Selim M. Arcasoy

Delayed access and survival in idiopathic pulmonary fibrosis: a cohort study.

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.

An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome

Bronchiolitis obliterans syndrome (BOS) is a major complication of lung transplantation that is associated with poor survival. The International Society for Heart and Lung Transplantation, American Thoracic Society, and European Respiratory Society convened a committee of international experts to describe and/or provide recommendations for 1) the definition of BOS, 2) the risk factors for developing BOS, 3) the diagnosis of BOS, and 4) the management and prevention of BOS. A pragmatic evidence synthesis was performed to identify all unique citations related to BOS published from 1980 through to March, 2013. The expert committee discussed the available research evidence upon which the updated definition of BOS, identified risk factors and recommendations are based. The committee followed the GRADE (Grading of Recommendation, Assessment, Development and Evaluation) approach to develop specific clinical recommendations. The term BOS should be used to describe a delayed allograft dysfunction with persistent decline in forced expiratory volume in 1 s that is not caused by other known and potentially reversible causes of post-transplant loss of lung function. The committee formulated specific recommendations about the use of systemic corticosteroids, cyclosporine, tacrolimus, azithromycin and about re-transplantation in patients with suspected and confirmed BOS. The diagnosis of BOS requires the careful exclusion of other post-transplant complications that can cause delayed lung allograft dysfunction, and several risk factors have been identified that have a significant association with the onset of BOS. Currently available therapies have not been proven to result in significant benefit in the prevention or treatment of BOS. Adequately designed and executed randomised controlled trials that properly measure and report all patient-important outcomes are needed to identify optimal therapies for established BOS and effective strategies for its prevention. Diagnosis of BOS requires careful exclusion of other complications that can cause delayed lung allograft dysfunction http://ow.ly/AZmbr

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.

Extracorporeal membrane oxygenation as a bridge to lung transplantation and recovery

OBJECTIVE Respiratory failure develops in many patients on lung transplant waiting lists before a suitable donor organ becomes available. Extracorporeal membrane oxygenation may be used to bridge such patients to recovery or lung transplantation. METHODS This is a review of a single-institutions experience with placing patients on extracorporeal membrane oxygenation with the intention of bridging them to lung transplantation. End points included successful bridging, duration of extracorporeal membrane oxygenation support, extubation, weaning from extracorporeal membrane oxygenation, overall survival, and extracorporeal membrane oxygenation-related complications. During an approximate 5-year period, acute respiratory failure developed in 18 patients (median age, 34 years) on the institutions lung transplant waiting list (8 hypoxemic, 9 hypercarbic, and 1 combined) who were placed on extracorporeal membrane oxygenation (13 venovenous and 5 venoarterial). RESULTS All patients achieved appropriate extracorporeal membrane oxygenation blood flow rates (median, 4.05 L/min) and good gas exchange (median, on extracorporeal membrane oxygenation partial pressure of arterial carbon dioxide 43 mm Hg and partial pressure of arterial oxygen 196 mm Hg). Thirteen patients (72%) were successfully bridged: 10 to transplant and 3 returned to baseline function. Eleven patients (61%) survived beyond 3 months, including the 10 (56%) who underwent transplantation and are still alive. The median duration of extracorporeal membrane oxygenation support for patients who underwent transplantation was 6 days (3.5-31 days) versus 13.5 days (11-19 days) for those who did not undergo transplantation (P = .45). Six patients (33%) were extubated on extracorporeal membrane oxygenation, 4 of whom underwent transplantation. Four patients (22%) who were too unstable for conventional interhospital transfer were transported on extracorporeal membrane oxygenation to Columbia University Medical Center. This subgroup had a 75% bridge to transplant or recovery rate and 100% survival in transplanted patients. CONCLUSIONS Extracorporeal membrane oxygenation is a safe and effective means of bridging well-selected patients with refractory respiratory failure to lung transplantation or return to their baseline condition.

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.

Obesity and Primary Graft Dysfunction after Lung Transplantation: The Lung Transplant Outcomes Group Obesity Study

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/m(2) 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.

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.

Potential Refinements of The International Society for Heart And Lung Transplantation Primary Graft Dysfunction Grading System

Primary graft dysfunction (PGD) is responsible for significant morbidity and mortality after lung transplantation and The International Society for Heart and Lung Transplantation (ISHLT) Working Group on PGD has recently reported standardized consensus criteria, based on the recipient arterial blood-gas analysis and chest X-ray findings, to define PGD and determine its severity (grade range, 0–3). The grading system has been shown to predict post-transplant outcomes; however, further evaluation and refinement of the validity of the grading system is an important next step to enhance its utility. In this review, we describe advantage and disadvantages of the current PGD grading system based on series of analyses we have conducted and possible options for its potential refinement. The suggested revisions are (1) additional assessment time points at 6 and 12 hours should be included, (2) only bilateral infiltrates on chest X-ray (not unilateral infiltrates) should be considered as an infiltrate in bilateral lung transplants, (3) information from the chest X-ray is useful within 6 hours of final lung reperfusion (T0) but is not necessary to classify grade 3 at 12 to 72 hours, (4) apply PGD grade to single and bilateral lung transplant separately, (5) all extubated patients should be considered as grade 0 to 1, (6) note if PGD grade is being defined by specific inclusion and exclusion criteria, including extubation, with clear chest X-ray, on nitric oxide or extracorporeal membrane oxygenation. Although, further evaluations of the PGD definition and grading system are needed, the suggested refinements in this review may further enhance the reliability and validity of the PGD grading system as an important new lung transplant study instrument.

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.