Jessie S. Wilt

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.

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.

Racial and Ethnic Disparities in Survival in Lung Transplant Candidates with Idiopathic Pulmonary Fibrosis

Minority patients have worse outcomes than nonminority patients in a variety of pulmonary diseases. We aimed to compare the survival of Black and Hispanic patients to that of others with idiopathic pulmonary fibrosis (IPF). We performed a retrospective cohort study of patients with IPF who were evaluated for lung transplantation at our center. Kaplan‐Meier survival curves and Cox proportional hazards models were used to compare survival between groups. Black and Hispanic patients had spirometry, lung volumes and diffusion capacity that were similar to others, but had worse exercise capacity. Minority patients had a significantly increased risk of death compared to others independent of transplantation status (hazard ratio = 3.3, 95% CI 1.2–8.9, p = 0.02). Differences in exercise capacity, pulmonary hemodynamics and socioeconomic factors appeared to account for some of the differences in survival. Black and Hispanic patients with IPF had an increased risk of death following referral for lung transplantation. This finding may be due to differences in disease progression and/or differences in access to medical care among minority patients. Future studies should confirm our findings in a larger cohort. The elimination of racial and ethnic disparities in outcome should be a priority for clinicians and researchers in this field.

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.

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.

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.

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) </= 59 ml/min/1.73 m(2) or renal replacement therapy, for at least 3 months. RESULTS Patients were a mean age of 51 +/- 14 years, 55% women, and 83% non-Hispanic white. CKD developed in 62% by 1 year after lung transplantation. Older age, female gender, a diagnosis of sarcoidosis, and diabetes mellitus independently increased the risk of CKD (all p < 0.05). The MDRD equation was significantly better than CrCl at predicting CKD Stage 3 or higher at 1 year after transplantation, with an area under the receiver operating characteristic curve of 0.71 for MDRD (95% confidence interval [CI], 0.61-0.81) and 0.51 for CrCl (95% CI, 0.40-0.61) (P < 0.001). CONCLUSIONS Older age, female gender, and diabetes mellitus increased the risk of developing CKD after lung transplant. The MDRD estimate of GFR at listing was a better predictor of CKD than CrCl. MDRD estimates should be used during lung transplant evaluation for risk stratification for CKD.

Tacrolimus and Azathioprine Versus Cyclosporine and Mycophenolate Mofetil After Lung Transplantation: A Retrospective Cohort Study

BACKGROUND The efficacy and safety of different combinations of immunosuppressive regimens after lung transplantation are unknown. METHODS We examined 120 consecutive transplant recipients between July 2001 and July 2005, of whom 37 received cyclosporine and mycophenolate mofetil (Cyc/MMF) and 83 received tacrolimus and azathioprine (Tac/Aza) as the initial immunosuppressive regimen along with an interleukin-2 antagonist induction therapy. The primary outcome was the rate of histologically confirmed acute rejection. RESULTS The rate of acute rejection did not vary by treatment regimen (0.42 vs 0.34 episodes per 100 person-days in Cyc/MMF and Tac/Aza groups, respectively, p = 0.22). The mean cumulative lymphocytic bronchiolitis score was greater in the Cyc/MMF group (1.8 +/- 1.9) compared with the Tac/Aza group (1.2 +/- 2.0; p = 0.03). Pulmonary function at 1 year was better in the Tac/Aza group, even when adjusted for recipient age, gender, and transplant procedure. Survival and the rate of bronchiolitis obliterans syndrome did not vary by group. CONCLUSIONS Outcomes after lung transplantation did not meaningfully vary between those assigned to Cyc/MMF compared with Tac/Aza combined with IL-2 inhibitor induction therapy.

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.