Economic Outcomes of Extracorporeal Membrane Oxygenation With and Without Ambulation as a Bridge to Lung Transplantation.

BACKGROUND: An increasing number of centers are using active rehabilitation and ambulation for critically ill patients on extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation. This investigation assessed the economic impact at a single center of ambulatory versus non-ambulatory ECMO strategies as a bridge to lung transplantation. METHODS: We conducted a single-center retrospective cohort analysis of all subjects supported with ECMO as a bridge to lung transplantation (N = 9) from 2007 to 2012. Subjects who were rehabilitated while supported with ECMO before lung transplantation were compared with those who were not rehabilitated during ECMO. Hospital cost data for the month before transplantation through 12 months after the initial post-transplant hospital discharge were compared. RESULTS: The median cost (interquartile range [IQR]) in the 30 d before transplant for the ambulatory cohort was $88,137 (IQR $38,589-$122,111) compared with $52,124 (IQR $23,824-$69,929) for the non-ambulatory cohort (P = .08). The median post-transplant ICU cost for the ambulatory cohort was $38,468 (IQR $23,611-$64,126) compared with $143,407 (IQR $112,199-$168,993) for the non-ambulatory cohort (P = .01). The median total hospital cost for subjects supported with ambulatory ECMO was $213,086 (IQR $166,767-$264,536) compared with $273,291 (IQR $237,299-$374,175) for non-ambulatory ECMO subjects (P = .05). The median total cost for the ambulatory cohort was $268,194 (IQR $219,972-$517,320) compared with $300,307 (IQR $274,262-$394,913) for the non-ambulatory cohort (P = .14). CONCLUSIONS: Subjects supported with ambulatory ECMO had a 22% ($60,204) reduction in total hospital cost, 73% ($104,939) reduction in post-transplant ICU cost, and 11% ($32,133) reduction in total cost compared with non-ambulatory ECMO subjects. This analysis demonstrates the potential economic benefit of rehabilitation and ambulation during ECMO compared with a traditional strategy.

Ambulatory extracorporeal membrane oxygenation as a bridge to lung transplantation: walking while waiting.

The proportion of critically ill patients awaiting lung transplantation has increased since the implementation of the Lung Allocation Score (LAS) in 2005. Critically ill patients comprise a sizable proportion of wait-list mortality and are known to experience increased posttransplant complications. These critically ill patients have been successfully bridged to lung transplantation with extracorporeal membrane oxygenation (ECMO), but historically these patients have required excessive sedation, been immobile, and have had difficult functional recovery in the posttransplant period and high mortality. One solution to the deconditioning often seen in critically ill patients is the implementation of rehabilitation and ambulation while awaiting transplantation on ECMO. Ambulatory ECMO programs of this nature have been developed in an attempt to provide rehabilitation, physical therapy, and minimization of sedation prior to lung transplantation to improve both surgical and posttransplant outcomes. Favorable outcomes have been reported using this novel approach, but how and where this strategy should be implemented remain unclear. In this commentary, we review the currently available literature for ambulation and rehabilitation during ECMO support as a bridge to lung transplantation, discuss future directions for this technology, and address the important issues of resource allocation and regionalization of care as they relate to ambulatory ECMO.

Implications for human leukocyte antigen antibodies after lung transplantation: a 10-year experience in 441 patients.

BACKGROUND: Long-term survival after lung transplant is limited by the development of chronic and progressive airflow obstruction, a condition known as bronchiolitis obliterans syndrome (BOS). While prior studies strongly implicate cellular rejection as a strong risk factor for BOS, less is known about the clinical significance of human leukocyte antigen (HLA) antibodies and donor HLA-specific antibodies in long-term outcomes. METHODS: A single-center cohort of 441 lung transplant recipients, spanning a 10-year period, was prospectively screened for HLA antibodies after transplant using flow cytometry-based methods. The prevalence of and predictors for HLA antibodies were determined. The impact of HLA antibodies on survival after transplant and the development of BOS were determined using Cox models. RESULTS: Of the 441 recipients, 139 (32%) had detectable antibodies to HLA. Of these 139, 54 (39%) developed antibodies specific to donor HLA. The detection of posttransplant HLA antibodies was associated with BOS (HR, 1.54; P=.04) and death (HR, 1.53; P=.02) in multivariable models. The detection of donor-specific HLA antibodies was associated with death (HR, 2.42; P<.0001). The detection of posttransplant HLA antibodies was associated with pretransplant HLA-antibody detection, platelet transfusions, and the development of BOS and cytomegalovirus pneumonitis. CONCLUSIONS: Approximately one-third of lung transplant recipients have detectable HLA antibodies, which are associated with a worse prognosis regarding graft function and patient survival.

Rationing in urologic oncology: lessons from sipuleucel-T for advanced prostate cancer.

OBJECTIVES: As complex novel cancer drugs are developed, supply may transiently fail to meet demand as production capacity established for research purposes is scaled up to meet anticipated clinical volume. There are no clear guidelines for how clinicians and medical centers should allocate scarce cancer care resources among patients who may benefit from the intervention. MATERIALS AND METHODS: We describe a recent scenario in which demand exceeded supply for a novel immunotherapy, sipuleucel-T, that was newly approved by the FDA for castration-resistant prostate cancer. Production of this autologous cellular therapy was initially limited to one facility with supply projected to serve only 2,000 out of approximately 30,000 potentially eligible patients in the United States. RESULTS AND CONCLUSIONS: We propose basic guidelines that should be followed when allocating scarce cancer therapies and highlight ongoing challenges that must be resolved both with regard to rationing cancer care and with regard to access to high cost novel interventions in oncology in general.

Increased Nitric Oxide Production Prevents Airway Hyperresponsiveness in Caveolin-1 Deficient Mice Following Endotoxin Exposure.

BACKGROUND: Caveolin-1, the hallmark protein of caveolae, is highly expressed within the lung in the epithelium, endothelium, and in immune cells. In addition to its classical roles in cholesterol metabolism and endocytosis, caveolin-1 has also been shown to be important in inflammatory signaling pathways. In particular, caveolin-1 is known to associate with the nitric oxide synthase enzymes, downregulating their activity. Endotoxins, which are are composed mainly of lipopolysaccharide (LPS), are found ubiquitously in the environment and can lead to the development of airway inflammation and increased airway hyperresponsiveness (AHR). METHODS: We compared the acute responses of wild-type and caveolin-1 deficient mice after LPS aerosol, a well-accepted mode of endotoxin exposure, to investigate the role of caveolin-1 in the development of environmental lung injury. RESULTS: Although the caveolin-1 deficient mice had greater lung inflammatory indices compared to wild-type mice, they exhibited reduced AHR following LPS exposure. The uncoupling of inflammation and AHR led us to investigate the role of caveolin-1 in the production of nitric oxide, which is known to act as a bronchodilator. The absence of caveolin-1 resulted in increased nitrite levels in the lavage fluid in both sham and LPS treated mice. Additionally, inducible nitric oxide synthase expression was increased in the lung tissue of caveolin-1 deficient mice following LPS exposure and administration of the potent and specific inhibitor 1400W increased AHR to levels comparable to wild-type mice. CONCLUSIONS: We attribute the relative airway hyporesponsiveness in the caveolin-1 deficient mice after LPS exposure to the specific role of caveolin-1 in mediating nitric oxide production.

Update on infectious complications following lung transplantation.

PURPOSE OF REVIEW: Lung transplantation is an important therapeutic treatment for many patients with life-threatening pulmonary diseases; however, long-term survival is still relatively limited compared with other solid organ transplants. Over the last year, several articles have been published helping to increase our knowledge of infections in lung transplant recipients. In particular, important new information has been published recently regarding cytomegalovirus (CMV) and fungal infections following lung transplantation. RECENT FINDINGS: Recent studies indicate prolonged (≥12 months) antiviral prophylaxis for CMV after lung transplant may be beneficial in high-risk transplant recipients. Epidemiologic studies show invasive fungal infections are increasingly being recognized following solid organ transplantation, particularly with Aspergillus and Candida species. Pulmonary infections with CMV and Aspergillus are likely contributors to the development of bronchiolitis obliterans syndrome (BOS). SUMMARY: Lung transplantation has many potential posttransplant complications with infection being a major contributor. More information has become available regarding CMV prophylaxis, CMV treatment, pulmonary fungal infection epidemiology, and the role of both CMV and Aspergillus on the development of BOS, which helps toward the goal of increasing long-term survival in lung transplant recipients.

Survival after bronchiolitis obliterans syndrome among bilateral lung transplant recipients.

RATIONALE: Despite the importance of bronchiolitis obliterans syndrome (BOS) in lung transplantation, little is known regarding the factors that influence survival after the onset of this condition, particularly among bilateral transplant recipients. OBJECTIVES: To identify factors that influence survival after the onset of BOS among bilateral lung transplant recipients. METHODS: The effect of demographic or clinical factors, occurring before BOS, upon survival after the onset of BOS was studied in 95 bilateral lung transplant recipient using Cox proportional hazards models. MEASUREMENTS AND MAIN RESULTS: Although many factors, including prior acute rejection or rejection treatments, were not associated with survival after BOS, BOS onset within 2 years of transplantation (early-onset BOS), or BOS onset grade of 2 or 3 (high-grade onset) were predictive of significantly worse survival (early onset P = 0.04; hazard ratio, 1.84; 95% confidence interval, 1.03-3.29; high-grade onset P = 0.003; hazard ratio, 2.40; 95% confidence interval, 1.34-4.32). The effects of both early onset and high-grade onset on survival persisted in multivariable analysis and after adjustment for concurrent treatments. Results suggested an interaction might exist between early onset and high-grade onset. In particular, high-grade onset of BOS, regardless of its timing after transplant, is associated with a very poor prognosis. CONCLUSIONS: The course of BOS after bilateral lung transplantation is variable. Distinct patterns of survival after BOS are evident and related to timing or severity of onset. Further characterization of these subgroups should provide a more rational basis from which to design, stratify, and assess response in future BOS treatment trials.

Complex bacterial infections pre- and posttransplant.

Infections complications following lung transplantation are associated with significant morbidity and mortality. Management of infections is most challenging in patients with cystic fibrosis (CF), but all lung transplant recipients are at heightened risk for opportunistic infections. Particularly in CF, pretransplant infections with PSEUDOMONAS AERUGINOSA, other highly resistant bacteria (e.g., STENOTROPHOMONAS, BURKHOLDERIA), and mycobacteria play a major role in recipient selection and post-lung transplant outcomes. Understanding the clinical impact and management strategies for each of these different pathogens is critical to maximizing the benefit of lung transplantation. In the review, we discuss each of these infections both as pretransplant risk factors as well as posttransplant pathogens and the individual issues that arise with each infection.

Update on medical complications involving the lungs.

PURPOSE OF REVIEW: Lung transplant is now an accepted treatment for end-stage lung disease with improving survival and an increasing number of transplants being performed every year. Recognition of the common medical complications after lung transplant is important for timely diagnosis and treatment. This review will highlight the clinical presentation, diagnosis, and treatment of several noninfectious pulmonary complications that are encountered in lung transplant recipients. RECENT FINDINGS: The review focuses on several broad areas of medical complications after lung transplant, including native lung complications, malignancies, venous thromboembolism, drug toxicity, and pleural disease. Each of these problems is a significant cause of morbidity and mortality after lung transplant. We review the recent publications in these areas that have identified improved ways to diagnose and treat these complications. SUMMARY: Despite its relatively short history, the field of lung transplantation has made significant progress over the past 25 years. The medical advances surrounding lung transplant are not only related to the surgical procedure and immunosuppression, but also to the ability of physicians to diagnose and treat the common complications after transplant. Improvements in the diagnosis and management of these posttransplant medical complications will hopefully lead to even greater survival after lung transplantation in the future.

Counteracting signaling activities in lipid rafts associated with the invasion of lung epithelial cells by Pseudomonas aeruginosa.

Pseudomonas aeruginosa has the capacity to invade lung epithelial cells by co-opting the intrinsic endocytic properties of lipid rafts, which are rich in cholesterol, sphingolipids, and proteins, such as caveolin-1 and -2. We compared intratracheal Pseudomonas infection in wild type and caveolin-deficient mice to investigate the role of caveolin proteins in the pathogenesis of Pseudomonas pneumonia. Unlike wild type mice, which succumb to pneumonia, caveolin-deficient mice are resistant to Pseudomonas. We observed that Pseudomonas invasion of lung epithelial cells is dependent on caveolin-2 but not caveolin-1. Phosphorylation of caveolin-2 by Src family kinases is an essential event for Pseudomonas invasion. Our studies also reveal the existence of a distinct signaling mechanism in lung epithelial cells mediated by COOH-terminal Src kinase (Csk) that negatively regulates Pseudomonas invasion. Csk migrates to lipid raft domains, where it decreases phosphorylation of caveolin-2 by inactivating c-Src. Whereas Pseudomonas co-opts the endocytic properties of caveolin-2 for invasion, there also exists in these cells an intrinsic Csk-dependent cellular defense mechanism aimed at impairing this activity. The success of Pseudomonas in co-opting lipid raft-mediated endocytosis to invade lung epithelial cells may depend on the relative strengths of these counteracting signaling activities.

The expanding roles of caveolin proteins in microbial pathogenesis.

Caveolin proteins have been implicated in a wide range of cellular functions including lipid raft mediated endocytosis and regulation of cell signaling cascades. Recent discoveries have shown that these proteins are involved not only in regulating these homeostatic cellular functions, but also in the host response to a wide range of different infections. Both caveolin-1 and 2 have been shown to play important roles in pathogen uptake. While caveolin-1 is the most well studied member of this family, a growing body of evidence has now recognized the role of caveolin-2 in these host pathogen interactions and novel host defense mechanisms.

Lung transplantation at Duke University.

Clinical lung transplantation continues to grow worldwide. Advances in donor selection and management have been critical to support the expanded growth of lung transplant as a therapeutic option for patients with advanced lung disease. In recent years, allocation in the US has changed to a disease severity based system that has led to a dramatic reduction of deaths on the waiting list with concomitant increases in transplantation of recipients who are now sicker, older, and more likely to have interstitial lung disease. Increased experience with the LAS will help to further refine optimal recipient selection and balance urgency with utility. Our center's experience demonstrates survival is comparable post-LAS as compared to pre-LAS despite transplantation of increasingly ill recipients. After transplantation, the incidence of severe PGD has decreased in recent years with advances in donor lung management and perseveration. In cases of severe PGD, VV ECMO has provided our center with a successful method of supporting patients and reducing mortality immediately following transplantation. Long-term outcomes after lung transplantation continue to be limited by BOS, a condition of progressive allograft dysfunction. Our center has led research that identified gastric reflux as a potential contributing factor to posttransplant allograft dysfunction and suggested that Nissen fundoplication surgery might help prevent the development of BOS. Continued refinements in donor management and selection, prevention and treatment of PGD, and enhanced understanding of the mechanisms of BOS will support further growth of lung transplantation and further improvements in overall posttransplant outcomes.

The role of lipid rafts in the pathogenesis of bacterial infections.

Numerous pathogens have evolved mechanisms of co-opting normal host endocytic machinery as a means of invading host cells. While numerous pathogens have been known to enter cells via traditional clathrin-coated pit endocytosis, a growing number of viral and bacterial pathogens have been recognized to invade host cells via clustered lipid rafts. This review focuses on several bacterial pathogens that have evolved several different mechanisms of co-opting clustered lipid rafts to invade host cells. Although these bacteria have diverse clinical presentations and many differences in their pathogenesis, they each depend on the integrity of clustered lipid rafts for their intracellular survival. Bacterial invasion via clustered lipid rafts has been recognized as an important virulence factor for a growing number of bacterial pathogens in their battle against host defenses.

Pseudomonas invasion of type I pneumocytes is dependent on the expression and phosphorylation of caveolin-2.

Pseudomonas aeruginosa is a major cause of pneumonia in patients with cystic fibrosis and other immuncompromising conditions. Here we showed that P. aeruginosa invades type I pneumocytes via a lipid raft-mediated mechanism. P. aeruginosa invasion of rat primary type I-like pneumocytes as well as a murine lung epithelial cell line 12 (MLE-12) is inhibited by drugs that remove membrane cholesterol and disrupt lipid rafts. Confocal microscopy demonstrated co-localization of intracellular P. aeruginosa with lipid raft components including caveolin-1 and -2. We generated caveolin-1 and -2 knockdowns in MLE-12 cells by using RNA interference techniques. Decreased expression of caveolin-2 significantly impaired the ability of P. aeruginosa to invade MLE-12 cells. In addition, the lipid raft-dependent tyrosine phosphorylation of caveolin-2 appeared to be a critical regulator of P. aeruginosa invasion.