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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.  Delayed Access and Survival in Idiopathic Pulmonary Fibrosis 
Rationale: Idiopathic pulmonary fibrosis is often initially misdiagnosed. Delays in accessing subspecialty care could lead to worse outcomes among those with idiopathic pulmonary fibrosis.
Objectives: To examine the association between delayed access to subspecialty care and survival time in idiopathic pulmonary fibrosis.
Methods: We performed a prospective cohort study of 129 adults who met American Thoracic Society criteria for idiopathic pulmonary fibrosis evaluated at a tertiary care center. Delay was defined as the time from the onset of dyspnea to the date of initial evaluation at a tertiary care center. We used competing risk survival methods to examine survival time and time to transplantation.
Measurements and Main Results: The mean age was 63 years and 76% were men. The median delay was 2.2 years (interquartile range 1.0–3.8 yr), and the median follow-up time was 1.1 years. Age and lung function at the time of evaluation did not vary by delay. A longer delay was associated with an increased risk of death independent of age, sex, forced vital capacity, third-party payer, and educational attainment (adjusted hazard ratio per doubling of delay was 1.3, 95% confidence interval 1.03 to 1.6). Longer delay was not associated with a lower likelihood of undergoing lung transplantation.
Conclusions: Delayed access to a tertiary care center is associated with a higher mortality rate in idiopathic pulmonary fibrosis independent of disease severity. Early referral to a specialty center should be considered for those with known or suspected interstitial lung disease.
doi:10.1164/rccm.201104-0668OC
PMCID: PMC3208648  PMID: 21719755
access to healthcare; healthcare disparities; idiopathic pulmonary fibrosis; interstitial lung disease; survival
4.  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
5.  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
6.  Obesity and Underweight Are Associated with an Increased Risk of Death after Lung Transplantation 
Rationale: Obesity is considered a relative contraindication to lung transplantation, based on studies that have not accounted for key confounders. Little is known about the risk of death for underweight candidates after transplantation.
Objectives: To examine the associations of pretransplant obesity and underweight with the risk of death after lung transplantation.
Methods: We examined 5,978 adults with cystic fibrosis, chronic obstructive pulmonary disease, and diffuse parenchymal lung disease who underwent lung transplantation in the United States between 1995 and 2003. We used Cox models and generalized additive models to examine the association between pretransplant body mass index and the risk of death after lung transplantation with adjustment for donor and recipient factors.
Measurements and Main Results: The median follow-up time was 4.2 years. Compared with normal weight recipients, the multivariable-adjusted rates of death were 15% higher for underweight recipients (95% confidence interval, 3 to 28%), 15% higher for overweight recipients (95% confidence interval, 6 to 26%), and 22% higher for obese recipients (95% confidence interval, 8 to 39%). These relationships persisted when stratified by diagnosis. The multivariable-adjusted population attributable fraction was 12% at 1 year and 8% at 5 years.
Conclusions: Both obesity and underweight are independent risk factors for death after lung transplantation, contributing to up to 12% of deaths in the first year after transplantation. Primary care providers and pulmonologists should promote a healthy weight for patients with lung disease long before transplantation is considered.
doi:10.1164/rccm.200903-0425OC
PMCID: PMC2773915  PMID: 19608717
anthropometry; body mass index; generalized additive models; lung transplantation; obesity
7.  Cigarette Smoking Is Associated with Subclinical Parenchymal Lung Disease 
Rationale: Cigarette smoking is a risk factor for diffuse parenchymal lung disease. Risk factors for subclinical parenchymal lung disease have not been described.
Objectives: To determine if cigarette smoking is associated with subclinical parenchymal lung disease, as measured by spirometric restriction and regions of high attenuation on computed tomography (CT) imaging.
Methods: We examined 2,563 adults without airflow obstruction or clinical cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis, a population-based cohort sampled from six communities in the United States. Cumulative and current cigarette smoking were assessed by pack-years and urine cotinine, respectively. Spirometric restriction was defined as a forced vital capacity less than the lower limit of normal. High attenuation areas on the lung fields of cardiac CT scans were defined as regions having an attenuation between −600 and −250 Hounsfield units, reflecting ground-glass and reticular abnormalities. Generalized additive models were used to adjust for age, gender, race/ethnicity, smoking status, anthropometrics, center, and CT scan parameters.
Measurements and Main Results: The prevalence of spirometric restriction was 10.0% (95% confidence interval [CI], 8.9–11.2%) and increased relatively by 8% (95% CI, 3–12%) for each 10 cigarette pack-years in multivariate analysis. The median volume of high attenuation areas was 119 cm3 (interquartile range, 100–143 cm3). The volume of high attenuation areas increased by 1.6 cm3 (95% CI, 0.9–2.4 cm3) for each 10 cigarette pack-years in multivariate analysis.
Conclusions: Smoking may cause subclinical parenchymal lung disease detectable by spirometry and CT imaging, even among a generally healthy cohort.
doi:10.1164/rccm.200812-1966OC
PMCID: PMC2742759  PMID: 19542480
cigarette smoking; computed tomography; interstitial lung disease; restrictive lung disease; spirometry
8.  Racial Differences in Waiting List Outcomes in Chronic Obstructive Pulmonary Disease 
Rationale: Blacks with chronic illness have poorer outcomes than whites in the United States. The health outcomes of minorities with chronic obstructive pulmonary disease (COPD) on the lung transplant waiting list have not been studied.
Objectives: To compare outcomes of black and white patients with COPD after listing for lung transplantation in the United States.
Methods: Retrospective cohort study of all 280 non-Hispanic black and 5,272 non-Hispanic white adults 40 years and older with COPD listed for lung transplantation in the United States between 1995 and 2004.
Measurements and Main Results: Blacks with COPD were more likely to have pulmonary hypertension, obesity, and diabetes; to lack private health insurance; and to live in poorer neighborhoods than whites. Blacks were less likely to undergo transplantation after listing compared with whites, despite adjustment for age, lung function, pulmonary hypertension, cardiovascular risk factors, insurance coverage, and poverty level (adjusted hazard ratio, 0.83; 95% confidence interval, 0.70–0.98; P = 0.03). This was accompanied by a greater risk of dying or being removed from the list among blacks (unadjusted hazard ratio, 1.31; 95% confidence interval, 1.05–1.63; P = 0.02).
Conclusions: After listing for lung transplantation, black patients with COPD were less likely to undergo transplantation and more likely to die or be removed from the list compared with white patients. Unequal access to care may have contributed to these differences.
doi:10.1164/rccm.200708-1260OC
PMCID: PMC2258441  PMID: 18006881
racial disparities; lung transplantation; survival; competing risks; black or African American
9.  Six-Minute-Walk Distance Predicts Waiting List Survival in Idiopathic Pulmonary Fibrosis 
Rationale: Functional studies may be useful to predict survival in idiopathic pulmonary fibrosis (IPF). Various cutoffs of 6-min-walk distance (6MWD) have been suggested to identify patients at a high risk of death.
Objectives: To examine the association between 6MWD and survival in patients with IPF listed for lung transplantation, and to identify sensitive and specific cutoffs for predicting death at 6 mo.
Methods: We performed a retrospective cohort study of 454 patients classified as having IPF listed for lung transplantation with the United Network for Organ Sharing between June 30, 2004 and July 22, 2005.
Measurements and Main Results: Lower 6MWD was associated with an increased mortality rate (p value for linear trend < 0.0001). Patients with a walk distance less than 207 m had a more than fourfold greater mortality rate than those with a walk distance of 207 m or more, despite adjustment for demographics, anthropomorphics, FVC % predicted, pulmonary hypertension, and medical comorbidities (adjusted rate ratio, 4.7; 95% confidence interval, 2.5–8.9; p < 0.0001). 6MWD was a significantly better predictor of 6-mo mortality than was FVC % predicted (c-statistic = 0.73 vs. 0.59, respectively; p = 0.02).
Conclusions: Lower 6MWD was strongly and independently associated with an increased mortality rate for wait-listed patients classified as having IPF. 6MWD was a better predictor of death at 6 mo than was FVC % predicted.
doi:10.1164/rccm.200604-520OC
PMCID: PMC2648057  PMID: 16778159
cohort; exercise test; lung diseases, interstitial; lung transplantation
10.  Immunoglobulin G Levels before and after Lung Transplantation 
Rationale: The determinants of immunoglobulin G (IgG) level and the risk of hypogammaglobulinemia (HGG) in patients with severe lung disease before and after lung transplantation are unknown.
Objectives: We aimed to identify predictors of low IgG levels before and after lung transplantation.
Methods: We performed a retrospective cohort study of 40 consecutive lung transplant recipients at our center. Total IgG levels were measured before and serially after transplantation. Mild HGG was defined as IgG levels from 400–699 mg/dl; severe HGG was defined as IgG levels < 400 mg/dl.
Measurements and Main Results: Before transplantation, six (15%) patients had mild HGG, and none had severe HGG. Patients with chronic obstructive pulmonary disease had lower IgG levels compared with patients with other diseases (independent of corticosteroid use and age; p = 0.001) and an increased risk of mild HGG (p = 0.005). The cumulative incidences of mild and severe HGG significantly increased after transplantation (58 and 15%, respectively, both p < 0.04 compared with pretransplant prevalences). Lower pretransplant IgG level and treatment with mycophenolate mofetil were associated with lower IgG levels after transplantation (both p < 0.05). Only lower pretransplant IgG levels were significantly associated with an increased risk of severe HGG after transplantation (p = 0.02).
Conclusions: Mild HGG is common in patients with severe chronic obstructive pulmonary disease, and the incidences of mild and severe HGG increase significantly early after lung transplantation. Baseline IgG levels and treatment with mycophenolate mofetil affect post-transplant IgG levels.
doi:10.1164/rccm.200510-1609OC
PMCID: PMC2662910  PMID: 16399990
hypogammaglobulinemia; immunosuppression; infection; lung transplantation

Results 1-10 (10)