Variation in PTX3 Is Associated with Primary Graft Dysfunction after Lung Transplantation

Rationale: Elevated long pentraxin-3 (PTX3) levels are associated with the development of primary graft dysfunction (PGD) after lung transplantation. Abnormalities in innate immunity, mediated by PTX3 release, may play a role in PGD pathogenesis. Objectives: Our goal was to test whether variants in the gene encoding PTX3 are risk factors for PGD. Methods: We performed a candidate gene association study in recipients from the multicenter, prospective Lung Transplant Outcomes Group cohort enrolled between July 2002 and July 2009. The primary outcome was International Society for Heart and Lung Transplantation grade 3 PGD within 72 hours of transplantation. Targeted genotyping of 10 haplotype-tagging PTX3 single-nucleotide polymorphisms (SNPs) was performed in lung transplant recipients. The association between PGD and each SNP was evaluated by logistic regression, adjusting for pretransplantation lung disease, cardiopulmonary bypass use, and population stratification. The association between SNPs and plasma PTX3 levels was tested across genotypes in a subset of recipients with idiopathic pulmonary fibrosis. Measurements and Main Results: Six hundred fifty-four lung transplant recipients were included. The incidence of PGD was 29%. Two linked 5' region variants, rs2120243 and rs2305619, were associated with PGD (odds ratio, 1.5; 95% confidence interval, 1.1 to 1.9; P = 0.006 and odds ratio, 1.4; 95% confidence interval, 1.1 to 1.9; P = 0.007, respectively). The minor allele of rs2305619 was significantly associated with higher plasma PTX3 levels measured pretransplantation (P = 0.014) and at 24 hours (P = 0.047) after transplantation in patients with idiopathic pulmonary fibrosis. Conclusions: Genetic variants of PTX3 are associated with PGD after lung transplantation, and are associated with increased PTX3 plasma levels.     

Primary Graft Dysfunction and Mortality Following Lung Transplantation: A Role for Proadrenomedullin Plasma Levels

Primary graft dysfunction (PGD) after lung transplantation (LT) is a heterogeneous syndrome that comprises clinical presentations with diverse grades of severity. Proadrenomedullin (proADM) levels may be associated with PGD and may enhance its relationship with outcomes. We prospectively included 100 LT recipients. Plasma levels of proADM were measured at 24, 48 and 72 h after admission to the intensive care unit (ICU). We assessed their relationship with PGD grade and ICU mortality. Fifty patients (50%) presented grade 3 PGD at ICU admission. Twenty‐two patients (22%) developed grade 3 PGD at 72 h, the only grade associated with higher mortality (odds ratio 6.84, 95% confidence interval [CI] 1.47–38.44). ProADM levels measured at 24 h (3.25 vs. 1.61 nmol/L; p = 0.016) and 72 h (2.17 vs. 1.35 nmol/L; p = 0.011) were higher in these patients than the rest of the population. When we added the individual predictive utility of grade 3 PGD at 72 h for ICU mortality (area under the curve [AUC] 0.72, 95% CI 0.53–0.90) to that of ProADM at 72 h, the predictive value of the model improved (AUC 0.81, 95% CI 0.65–0.97). Higher levels of proADM measured following LT are associated with grade 3 PGD at 72 h. ProADM enhances the association of this entity with mortality.     

The Predicting Response to Inhaled Corticosteroid Efficacy (PRICE) trial

BACKGROUND: Although guidelines recommend anti-inflammatory therapy for persistent asthma, recent studies suggest that 25% to 35% of patients with asthma may not improve lung function with inhaled corticosteroids. OBJECTIVE: To evaluate potential biomarkers of predicting short-term (6-week) response to inhaled corticosteroid with subsequent evaluation of responders and nonresponders to asthma control over a longer interval (16 additional weeks). METHODS: Eighty-three subjects with asthma off steroid were enrolled in this multicenter study. Biomarkers and asthma characteristics were evaluated as predictors of inhaled corticosteroid response over a 6-week trial for changes in FEV(1) and methacholine PC(20). After this, an additional 4-month trial evaluated asthma control. RESULTS: Although multiple baseline predictors had significant correlations with improvements for short-term inhaled steroid success, the only strong correlations (r >or= +/- 0.6) were albuterol reversibility (r = 0.83; P < .001), FEV(1)/forced vital capacity (r = -0.75; P < .001), and FEV(1) % predicted (r = -0.71; P < .001). Dividing the subjects in the short-term inhaled steroid trial into responders (>5% FEV(1) improvement) and nonresponders (相似文献