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1.  Frailty Phenotypes, Disability, and Outcomes in Adult Candidates for Lung Transplantation 
Rationale: Frailty is associated with morbidity and mortality in abdominal organ transplantation but has not been examined in lung transplantation.
Objectives: To examine the construct and predictive validity of frailty phenotypes in lung transplant candidates.
Methods: In a multicenter prospective cohort, we measured frailty with the Fried Frailty Phenotype (FFP) and Short Physical Performance Battery (SPPB). We evaluated construct validity through comparisons with conceptually related factors. In a nested case–control study of frail and nonfrail subjects, we measured serum IL-6, tumor necrosis factor receptor 1, insulin-like growth factor I, and leptin. We estimated the association between frailty and disability using the Lung Transplant Valued Life Activities disability scale. We estimated the association between frailty and risk of delisting or death before transplant using multivariate logistic and Cox models, respectively.
Measurements and Main Results: Of 395 subjects, 354 completed FFP assessments and 262 completed SPPB assessments; 28% were frail by FFP (95% confidence interval [CI], 24–33%) and 10% based on the SPPB (95% CI, 7–14%). By either measure, frailty correlated more strongly with exercise capacity and grip strength than with lung function. Frail subjects tended to have higher plasma IL-6 and tumor necrosis factor receptor 1 and lower insulin-like growth factor I and leptin. Frailty by either measure was associated with greater disability. After adjusting for age, sex, diagnosis, and transplant center, both FFP and SPPB were associated with increased risk of delisting or death before lung transplant. For every 1-point worsening in score, hazard ratios were 1.30 (95% CI, 1.01–1.67) for FFP and 1.53 (95% CI, 1.19–1.59) for SPPB.
Conclusions: Frailty is prevalent among lung transplant candidates and is independently associated with greater disability and an increased risk of delisting or death.
PMCID: PMC4731703  PMID: 26258797
biomarker; body composition; disability; frailty; lung transplantation
2.  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.
PMCID: PMC2662910  PMID: 16399990
hypogammaglobulinemia; immunosuppression; infection; lung transplantation
3.  Pulmonary arteriole gene expression signature in idiopathic pulmonary fibrosis 
The European respiratory journal  2013;41(6):1324-1330.
A third of patients with idiopathic pulmonary fibrosis (IPF) develop pulmonary hypertension (PH-IPF), which is associated with increased mortality. Whether an altered gene expression profile in the pulmonary vasculature precedes the clinical onset of PH-IPF is unknown. We compared gene expression in the pulmonary vasculature of IPF patients with and without PH with controls.
Pulmonary arterioles were isolated using laser capture microdissection from 16 IPF patients: eight with PH (PH-IPF) and eight with no PH (NPH-IPF), and seven controls. Probe was prepared from extracted RNA, and hybridised to Affymetrix Hu133 2.0 Plus genechips. Biometric Research Branch array tools and Ingenuity Pathway Analysis software were used for analysis of the microarray data.
Univariate analysis revealed 255 genes that distinguished IPF arterioles from controls (p<0.001). Mediators of vascular smooth muscle and endothelial cell proliferation, Wnt signalling and apoptosis were differentially expressed in IPF arterioles. Unsupervised and supervised clustering analyses revealed similar gene expression in PH-IPF and NPH-IPF arterioles.
The pulmonary arteriolar gene expression profile is similar in IPF patients with and without coexistent PH. Pathways involved in vascular proliferation and aberrant apoptosis, which may contribute to pulmonary vascular remodelling, are activated in IPF patients.
PMCID: PMC4720265  PMID: 23728404
DNA microarray; laser capture microdissection; pulmonary arterial hypertension; usual interstitial pneumonia
4.  Body Composition and Mortality after Adult Lung Transplantation in the United States 
Rationale: Obesity and underweight are contraindications to lung transplantation based on their associations with mortality in studies performed before implementation of the lung allocation score (LAS)–based organ allocation system in the United States
Objectives: To determine the associations of body mass index (BMI) and plasma leptin levels with survival after lung transplantation.
Methods: We used multivariable-adjusted regression models to examine associations between BMI and 1-year mortality in 9,073 adults who underwent lung transplantation in the United States between May 2005 and June 2011, and plasma leptin and mortality in 599 Lung Transplant Outcomes Group study participants. We measured body fat and skeletal muscle mass using whole-body dual X-ray absorptiometry in 142 adult lung transplant candidates.
Measurements and Main Results: Adjusted mortality rates were similar among normal weight (BMI 18.5–24.9 kg/m2), overweight (BMI 25.0–29.9), and class I obese (BMI 30–34.9) transplant recipients. Underweight (BMI < 18.5) was associated with a 35% increased rate of death (95% confidence interval, 10–66%). Class II–III obesity (BMI ≥ 35 kg/m2) was associated with a nearly twofold increase in mortality (hazard ratio, 1.9; 95% confidence interval, 1.3–2.8). Higher leptin levels were associated with increased mortality after transplant surgery performed without cardiopulmonary bypass (P for interaction = 0.03). A BMI greater than or equal to 30 kg/m2 was 26% sensitive and 97% specific for total body fat–defined obesity.
Conclusions: A BMI of 30.0–34.9 kg/m2 is not associated with 1-year mortality after lung transplantation in the LAS era, perhaps because of its low sensitivity for obesity. The association between leptin and mortality suggests the need to validate alternative methods to measure obesity in candidates for lung transplantation. A BMI greater than or equal to 30 kg/m2 may no longer contraindicate lung transplantation.
PMCID: PMC4299586  PMID: 25233138
obesity; sarcopenia; adiposity; leptin; biomarker
5.  Donor age and early graft failure after lung transplantation: a cohort study 
Lungs from older adult organ donors are often unused because of concerns for increased mortality. We examined associations between donor age and transplant outcomes among 8,860 adult lung transplant recipients using Organ Procurement and Transplantation Network and Lung Transplant Outcomes Group data. We used stratified Cox proportional hazard models and generalized linear mixed models to examine associations between donor age and both 1-year graft failure and primary graft dysfunction. The rate of 1-year graft failure was similar among recipients of lungs from donors age 18–64 years, but severely ill recipients (LAS > 47.7 or use of mechanical ventilation) of lungs from donors age 56–64 years had increased rates of 1-year graft failure (p-values for interaction = 0.04 and 0.02, respectively). Recipients of lungs from donors <18 and ≥65 years had increased rates of 1-year graft failure (adjusted hazard ratio 1.23, 95% CI 1.01–1.50 and adjusted hazard ratio 2.15, 95% CI 1.47–3.15, respectively). Donor age was not associated with the risk of primary graft dysfunction. In summary, the use of lungs from donors age 56–64 years may be safe for adult candidates without a high LAS, and the use of lungs from pediatric donors is associated with a small increase in early graft failure.
PMCID: PMC4157369  PMID: 24034167
Age; lung transplantation; primary graft dysfunction; graft failure; prognosis
6.  Intravenous Immunoglobulin for Hypogammaglobulinemia after Lung Transplantation: A Randomized Crossover Trial 
PLoS ONE  2014;9(8):e103908.
We aimed to determine the effects of treatment with intravenous immunoglobulin on bacterial infections in patients with hypogammaglobulinemia (HGG) after lung transplantation.
We performed a randomized, double-blind, placebo-controlled two-period crossover trial of immune globulin intravenous (IVIG), 10% Purified (Gamunex, Bayer, Elkhart, IN) monthly in eleven adults who had undergone lung transplantation more than three months previously. We randomized study participants to three doses of IVIG (or 0.1% albumin solution (placebo)) given four weeks apart followed by a twelve week washout and then three doses of placebo (or IVIG). The primary outcome was the number of bacterial infections within each treatment period.
IVIG had no effect on the number of bacterial infections during the treatment period (3 during IVIG and 1 during placebo; odds ratio 3.5, 95% confidence interval 0.4 to 27.6, p = 0.24). There were no effects on other infections, use of antibiotics, or lung function. IVIG significantly increased trough IgG levels at all time points (least square means, 765.3 mg/dl during IVIG and 486.3 mg/dl during placebo, p<0.001). Four serious adverse events (resulting in hospitalization) occurred during the treatment periods (3 during active treatment and 1 during the placebo period, p = 0.37). Chills, flushing, and nausea occurred during one infusion of IVIG.
Treatment with IVIG did not reduce the short-term risk of bacterial infection in patients with HGG after lung transplantation. The clinical efficacy of immunoglobulin supplementation in HGG related to lung transplantation over the long term or with recurrent infections is unknown.
Trial Registration NCT00115778
PMCID: PMC4121238  PMID: 25090414
7.  Plasma Monocyte Chemotactic Protein-1 (MCP-1) Levels at 24 hours are a Biomarker of Primary Graft Dysfunction Following Lung Transplantation 
MCP-1, also known as CCL2, is a monocyte-attracting chemokine produced in lung epithelial cells. We previously reported an association of increased levels of plasma MCP-1 with primary graft dysfunction (PGD) after lung transplantation in a nested case control study of extreme phenotypes using a multiplex platform. In this study, we sought to evaluate the relationship between plasma MCP-1 levels as a biomarker across the full spectrum of PGD. We performed a prospective cohort study of 108 lung transplant recipients within the Lung Transplant Outcomes Group cohort. Plasma MCP-1 levels were measured pre-transplantation, 6 and 24 hours after transplantation. The primary outcome was development of grade 3 PGD within 72 hours of transplant, with secondary analyses at the 72- hour timepoint. Multivariable logistic regression was used to evaluate confounding. 30 subjects (28%) developed PGD. Median MCP-1 measured at 24 hours post transplant was elevated in subjects with PGD (167.95 vs. 103.5 pg/mL p=0.04). MCP-1 levels at 24 hours were associated with increased odds of grade 3 PGD after lung transplantation (OR for each 100 pg/mL 1.24, 95% CI 1.00, 1.53), and with grade 3 PGD present at the 72-hour timepoint (OR for each 100 pg/mL 1.57, 95% CI 1.18, 2.08), independent of confounding variables in multivariable analyses. MCP-1 levels measured pre-operatively and 6 hours after transplant were not significantly associated with PGD. Persistent elevations in MCP-1 levels at 24 hours are a biomarker of grade 3 PGD post-transplantation. Monocyte chemotaxis may play a role in the pathogenesis of PGD.
PMCID: PMC3500407  PMID: 22989614
Primary Graft Dysfunction; Lung transplantation; Monocyte Chemotactic Protein-1; Acute Lung Injury; Biomarker
8.  Titrated oxygen requirement and prognostication in idiopathic pulmonary fibrosis 
The European Respiratory Journal  2011;39(2):359-365.
The supplemental oxygen flow rate is a common bedside measure of gas exchange impairment. We aimed to determine whether a titrated oxygen requirement predicted mortality in idiopathic pulmonary fibrosis.
We examined 104 adults with idiopathic pulmonary fibrosis enrolled in a prospective cohort study and a validation cohort of 151 adults with a variety of interstitial lung diseases. The titrated oxygen requirement was defined as the lowest oxygen flow rate required to maintain an oxyhemoglobin saturation of 96% while standing. Cox proportional hazards models and time-dependent receiver operating characteristic curves were used to examine survival time.
A higher titrated oxygen requirement was associated with a greater mortality rate independent of forced vital capacity and six-minute walk test results in idiopathic pulmonary fibrosis (adjusted hazard ratio per 1 L/min = 1.10, 95% confidence interval 1.01 to 1.20). The titrated oxygen requirement was at least as accurate as pulmonary function and six-minute walk testing at predicting 1-year mortality. Findings were similar in other interstitial lung diseases.
The titrated oxygen requirement is a simple, inexpensive bedside measurement that aids prognostication in idiopathic pulmonary fibrosis.
PMCID: PMC3236811  PMID: 21885386
Idiopathic pulmonary fibrosis; Interstitial lung diseases; Outcome prediction; Pulmonary fibrosis; Pulmonary gas exchange
9.  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.
PMCID: PMC3208644  PMID: 21799077
acute lung injury; leptin; lung transplantation; obesity; primary graft dysfunction
10.  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.
PMCID: PMC3208648  PMID: 21719755
access to healthcare; healthcare disparities; idiopathic pulmonary fibrosis; interstitial lung disease; survival
11.  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.
PMCID: PMC2773915  PMID: 19608717
anthropometry; body mass index; generalized additive models; lung transplantation; obesity
12.  Platelet activation in the postoperative period after lung transplantation 
During lung transplantation, cells in the pulmonary parenchyma are subjected to ischemia, hypothermic storage, and reperfusion injury. Platelets, whose granular contents include adhesion receptors, chemokines, and coactivating substances that activate inflammatory and coagulant cascades, likely play a critical role in the lung allograft response to ischemia and reperfusion. The platelet response to the pulmonary allograft, however, has never been studied. Here we report significant platelet activation immediately after lung transplantation.
We performed a prospective cohort study comparing markers of platelet activation in patients undergoing lung transplantation and patients undergoing nontransplant thoracotomy. Plasma levels of soluble P-selectin, soluble CD40 ligand, and platelet–leukocyte conjugates were measured before surgery, after skin closure, and at 6 postoperative hours.
Both soluble P-selectin and soluble CD40 ligand levels increased significantly after lung transplantation but not after thoracotomy. Additionally, platelet–monocyte conjugate fluorescence was significantly higher after lung transplantation than after thoracotomy alone.
These findings suggest that platelet activation is significantly increased after lung transplantation beyond that expected from the postoperative state. The increase in circulating platelet–monocyte conjugates suggests an important interaction between platelets and inflammatory cells. Further research should examine whether platelet activation affects early graft function after lung transplantation.
PMCID: PMC2829430  PMID: 18329493
13.  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.
PMCID: PMC2258441  PMID: 18006881
racial disparities; lung transplantation; survival; competing risks; black or African American
14.  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.
PMCID: PMC2648057  PMID: 16778159
cohort; exercise test; lung diseases, interstitial; lung transplantation

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