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.

Outcomes after lung retransplantation in the modern era.

RATIONALE: Characteristics of and survival estimates for recipients of lung retransplantation in the modern era are unknown. OBJECTIVES: To compare lung retransplant patients in the modern era with historical retransplant patients, to compare retransplant patients with initial transplant patients in the modern era, and to determine the predictors of the risk of death after lung retransplantation. METHODS: We performed a retrospective cohort study of patients who underwent lung retransplantation between January 2001 and May 2006 in the United States (modern retransplant cohort). The characteristics and survival of this cohort were compared with those of patients who underwent first lung retransplantation between January 1990 and December 2000 (historical retransplant cohort) and patients who underwent initial lung transplantation between January 2001 and May 2006 (modern initial transplant cohort). MEASUREMENTS AND MAIN RESULTS: Modern retransplant recipients (n = 205) had a lower risk of death compared with that of the historical retransplant cohort (n = 184) (hazard ratio, 0.7; 95% confidence interval, 0.5-0.9; P = 0.006). However, modern retransplant recipients had a higher risk of death than that of patients who underwent initial lung transplantation (n = 5,657) (hazard ratio, 1.3; 95% confidence interval, 1.2-1.5; P = 0.001), which appeared to be explained by a higher prevalence of certain comorbidities. Retransplantation at less than 30 days after the initial transplant procedure was associated with worse survival. CONCLUSIONS: Outcomes after lung retransplantation have improved; however, retransplantation continues to pose an increased risk of death compared with the initial transplant procedure. Retransplantation early after the initial transplant poses a particularly high mortality risk.

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.

Platelet-derived growth factor is increased in pulmonary capillary hemangiomatosis.

BACKGROUND: Pulmonary capillary hemangiomatosis (PCH) is a rare cause of pulmonary arterial hypertension with no effective medical therapy and a high risk of mortality. The pathogenesis of PCH is unknown. METHODS: We used gene expression analysis to compare lung tissue samples from two patients with PCH to those from seven control subjects. The nodules of proliferating capillaries in PCH patients were needle microdissected from cryostat sections. RNA extraction and labeling were followed by hybridization to U95Av2 oligonucleotide arrays (Affymetrix; Santa Clara, CA). In situ hybridization and immunohistochemistry were also performed. RESULTS: The gene expression profile of PCH allowed for unsupervised clustering from the profile of the lung tissue samples of control subjects. Platelet-derived growth factor (PDGF)-B gene (PDGFB), PDGF receptor (PDGFR)-beta gene (PDGFR-beta), mast cell-related genes, and type 2 pneumocyte-related genes were found to be overexpressed in PCH lesions. In situ hybridization as well as immunohistochemistry for PDGFB showed expression by type 2 pneumocytes and endothelial cells. Immunohistochemical staining for PDGFR-beta localized to pericytic/vascular smooth muscle cells surrounding the proliferating capillaries. CD117 staining confirmed an abundance of mast cells in the lesions, which also stained heavily for PDGFR-beta. CONCLUSIONS: The expression of the PDGFB and PDGFR-beta genes characterizes the nodular proliferations of PCH. Increased numbers of mast cells, pericytes, and type II pneumocytes accompany the endothelial proliferation. The up-regulation of these important angiogenic and antiapoptotic genes suggests a mechanism and potential therapeutic approaches for PCH.

Severe pulmonary hypertension due to chronic echinococcal pulmonary emboli treated with targeted pulmonary vascular therapy and hepatic resection.

Hydatid disease (human echinococcosis) is a zoonotic infection caused by larval forms (metacestodes) of the genus Echinococcus. Although pulmonary hypertension (PH) due to hydatid disease has been described, it is quite rare. We report a patient with chronic echinococcal embolic PH in whom treatment with novel PH therapies permitted successful resection of the hepatic cyst with a good outcome.

Risk factors for venous thromboembolism after lung transplantation.

BACKGROUND: The risk factors for venous thromboembolism (VTE) following lung transplantation are not well established. We aimed to estimate the incidence of VTE and to identify the risk factors for VTE after lung transplantation. METHODS: We performed a nested case-control study within the cohort of 121 patients who underwent lung transplantation at our center between August 2001 and July 2005. Control subjects were matched to case patients on the number of days from the time of transplant. Cox proportional hazards models were used to identify risk factors for VTE. RESULTS: Twenty-four patients had deep vein thromboses, and 6 patients had pulmonary emboli (3 patients had both) [22% of the cohort]. In multivariate models, older age (p < 0.05), diabetes mellitus (p = 0.03), and pneumonia (p = 0.02) were associated with a higher rate of VTE. CONCLUSIONS: VTE is a frequent complication of lung transplantation. Older age, diabetes, and pneumonia increase the rate of VTE. Future studies of intensive VTE prophylaxis may be warranted.

Osteoporosis in diffuse parenchymal lung disease.

STUDY OBJECTIVES: There are no studies focused on skeletal status in patients with diffuse parenchymal lung disease (DPLD). We hypothesized that patients with DPLD referred for lung transplantation would have a high prevalence of osteoporosis related to corticosteroid use or reduced pulmonary function and exercise capacity. DESIGN: Retrospective cohort study. SETTING: Tertiary care center. PATIENTS: Eighty-six patients with DPLD referred to our center for lung transplantation evaluation between March 1999 and April 2004. MEASUREMENTS AND RESULTS: Dual-energy X-ray absorptiometry was used to measure bone mineral density (BMD) at the lumbar spine, femoral neck, total hip, and radius at the time of referral. Criteria developed by the World Health Organization were used to define osteopenia and osteoporosis. Fifty-five patients (64%) had usual interstitial pneumonia-pattern lung disease, 14 patients (16%) had nonspecific interstitial pneumonia-pattern lung disease, and 17 patients (20%) had other forms of DPLD. Sixty-four patients (74%) were receiving corticosteroids, and 43 patients (50%) were receiving preventive therapy for osteoporosis. Eleven patients (13%; 95% confidence interval [CI], 7 to 22%) met criteria for osteoporosis at any site, and 49 patients (57%; 95% CI, 46 to 68%) had osteopenia. Lower body mass index (BMI) [adjusted odds ratio (OR), 1.3; 95% CI, 1.1 to 1.6; p = 0.007] and Hispanic ethnicity (adjusted OR, 9.7; 95% CI, 1.8 to 52; p = 0.008) were independently associated with an increased risk of osteoporosis. Linear regression analysis confirmed that BMD at the femoral neck and hip was directly associated with BMI (p < 0.002). These findings were not affected by adjustment for the use of corticosteroids or osteoporosis prophylaxis, pulmonary function, or exercise performance. CONCLUSIONS: Reduced BMD was common in patients with DPLD who were referred for lung transplantation. Lower BMD was associated with lower BMI, whereas there was no association with other clinical factors in our cohort. Hispanic patients with DPLD had a higher risk of osteoporosis than non-Hispanic patients, independent of other variables. Given their increased risk of bone loss, patients with DPLD should undergo screening for osteoporosis and receive prophylaxis and treatment according to published guidelines.

Outcomes of extended donor lung recipients after lung transplantation.

BACKGROUND: Lung transplantation is currently limited by the number of suitable donor organs. Many lung-transplant programs use lungs that do not meet the formal criteria for acceptability; however, the immediate and long-term consequences of this approach remain unclear. METHODS: We performed a retrospective cohort study of all patients who underwent lung transplantation at the Columbia University Medical Center from July 2001 to July 2003. We assessed the outcomes of recipients of extended donor lungs compared with those of recipients of optimal donor lungs after adjusting for confounding variables. RESULTS: Fifty-one patients underwent lung transplantation, of which 27 (53%) received extended donor lungs. Recipients of extended donor lungs had fewer intensive care unit-free days at 30 days (P=0.002) and a longer time to hospital discharge (P=0.007) than did recipients of optimal donor lungs. Extended donor recipients also had lower forced expiratory volume in 1 second % predicted at 1 year than did optimal donor recipients (P=0.03). There were no differences in the 30-day or longer-term survival of extended and optimal donor lung recipients. CONCLUSIONS: Recipients of extended donor lungs have a longer intensive care unit course, a prolonged hospital stay, and lower pulmonary function at 1 year than recipients of optimal lungs. Despite these differences, survival is similar between the two groups. The criteria for the optimal lung donor should be re-evaluated considering the current shortage of acceptable organs. Although some outcomes may differ with the use of extended donor lungs, the clinical impact of these differences should be assessed in future prospective multicenter studies.

Risk factors and outcomes of hypogammaglobulinemia after lung transplantation.

BACKGROUND: Hypogammaglobulinemia (HGG) frequently occurs after solid organ transplantation; however, the prevalence and implications of HGG after lung transplantation are not well defined. The authors aimed to define the prevalence, risk factors, and outcomes of patients with severe HGG after lung transplantation. METHODS.: The authors performed a retrospective cohort study of 57 lung transplant recipients at their center. Quantitative total and subclass immunoglobulin (Ig) G levels were obtained from patients. RESULTS: Thirty-four (60%; 95% confidence interval [CI], 46%-72%) patients had low IgG levels (IgG <700 mg/dL); of these, eight (14%; 95% CI, 6%-26%) had severe HGG (IgG <400 mg/dL). Female patients had a higher risk of severe HGG than male patients (25% vs. 0%, P=0.007), and patients who underwent transplantation for emphysema had a higher risk of severe HGG than others (P=0.04). Patients with bronchiolitis obliterans syndrome had a higher risk of severe HGG than those without (50% vs. 10%, P=0.03). Severe HGG was associated with an increased risk of pneumonia (P=0.01) and worse survival (P=0.04) but with neither the incidence of cytomegalovirus disease (P=0.54) nor a subsequent diagnosis of bronchiolitis obliterans syndrome (P=0.70). CONCLUSIONS: The authors have documented a high prevalence of HGG after lung transplantation. Emphysema, female gender, and bronchiolitis obliterans syndrome are risk factors for severe HGG. Patients with severe HGG had a higher cumulative incidence of pneumonia and worse survival. Studies of the efficacy and safety of IgG supplementation after lung transplantation should be pursued.

Exercise testing determines survival in patients with diffuse parenchymal lung disease evaluated for lung transplantation.

STUDY OBJECTIVES: Diffuse parenchymal lung disease is associated with a high risk of mortality despite early referral and listing for lung transplantation. We hypothesized that cardiopulmonary exercise test results and the distance walked in 6min (6MWTD) would be associated with survival in patients with diffuse parenchymal lung disease referred for lung transplantation. DESIGN: Retrospective cohort study. SETTING: Tertiary care center. PATIENTS: We included 51 consecutive patients with diffuse parenchymal lung disease who underwent exercise testing after referral to the Lung Transplant Program at the New York Presbyterian Hospital between January 2000 and December 2002. Thirty-three patients were listed, and 7 underwent transplantation during the study period. There were 17 deaths with 1 death post-transplantation. RESULTS: A 6MWTD < 350 m was associated with an increased risk of death (HR = 4.6, 95% CI 1.5-14.2, P = 0.009). Oxygen saturation with unloaded exercise (HR = 0.91, 95% CI 0.84-0.98, P = 0.015) and oxygen consumption at peak exercise adjusted for weight (HR = 0.88, 95% CI 0.79-0.99, P = 0.039) were also associated with the risk of death. A patient with oxygen saturation <95% during unloaded exercise had a 75% chance of dying on the list for transplantation. A patient with 6MWTD < 350 m had a 67% chance of dying on the list. CONCLUSIONS: Cardiopulmonary exercise test parameters and the 6MWTD were associated with the risk of death. Measures during exercise may be useful for determination of prognosis and for prioritizing patients with diffuse parenchymal lung disease for lung transplantation.

The modification of diet in renal disease (MDRD) and the prediction of kidney outcomes after lung transplantation.

BACKGROUND: Chronic kidney disease (CKD) is prevalent after lung transplantation. This study evaluated the ability of the 24-hour urine creatinine clearance (CrCl) and the Modification of Diet in Renal Disease (MDRD) equation at the time of listing to predict CKD after lung transplantation and to determine risk factors for CKD. METHODS: This was a retrospective cohort study of 122 patients who underwent lung transplantation at Columbia Presbyterian Medical Center between May 2002 and August 2006. The primary end point was CKD Stage 3 or higher, defined as glomerular filtration rate (GFR)

Platelet activation in the postoperative period after lung transplantation.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Assessment of kidney function in lung transplant candidates.

BACKGROUND: Glomerular filtration rate (GFR) is the best measure of kidney function; however, 24-hour creatinine clearance (CrCl) is the initial screening test used for lung transplant candidates at most centers. Although creatinine-based formulas that estimate GFR have been derived, none have been validated in patients with severe lung disease. METHODS: We performed a retrospective cohort study of patients evaluated for lung transplantation at Columbia Presbyterian Medical Center and compared the GFR estimated from the Modification of Diet in Renal Disease (MDRD) and other formulas to the CrCl. We then validated these results in a cohort of patients evaluated at the Hospital of the University of Pennsylvania. RESULTS: There were strong and statistically significant direct correlations between estimated GFR and CrCl. An estimated GFR of <95 ml/min by the MDRD was very sensitive at detecting kidney dysfunction by CrCl in the derivation cohort. In the validation cohort, the negative predictive value of this cut-off was 97%. CONCLUSIONS: Established formulas for estimating GFR are highly discriminating for kidney dysfunction in patients being evaluated for lung transplantation and may actually have greater validity than CrCl in some instances.

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.

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.

Successful bilateral lung transplantation for pulmonary fibrosis associated with the Hermansky-Pudlak syndrome.

Hermansky-Pudlak syndrome (HPS) is a genetic disorder characterized by oculocutaneous albinism, a bleeding diathesis, and in a subset of patients, pulmonary fibrosis. Lung transplantation, the only curative therapy for pulmonary fibrosis, has not been previously reported as a successful treatment strategy for patients with HPS because the bleeding diathesis was thought to contraindicate major thoracic surgery. We successfully performed bilateral sequential lung transplantation in a patient with pulmonary fibrosis and HPS after transfusion of 6 units of platelets. Lung transplantation is a viable therapeutic option in patients with pulmonary fibrosis and only a mild bleeding diathesis associated with HPS.

Surrogate markers and risk factors for chronic lung allograft dysfunction.

Obliterative bronchiolitis (OB) is the histologic correlate of chronic allograft dysfunction in pulmonary transplantation. The histologic diagnosis of OB is challenging, therefore a physiologic definition, bronchiolitis obliterans syndrome (BOS) based on pulmonary function tests has been used as a surrogate marker for OB for the last decade. BOS has proven to be the best available surrogate marker for OB and is predictive of the ultimate endpoints of graft and patient survival. Multiple other clinical markers have been reported and proposed as alternates for or complements to BOS grade, but all need further evaluation and validation in large, prospective clinical trials. Lastly, given the early occurrence and high incidence of chronic allograft dysfunction, the easily measurable endpoint of BOS grade, and our lack of understanding of ways to prevent or alter the course of BOS, lung transplant recipients represent an ideal population for clinical trials targeting prevention and treatment of chronic allograft dysfunction.