Peripheral Blood Gene Expression Changes Associated With Primary Graft Dysfunction After Lung Transplantation.

Recipient responses to primary graft dysfunction (PGD) after lung transplantation may have important implications to the fate of the allograft. We therefore evaluated longitudinal differences in peripheral blood gene expression in subjects with PGD. RNA expression was measured throughout the first transplant year in 106 subjects enrolled in the Clinical Trials in Organ Transplantation-03 study using a panel of 100 hypothesis-driven genes. PGD was defined as grade 3 in the first 72 posttransplant hours. Eighteen genes were differentially expressed over the first year based on PGD development, with significant representation from innate and adaptive immunity genes, with most differences identified very early after transplant. Sixteen genes were overexpressed in the blood of patients with PGD compared to those without PGD within 7 days of allograft reperfusion, with most transcripts encoding innate immune/inflammasome-related proteins, including genes previously associated with PGD. Thirteen genes were underexpressed in patients with PGD compared to those without PGD within 7 days of transplant, highlighted by T cell and adaptive immune regulation genes. Differences in gene expression present within 2 h of reperfusion and persist for days after transplant. Future investigation will focus on the long-term implications of these gene expression differences on the outcome of the allograft.

Preoperative plasma club (clara) cell secretory protein levels are associated with primary graft dysfunction after lung transplantation.

Inherent recipient factors, including pretransplant diagnosis, obesity and elevated pulmonary pressures, are established primary graft dysfunction (PGD) risks. We evaluated the relationship between preoperative lung injury biomarkers and PGD to gain further mechanistic insight in recipients. We performed a prospective cohort study of recipients in the Lung Transplant Outcomes Group enrolled between 2002 and 2010. Our primary outcome was Grade 3 PGD on Day 2 or 3. We measured preoperative plasma levels of five biomarkers (CC-16, sRAGE, ICAM-1, IL-8 and Protein C) that were previously associated with PGD when measured at the postoperative time point. We used multivariable logistic regression to adjust for potential confounders. Of 714 subjects, 130 (18%) developed PGD. Median CC-16 levels were elevated in subjects with PGD (10.1 vs. 6.0, p<0.001). CC-16 was associated with PGD in nonidiopathic pulmonary fibrosis (non-IPF) subjects (OR for highest quartile of CC-16: 2.87, 95% CI: 1.37, 6.00, p=0.005) but not in subjects with IPF (OR 1.38, 95% CI: 0.43, 4.45, p=0.59). After adjustment, preoperative CC-16 levels remained associated with PGD (OR: 3.03, 95% CI: 1.26, 7.30, p=0.013) in non-IPF subjects. Our study suggests the importance of preexisting airway epithelial injury in PGD. Markers of airway epithelial injury may be helpful in pretransplant risk stratification in specific recipients.

Donor surfactant protein D (SP-D) polymorphisms are associated with lung transplant outcome.

Chronic lung allograft dysfunction (CLAD) is the major factor limiting long-term success of lung transplantation. Polymorphisms of surfactant protein D (SP-D), an important molecule within lung innate immunity, have been associated with various lung diseases. We investigated the association between donor lung SP-D polymorphisms and posttransplant CLAD and survival in 191 lung transplant recipients consecutively transplanted. Recipients were prospectively followed with routine pulmonary function tests. Donor DNA was assayed by pyrosequencing for SP-D polymorphisms of two single-nucleotide variations altering amino acids in the mature protein N-terminal domain codon 11 (Met(11) Thr), and in codon 160 (Ala(160) Thr) of the C-terminal domain. CLAD was diagnosed in 88/191 patients, and 60/191 patients have died. Recipients of allografts that expressed the homozygous Met(11) Met variant of aa11 had significantly greater freedom from CLAD development and better survival compared to those with the homozygous Thr(11) Th variant of aa11. No significant association was noted for SP-D variants of aa160. Lung allografts with the SP-D polymorphic variant Thr(11) Th of aa11 are associated with development of CLAD and reduced survival. The observed genetic differences of the donor lung, potentially with their effects on innate immunity, may influence the clinical outcomes after lung transplantation.

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 8860 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 (PGD). The rate of 1-year graft failure was similar among recipients of lungs from donors age 18-64 years, but severely ill recipients (Lung Allocation Score [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 [HR] 1.23, 95% CI 1.01-1.50 and adjusted HR 2.15, 95% CI 1.47-3.15, respectively). Donor age was not associated with the risk of PGD. In summary, the use of lungs from donors age 56 to 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.

Hypoalbuminemia and early mortality after lung transplantation: a cohort study.

Hypoalbuminemia predicts disability and mortality in patients with various illnesses and in the elderly. The association between serum albumin concentration at the time of listing for lung transplantation and the rate of death after lung transplantation is unknown. We examined 6808 adults who underwent lung transplantation in the United States between 2000 and 2008. We used Cox proportional hazard models and generalized additive models to examine multivariable-adjusted associations between serum albumin and the rate of death after transplantation. The median follow-up time was 2.7 years. Those with severe (0.5-2.9 g/dL) and mild hypoalbuminemia (3.0-3.6 g/dL) had posttransplant adjusted mortality rate ratios of 1.35 (95% CI: 1.12-1.62) and 1.15 (95% CI: 1.04-1.27), respectively. For each 0.5 g/dL decrease in serum albumin concentration the 1-year and overall mortality rate ratios were 1.48 (95% CI: 1.21-1.81) and 1.26 (95% CI: 1.11-1.43), respectively. The association between hypoalbuminemia and posttransplant mortality was strongest in recipients with cystic fibrosis and interstitial lung disease. Hypoalbuminemia is an independent risk factor for death after lung transplantation.

Titrated oxygen requirement and prognostication in idiopathic pulmonary fibrosis.

The supplemental oxygen flow rate is a common bedside measure of gas exchange impairment. We aimed to determine whether a titrated oxygen requirement (TOR) predicted mortality in idiopathic pulmonary fibrosis (IPF). We examined 104 adults with IPF enrolled in a prospective cohort study and a validation cohort of 151 adults with a variety of interstitial lung diseases (ILDs). The TOR was defined as the lowest oxygen flow rate required to maintain an oxyhaemoglobin saturation of 96% while standing. Cox proportional hazards models and time-dependent receiver operating characteristic curves were used to examine survival time. A higher TOR was associated with a greater mortality rate independent of forced vital capacity and 6-min walk test results in IPF (adjusted hazard ratio (per 1 L·min(-1)) 1.16, 95% CI 1.06-1.27). The TOR was at least as accurate as pulmonary function and 6-min walk testing at predicting 1-yr mortality. Findings were similar in other ILDs. The TOR is a simple, inexpensive bedside measurement that aids prognostication in IPF.

Pathologic interpretation of transbronchial biopsy for acute rejection of lung allograft is highly variable.

Despite the standardization of pathologic grading of acute rejection in transbronchial lung biopsies following lung transplantation, the reproducibility of pathologic diagnosis has not been adequately evaluated. To determine the interobserver variability for pathologic grading of acute rejection, 1566 biopsies from 845 subjects in the Lung Allograft Rejection Gene Expression Observational study were regraded by a pathology panel blinded to the original diagnosis and compared to the grade of acute rejection assigned by individual center pathologists. The study panel confirmed 49.1% of center pathologists' A0 grades, but upgraded 5.7% to A1 and 2.7% to grade ≥ A2 rejection; 42.5% were regraded as AX. Of 268 grade A1 samples, 21.2% were confirmed by the pathology panel; 18.7% were upgraded to ≥ A2 and 35.8% were downgraded to A0 with 24.3% being regraded as AX. Lastly, 53.5% of ≥ A2 cases were confirmed, but 15.7% were downgraded to grade A0 and 18.4% cases to A1, while 12.4% were regraded as AX. The kappa value for interobserver agreement was 0.183 (95%CI 0.147-0.220, p < 0.001). The results for B grade interpretation were similar. Suboptimal sampling is common and a high degree of variability exists in the pathologic interpretation of acute rejection in transbronchial biopsies.

Elevated plasma long pentraxin-3 levels and primary graft dysfunction after lung transplantation for idiopathic pulmonary fibrosis.

Primary graft dysfunction (PGD) after lung transplantation may result from ischemia reperfusion injury (IRI). The innate immune response to IRI may be mediated by Toll-like receptor and IL-1-induced long pentraxin-3 (PTX3) release. We hypothesized that elevated PTX3 levels were associated with PGD. We performed a nested case control study of lung transplant recipients with idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD) from the Lung Transplant Outcomes Group cohort. PTX3 levels were measured pretransplant, and 6 and 24 h postreperfusion. Cases were subjects with grade 3 PGD within 72 h of transplantation and controls were those without grade 3 PGD. Generalized estimating equations and multivariable logistic regression were used for analysis. We selected 40 PGD cases and 79 non-PGD controls. Plasma PTX3 level was associated with PGD in IPF but not COPD recipients (p for interaction < 0.03). Among patients with IPF, PTX3 levels at 6 and 24 h were associated with PGD (OR = 1.6, p = 0.02 at 6 h; OR = 1.4, p = 0.008 at 24 h). Elevated PTX3 levels were associated with the development of PGD after lung transplantation in IPF patients. Future studies evaluating the role of innate immune activation in IPF and PGD are warranted.

Emergent lung retransplantation after discovery of two primary malignancies in the donor.

A 50-year-old woman underwent single lung transplantation for advanced chronic obstructive pulmonary disease. Shortly after the procedure, it was discovered that the donor suffered from both a renal cell carcinoma and a spindle-cell sarcoma of the ascending aorta, which had metastasized to the spleen. The patient was emergently listed for a retransplantation and underwent bilateral lung transplantation after a new donor became available 4 days after the initial transplantation procedure. After 24 months, the patient is without evidence of malignancy. This case illustrates the role of immediate retransplantation for patients who have inadvertently received thoracic organs from donors harboring occult malignancies.

Thrombolytic therapy of pulmonary embolism: a comprehensive review of current evidence.

Pulmonary embolism (PE) is a common disorder that is accompanied by significant morbidity and mortality. Although anticoagulation is the standard treatment for PE, thrombolytic therapy, with its ability to produce rapid clot lysis, has long been considered an attractive alternative. Although many studies have been performed over the past three decades, however, the indications for the use of thrombolytic agents in patients with PE remain controversial. In this article, we review the medical literature and provide evidence-based guidelines for the use of thrombolytic therapy. We will also discuss the practical aspects of PE thrombolysis.

Apical perfusion fraction as a predictor of short-term functional outcome following bilateral lung volume reduction surgery.

STUDY OBJECTIVES: To examine whether relative hypoperfusion to the apical one third of the lungs as determined by lung scintigraphy predicts a favorable functional outcome following bilateral lung volume reduction surgery (LVRS). METHODS: We performed a retrospective analysis of 128 patients who underwent bilateral LVRS. An apical perfusion fraction (AP%), defined as the percentage of total lung perfusion to the apical one third of both lungs, was derived for each patient by quantitative scintigraphy technique. Pulmonary function testing and 6-min walk test (6MWT) data were obtained preoperatively and 3 to 6 months postoperatively. RESULTS: The mean (+/- SD) improvement in FEV(1) was 309 +/- 240 mL, 209 +/- 293 mL, and 116 +/- 224 mL for patients with an AP% of 20%, respectively (p = 0.01, analysis of variance [ANOVA]). The likelihood of experiencing an increase in FEV(1) >or= 200 mL was 68% for those with an AP% 20%. Preoperative and postoperative 6MWT data were available for 109 of 128 patients. Improvement was 250 +/- 252 feet, 205 +/- 299 feet, and 77 +/- 200 feet for patients with AP% 20%, respectively (p = 0.04, ANOVA). While 50% of those with an AP% or= 180 feet, only 21% of those with an AP% > 20% did so. CONCLUSION: This retrospective analysis suggests that quantification of apical perfusion by nuclear scintigraphy assists in predicting the likelihood of short-term functional improvement after LVRS.

Characteristics and outcomes of patients with sarcoidosis listed for lung transplantation.

STUDY OBJECTIVES: To characterize the course of patients with advanced sarcoidosis who have been listed for lung transplantation and to identify prognostic factors for death while they are on the waiting list. DESIGN: Retrospective cohort study. SETTING: Tertiary-care university hospital. PATIENTS: Forty-three patients with sarcoidosis who have been listed for lung transplantation at the University of Pennsylvania Medical Center. METHODS: A multivariable explanatory analysis using a Cox proportional hazards model was performed to determine risk factors that are independently associated with mortality while patients await transplantation. RESULTS: Twenty-three of the 43 patients (53%) died while awaiting transplantation. The survival rate of listed patients (as determined by the Kaplan-Meier method) was 66% at 1 year, 40% at 2 years, and 31% at 3 years. In a univariate analysis, the following factors were significantly associated with death on the waiting list: PaO(2) < or = 60 mm Hg (relative risk [RR], 3.4; 95% confidence interval [CI], 1.2 to 9.3); mean pulmonary artery pressure > or = 35 mm Hg (RR, 3.2; 95% CI, 1.1 to 9.5); cardiac index < or = 2 L/min/m(2) (RR, 2.8; 95% CI, 1.2 to 6.6), and right atrial pressure (RAP) > or = 15 mm Hg (RR, 7.6; 95% CI, 3.0 to 19.3). Multivariable analysis revealed that RAP > or = 15 mm Hg was the only independent prognostic variable (RR, 5.2; 95% CI, 1.6 to 16.7; p = 0.006). Twelve patients underwent lung transplantation. Survival after transplantation determined by the Kaplan-Meier method was 62% at both 1 and 2 years, and 50% at 3 years. CONCLUSIONS: Patients with advanced sarcoidosis awaiting lung transplantation have a high mortality rate with a median survival of < 2 years. Mortality is most closely linked to elevated RAP. While earlier referral may diminish the mortality rate of patients on the waiting list for transplantation, further improvements in posttransplantation outcomes will be necessary to ensure that this procedure truly bestows a survival benefit.

Bronchogenic carcinoma complicating lung transplantation.

BACKGROUND: Malignancy is a well-recognized complication of solid-organ transplantation. Although a variety of malignancies have been reported in lung transplant recipients, a paucity of information exists regarding the incidence and clinical course of bronchogenic carcinoma in this patient population. METHODS: We conducted a retrospective cohort study of our lung transplant experience at the University of Pennsylvania. RESULTS: We identified 6 patients with bronchogenic carcinoma detected at the time of, or developing after, transplantation. The incidence of bronchogenic carcinoma was 2.4%. All patients with lung cancer had a history of smoking, with an average of 79 +/- 39 pack-years. A total of 5 patients had chronic obstructive pulmonary disease, and 1 had idiopathic pulmonary fibrosis. Lung cancers were all of non-small-cell histology and first developed in native lungs. Three patients had bronchogenic carcinoma at the time of surgery. The remaining 3 patients were diagnosed between 280 and 1,982 days post-transplantation. Of the 6 patients, 4 presented with a rapid course suggestive of an infectious process. The 1- and 2-year survival rates after diagnosis were 33% and 17%, respectively. CONCLUSION: Lung transplant recipients are at risk for harboring or developing bronchogenic carcinoma in their native lungs. Rapid progression to locally advanced or metastatic disease commonly occurs, at times mimicking an infection. Bronchogenic carcinoma should be considered in the differential diagnosis of pleuroparenchymal processes involving the native lung.

Bilateral versus single lung transplantation for chronic obstructive pulmonary disease: intermediate-term results.

BACKGROUND: There is controversy regarding the transplant procedure of choice in chronic obstructive pulmonary disease. We reviewed our intermediate-term outcomes with single lung transplantation (SLT) versus bilateral lung transplantation (BLT). METHODS: We retrospectively reviewed 130 patients with chronic obstructive pulmonary disease: 84 underwent SLT, 46 BLT. The mean age was 51.1 +/- 1.2 years for those who underwent BLT and 56.2 +/- 0.7 years for those who underwent SLT (p < 0.0001). Male patients represented 65% of the BLT group and 46% of the SLT group (p = 0.04). Spirometry and 6-minute walk tests were obtained preoperatively and at 3- to 6-month intervals. Posttransplant survival and survival from time of onset of bronchiolitis obliterans syndrome were calculated by Kaplan-Meier method. The mean follow-up was 32.4 months. RESULTS: The 90-day mortality rate was 13.0% For BLT and 15.5% for SLT (p = 0.71). Actuarial survival rates at 1, 3, and 5 years were 82.6%, 74.6%, and 61.9% for BLT and 72.2%, 63.4%, and 57.4% for SLT; the favorable survival trend with BLT did not achieve statistical significance. There were no differences in preoperative spirometry or 6-minute walk tests. The improvements in forced expiratory volume in one second, forced vital capacity (FVC), and 6 MWT were significantly greater following BLT. The incidence of bronchiolitis obliterans syndrome was 22.4% in SLT and 22.2% in BLT; survival following onset of bronchiolitis obliterans syndrome was similar. CONCLUSIONS: For patients with chronic obstructive pulmonary disease, BLT is associated with superior lung function, exercise tolerance, and a trend toward enhanced survival. Younger candidates may be best suited for BLT. Given the limited donor lungs, SLT remains the preferred alternative for all other patients.

Non-Hodgkin's lymphoma presenting as Pancoast's syndrome.

Pancoast's syndrome is generally caused by primary or metastatic epithelial tumors. Other causes of the syndrome are unusual but well described. The present case report describes a rare case of Pancoast's syndrome caused by non-Hodgkin's lymphoma. This report emphasises the importance of establishing a firm pathologic diagnosis of the etiology of Pancoast's syndrome before instituting treatment.

Clinical aspects of obstructive lung disease.

Obstructive pulmonary diseases are diverse with an extensive differential diagnosis. Most cases can be diagnosed after a systematic evaluation that includes detailed history, physical examination, routine laboratory testing, radiologic and pulmonary physiologic tests. More specific studies are indicated only in a few patients.

Racial and ethnic disparities in idiopathic pulmonary fibrosis: A UNOS/OPTN database analysis.

We previously reported poorer survival among non-Hispanic blacks and Hispanics with idiopathic pulmonary fibrosis (IPF) compared to non-Hispanic whites at our center. In the current study, we hypothesized that these disparities would exist in a nationwide cohort of wait-listed patients with IPF. We performed a retrospective cohort study of 2635 patients with IPF listed for lung transplantation between 1995 and 2003 at 94 transplant centers in the United States. The age-adjusted mortality rate was higher among non-Hispanic blacks [hazard ratio (HR) = 1.24, 95% confidence interval (CI) 1.06-1.45, p = 0.009] and Hispanics (HR = 1.29, 95% CI 1.06-1.56, p = 0.01) compared to non-Hispanic whites. These findings persisted after adjustment for transplantation, medical comorbidities and socioeconomic status. Worse lung function at the time of listing appeared to explain some of these differences (HR for non-Hispanic blacks after adjustment for forced vital capacity percent predicted = 1.16, 95% CI 0.98-1.36, p = 0.09; HR for Hispanics = 1.21, 95% CI 0.99-1.48, p = 0.056). In summary, black and Hispanic patients with IPF have worse survival than whites after listing for lung transplant.