Frank D'Ovidio

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.

High Lung Allocation Score Is Associated With Increased Morbidity and Mortality Following Transplantation

BACKGROUND The lung allocation score (LAS) was initiated in May 2005 to allocate lungs based on medical urgency and posttransplant survival. The purpose of this study was to determine if there is an association between an elevated LAS at the time of transplantation and increased postoperative morbidity and mortality. METHODS The United Network for Organ Sharing provided de-identified patient-level data. Analysis included lung transplant recipients aged >or= 12 years who received transplants between April 5, 2006, and December 31, 2007 (n = 3,836). Recipients were stratified into three groups: LAS < 50 (n = 3,161, 83.87%), LAS 50 to 75 (n = 411, 10.9%), and LAS >or= 75 (n = 197, 5.23%), referred to as low LAS (LLAS), intermediate LAS (ILAS), and high LAS (HLAS), respectively. The primary outcome was posttransplant graft survival at 1 year. Secondary outcomes included length of stay and in-hospital complications. RESULTS HLAS recipients had significantly worse actuarial survival at 90 days and 1 year compared with LLAS recipients. When transplant recipients were stratified by disease etiology, a trend of decreased survival with elevated LAS was observed across all major causes of lung transplant. HLAS recipients were more likely to require dialysis or to have infections compared with LLAS recipients (P < .001). In addition, length of stay was higher in the HLAS group when compared with the LLAS group (P < .001). CONCLUSIONS HLAS is associated with decreased survival and increased complications during the transplant hospitalization. Whereas the LAS has improved organ allocation through decreased waiting list deaths and waiting list times, lower survival and higher morbidity among HLAS recipients suggests that continued review of LAS scoring is needed to ensure optimal long-term transplant survival.

Minimally Invasive Thymectomy and Open Thymectomy: Outcome Analysis of 263 Patients

BACKGROUND An open thymectomy is a morbid procedure. If a minimally invasive thymectomy is performed without compromising the tenets of thymic surgery, it has the potential for decreasing morbidity and may offer similar clinical and oncologic results. METHODS This is an institutional review board-approved, retrospective study of a single centers experience with both open (transsternal) and minimally invasive (video-assisted thoracoscopic surgery) thymectomy. Survival estimates and statistical comparisons were calculated using standard software. RESULTS From 2000 to 2011, 263 patients (93 men; median age, 49 years; interquartile range, 37 to 60 years) underwent thymectomy for indications including myasthenia gravis (n=139) and mediastinal mass (n=108). Seventy-seven thymectomies were performed by minimally invasive approach. Both groups were equally stratified by sex, body mass index, World Health Organization and Masaoka-Koga staging, incidence of myasthenia gravis, and comorbidities except hyperlipidemia and diabetes. The minimally invasive thymectomy cohort had significantly shorter hospital (p<0.01) and intensive care unit lengths of stay (p<0.01) and a lower estimated blood loss (p<0.01). There was an insignificant difference in postoperative cardiac and respiratory complication rates as well as vocal cord paralysis (p=0.60). There was no difference in terms of operative room times (p=0.88) or volume of blood products transfused (p=0.16) between the two groups. Higher estimated blood loss was associated with higher intensive care unit admission rates (p<0.01). All minimally invasive thymoma resections were complete, with negative margins. CONCLUSIONS Minimally invasive thymectomy is safe and achieves a comparable resection and postoperative complication profile when used selectively for all indications, including myasthenia gravis and small thymomas without vascular invasion.

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.

Who is the high-risk recipient? Predicting mortality after lung transplantation using pretransplant risk factors.

OBJECTIVES The purpose of this study was to create a preoperative risk stratification score (RSS) based on pretransplant recipient characteristics that could be used to predict mortality following lung transplantation. METHODS United Network for Organ Sharing provided de-identified patient-level data. The study population included 8780 adult recipients (age > 12 years) having lung transplantation from January 1, 1999, to December 31, 2006. Multivariate logistic regression (backward, P > .10) was performed. Using the odds ratio for each identified variable, an RSS was devised. The RSS included only pretransplant recipient variables and excluded donor variables. RESULTS The strongest negative predictors of 1-year survival included extracorporeal membrane oxygenation, decreased estimated glomerular filtration rate, total bilirubin >2.0 mg/dL, recipient age, hospitalization at time of transplant, O(2) dependence, cardiac index <2, steroid dependence, donor:recipient weight ratio <0.7, all non-cystic fibrosis/chronic obstructive pulmonary disease etiologies, and female donor-to-male recipient. Threshold analysis identified 4 discrete groups: low risk, moderate, elevated risk, and high risk. The 1-year actuarial survival was 80.4% for the entire group, compared with 56.8% in the high-risk group (RSS > 7.2, n = 490; 6%). CONCLUSION Pretransplant recipient variables significantly influence both early and late survival following lung transplantation. Some patients face a higher than average risk of mortality during their first year posttransplant, which challenges the goals of equitable organ allocation. RSS may improve organ allocation strategies by avoiding the potential negative impact of performing transplantation in extremely high-risk candidates.

Despite Decreased Wait-List Times for Lung Transplantation, Lung Allocation Scores Continue to Increase

BACKGROUND In May 2005, the lung allocation score (LAS) was introduced as a means of allocating donor lungs in order to decrease wait-list mortality and prioritize candidates based on medical urgency and posttransplant survival. The purpose of this study was to assess changes in recipient wait-list times and mean LAS since the introduction of the LAS model. METHODS The United Network for Organ Sharing provided de-identified patient-level data. The study population consisted of all patients in the United States with a reported LAS (n = 3529) undergoing lung transplantation between May 7, 2005 and November 7, 2007. The study period was divided into 6-month intervals. The Kruskal-Wallis test was used to assess differences in variables with nonparametric distributions. The nonparametric trends test was used to determine significance of trends over time. RESULTS There was a significant decrease in wait-list time during the study period, while LAS among transplant recipients increased (p < 0.001). There was no significant change in FVC (49.3 +/- 17.5%, p = 0.48) or pulmonary capillary wedge pressure (11.1 +/- 5.8 mm Hg, p = 0.23); however, there was a significant increase in age (51.5 +/- 13.9 years, p < 0.001) during the study period. When stratified by etiology, the LAS increased for both interstitial pulmonary fibrosis and COPD patients (p < 0.001). Moreover, the overall number of patients listed for transplantation as well as the LAS among transplant candidates increased (p < 0.001). CONCLUSIONS Two years after initiation of the LAS model, wait-list times continue to decrease while mean LAS continued to increase. This increase in LAS among transplant recipients was observed most notably in patients with interstitial pulmonary fibrosis and COPD, and reflected in an increased mean LAS at the time of listing.

Blockade of receptor for advanced glycation end product attenuates pulmonary reperfusion injury in mice.

OBJECTIVE The receptor for advanced glycation end products (RAGE) is expressed at high levels in the lung, particularly in type 1 alveolar cells, and has been shown to amplify injury triggered by acute stress. Previous studies suggest serum concentrations of soluble RAGE increase during pulmonary reperfusion injury after transplantation. RAGE blockade has been shown to suppress hepatic and cardiac ischemia and reperfusion injury in mice. Thus we tested the hypothesis that RAGE mediates tissue-injury mechanisms in ischemia and reperfusion injury in the lung. METHODS C57BL/6 mice were subjected to 30 minutes of pulmonary ischemia by clamping the left hilum, followed by 60 minutes of reperfusion. Lung function was assessed by means of blood gas analysis, and capillary leak was assessed by injecting fluorescein isothiocyanate-labeled albumin and comparing fluorescence in bronchial lavage fluid with that in serum. Histologic analysis of the lung was performed by a pathologist naive to the experimental conditions. RESULTS In animals subjected to RAGE blockade, significant increases in Po(2) (108 vs 73 mm Hg, P = .0094) and more than 3-fold decrease in capillary leak Relative Fluorescent Units (RFU, 6.12 vs 1.75; P = .001) were observed. Histologic examination revealed significant injury reduction in soluble RAGE-treated animals versus control animals. RAGE knockout mice exhibited a protected phenotype when exposed to pulmonary ischemia and reperfusion. Additionally, interleukin 8 production and nuclear factor kappaB activation were increased in control mice. CONCLUSION Abrogation of RAGE signaling attenuates pulmonary ischemia and reperfusion injury. This study suggests that RAGE might play a central role in pulmonary reperfusion injury and in transplantation and that blockade of RAGE might offer a potential target to abrogate pulmonary reperfusion injury in clinical transplantation.

Survival of adults with systemic sclerosis following lung transplantation: a nationwide cohort study.

Many transplant programs are hesitant to offer lung transplantation to patients with systemic sclerosis (SSc) due to concerns about extrapulmonary involvement that might affect survival. The aim of this study was to determine whether adults with SSc have higher 1‐year mortality rates after lung transplantation compared to those with interstitial lung disease (ILD) or pulmonary arterial hypertension (PAH) not due to SSc.

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.