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1.  Clinical Risk Factors for Primary Graft Dysfunction after Lung Transplantation 
Rationale: Primary graft dysfunction (PGD) is the main cause of early morbidity and mortality after lung transplantation. Previous studies have yielded conflicting results for PGD risk factors.
Objectives: We sought to identify donor, recipient, and perioperative risk factors for PGD.
Methods: We performed a 10-center prospective cohort study enrolled between March 2002 and December 2010 (the Lung Transplant Outcomes Group). The primary outcome was International Society for Heart and Lung Transplantation grade 3 PGD at 48 or 72 hours post-transplant. The association of potential risk factors with PGD was analyzed using multivariable conditional logistic regression.
Measurements and Main Results: A total of 1,255 patients from 10 centers were enrolled; 211 subjects (16.8%) developed grade 3 PGD. In multivariable models, independent risk factors for PGD were any history of donor smoking (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.2–2.6; P = 0.002); FiO2 during allograft reperfusion (OR, 1.1 per 10% increase in FiO2; 95% CI, 1.0–1.2; P = 0.01); single lung transplant (OR, 2; 95% CI, 1.2–3.3; P = 0.008); use of cardiopulmonary bypass (OR, 3.4; 95% CI, 2.2–5.3; P < 0.001); overweight (OR, 1.8; 95% CI, 1.2–2.7; P = 0.01) and obese (OR, 2.3; 95% CI, 1.3–3.9; P = 0.004) recipient body mass index; preoperative sarcoidosis (OR, 2.5; 95% CI, 1.1–5.6; P = 0.03) or pulmonary arterial hypertension (OR, 3.5; 95% CI, 1.6–7.7; P = 0.002); and mean pulmonary artery pressure (OR, 1.3 per 10 mm Hg increase; 95% CI, 1.1–1.5; P < 0.001). PGD was significantly associated with 90-day (relative risk, 4.8; absolute risk increase, 18%; P < 0.001) and 1-year (relative risk, 3; absolute risk increase, 23%; P < 0.001) mortality.
Conclusions: We identified grade 3 PGD risk factors, several of which are potentially modifiable and should be prioritized for future research aimed at preventative strategies.
Clinical trial registered with www.clinicaltrials.gov (NCT 00552357).
doi:10.1164/rccm.201210-1865OC
PMCID: PMC3733407  PMID: 23306540
lung transplantation; clinical risk factors; primary graft dysfunction
2.  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.
doi:10.1164/rccm.201204-0692OC
PMCID: PMC3480532  PMID: 22822025
primary graft dysfunction; single-nucleotide polymorphism; long pentraxin 3; lung transplantation
3.  Inflammasome-regulated Cytokines Are Critical Mediators of Acute Lung Injury 
Rationale: Despite advances in clinical management, there are currently no reliable diagnostic and therapeutic targets for acute respiratory distress syndrome (ARDS). The inflammasome/caspase-1 pathway regulates the maturation and secretion of proinflammatory cytokines (e.g., IL-18). IL-18 is associated with injury in animal models of systemic inflammation.
Objectives: We sought to determine the contribution of the inflammasome pathway in experimental acute lung injury and human ARDS.
Methods: We performed comprehensive gene expression profiling on peripheral blood from patients with critical illness. Gene expression changes were assessed using real-time polymerase chain reaction, and IL-18 levels were measured in the plasma of the critically ill patients. Wild-type mice or mice genetically deficient in IL-18 or caspase-1 were mechanically ventilated using moderate tidal volume (12 ml/kg). Lung injury parameters were assessed in lung tissue, serum, and bronchoalveolar lavage fluid.
Measurements and Main Results: In mice, mechanical ventilation enhanced IL-18 levels in the lung, serum, and bronchoalveolar lavage fluid. IL-18–neutralizing antibody treatment, or genetic deletion of IL-18 or caspase-1, reduced lung injury in response to mechanical ventilation. In human patients with ARDS, inflammasome-related mRNA transcripts (CASP1, IL1B, and IL18) were increased in peripheral blood. In samples from four clinical centers, IL-18 was elevated in the plasma of patients with ARDS (sepsis or trauma-induced ARDS) and served as a novel biomarker of intensive care unit morbidity and mortality.
Conclusions: The inflammasome pathway and its downstream cytokines play critical roles in ARDS development.
doi:10.1164/rccm.201201-0003OC
PMCID: PMC3373064  PMID: 22461369
acute respiratory distress syndrome; inflammasome; interleukin-18; mechanical ventilation
4.  ANGPT2 Genetic Variant Is Associated with Trauma-associated Acute Lung Injury and Altered Plasma Angiopoietin-2 Isoform Ratio 
Rationale: Acute lung injury (ALI) acts as a complex genetic trait, yet its genetic risk factors remain incompletely understood. Large-scale genotyping has not previously been reported for ALI.
Objectives: To identify ALI risk variants after major trauma using a large-scale candidate gene approach.
Methods: We performed a two-stage genetic association study. We derived findings in an African American cohort (n = 222) using a cardiopulmonary disease–centric 50K single nucleotide polymorphism (SNP) array. Genotype and haplotype distributions were compared between subjects with ALI and without ALI, with adjustment for clinical factors. Top performing SNPs (P < 10−4) were tested in a multicenter European American trauma-associated ALI case-control population (n = 600 ALI; n = 2,266 population-based control subjects) for replication. The ALI-associated genomic region was sequenced, analyzed for in silico prediction of function, and plasma was assayed by ELISA and immunoblot.
Measurements and Main Results: Five SNPs demonstrated a significant association with ALI after adjustment for covariates in Stage I. Two SNPs in ANGPT2 (rs1868554 and rs2442598) replicated their significant association with ALI in Stage II. rs1868554 was robust to multiple comparison correction: odds ratio 1.22 (1.06–1.40), P = 0.0047. Resequencing identified predicted novel splice sites in linkage disequilibrium with rs1868554, and immunoblots showed higher proportion of variant angiopoietin-2 (ANG2) isoform associated with rs1868554T (0.81 vs. 0.48; P = 0.038).
Conclusions: An ANGPT2 region is associated with both ALI and variation in plasma angiopoietin-2 isoforms. Characterization of the variant isoform and its genetic regulation may yield important insights about ALI pathogenesis and susceptibility.
doi:10.1164/rccm.201005-0701OC
PMCID: PMC3114062  PMID: 21257790
acute lung injury; acute respiratory distress syndrome; functional genetic polymorphism; genetic association study
5.  Obesity and Primary Graft Dysfunction after Lung Transplantation 
Rationale: Obesity has been linked to acute lung injury and is a risk factor for early mortality after lung transplantation.
Objectives: To examine the associations of obesity and plasma adipokines with the risk of primary graft dysfunction after lung transplantation.
Methods: We performed a prospective cohort study of 512 adult lung transplant recipients with chronic obstructive pulmonary disease or interstitial lung disease enrolled in the Lung Transplant Outcomes Group Study. In a nested case-control study, we measured plasma leptin, adiponectin, and resistin before lung transplantation and 6 and 24 hours after lung transplantation in 40 cases of primary graft dysfunction and 80 control subjects. Generalized linear mixed models and logistic regression were used to estimate risk ratios and odds ratios.
Measurements and Main Results: Grade 3 primary graft dysfunction developed within 72 hours of transplantation in 29% participants. Obesity was associated with a twofold increased risk of primary graft dysfunction (adjusted risk ratio 2.1; 95% confidence interval, 1.7–2.6). The risk of primary graft dysfunction increased by 40% (confidence interval, 30–50%) for each 5 kg/m2 increase in body mass index after accounting for center, diagnosis, cardiopulmonary bypass, and transplant procedure. Higher plasma leptin levels were associated with a greater risk of primary graft dysfunction (sex-adjusted P = 0.02). The associations of both obesity and leptin with primary graft dysfunction tended to be stronger among those who did not undergo cardiopulmonary bypass.
Conclusions: Obesity is an independent risk factor for primary graft dysfunction after lung transplantation.
doi:10.1164/rccm.201104-0728OC
PMCID: PMC3208644  PMID: 21799077
acute lung injury; leptin; lung transplantation; obesity; primary graft dysfunction
6.  Bronchial Secretory Immunoglobulin A Deficiency Correlates With Airway Inflammation and Progression of Chronic Obstructive Pulmonary Disease 
Rationale: Although airway inflammation can persist for years after smoking cessation in patients with chronic obstructive pulmonary disease (COPD), the mechanisms of persistent inflammation are largely unknown.
Objectives: We investigated relationships between bronchial epithelial remodeling, polymeric immunoglobulin receptor (pIgR) expression, secretory IgA (SIgA), airway inflammation, and mural remodeling in COPD.
Methods: Lung tissue specimens and bronchoalveolar lavage were obtained from lifetime nonsmokers and former smokers with or without COPD. Epithelial structural changes were quantified by morphometric analysis. Expression of pIgR was determined by immunostaining and real-time polymerase chain reaction. Immunohistochemistry was performed for IgA, CD4 and CD8 lymphocytes, and cytomegalovirus and Epstein-Barr virus antigens. Total IgA and SIgA were measured by ELISA and IgA transcytosis was studied using cultured human bronchial epithelial cells.
Measurements and Main Results: Areas of bronchial mucosa covered by normal pseudostratified ciliated epithelium were characterized by pIgR expression with SIgA present on the mucosal surface. In contrast, areas of bronchial epithelial remodeling had reduced pIgR expression, localized SIgA deficiency, and increased CD4+ and CD8+ lymphocyte infiltration. In small airways (<2 mm), these changes were associated with presence of herpesvirus antigens, airway wall remodeling, and airflow limitation in patients with COPD. Patients with COPD had reduced SIgA in bronchoalveolar lavage. Air–liquid interface epithelial cell cultures revealed that complete epithelial differentiation was required for normal pIgR expression and IgA transcytosis.
Conclusions: Our findings indicate that epithelial structural abnormalities lead to localized SIgA deficiency in COPD airways. Impaired mucosal immunity may contribute to persistent airway inflammation and progressive airway remodeling in COPD.
doi:10.1164/rccm.201010-1629OC
PMCID: PMC3265275  PMID: 21512171
polymeric immunoglobulin receptor; bronchial epithelium; cell differentiation; epithelial remodeling; mucosal host defense
7.  Beyond Mortality 
Mortality in National Heart, Lung and Blood Institute–sponsored clinical trials of treatments for acute lung injury (ALI) has decreased dramatically during the past two decades. As a consequence, design of such trials based on a mortality outcome requires ever-increasing numbers of patients. Recognizing that advances in clinical trial design might be applicable to these trials and might allow trials with fewer patients, the National Heart, Lung and Blood Institute convened a workshop of extramural experts from several disciplines. The workshop assessed the current state of clinical research addressing ALI, identified research needs, and recommended: (1) continued performance of trials evaluating treatments of patients with ALI; (2) development of strategies to perform ALI prevention trials; (3) observational studies of patients without ALI undergoing prolonged mechanical ventilation; and (4) development of a standardized format for reporting methods, endpoints, and results of ALI trials.
doi:10.1164/rccm.201001-0024WS
PMCID: PMC2874454  PMID: 20224063
clinical trials; acute respiratory distress syndrome; pulmonary diseases; edema; inflammation
8.  Plasma Levels of Receptor for Advanced Glycation End Products, Blood Transfusion, and Risk of Primary Graft Dysfunction 
Rationale: The receptor for advanced glycation end products (RAGE) is an important marker of lung epithelial injury and may be associated with impaired alveolar fluid clearance. We hypothesized that patients with primary graft dysfunction (PGD) after lung transplantation would have higher RAGE levels in plasma than patients without PGD.
Objectives: To test the association of soluble RAGE (sRAGE) levels with PGD in a prospective, multicenter cohort study.
Methods: We measured plasma levels of sRAGE at 6 and 24 hours after allograft reperfusion in 317 lung transplant recipients at seven centers. The primary outcome was grade 3 PGD (PaO2/FiO2 < 200 with alveolar infiltrates) within the first 72 hours after transplantation.
Measurements and Main Results: Patients who developed PGD had higher levels of sRAGE than patients without PGD at both 6 hours (median 9.3 ng/ml vs. 7.5 ng/ml, respectively; P = 0.028) and at 24 hours post-transplantation (median 4.3 ng/ml vs. 1.9 ng/ml, respectively; P < 0.001). Multivariable logistic regression analyses indicated that the relationship between levels of sRAGE and PGD was attenuated by elevated right heart pressures and by the use of cardiopulmonary bypass. Median sRAGE levels were higher in subjects with cardiopulmonary bypass at both 6 hours (P = 0.003) and 24 hours (P < 0.001). sRAGE levels at 6 hours were significantly associated with intraoperative red cell transfusion (Spearman's ρ = 0.39, P = 0.002 in those with PGD), and in multivariable linear regression analyses this association was independent of confounding variables (P = 0.02).
Conclusions: Elevated plasma levels of sRAGE are associated with PGD after lung transplantation. Furthermore, plasma sRAGE levels are associated with blood product transfusion and use of cardiopulmonary bypass.
doi:10.1164/rccm.200901-0118OC
PMCID: PMC2778153  PMID: 19661249
primary graft dysfunction; reperfusion injury; lung transplantation; receptor for advanced glycation end products; acute lung injury
9.  Higher Urine Nitric Oxide Is Associated with Improved Outcomes in Patients with Acute Lung Injury 
Rationale: Nitrogen oxide (NO) species are markers for oxidative stress that may be pathogenic in acute lung injury (ALI).
Objectives: We tested two hypotheses in patients with ALI: (1) higher levels of urine NO would be associated with worse clinical outcomes, and (2) ventilation with lower Vt would reduce urine NO as a result of less stretch injury.
Methods: Urine NO levels were measured by chemiluminescence in 566 patients enrolled in the National Heart Lung and Blood Institute Acute Respiratory Distress Syndrome Network trial of 6 ml/kg versus 12 ml/kg Vt ventilation. The data were expressed corrected and uncorrected for urine creatinine (Cr).
Results: Higher baseline levels of urine NO to Cr were associated with lower mortality (odds ratio, 0.43 per log(10) increase in the ratio), more ventilator-free days (mean increase, 1.9 d), and more organ-failure–free days (mean increase, 2.3 d) on multivariate analysis (p < 0.05 for all analyses). Similar results were obtained using urine NO alone. NO to Cr levels were higher on Day 3 in the 6 ml/kg than in the 12 ml/kg Vt group (p = 0.04).
Conclusions: Contrary to our hypothesis, higher urine NO was associated with improved outcomes in ALI at baseline and after treatment with the 6 ml/kg Vt strategy. Higher endogenous NO may reflect less severe lung injury and better preservation of the pulmonary and systemic endothelium or may serve a protective function in patients with ALI.
doi:10.1164/rccm.200607-947OC
PMCID: PMC1899263  PMID: 17082495
acute respiratory distress syndrome; nitrogen oxide species; pulmonary endothelium; tidal volume; pulmonary edema
10.  Association of Protein C and Type 1 Plasminogen Activator Inhibitor with Primary Graft Dysfunction 
Background: Acute lung injury is characterized by hypercoagulability and impaired fibrinolysis. We hypothesized that lower protein C and higher type 1 plasminogen activator inhibitor (PAI-1) levels in plasma would be associated with primary graft dysfunction (PGD) after lung transplantation.
Design: Prospective, multicenter cohort study.
Methods: We measured plasma levels of protein C and PAI-1 before lung transplantation and 6, 24, 48, and 72 h after allograft reperfusion in 128 lung transplant recipients at six centers. The primary outcome was grade 3 PGD (PaO2/FiO2 < 200 with alveolar infiltrates) 72 h after transplantation. Biomarker profiles were evaluated using logistic regression and generalized estimating equations.
Results: Patients who developed PGD had lower protein C levels 24 h posttransplantation than did patients without PGD (mean ± SD [relative to control]: 64 ± 27 vs. 92 ± 41%, respectively; p = 0.002). Patients with PGD also had PAI-1 levels that were almost double those of patients without PGD at 24 h (213 ± 144 vs. 117 ± 89 ng/ml, respectively; p < 0.001). Throughout the 72-h postoperative period, protein C levels were significantly lower (p = 0.007) and PAI-1 levels were higher (p = 0.026) in subjects with PGD than in others. These differences persisted despite adjustment for potential confounders in multivariate analyses. Higher recipient pulmonary artery pressures, measured immediately pretransplantation, were associated with higher PAI-1 levels and increased risk of PGD.
Conclusion: Lower postoperative protein C and higher PAI-1 plasma levels are associated with PGD after lung transplantation. Impaired fibrinolysis and enhanced coagulation may be important in PGD pathogenesis.
doi:10.1164/rccm.200606-827OC
PMCID: PMC1899260  PMID: 17023732
primary graft dysfunction; reperfusion injury; lung transplantation; type 1 plasminogen activator inhibitor; protein C
11.  Receptor for Advanced Glycation End-Products Is a Marker of Type I Cell Injury in Acute Lung Injury 
Rationale: Receptor for advanced glycation end-products (RAGE) is one of the alveolar type I cell–associated proteins in the lung.
Objectives: To test the hypothesis that RAGE is a marker of alveolar epithelial type I cell injury.
Methods: Rats were instilled intratracheally with 10 mg/kg lipopolysaccharide or hydrochloric acid. RAGE levels were measured in the bronchoalveolar lavage (BAL) and serum in the rats and in the pulmonary edema fluid and plasma from patients with acute lung injury (ALI; n = 22) and hydrostatic pulmonary edema (n = 11).
Main Results: In the rat lung injury studies, RAGE was released into the BAL and serum as a single soluble isoform sized ∼ 48 kD. The elevated levels of RAGE in the BAL correlated well with the severity of experimentally induced lung injury. In the human studies, the RAGE level in the pulmonary edema fluid was significantly higher than the plasma level (p < 0.0001). The median edema fluid/plasma ratio of RAGE levels was 105 (interquartile range, 55–243). The RAGE levels in the pulmonary edema fluid from patients with ALI were higher than the levels from patients with hydrostatic pulmonary edema (p < 0.05), and the plasma RAGE level in patients with ALI were significantly higher than the healthy volunteers (p < 0.001) or patients with hydrostatic pulmonary edema (p < 0.05).
Conclusion: RAGE is a marker of type I alveolar epithelial cell injury based on experimental studies in rats and in patients with ALI.
doi:10.1164/rccm.200509-1477OC
PMCID: PMC2662912  PMID: 16456142
acute respiratory distress syndrome; alveolar epithelium; biological markers; pulmonary edema

Results 1-11 (11)