MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease.

BACKGROUND: Given the phenotypic similarities between rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (hereafter, RA-ILD) and idiopathic pulmonary fibrosis, we hypothesized that the strongest risk factor for the development of idiopathic pulmonary fibrosis, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD among patients with RA. METHODS: Using a discovery population and multiple validation populations, we tested the association of the MUC5B promoter variant rs35705950 in 620 patients with RA-ILD, 614 patients with RA without ILD, and 5448 unaffected controls. RESULTS: Analysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.8; 95% confidence interval [CI], 2.8 to 5.2; P=9.7×10-17). The MUC5B promoter variant was also significantly overrepresented among patients with RA-ILD, as compared with unaffected controls, in an analysis of the multiethnic case series (adjusted odds ratio, 5.5; 95% CI, 4.2 to 7.3; P=4.7×10-35) and in a combined analysis of the discovery population and the multiethnic case series (adjusted odds ratio, 4.7; 95% CI, 3.9 to 5.8; P=1.3×10-49). In addition, the MUC5B promoter variant was associated with an increased risk of ILD among patients with RA (adjusted odds ratio in combined analysis, 3.1; 95% CI, 1.8 to 5.4; P=7.4×10-5), particularly among those with evidence of usual interstitial pneumonia on high-resolution computed tomography (adjusted odds ratio in combined analysis, 6.1; 95% CI, 2.9 to 13.1; P=2.5×10-6). However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone. CONCLUSIONS: We found that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging. (Funded by Société Française de Rhumatologie and others.).

Methotrexate and rheumatoid arthritis associated interstitial lung disease.

QUESTION ADDRESSED BY THE STUDY: Methotrexate (MTX) is a key anchor drug for rheumatoid arthritis (RA) management. Fibrotic interstitial lung disease (ILD) is a common complication of RA. Whether MTX exposure increases the risk of ILD in patients with RA is disputed. We aimed to evaluate the association of prior MTX use with development of RA-ILD. METHODS: Through a case-control study design with discovery and international replication samples, we examined the association of MTX exposure with ILD in 410 patients with chronic fibrotic ILD associated with RA (RA-ILD) and 673 patients with RA without ILD. Estimates were pooled over the different samples using meta-analysis techniques. RESULTS: Analysis of the discovery sample revealed an inverse relationship between MTX exposure and RA-ILD (adjusted OR 0.46, 95% CI 0.24-0.90; p=0.022), which was confirmed in the replication samples (pooled adjusted OR 0.39, 95% CI 0.19-0.79; p=0.009). The combined estimate using both the derivation and validation samples revealed an adjusted OR of 0.43 (95% CI 0.26-0.69; p=0.0006). MTX ever-users were less frequent among patients with RA-ILD compared to those without ILD, irrespective of chest high-resolution computed tomography pattern. In patients with RA-ILD, ILD detection was significantly delayed in MTX ever-users compared to never-users (11.4±10.4 years and 4.0±7.4 years, respectively; p<0.001). ANSWER TO THE QUESTION: Our results suggest that MTX use is not associated with an increased risk of RA-ILD in patients with RA, and that ILD was detected later in MTX-treated patients.

Long-term efficacy and safety of 2CdA (cladribine) in extra-pulmonary adult-onset Langerhans cell histiocytosis: analysis of 23 cases from the French Histiocytosis Group and systematic literature review.

Langerhans cell histiocytosis (LCH) is a rare protean disease that usually affects children. Few data are available for management of adult-onset cases. A complete picture of the efficacy and safety of 2CdA (2-chlorodeoxyadenosine, cladribine) is lacking. We report a retrospective multicentre study of 23 adult LCH (a-LCH) patients who received single-agent 2CdA and a systematic literature review. All had previously received systemic therapy (vinblastine, n = 19). Response to 2CdA was evaluable in 22 cases. Overall response rate (ORR) was 91%. Complete response (CR) occurred in 11 cases (50%). Nine patients (39%) developed grade 3-4 neutropenia and/or severe infection. A literature review yielded 48 additional cases. A pooled analysis confirmed our findings (ORR: 88%, CR: 49%). CRs were rare with cumulative dose <50 mg/m2 . Disease progression rates were 20% and 30% at two and five years, respectively. Partial response (PR) to 2CdA was predictive of disease progression. Among eight re-treated patients, five went into CR, two in PR, and one died. Single-agent 2CdA is effective in reactivated a-LCH, including at intermediate doses. Toxicity, significant but acceptable, warrants infectious prophylaxis. Complete responders may enter prolonged remission. Further studies are needed to determine 2CdA sequencing with other agents (vinblastine, cytarabine).

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.

Automated Volumetric Quantification of Emphysema Severity by Using Ultrashort Echo Time MRI: Validation in Participants with Chronic Obstructive Pulmonary Disease.

Background The validity of three-dimensional (3D) ultrashort echo time (UTE) MRI for the assessment of emphysema in patients with chronic obstructive pulmonary disease (COPD) at high spatial resolution is, to the knowledge of the authors, unknown. Purpose To assess whether noncontrast agent-enhanced 3D UTE MRI at submillimeter spatial resolution can be used to determine the extent of emphysema by using both qualitative visual scoring and fully automated volumetric quantification. Materials and Methods Twenty-eight participants with COPD and 10 control participants (mean age, 70 years ± 7 [standard deviation] and 64 years ± 4, respectively) were prospectively enrolled between 2015 and 2017. Participants underwent pulmonary function testing, CT, and MRI. CT was used as the reference standard. Qualitative scoring of emphysema extent was performed by two readers. Fully automated quantification of percentage of low-attenuation volume by using a threshold of -950 HU (%LAV-950HU) at CT and percentage of low-signal-intensity volume by using an adaptive threshold of 0.20 (%LSV0.20) at MRI were the respective emphysema indexes. Comparison of means was performed by using Student t test, correlation was determined by using Pearson test, agreement was found by using weighted κ index, and reproducibility was determined by using intraclass correlation coefficient. Diagnostic performance was assessed by calculating the area under the receiver operating characteristics curve (AUC). Results With qualitative scoring, agreement between UTE MRI and CT was good (weighted κ, 0.79; 95% confidence interval: 0.71, 0.83). With automated volumetric quantification, %LSV0.20 was significantly correlated with %LAV-950HU in participants with COPD (r, -0.80; P < .001) and correlated with forced expiratory volume in 1 second percentage predicted (r, -0.55; P = .002). %LSV0.20 was significantly higher in participants with COPD than in control participants (P < .001). The diagnostic performance and reproducibility of %LSV0.20 were good (AUC, 1.00 [95% confidence interval: 0.88, 1.00], and intraclass correlation coefficient, > 0.99, respectively). Conclusion A fully automated method with three-dimensional ultrashort echo time MRI reproducibly quantified the volumetric extent of emphysema in participants with chronic obstructive pulmonary disease. © RSNA, 2019 Online supplemental material is available for this article.

Widening the landscape of heritable pulmonary hypertension mutations in paediatric and adult cases.

BACKGROUND: Heritable forms of pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis (PVOD/PCH) diverge by lung histopathological lesions, clinical and para-clinical presentation, their responsible genes, and mode of transmission. Since the identification of the BMPR2 gene in families affected by PAH, mutations in several other genes have been discovered for both forms. The mutation landscape in these new genes is not yet well known. METHODS: We set up a next-generation sequencing-based targeted sequencing gene panel allowing known genes for PAH and PVOD/PCH to be analysed simultaneously. Genetic analysis was prospectively performed on 263 PAH and PVOD/PCH patients (adult and paediatric cases). RESULTS: Pathogenic mutations were identified in 19.5% of sporadic PAH patients (n=180), 54.5% of familial PAH patients and 13.3% of PVOD/PCH patients. BMPR2 was the most frequently mutated gene, followed by TBX4 in both paediatric and adult PAH. BMP9 mutations were identified in 1.2% of adult PAH cases. EIF2AK4 biallelic mutations were restricted to PVOD/PCH. A truncating mutation and a predicted loss-of-function variant were also identified in BMP10 in two severely affected sporadic PAH female patients. CONCLUSION: Our results confirm that mutations are found in genes beyond BMPR2 in heritable PAH, emphasise the role of TBX4 and BMP9, and designate BMP10 as a new PAH gene.

Management and long-term outcomes of sarcoidosis-associated pulmonary hypertension.

Studies reporting the effects of modern strategies with pulmonary arterial hypertension (PAH)-targeted therapies in sarcoidosis-associated pulmonary hypertension (S-APH) are limited.Clinical and haemodynamic data from newly diagnosed patients with severe S-APH (mean pulmonary artery pressure (mPAP) >35 mmHg or mPAP 25-35 mmHg with cardiac index <2.5 L·min-1·m-2) were collected from the French Pulmonary Hypertension Registry between 2004 and 2015.Data from 126 patients with severe S-APH were analysed (mean±sd age 57.5±11.6 years, 74% radiological stage IV). 97 patients (77%) received PAH-targeted therapy and immunosuppressive therapy was initiated or escalated in 33 patients at the time of pulmonary hypertension diagnosis. Four months after PAH-targeted therapy initiation, mean±sd pulmonary vascular resistance decreased from 9.7±4.4 to 6.9±3.0 Wood units (p<0.001), without significant improvement in exercise capacity. Among the 11 patients treated only with immunosuppressive therapy, a haemodynamic improvement was observed in four patients, including two with compressive lymph nodes. After a median follow-up of 28 months, 39 patients needed PAH-targeted therapy escalation, nine underwent lung transplantation and 42 had died. Survival at 1, 3 and 5 years was 93%, 74% and 55%, respectively.PAH-targeted therapy improved short-term pulmonary haemodynamics in severe S-APH without change in exercise capacity. Immunosuppressive therapy improved haemodynamics in selected patients. Pulmonary hypertension in sarcoidosis remains associated with a poor prognosis.

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.

Shared genetic predisposition in rheumatoid arthritis-interstitial lung disease and familial pulmonary fibrosis.

Despite its high prevalence and mortality, little is known about the pathogenesis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Given that familial pulmonary fibrosis (FPF) and RA-ILD frequently share the usual pattern of interstitial pneumonia and common environmental risk factors, we hypothesised that the two diseases might share additional risk factors, including FPF-linked genes. Our aim was to identify coding mutations of FPF-risk genes associated with RA-ILD.We used whole exome sequencing (WES), followed by restricted analysis of a discrete number of FPF-linked genes and performed a burden test to assess the excess number of mutations in RA-ILD patients compared to controls.Among the 101 RA-ILD patients included, 12 (11.9%) had 13 WES-identified heterozygous mutations in the TERT, RTEL1, PARN or SFTPC coding regions. The burden test, based on 81 RA-ILD patients and 1010 controls of European ancestry, revealed an excess of TERT, RTEL1, PARN or SFTPC mutations in RA-ILD patients (OR 3.17, 95% CI 1.53-6.12; p=9.45×10-4). Telomeres were shorter in RA-ILD patients with a TERT, RTEL1 or PARN mutation than in controls (p=2.87×10-2).Our results support the contribution of FPF-linked genes to RA-ILD susceptibility.

Blood fibrocytes are recruited during acute exacerbations of chronic obstructive pulmonary disease through a CXCR4-dependent pathway.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by peribronchial fibrosis. The chronic course of COPD is worsened by recurrent acute exacerbations. OBJECTIVE: The aim of the study was to evaluate the recruitment of blood fibrocytes in patients with COPD during exacerbations and, subsequently, to identify potential mechanisms implicated in such recruitment. METHODS: Using flow cytometry, we quantified circulating fibrocytes and characterized their chemokine receptor expression in 54 patients with COPD examined during an acute exacerbation (V1) and 2 months afterward (V2) and in 40 control subjects. The role of the chemokines CXCL12 and CCL11 in fibrocyte migration was investigated by using a chemotaxis assay. Patients were followed for up to 3 years after V1. RESULTS: We demonstrated a significantly increased number of circulating fibrocytes at V1 compared with control subjects. The number of circulating fibrocytes decreased at V2. A high percentage of circulating fibrocytes during exacerbation was associated with increased risk of death. The percentage of fibrocytes at V2 was negatively correlated with FEV1, forced vital capacity, FEV1/forced vital capacity ratio, transfer lung capacity of carbon monoxide, and Pao2. Fibrocytes highly expressed CXCR4 and CCR3, the chemokine receptors for CXCL12 and CCL11, respectively. Fibrocytes collected from patients with COPD at V1 had increased chemotactic migration in response to CXCL12 but not to CCL11 compared with those from control subjects. Plerixafor, a CXCR4 antagonist, decreased fibrocyte migration to plasma from patients with exacerbating COPD. CONCLUSION: Blood fibrocytes are recruited during COPD exacerbations and related to mortality and low lung function. The CXCL12/CXCR4 axis is involved in such fibrocyte recruitment (Firebrob study; ClinicalTrials NCT01196832).

CT evaluation of small pulmonary vessels area in patients with COPD with severe pulmonary hypertension.

RATIONALE: Severe pulmonary hypertension (PH) is very uncommon in COPD, and a distinct phenotype has been hypothesised. We aimed to evaluate whether CT can help to recognise this condition non-invasively by measuring small pulmonary vessels. MATERIAL AND METHODS: Patients with COPD who underwent pulmonary function tests, unenhanced CT of the chest and right heart catheterisation (RHC) during a period of stability were included in the study. From 105 included patients, 20 patients with COPD with severe PH (mean pulmonary arterial pressure, mPAP>35 mm Hg) were compared with 20 FEV1-matched and age-matched patients with COPD with mild or without PH (mPAP<35 mm Hg). The percentage of total cross-sectional area of vessels less than 5 mm(2) normalised by lung area (%CSA<5) and 5-10 mm(2) (%CSA5-10), the mean number of cross-sectioned vessels (CSNs) and bronchial wall thickness (WT) were measured on CT examination and compared between groups. Paw scores combining PaO2 measurement and CT parameters best correlated with mPAP were compared by receiver operating characteristic analysis to predict severe PH in COPD. RESULTS: Patients with severe PH COPD had higher %CSA and CSN values than those of patients with COPD without severe PH. Using multiple regression analysis, %CSA<5 and WT were the best predictors of mPAP in patients with and without severe PH, respectively. A score combining %CSA<5, PaO2 and WT best predicted severe PH in patients with COPD. CONCLUSIONS: CT measurements of small vessels support a distinct vessel-related phenotype in patients with COPD with severe PH, and combined with WT and PaO2 parameters in the paw score, which may offer a non-invasive tool to select patients for RHC.

Computed tomographic measurement of airway remodeling and emphysema in advanced chronic obstructive pulmonary disease. Correlation with pulmonary hypertension.

RATIONALE: Pulmonary hypertension (PH) is an established complication of advanced chronic obstructive pulmonary disease (COPD) associated with increased mortality. The mechanisms coupling PH and bronchial obstruction are unknown; in particular, PH appears to be unrelated to emphysema. We hypothesized that computed tomographic (CT) measurement of airway remodeling instead of emphysema may correlate with PH in COPD. OBJECTIVES: We aimed to describe the clinical and CT characteristics of patients with COPD with or without PH and to correlate CT measurements of airway remodeling and emphysema with PH. METHODS: Data were retrieved from 60 COPD patients who underwent both right heart catheterization and computed tomography in a period of stability and had no other disease known to cause PH. CT measurement of airway wall thickness (WT-Pi10) was used to assess airway remodeling and low lung area percentage (LAA%) to quantify emphysema extent. MEASUREMENTS AND MAIN RESULTS: Thirty-four of the sixty patients with COPD had PH (mean pulmonary arterial pressure [PAPm] ≥ 25 mm Hg). There was no difference between the two groups regarding age, sex, and spirometric results, whereas there was more profound hypoxemia in the PH group. WT-Pi10 was increased in the patients with COPD and PH and correlated with PAPm (ρ = 0.62; P < 0.001). Conversely, there was no difference or correlation between PAPm and LAA% (ρ = 0.12; P = 0.33). In multivariate analysis (R(2) = 0.53), WT-Pi10 was the independent predictor most associated with PAPm elevation, as compared to hypoxia (PaO2) or pulmonary arterial enlargement (diameter ratio between the pulmonary arterial truncus and the ascending aorta). CONCLUSIONS: This study demonstrates, for the first time to our knowledge, an association between structural alterations of bronchi and PH in COPD. Unlike quantification of emphysema, CT measurement of airway remodeling correlates with PAPm and could be used to estimate the severity of PH in COPD. Airway remodeling burden is not limited to airflow limitation in the assessment of COPD severity and mortality.

Dual-energy CT perfusion and angiography in chronic thromboembolic pulmonary hypertension: diagnostic accuracy and concordance with radionuclide scintigraphy.

OBJECTIVES: To evaluate the diagnostic accuracy of dual-energy computed tomography (DECT) perfusion and angiography versus ventilation/perfusion (V/Q) scintigraphy in chronic thromboembolic pulmonary hypertension (CTEPH), and to assess the per-segment concordance rate of DECT and scintigraphy. METHODS: Forty consecutive patients with proven pulmonary hypertension underwent V/Q scintigraphy and DECT perfusion and angiography. Each imaging technique was assessed for the location of segmental defects. Diagnosis of CTEPH was established when at least one segmental perfusion defect was detected by scintigraphy. Diagnostic accuracy of DECT perfusion and angiography was assessed and compared with scintigraphy. In CTEPH patients, the per-segment concordance between scintigraphy and DECT perfusion/angiography was calculated. RESULTS: Fourteen patients were diagnosed with CTEPH and 26 with other aetiologies. DECT perfusion and angiography correctly identified all CTEPH patients with sensitivity/specificity values of 1/0.92 and 1/0.93, respectively. At a segmental level, DECT perfusion showed moderate agreement (κ = 0.44) with scintigraphy. Agreement between CT angiography and scintigraphy ranged from fair (κ = 0.31) to slight (κ = 0.09) depending on whether completely or partially occlusive patterns were considered, respectively. CONCLUSIONS: Both DECT perfusion and angiography show satisfactory performance for the diagnosis of CTEPH. DECT perfusion is more accurate than angiography at identifying the segmental location of abnormalities. KEY POINTS: • Chronic thromboembolic pulmonary hypertension (CTEPH) is potentially treatable by surgery. • Dual-energy computed tomography (DECT) allows angiography and perfusion using a single acquisition. • Both DECT perfusion and angiography showed satisfactory diagnostic performance in CTEPH. • DECT perfusion was more accurate than angiography in identifying segmental abnormalities.

Evolution of donor-specific antibodies (DSA) and incidence of de novo DSA in solid organ transplant recipients after switch to everolimus alone or associated with low dose of calcineurin inhibitors.

BACKGROUND: Everolimus (EVR) is used in organ transplantation to minimize calcineurin inhibitors (CNI). Some studies pointed out an increase in rejection and de novo donor-specific antibodies (DSA) incidence in kidney transplant patients after switch to EVR and CNI withdrawal. The aims of our study were to determine the evolution of anti-HLA antibodies and the incidence of de novo DSA in transplant recipients after conversion to EVR. METHODS: Heart, lung, kidney, and liver transplant recipients were included in a retrospective, monocentric case-control study. Anti-HLA antibodies were identified at transplantation, pre-switch, and at three, six, and 12 months post-switch. RESULTS: Conversion to EVR was performed about six yr after the transplant, and low-dose CNI was maintained in 60% of patients. We found no statistical difference for rejection, evolution of preformed anti-HLA antibodies or de novo DSA, after conversion to EVR or not. Incidence of anti-class II DSA tended to increase at month 12 whatever the immunosuppressive regimen. CONCLUSIONS: Late conversion to EVR appears to be safe and to not modify the natural evolution of anti-HLA antibodies in organ transplantation. As 60% of patients received EVR and low doses of CNI, it seems that such combinations could be used with a good outcome.

Cardiopulmonary bypass during a second-lung implantation improves postoperative oxygenation after sequential double-lung transplantation.

OBJECTIVES: During sequential double-lung transplantation (DLT), the newly implanted first lung receives the entire cardiac output during the implantation of the second one. This may be responsible for the increased hydrostatic pressure that causes severe interstitial and alveolar edema that can lead to allograft dysfunction. The authors tested the hypothesis that CPB started after first graft implantation and before second recipient lung removal should improve post-transplantation oxygenation and clinical outcomes. DESIGN: Observational during 2 consecutive 1-year periods. SETTING: University hospital. PARTICIPANTS: Nine consecutive patients undergoing sequential DLT with CPB started after first graft implantation and before second recipient lung removal were compared to controls, who were 10 consecutive patients who underwent sequential DLT but without CPB the year before. MEASUREMENTS AND MAIN RESULTS: Oxygenation after transplantation was assessed. The use of CPB during the implantation of the second lung was associated with an increased mean postoperative ratio of PaO2 to the fraction of inspired oxygen at 1 hour (363±51 v 240±113, p = 0.01) and 6 hours (430±111 v 280±103, p = 0.03). The mean duration of CPB was 111±19 min. The occurrence of primary graft dysfunction and the need for extracorporeal membrane oxygenation tended to be lower, but did not reach significance. Similarly, mortality rate was comparable between both groups, as was the rate of blood transfusions. CONCLUSIONS: The authors' results suggest that the use of CPB started after first graft implantation and before second recipient lung removal appears to benefit oxygenation and reduces the occurrence of severe pulmonary edema in the first transplanted lung.

Pulmonary hypertension associated with benfluorex exposure.

Benfluorex was marketed in France until 2009, despite its similar pharmacological properties with fenfluramine and its derivatives known to be a cause of pulmonary arterial hypertension (PAH). The aim of this study is to report clinical and haemodynamic characteristics for patients suffering from pulmonary hypertension (PH) associated with benfluorex exposure that had been identified by the French PAH Network. 85 cases of PH associated with benfluorex exposure were identified by the French PAH Network from June 1999 to March 2011. Of these, 70 patients had confirmed pre-capillary PH. The median duration of exposure was 30 months, with a median of 108 months between start of exposure and diagnosis of the pulmonary vascular disease. 33% of all patients also had prior exposure to fenfluramine or dexfenfluramine, and an additional risk factor for PH was identified in 20 (30%) out of 70 patients with pre-capillary PH. A quarter of patients in this current series showed coexisting PH and mild-to-moderate cardiac valve involvement. The results of our study, together with the accumulated data regarding the known toxic effects of fenfluramine and dexfenfluramine, strongly suggest that benfluorex exposure is a potent trigger for PAH.

Mean bronchial wall attenuation value in chronic obstructive pulmonary disease: comparison with standard bronchial parameters and correlation with function.

OBJECTIVE: The objective of our study was to evaluate bronchial wall attenuation values quantified using CT in patients with chronic obstructive pulmonary disease (COPD). SUBJECTS AND METHODS: Ninety patients (81 men, nine women; age range, 21-80 years; mean age, 56 years) underwent CT and pulmonary function tests (PFTs). Bronchial wall attenuation value, wall area, and lumen area were averaged over four segmental bronchi in control subjects (n = 30), smokers with COPD (n = 30), and smokers without COPD (n = 30). The bronchial wall thickness, wall area-to-lumen area ratio, and wall area-to-total area ratio were computed. The extent of emphysema was measured as the percentage of area with an attenuation of less than -950 HU. Parameters were compared among groups and were correlated with PFT results. Receiver operating characteristic curves were obtained for each parameter and areas under the curve were compared. Variables responsible for changes in wall attenuation values and those accounting for obstructive indexes were assessed using multiple regressions. RESULTS: The wall attenuation value was the only parameter discriminating between each pair of groups (mean ± SD, -293 ± 71 HU in COPD patients, -387 ± 70 HU in smokers, and -457 ± 69 HU in control subjects). The area under the curve of the wall attenuation value was greater than that of any other CT bronchial parameter to separate smokers from COPD patients. Wall attenuation value correlated with PFT results and was influenced by the wall area-to-lumen area ratio. The wall attenuation value, extent of emphysema, and standard bronchial parameters independently influenced obstructive indexes. CONCLUSION: The bronchial wall attenuation value is a powerful index for assessing tobacco-related bronchial wall changes in patients with COPD.

Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era.

BACKGROUND: Novel therapies have recently become available for pulmonary arterial hypertension. We conducted a study to characterize mortality in a multicenter prospective cohort of patients diagnosed with idiopathic, familial, or anorexigen-associated pulmonary arterial hypertension in the modern management era. METHODS AND RESULTS: Between October 2002 and October 2003, 354 consecutive adult patients with idiopathic, familial, or anorexigen-associated pulmonary arterial hypertension (56 incident and 298 prevalent cases) were prospectively enrolled. Patients were followed up for 3 years, and survival rates were analyzed. For incident cases, estimated survival (95% confidence intervals [CIs]) at 1, 2, and 3 years was 85.7% (95% CI, 76.5 to 94.9), 69.6% (95% CI, 57.6 to 81.6), and 54.9% (95% CI, 41.8 to 68.0), respectively. In a combined analysis population (incident patients and prevalent patients diagnosed within 3 years before study entry; n=190), 1-, 2-, and 3-year survival estimates were 82.9% (95% CI, 72.4 to 95.0), 67.1% (95% CI, 57.1 to 78.8), and 58.2% (95% CI, 49.0 to 69.3), respectively. Individual survival analysis identified the following as significantly and positively associated with survival: female gender, New York Heart Association functional class I/II, greater 6-minute walk distance, lower right atrial pressure, and higher cardiac output. Multivariable analysis showed that being female, having a greater 6-minute walk distance, and exhibiting higher cardiac output were jointly significantly associated with improved survival. CONCLUSIONS: In the modern management era, idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension remains a progressive, fatal disease. Mortality is most closely associated with male gender, right ventricular hemodynamic function, and exercise limitation.

Shared reactivity of V{delta}2(neg) {gamma}{delta} T cells against cytomegalovirus-infected cells and tumor intestinal epithelial cells.

Long-lasting expansion of Vdelta2(neg) gammadelta T cells is a hallmark of cytomegalovirus (CMV) infection in kidney transplant recipients. The ligands of these cells and their role remain elusive. To better understand their immune function, we generated gammadelta T cell clones from several transplanted patients. Numerous patient Vdelta1(+), Vdelta3(+), and Vdelta5(+) gammadelta T cell clones expressing diverse Vgamma chains, but not control Vgamma9Vdelta2(+) T clones, displayed strong reactivity against CMV-infected cells, as shown by their production of tumor necrosis factor-alpha. Vdelta2(neg) gammadelta T lymphocytes could also kill CMV-infected targets and limit CMV propagation in vitro. Their anti-CMV reactivity was specific for this virus among herpesviridae and required T cell receptor engagement, but did not involve major histocompatibility complex class I molecules or NKG2D. Vdelta2(neg) gammadelta T lymphocytes expressed receptors essential for intestinal homing and were strongly activated by intestinal tumor, but not normal, epithelial cell lines. High frequencies of CMV- and tumor-specific Vdelta2(neg) gammadelta T lymphocytes were found among patients' gammadelta T cells. In conclusion, Vdelta2(neg) gammadelta T cells may play a role in protecting against CMV and tumors, probably through mucosal surveillance of cellular stress, and represent a population that is largely functionally distinct from Vgamma9Vdelta2(+) T cells.