secrete IL-10 and express CD9. Thus, patients with a total CD9+ B cell frequency below 6.6% displayed significantly higher incidence of bronchiolitis obliterans syndrome (AUC = 0.836, PPV = 0.75, NPV = 1). These data are the first to associate IL-10-secreting CD24hi CD38hi transitional B cells expressing CD9 with better allograft outcome in lung transplant recipients. CD9-expressing B cells appear as a contributor to a favorable environment essential for the maintenance of long-term stable graft function and as a new predictive biomarker of bronchiolitis obliterans syndrome-free survival.

Impact of donor, recipient and matching on survival after high emergency lung transplantation in France.

INTRODUCTION: Since July 2007, the French high emergency lung transplantation (HELT) allocation procedure prioritises available lung grafts to waiting patients with imminent risk of death. The relative impacts of donor, recipient and matching on the outcome following HELT remain unknown. We aimed at deciphering the relative impacts of donor, recipient and matching on the outcome following HELT in an exhaustive administrative database. METHODS: All lung transplantations performed in France were prospectively registered in an administrative database. We retrospectively reviewed the procedures performed between July 2007 and December 2015, and analysed the impact of donor, recipient and matching on overall survival after the HELT procedure by fitting marginal Cox models. RESULTS: During the study period, 2335 patients underwent lung transplantation in 11 French centres. After exclusion of patients with chronic obstructive pulmonary disease/emphysema, 1544 patients were included: 503 HELT and 1041 standard lung transplantation allocations. HELT was associated with a hazard ratio for death of 1.41 (95% CI 1.22-1.64; p<0.0001) in univariate analysis, decreasing to 1.32 (95% CI 1.10-1.60) after inclusion of recipient characteristics in a multivariate model. A donor score computed to predict long-term survival was significantly different between the HELT and standard lung transplantation groups (p=0.014). However, the addition of donor characteristics to recipient characteristics in the multivariate model did not change the hazard ratio associated with HELT. CONCLUSIONS: This exhaustive French national study suggests that HELT is associated with an adverse outcome compared with regular allocation. This adverse outcome is mainly related to the severity status of the recipients rather than donor or matching characteristics.

Airway microbiota signals anabolic and catabolic remodeling in the transplanted lung.

BACKGROUND: Homeostatic turnover of the extracellular matrix conditions the structure and function of the healthy lung. In lung transplantation, long-term management remains limited by chronic lung allograft dysfunction, an umbrella term used for a heterogeneous entity ultimately associated with pathological airway and/or parenchyma remodeling. OBJECTIVE: This study assessed whether the local cross-talk between the pulmonary microbiota and host cells is a key determinant in the control of lower airway remodeling posttransplantation. METHODS: Microbiota DNA and host total RNA were isolated from 189 bronchoalveolar lavages obtained from 116 patients post lung transplantation. Expression of a set of 11 genes encoding either matrix components or factors involved in matrix synthesis or degradation (anabolic and catabolic remodeling, respectively) was quantified by real-time quantitative PCR. Microbiota composition was characterized using 16S ribosomal RNA gene sequencing and culture. RESULTS: We identified 4 host gene expression profiles, among which catabolic remodeling, associated with high expression of metallopeptidase-7, -9, and -12, diverged from anabolic remodeling linked to maximal thrombospondin and platelet-derived growth factor D expression. While catabolic remodeling aligned with a microbiota dominated by proinflammatory bacteria (eg, Staphylococcus, Pseudomonas, and Corynebacterium), anabolic remodeling was linked to typical members of the healthy steady state (eg, Prevotella, Streptococcus, and Veillonella). Mechanistic assays provided direct evidence that these bacteria can impact host macrophage-fibroblast activation and matrix deposition. CONCLUSIONS: Host-microbes interplay potentially determines remodeling activities in the transplanted lung, highlighting new therapeutic opportunities to ultimately improve long-term lung transplant outcome.

Lung transplantation after allogeneic stem cell transplantation: a pan-European experience.

Late-onset noninfectious pulmonary complications (LONIPCs) affect 6% of allogeneic stem cell transplantation (SCT) recipients within 5 years, conferring subsequent 5-year survival of 50%. Lung transplantation is rarely performed in this setting due to concomitant extrapulmonary morbidity, excessive immunosuppression and concerns about recurring malignancy being considered contraindications. This study assesses survival in highly selected patients undergoing lung transplantation for LONIPCs after SCT.SCT patients undergoing lung transplantation at 20 European centres between 1996 and 2014 were included. Clinical data pre- and post-lung transplantation were reviewed. Propensity score-matched controls were generated from the Eurotransplant and Scandiatransplant registries. Kaplan-Meier survival analysis and Cox proportional hazard regression models evaluating predictors of graft loss were performed.Graft survival at 1, 3 and 5 years of 84%, 72% and 67%, respectively, among the 105 SCT patients proved comparable to controls (p=0.75). Sepsis accounted for 15 out of 37 deaths (41%), with prior mechanical ventilation (HR 6.9, 95% CI 1.0-46.7; p<0.001) the leading risk factor. No SCT-specific risk factors were identified. Recurring malignancy occurred in four patients (4%). Lung transplantation <2 years post-SCT increased all-cause 1-year mortality (HR 7.5, 95% CI 2.3-23.8; p=0.001).Lung transplantation outcomes following SCT were comparable to other end-stage diseases. Lung transplantation should be considered feasible in selected candidates. No SCT-specific factors influencing outcome were identified within this carefully selected patient cohort.

Chronic effects of air pollution on lung function after lung transplantation in the Systems prediction of Chronic Lung Allograft Dysfunction (SysCLAD) study.

An irreversible loss in lung function limits the long-term success in lung transplantation. We evaluated the role of chronic exposure to ambient air pollution on lung function levels in lung transplant recipients (LTRs).The lung function of 520 LTRs from the Cohort in Lung Transplantation (COLT) study was measured every 6 months. The levels of air pollutants (nitrogen dioxide (NO2), particulate matter with an aerodynamic cut-off diameter of x µm (PMx) and ozone (O3)) at the patients' home address were averaged in the 12 months before each spirometry test. The effects of air pollutants on forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) in % predicted were estimated using mixed linear regressions. We assessed the effect modification of macrolide antibiotics in this relationship.Increased 12-month levels of pollutants were associated with lower levels of FVC % pred (-2.56%, 95% CI -3.86--1.25 for 5 µg·m-3 of PM10; -0.75%, 95% CI -1.38--0.12 for 2 µg·m-3 of PM2.5 and -2.58%, 95% CI -4.63--0.53 for 10 µg·m-3 of NO2). In patients not taking macrolides, the deleterious association between PM and FVC tended to be stronger and PM10 was associated with lower FEV1Our study suggests a deleterious effect of chronic exposure to air pollutants on lung function levels in LTRs, which might be modified with macrolides.

[Not Available]. / Traitement médicamenteux chez la femme transplantée avec un projet de grossesse : à propos de deux cas de transplantation pulmonaire et cardio-pulmonaire.

Advances in lung transplantation allow the women of childbearing age to consider becoming mothers. When planning to become pregnant, a therapeutic drug management of immunosuppressive drugs and associated therapies is required. It must take into account teratogenic and fetotoxic drugs, as well as pharmacokinetic changes encountered during pregnancy. Increasingly data are currently available on the management of immunosuppressive drugs and associated therapies during pregnancy. We report the case management of drug therapy before and during pregnancy in two patients after a lung or heart-lung transplantation. To prevent the emergence of complications for mother and child, a literature review has been necessary to manage drug therapies of each patient.

[Therapeutic Drug Management for Transplanted Women with a Planned Pregnancy: About Two Cases of Lung and Heart-lung Transplantation]. / Traitement médicamenteux chez la femme transplantée avec un projet de grossesse : à propos de deux cas de transplantation pulmonaire et cardio-pulmonaire.

Advances in lung transplantation allow the women of childbearing age to consider becoming mothers. When planning to become pregnant, a therapeutic drug management of immunosuppressive drugs and associated therapies is required. It must take into account teratogenic and fetotoxic drugs, as well as pharmacokinetic changes encountered during pregnancy. Increasingly data are currently available on the management of immunosuppressive drugs and associated therapies during pregnancy. We report the case management of drug therapy before and during pregnancy in two patients after a lung or heart-lung transplantation. To prevent the emergence of complications for mother and child, a literature review has been necessary to manage drug therapies of each patient.

Mid-term pulmonary sequelae after hospitalisation for COVID-19: The French SISCOVID cohort.

BACKGROUND: Even though COVID-19 clinical features, pathogenesis, complications, and therapeutic options have been largely described in the literature, long-term consequences in patients remain poorly known. METHODS: The French, multicentre, non-interventional SISCOVID study evaluated lung impairment three (M3) and six months (M6) after hospital discharge in patients recovered from COVID-19. Evaluation was based on clinical examination, pulmonary function tests, and chest computed tomography (CT-scan). RESULTS: Of the 320 included patients (mean age: 61 years; men: 64.1%), 205 had had a severe form of COVID-19, being hospitalised in an intensive care unit (ICU), and requiring high flow nasal cannula, non-invasive ventilation, or invasive mechanical ventilation. At M6, 54.1% of included patients had persistent dyspnoea (mMRC score ≥1), 20.1% severe impairment in gas diffusing capacity (DLCO <60% pred.), 21.6% restrictive ventilatory pattern (total lung capacity <80% pred.), and 40% a fibrotic-like pattern at CT-scan. Fibrotic-like pattern and restrictive ventilatory pattern were significantly more frequent in patients recovered from severe than non-severe COVID-19. Improved functional and radiological outcomes were observed between M3 and M6. At M6, age was an independent risk factor for severe DLco impairment and fibrotic-like pattern and severe COVID-19 form was independent risk factor for restrictive ventilatory profile and fibrotic-like pattern. CONCLUSION: Six months after discharge, patients hospitalised for COVID-19, especially those recovered from a severe form of COVID-19, frequently presented persistent dyspnoea, lung function impairment, and persistent fibrotic-like pattern, confirming the need for long-term post-discharge follow-up in these patients and for further studies to better understand long-term COVID-19 lung impairment.

Restrictive allograft dysfunction after lung transplantation: is there a place for nintedanib?-a case report.

One of the posttransplantation complications is represented by chronic lung allograft dysfunction, which has two main clinical presentations: bronchiolitis obliterans syndrome and restrictive allograft syndrome. The latter being challenging because of poor prognosis and only symptomatic treatment, and characterized by fibrotic process. A 63-year-old man was right lung-transplanted in 2009 due to idiopathic pulmonary fibrosis. In 2011, bronchiolitis obliterans syndrome was diagnosed evolving to restrictive allograft syndrome in 2016. An off-label treatment by nintedanib (150 mg twice a day) was introduced. Unfortunately, it was stopped 4 months later because of digestive intolerance, without any clinical improvement. Contrary to a previous case reported, our patient did not have any benefit of nintedanib. Antifibrotic agents' effects such as nintedanib on restrictive allograft syndrome should be assessed in further randomized double-blind placebo-controlled studies.

Clinical evaluation of pharmacists' interventions on multidisciplinary lung transplant outpatients' management: results of a 7-year observational study.

OBJECTIVES: Lung transplant (LT) recipients require multidisciplinary care because of the complexity of therapeutic management. Pharmacists are able to detect drug-related problems and provide recommendations to physicians through pharmacists' interventions (PIs). We aimed at assessing the clinical impact of PIs on therapeutic management in LT outpatients. DESIGN: Data were collected prospectively from an LT recipients cohort during 7 years. A multidisciplinary committee assessed retrospectively the clinical impact of accepted PIs. SETTING: French University Hospital. PARTICIPANTS: LT outpatients followed from 2009 to 2015. PRIMARY OUTCOME MEASURES: Clinical impact of PIs performed by pharmacists using the CLEO tool and the Pareto chart. RESULTS: 1449 PIs led to a change in patient therapeutic management and were mainly related to wrong dosage (39.6%) and untreated indication (19.6%). The clinical impact of PIs was 'avoids fatality', 'major' and 'moderate', in 0.1%, 7.0% and 57.9%, respectively. Immunosuppressants, antimycotics for systemic use and antithrombotic agents had the greatest clinical impact according to the Pareto chart. PIs related to drug-drug interactions (10%) mainly had a moderate and major clinical impact (82.3%, p<0.0001). CONCLUSION: Clinical pharmacists play a key role for detecting drug-related problems mostly leading to a change in therapeutic management among LT outpatients. Our study provides a new insight to analyse the clinical impact of PIs in order to target PIs which have most value and contribute to patient care through interdisciplinary approach.

Pneumocystis pneumonia after lung transplantation: A retrospective multicenter study.

BACKGROUND: Lung transplantation (LT) is an identified risk factor for Pneumocystis pneumonia (PCP). However, PCP management and outcomes remain poorly described in LT recipients and PCP incidence is rarely documented in this population. METHODS: PCP episodes that occurred in 9 French LT centers between January 2010 and October 2017 were included in this analysis. PCP was defined as compatible clinical and radiologic findings associated with fungal identification. RESULTS: Forty-seven PCP were included. The annual incidence rate of PCP was 2.7/1000 patients/year. Patients had a mean age of 53 ± 14 years. Median time from LT was 2.4 ± 3.0 years. Sixty-five percent of patients were not on prophylaxis at the time of PCP while all patients were receiving steroids at the time of PCP. Diagnosis was obtained by bronchoalveolar lavage in 91% (direct examination: 47%, PCR: 62%). The majority of patients were treated with trimethoprim-sulfamethoxazole (78%). Fifty-five percent of patients were hospitalized in ICU for organ failure (for which non-invasive ventilation was used for 21% and mechanical ventilation for 23%). Mortality rate was 15% at day 28 and reached 23% at day 90. Mortality was associated with decreased FEV1, everolimus treatment, Pseudomonas aeruginosa coinfection, fungal coinfection (especially Aspergillus sp.), mechanical ventilation and vasopressors. PCP primary prophylaxis, steroid modification during PCP and the number of immunosuppressive molecules were not associated with mortality. CONCLUSION: PCP is associated with a high mortality in LT. Our data suggest the need for a lifetime PCP prophylaxis in LT recipients. The benefit of adjuvant steroids remains unclear.

Mucormycosis in intensive care unit: surgery is a major prognostic factor in patients with hematological malignancy.

BACKGROUND: Mucormycosis is an invasive fungal infection, with an increasing incidence especially in patients with hematological malignancies. Its prognosis is poor because of its high invasive power and its intrinsic low susceptibility to antifungal agents. We aimed to describe the epidemiology of mucormycosis in intensive care units (ICU) and evaluate the outcomes. We performed a retrospective multi-center study in 16 French ICUs between 2008 and 2017. We compared the patients who survived in ICU and the patients who did not to identify factors associated with ICU survival. Then, we focused on the subgroup of patients with hematological malignancies. RESULTS: Mucormycosis was diagnosed in 74 patients during the study period. Among them, 60 patients (81%) were immunocompromised: 41 had hematological malignancies, 9 were solid organ transplant recipients, 31 received long-term steroids, 11 had diabetes, 24 had malnutrition. Only 21 patients survived to ICU stay (28.4%) with a median survival of 22 days (Q1-Q3 = 9-106) and a survival rate at day 28 and day 90, respectively, of 35.1% and 26.4%. Survivors were significantly younger (p = 0.001), with less frequently hematological malignancies (p = 0.02), and less malnutrition (p = 0.05). Median survival in patients with hematological malignancies (n = 41) was 15 days (Q1-Q3 = 5-23.5 days). In this subgroup, curative surgery was a major factor associated with survival in multivariate analysis (odds ratio = 0.71, [0.45-0.97], p < 0.001). CONCLUSION: Overall prognosis of mucormycosis in ICU remains poor, especially in patients with hematological malignancies. In this subgroup of patients, a therapeutic strategy including curative surgery was the main factor associated with survival.

Early Identification of Chronic Lung Allograft Dysfunction: The Need of Biomarkers.

A growing number of patients with end-stage lung disease have benefited from lung transplantation (LT). Improvements in organ procurement, surgical techniques and intensive care management have greatly increased short-term graft survival. However, long-term outcomes remain limited, mainly due to the onset of chronic lung allograft dysfunction (CLAD), whose diagnosis is based on permanent loss of lung function after the development of irreversible lung lesions. CLAD is associated with high mortality and morbidity, and its exact physiopathology is still only partially understood. Many researchers and clinicians have searched for CLAD biomarkers to improve diagnosis, to refine the phenotypes associated with differential prognosis and to identify early biological processes that lead to CLAD to enable an early intervention that could modify the inevitable degradation of respiratory function. Donor-specific antibodies are currently the only biomarkers used in routine clinical practice, and their significance for accurately predicting CLAD is still debated. We describe here significant studies that have highlighted potential candidates for reliable and non-invasive biomarkers of CLAD in the fields of imaging and functional monitoring, humoral immunity, cell-mediated immunity, allograft injury, airway remodeling and gene expression. Such biomarkers would improve CLAD prediction and allow differential LT management regarding CLAD risk.

Pregnancy after lung and heart-lung transplantation: a French multicentre retrospective study of 39 pregnancies.

Pregnancy after lung and heart-lung transplantation remains rare. This French study deals with change in lung function after a pregnancy and the maternal and newborn outcomes. We retrospectively included 39 pregnancies in 35 women aged >20 years. Data on patients, course of pregnancies and newborns were collected from nine transplantation centres. Mean age at time of pregnancy was 28 years. Cystic fibrosis affected 71% of patients. Mean±sd time between transplantation and pregnancy was 63±44 months. 26 births occurred (67%) with a mean term of 36 weeks of amenorrhoea and a mean birthweight of 2409 g. Prematurity was observed in 11 cases (43%). Forced expiratory volume in 1 s was 83.9% of predicted before pregnancy and 77.3% of predicted 1 year after the end of pregnancy (p=0.04). 10 patients developed chronic lung allograft dysfunction after delivery. Nine patients died at a mean±sd time after transplantation of 8.2±7 years and a mean±sd time after pregnancy of 4.6±6.5 years. These data show that pregnancy remains feasible in lung and heart-lung transplant recipients, with more frequent maternal and newborn complications than in the general population. Survival in this cohort appears to be similar to the global survival observed in lung transplant recipients. Planned pregnancy and multidisciplinary follow-up are crucial.

Favorable Evolution of Cryptococcal Meningitis in the Context of Flucytosine Resistance.

Cryptococcal meningitis is a critical illness affecting 0.2% to 5% solid-organ transplant recipients with a 40% to 50% mortality. We report the case of a 48-year-old lung transplant recipient, who, 15 months after a right lung graft, kept parakeets and developed meningitis due to Cryptococcus neoformans. Immunosuppressive treatment was based on a quadruple sequential immunosuppressive therapy that included induction therapy with thymoglobulin, followed by corticosteroids, calcineurin inhibitors, and mycophenolate mofetil. Antifungal susceptibility testing of Cryptococcus neoformans showed resistance to flucytosine and intermediate sensitivity to fluconazole. Initial treatment adhered to international guidelines; however, the patient could not tolerate an effective double-antifungal therapy during the first 2 months of treatment. Despite this delayed treatment for an aggressive infection in an immunocompromised patient, the patient survived without relapse and received maintenance treatment with fluconazole during the course of 3 years. Administration of calcineurin inhibitors as immunosuppressive treatment may partly explain this outcome, as this therapeutic class is known to protect from severe forms of cryptococcal meningitis.

Donor Club Cell Secretory Protein G38A Polymorphism Is Associated With a Decreased Risk of Primary Graft Dysfunction in the French Cohort in Lung Transplantation.

BACKGROUND: Club Cell Secretory Protein (CCSP) G38A polymorphism has recently been involved in lung epithelial susceptibility to external injuries. Lung transplantation (LT) is currently limited by ischemia-reperfusion injury leading to primary graft dysfunction (PGD). We thus hypothesized that donor CCSP G38A polymorphism might impact the risk of PGD after LT. METHODS: We focused on LT included in the French multicentric Cohort in Lung Transplantation (COLT), performed between January 2009 and December 2014, and associated with preoperative blood samples from the donor and the recipient. Characteristics of the donors, recipients, procedures, early and late outcomes were prospectively recorded in COLT. The CCSP serum concentration and CCSP gene G38A polymorphism were retrospectively determined in a blind manner. Their association with grade 3 PGD was studied in univariate and multivariate analysis. RESULTS: The study group included 104 LT donors and recipients, 84 with grade 0 to 2 PGD and 20 with grade 3 PGD. Preoperative CCSP serum concentration was significantly higher in the donors (median, 22.54 ng/mL; interquartile range, 9.6-43.9) than in the recipients (median, 7.03 ng/mL; interquartile range, 0.89-19.2; P < 0.001) but none impacted the risk of grade 3 PGD (P = 0.93 and P = 0.69, respectively). Donor CCSP G38A polymorphism was associated with a decreased risk of grade 3 PGD in univariate (AG + AA 3/21 = 14.2% vs GG 10/26 = 38.4%, P = 0.044) and multivariate analysis (odds ratio associated with AG + AA, 0.22; 95% confidence interval, 0.041-0.88; P = 0.045), but recipient CCSP G38A polymorphism was not. CONCLUSIONS: Donor CCSP G38A polymorphism is associated with a decreased risk of severe PGD after LT in the COLT study. These findings should be confirmed in the frame of a prospective study.

High circulating CD4+CD25hiFOXP3+ T-cell sub-population early after lung transplantation is associated with development of bronchiolitis obliterans syndrome.

BACKGROUND: Chronic bronchiolitis obliterans syndrome (BOS) remains a major limitation for long-term survival after lung transplantation. The immune mechanisms involved and predictive biomarkers have yet to be identified. The purpose of this study was to determine whether peripheral blood T-lymphocyte profile could predict BOS in lung transplant recipients. METHODS: An in-depth profiling of CD4+ and CD8+ T cells was prospectively performed on blood cells from stable (STA) and BOS patients with a longitudinal follow-up. Samples were analyzed at 1 and 6 months after transplantation, at the time of BOS diagnosis, and at an intermediate time-point at 6 to 12 months before BOS diagnosis. RESULTS: Although no significant difference was found for T-cell compartments at BOS diagnosis or several months beforehand, we identified an increase in the CD4+CD25hiFoxP3+ T-cell sub-population in BOS patients at 1 and 6 months after transplantation (3.39 ± 0.40% vs 1.67 ± 0.22% in STA, p < 0.001). A CD4+CD25hiFoxP3+ T-cell threshold of 2.4% discriminated BOS and stable patients at 1 month post-transplantation. This was validated on a second set of patients at 6 months post-transplantation. Patients with a proportion of CD4+CD25hiFoxP3+ T cells up to 2.4% in the 6 months after transplantation had a 2-fold higher risk of developing BOS. CONCLUSIONS: This study is the first to report an increased proportion of circulating CD4+CD25hiFoxP3+ T cells early post-transplantation in lung recipients who proceed to develop BOS within 3 years, which supports its use as a BOS predictive biomarker.