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Antimicrobial stewardship programs (ASPs) have made immense strides in optimizing antibiotic, antifungal, and antiviral use in clinical settings. However, although ASPs are required institutionally by regulatory agencies in the United States and Canada, they are not mandated for transplant centers or programs specifically. Despite the fact that solid organ transplant recipients in particular are at increased risk of infections from multidrug-resistant organisms, due to host and donor factors and immunosuppressive therapy, there currently are little rigorous data regarding stewardship practices in solid organ transplant populations, and thus, no transplant-specific requirements currently exist. Further complicating matters, transplant patients have a wide range of variability regarding their susceptibility to infection, as factors such as surgery of transplant, intensity of immunosuppression, and presence of drains or catheters in situ may modify the risk of infection. As such, it is not feasible to have a “one-size-fits-all” style of stewardship for this patient population. The objective of this white paper is to identify opportunities, risk factors, and ASP strategies that should be assessed with solid organ transplant recipients to optimize antimicrobial use, while producing an overall improvement in patient outcomes. We hope it may serve as a springboard for development of future guidance and identification of research opportunities.

Transplantation is an important component of treatment for pulmonary arterial hypertension (PAH) patients with severe limitations despite optimal medical therapy. Although the risks of transplantation remain significant, appropriate candidates may achieve excellent functional outcomes and long-term survival. As PAH therapy and transplantation have advanced, the approaches to transplant referral and listing have changed. This article will review criteria and thresholds for transplant referral and listing, novel approaches to expanding the pool of donor organs, options for bridging to transplantation, and the ways in which the current system for organ allocation have evolved. Knowledge of these concepts will help to ensure timely referral and navigation of the course to successful transplantation for PAH patients.

The burden of post-traumatic stress disorder (PTSD) symptoms may be associated with worse outcomes after transplantation. Little is known about the prevalence and correlates of PTSD symptoms in lung transplant recipients.We conducted a cross-sectional study of lung transplant recipients between April 2008 and February 2010 at a single center. The PTSD Checklist was used to determine the burden of PTSD symptomatology (total score) and percent of subjects with a provisional PTSD diagnosis (validated algorithms). We assessed the relationship between PTSD symptom burden and patient characteristics with multivariable logistic modeling.We enrolled 210 subjects (response rate 91%). Most patients were female (50%), and Caucasian (89%). The median age was 59 (interquartile range [IQR] 48 to 63) years and the median time between transplant and follow-up was 2.4 (IQR 0.7 to 5.3) years. Clinically significant PTSD symptomatology was observed in 12.6% (8.4% to 17.9%) of subjects. Subjects were more likely to endorse symptoms of re-experiencing (29.5%) and arousal (33.8%) than avoidant symptoms (18.4%). Multivariable linear regression showed higher PTSD symptom scores among recipients who were: younger (p0.001); without private insurance (p = 0.001); exposed to trauma (p0.001); or diagnosed with bronchiolitis obliterans syndrome (p = 0.005).Overall prevalence of PTSD (12.6%) in our study was two times higher than the general population. Patient characteristics found to be associated with an increased burden of PTSD symptoms may be useful to consider in future interventions designed to reduce this comorbidity.

Parainfluenza virus (PIV) may cause life‐threatening pneumonia in lung transplant patients and there are no proven effective therapies. We report the use of inhaled DAS181, a novel sialidase fusion protein, to treat severe PIV type 3 pneumonia in a lung transplant patient. Treatment was well tolerated and associated with improvement in oxygenation and symptoms, along with rapid clearance of PIV. DAS181 should be systematically evaluated for treatment of PIV infection in transplant recipients.

Screening for disease before the arrival of symptoms is an intuitive cornerstone of preventive medicine and good clinical practice in many cases. However, screening is not appropriate for all conditions. Disease, test, and treatment should all be considered when developing a rational approach to screening.1–4 Specifically, screening may be warranted if the target disease has significant morbidity and mortality. Testing in specific populations should be able to detect early disease, have relatively low risk, and a low rate of pseudo-disease detection (including both false positive results and true disease which naturally regresses). Lastly, treatments should be more effective if employed early.56 This article reviews the available literature addressing these key aspects of screening for pulmonary arterial hypertension (PAH).

Successful lung and heart-lung transplantations were achieved nearly 3 decades ago at a time when medical therapeutic options for patients with pulmonary arterial hypertension were extremely limited. While the medical arsenal for treatment of pulmonary arterial hypertension has expanded considerably since this time, lung and heart-lung transplantations continue to offer potential for improved survival and quality of life for patients who experience disease progression despite medical therapy. The majority of patients with pulmonary hypertension requiring transplantation can be successfully treated with lung transplantation and do not require combined heart-lung transplantation. Advances in surgical techniques, medical management, donor and recipient selection, pharmacologic therapies, and clinical outcomes assessment have led to ongoing improvements in short- and long-term outcomes. Long-term success requires appropriate candidate and donor selection, experienced surgical and medical teams, diligent medical follow-up by the transplant team in collaboration with community medical providers, and excellent patient adherence with post-transplant care and therapy. This article addresses short- and long-term management and complications associated with lung transplantation. Outcomes after transplantation, immunosuppressive management, acute and chronic rejection, medical morbidities, and underlying diagnosis-specific concerns are discussed.

Background CT scan measures of emphysema and airway disease have been correlated with lung function in cohorts of subjects with a range of COPD severity. The contribution of CT scan-assessed airway disease to objective measures of lung function and respiratory symptoms such as dyspnea in severe emphysema is less clear. Methods Using data from 338 subjects in the National Emphysema Treatment Trial (NETT) Genetics Ancillary Study, densitometric measures of emphysema using a threshold of −950 Hounsfield units (%LAA-950) and airway wall phenotypes of the wall thickness (WT) and the square root of wall area (SRWA) of a 10-mm luminal perimeter airway were calculated for each subject. Linear regression analysis was performed for outcome variables FEV 1 and percent predicted value of FEV 1 with CT scan measures of emphysema and airway disease. Results In univariate analysis, there were significant negative correlations between %LAA-950 and both the WT ( r = −0.28, p = 0.0001) and SRWA ( r = −0.19, p = 0.0008). Airway wall thickness was weakly but significantly correlated with postbronchodilator FEV 1 % predicted (R = −0.12, p = 0.02). Multivariate analysis showed significant associations between either WT or SRWA (β = −5.2, p = 0.009; β = −2.6, p = 0.008, respectively) and %LAA-950 (β = −10.6, p = 0.03) with the postbronchodilator FEV 1 % predicted. Male subjects exhibited significantly thicker airway wall phenotypes (p = 0.007 for WT and p = 0.0006 for SRWA). Conclusions Airway disease and emphysema detected by CT scanning are inversely related in patients with severe COPD. Airway wall phenotypes were influenced by gender and associated with lung function in subjects with severe emphysema.

Background Prior to implementation of the lung allocation score (LAS) system, allocation of donor lungs was based on accrued time on the waiting list and was potentially influenced by center-specific thresholds for listing. The impact of LAS implementation on patient characteristics and survival is unknown. Methods United Network of Organ Sharing data were obtained on all lung transplant candidates listed and all patients undergoing transplantation in region 6 between May 4, 2003, and May 4, 2006. Each data set was divided into two cohorts: 2 years before LAS implementation, and 1 year after LAS implementation. LAS was calculated and compared by cohort. Pre-LAS and post-LAS differences in patient characteristics were examined. Waiting list and posttransplant survival rates for each cohort were examined using Kaplan-Meier estimates and Cox regression. Results After LAS implementation, the distribution of diagnoses in patients undergoing transplantation significantly changed (p = 0.02), while the distribution of diagnoses in those listed did not (p = 0.17). Characteristics of patients on the waiting list were similar, except that a higher proportion of nonwhite patients were listed (p = 0.04) and lower FVC (p Conclusions After LAS implementation, the distribution of diagnoses in lung transplant recipients was significantly changed, while that of candidates was not. Posttransplant and waiting list survival were not affected by the LAS system, but power was limited. Larger and long-term survival studies are needed to determine if the LAS system improves overall allocation and survival for patients interested in lung transplantation.

Clinicians should be cognizant of the symptoms and risk factors associated with pulmonary hypertension (PH). While known PH poses significant therapeutic challenges, occult PH carries the added potential for unanticipated complications when treating concurrent medical illnesses. PH may occur with underlying medical conditions and risk factors or may occur de novo as idiopathic pulmonary arterial hypertension (IPAH). Symptoms of PH are frequently attributed to more common conditions, and their nonspecific nature and insidious onset may lead to delay in presentation, evaluation, and diagnosis. Initial symptoms are dyspnea, fatigue, chest pain, and palpitations. Lower extremity edema, presyncope, and syncope are symptoms of more advanced disease. Thorough evaluation of symptoms and identification of patients with risk factors for PH are critical in making a timely diagnosis. History and physical examination can identify patients with suspected PH. Further testing is necessary for definitive diagnosis, classification, assessment of severity, and guiding therapeutic decisions.

Epoprostenol and the structurally related compounds treprostinil, iloprost, and beraprost are collectively referred to as prostanoids. The discovery of epoprostenol in 1976 and unequivocal demonstration of its efficacy in 1996 dramatically altered the approach to therapy for pulmonary arterial hypertension (PAH). Development of prostanoids available through multiple routes of administration and the discovery and development of other agents acting through alternative pathways continue to expand the array of therapeutic options. The use of prostanoids in combination with other PAH drugs and for treating pulmonary hypertensive disorders outside of the PAH classification are areas of ongoing research.

BACKGROUND Chronic lung allograft dysfunction (CLAD) is a major cause of allograft loss post-lung transplantation. Prior studies have examined the association between respiratory virus infection (RVI) and CLAD were limited by older diagnostic techniques, study design, and case numbers. We examined the association between symptomatic RVI and CLAD using modern diagnostic techniques in a large contemporary cohort of lung transplant recipients (LTRs). METHODS We retrospectively assessed clinical variables including acute rejection, cytomegalovirus pneumonia, upper and lower RVI, and the primary endpoint of CLAD (determined by 2 independent reviewers) in 250 LTRs in a single university transplantation program. Univariate and multivariate Cox models were used to analyze the relationship between RVI and CLAD in a time-dependent manner, incorporating different periods of risk following RVI diagnosis. RESULTS Fifty patients (20%) were diagnosed with CLAD at a median of 95 weeks post-transplantation, and 79 (32%) had 114 episodes of RVI. In multivariate analysis, rejection and RVI were independently associated with CLAD (adjusted hazard ratio [95% confidence interval]) 2.2 (1.2-3.9), P = .01 and 1.9 (1.1-3.5), P = .03, respectively. The association of RVI with CLAD was stronger the more proximate the RVI episode: 4.8 (1.9-11.6), P < .01; 3.4 (1.5-7.5), P < .01; and 2.4 (1.2-5.0), P = .02 in multivariate analysis for 3, 6, and 12 months following RVI, respectively. CONCLUSIONS Symptomatic RVI is independently associated with development of CLAD, with increased risk at shorter time periods following RVI. Prospective studies to characterize the virologic determinants of CLAD and define the underlying mechanisms are warranted.

Background Obese patients with idiopathic pulmonary fibrosis (IPF) have higher 90-day mortality after lung transplantation. We sought to determine whether body mass index (BMI) differentially modified the effect of transplant procedure type on 90-day mortality in IPF patients. Methods We analyzed data from the Organ Procurement and Transplantation Network (OPTN) for all patients with IPF who were transplanted between 2000 and 2010. Post-transplant survival was examined using Kaplan–Meier estimates. Multivariable logistic regression modeling was used to determine the difference in 90-day survival. The primary variable of interest was the interaction term between body mass index (BMI) and transplant type. Results A total of 3,389 (58% single-lung transplant [SLT] and 42% bilateral lung transplant [BLT]) subjects were included. Multivariable logistic regression modeling demonstrated a statistically significant interaction between BMI and transplant type ( p = 0.047). Patients with a BMI > 30 kg/m 2 who received a BLT are 1.71 times (95% CI [1.03 to 2.85], p = 0.038) more likely to die within 90 days than BLT recipients with a BMI of 18.5 to 30 kg/m 2 . Conclusions Our results suggest that obese patients who receive a BLT may be at higher risk of 90-day mortality compared with patients of normal weight. Further study is needed to obtain more detailed information about comorbidities and other risk factors for early death that are not included in the OPTN database.

Advances in surgical technique, immunosuppression, and perioperative care have permitted successful application of lung transplantation to a variety of nonmalignant pulmonary disorders of the airways, lung parenchyma, and pulmonary vasculature. This option is available to selected candidates under the age of 65 years whose life expectancy and functional status are severely limited because of advanced lung disease but who remain ambulatory and free of significant comorbid disease. The majority of transplant recipients experience marked improvement in quality of life, but long-term survival remains an elusive goal for many patients. Five-year survival following lung transplantation is only 45%. 13 With the increasingly diverse indications for lung transplantation, it has become evident that the nature of the underlying disease process must be taken into account in many facets of candidate selection and recipient management. In this regard, an intimate appreciation of the natural history and prognostic indices of the individual disease states is essential in making appropriate decisions about the timing of transplantation. The decision to replace one or both lungs may rest on the particular pathophysiology of the underlying disease and the implications of leaving a native lung in place. Finally, the post-transplant course may be complicated by factors related to the native disease rather than those generic to transplantation and immunosuppression. This article provides a disease-specific approach to lung transplantation, highlighting issues particular to the primary diseases for which transplantation is commonly performed.

Background Improving long-term survival after lung transplantation can be facilitated by identifying patient characteristics that are predictors of positive long-term outcomes. Validated survival modeling is important for guiding clinical decision-making, case-mix adjustment in comparative effectiveness research and refinement of the lung allocation system (LAS). Methods We used the registry of the International Society for Heart and Lung Transplantation (ISHLT) to develop and validate a predictive model of 5-year survival after lung transplantation. A total of 18,072 eligible cases were randomly split into development and validation datasets. Pre-transplant recipient variables considered included age, gender, diagnosis, body mass index, serum creatinine, hemodynamic variables, pulmonary function variables, viral status and comorbidities. Predictors were considered in a stepwise approach with the Akaike Information Criteria (AIC). Time-dependent receiver operator characteristic (ROC) curves assessed predictive ability. A 1-year conditional model and three models for disease subgroups were considered. ROC methods were used to characterize the predictive potential of the LAS post-transplant model at 1 and 5 years. Results The baseline model included age, diagnosis, creatinine, bilirubin, oxygen requirement, cardiac output, Epstein–Barr virus status, transfusion history and diabetes history. Prediction of long-term survival was poor (area under the curve [AUC] = 0.582). Neither the 1-year conditional model (AUC = 0.573) nor models designed for separate diseases (AUC = 0.553 to 0.591) improved survival prediction. The predictive ability of the LAS post-transplant parameters was similar to that of our model (1-year AUC = 0.580 and 5-year AUC = 0.566). Conclusions Models developed from pre-transplant characteristics poorly predict long-term survival. Models for separate diseases and 1-year conditional models did not improve prediction. Better databases and approaches to predict survival are needed to improve lung allocation.

Prior to implementation of the lung allocation score (LAS) system, allocation of donor lungs was based on accrued time on the waiting list and was potentially influenced by center-specific thresholds for listing. The impact of LAS implementation on patient characteristics and survival is unknown.United Network of Organ Sharing data were obtained on all lung transplant candidates listed and all patients undergoing transplantation in region 6 between May 4, 2003, and May 4, 2006. Each data set was divided into two cohorts: 2 years before LAS implementation, and 1 year after LAS implementation. LAS was calculated and compared by cohort. Pre-LAS and post-LAS differences in patient characteristics were examined. Waiting list and posttransplant survival rates for each cohort were examined using Kaplan-Meier estimates and Cox regression.After LAS implementation, the distribution of diagnoses in patients undergoing transplantation significantly changed (p = 0.02), while the distribution of diagnoses in those listed did not (p = 0.17). Characteristics of patients on the waiting list were similar, except that a higher proportion of nonwhite patients were listed (p = 0.04) and lower FVC (p0.001) was observed after LAS implementation. Similarly, characteristics of patients undergoing transplantation did not change, except that posttransplant hospital length of stay was shorter (p = 0.01) after LAS implementation. Calculated LAS was higher after LAS implementation (p = 0.006). After controlling for age and diagnosis, neither waiting list nor transplant survival was significantly different (p = 0.93 and p = 0.81, respectively).After LAS implementation, the distribution of diagnoses in lung transplant recipients was significantly changed, while that of candidates was not. Posttransplant and waiting list survival were not affected by the LAS system, but power was limited. Larger and long-term survival studies are needed to determine if the LAS system improves overall allocation and survival for patients interested in lung transplantation.

Pheochromocytoma is a notorious clinical entity. Although suspicion is aroused by severe hypertension in young patients, this sign is often absent. We present a case in which early absence of hypertension and nonspecific signs and symptoms led to failure of prompt diagnosis. The delay proved fatal when the patient developed fulminant pheochromocytoma crisis. This case illustrates a variety of clinical features seen from the vantage of the evolution of the disease as it went unrecognized. The patient's course underscores the importance of familiarity with the gamut of manifestations for timely diagnosis, and the priority of the latter given the looming risk of overwhelming complications.

Pulmonary alveolar microlithiasis (PAM) is characterized by deposition of calcium phosphate within the alveolar airspaces. There is currently no effective medical therapy and affected individuals may progress to end-stage lung disease requiring transplantation. Two patients with PAM underwent bilateral sequential lung transplantation. This study reviews the clinical manifestations of PAM and discusses the particular difficulties that may be encountered in the use of lung transplantation as treatment for this uncommon disease. Also addressed is the question of recurrence in the allograft.

Multiple conditions result in development of pulmonary hypertension. Pulmonary arterial hypertension (PAH) is the subclassification of pulmonary hypertension, in which known or unknown underlying conditions lead to similar intrinsic alterations in the pulmonary vasculature. PAH is a progressive condition characterized by restricted blood flow through the pulmonary circulation leading to poor survival in the absence of effective therapy. Over the last two decades, new therapeutic agents have substantially improved the course and prognosis for PAH patients. Three available classes of drugs, ie, prostacyclins, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors provide multiple options for treatment of PAH. Endothelin receptor antagonists and phosphodiesterase-5 inhibitors are administered orally, whereas prostacyclin therapies are delivered by continuous intravenous or subcutaneous infusion, or as aerosols by nebulization. Because of the risks and inconveniences associated with administration, prostacyclins are typically reserved for patients with more advanced disease or progression despite oral therapy. Inhaled administration may be a safer and easier route for prostacyclin administration. Treprostinil is a prostacyclin analog that has been demonstrated to be effective when administered by continuous subcutaneous or intravenous infusion, and more recently by nebulization.

with lymphangioleiomyomatosis. These patients may have spontaneous pneumothorax or chylothorax or may require evaluation of interstitial lung disease. Because of the rarity of this disease, the diagnosis of lymphangioleiomyomatosis may not always be considered by referring clinicians. Proper diagnosis may lead to significant alterations in patient management, and it is therefore important for thoracic surgeons to be familiar with this rare disease. We recently established a previously missed diagnosis of lymphangioleiomyomatosis in a 59-year-old woman who had a spontaneous chylothorax. Case report. The patient is a 59-year-old nonsmoking woman who had undergone hysterectomy and oophorectomy for uterine fibroid tumors at the age of 45 years and had since been receiving estrogen supplements. Six years before presentation to us she was admitted to an outside hospital with shortness of breath attributed to a significant left pleural effusion. The fluid was drained and reported to be chylous. A computed tomogram (CT) of the chest did not show any parenchymal abnormalities. The effusion did not recur, and further work-up was not pursued. In the interim, the patient had progressive dyspnea and was told she had emphysema. Pulmonary function tests showed severe obstruction unresponsive to bronchodilators, with normal lung volumes and a diffusion impairment. The patient became more symptomatic over the 3 weeks before admission to our thoracic surgery service. Chest x-ray films demonstrated a significant right pleural effusion and a diffuse interstitial pattern. A tube inserted in the right side of the chest drained 800 mL of milky fluid. A trial of thoracic duct embolization failed, and the patient continued to have 300 to 500 mL of chylous drainage daily. She remained dyspneic and hypoxemic. In the setting of a chylous effusion, increased interstitial markings, and airflow obstruction, the attending surgeon considered a diagnosis of lymphangioleiomyomatosis. A high-resolution CT scan showed diffuse cystic disease in both lung fields consistent with lymphangioleiomyomatosis (Fig 1). Talc pleurodesis was performed successfully. The estrogen supplement that she had been receiving was discontinued and progesterone therapy was initiated. After 1 year’s follow-up, the patient has stable lung function and no recurrence of the chylothorax. Discussion. Pulmonary lymphangioleiomyomatosis is a rare, idiopathic disease that most often affects women of reproductive age. The average age at presentation is 33 years.1 Postmenopausal presentation, as in this case, is rare 622 Brief communications The Journal of Thoracic and Cardiovascular Surgery March 2000

The PF group had a higher mortality rate while on the waiting list. Of those that were transplanted, LOS in ICU and LOS in hospital were significantly longer and overall morality rates were higher. Preoperatively the PF group received the greatest benefit from rehabilitative interventions that promoted symptom management. Postoperatively the rate of recovery for mobility and independence with self-care was slower than the other groups but the overall improvements in quality of life were similar at 1and 5 years. Conclusions: Observing trends in functional outcomes following lung transplantation can inform clinicians and patients considering the procedure about the potential clinical course. Our data indicates that PF patients ultimately achieve similar improvements in quality of life and other measures of function and mobility. While patients with PF benefit from transplant, their potential mortality pre and perioperatively is higher and their duration to recovery post-transplant is longer than other diagnostic groups.

Airway epithelial cells cultured at an air–liquid interface bear many hallmarks of in vivo cells and are used extensively to study the biology of the lung epithelium. Because miRNAs regulate many cellular functions, we postulated that miRNA profiling would provide an unbiased assessment of the effects of in vitro culturing. RNA was extracted from primary airway epithelial cells either immediately after cell procurement (in vivo condition) or after air–liquid interface culture was established (in vitro condition). We assessed 742 miRNAs and determined differential expression between in vivo and in vitro conditions. Air–liquid interface culturing of airway epithelial cells caused widespread changes in miRNA expression. A similarly extensive alteration in gene expression was observed in an independent set of publicly available microarray data. We integrated miRNA and gene expression results to identify culture-induced differences in transcriptional programs (including several involved in epithelial injury and repair). Air–liquid interface cultures are useful models for studying airway biology, but the present findings indicate that, despite phenotypic similarities with primary cells, these culture systems profoundly perturb miRNA and gene expression. Studies of lung epithelium based on in vitro culture should therefore be designed and interpreted with an appreciation of the limitations of air–liquid interface culture systems.

Other than lung transplantation (LT), no specific therapies exist for end-stage lung disease resulting from hematopoietic stem cell transplantation (HCT)-related complications, such as bronchiolitis obliterans syndrome (BOS). We report the indications and outcomes in patients who underwent LT after HCT for hematologic disease from a retrospective case series at our institution and a review of the medical literature. We identified a total of 70 cases of LT after HCT, including 9 allogeneic HCT recipients from our institution who underwent LT between 1990 and 2010. In our cohort, the median age was 16 years (range, 10 to 35 years) at the time of HCT and 34 years (range, 17 to 44 years) at the time of LT, with a median interval between HCT and LT of 10 years (range, 2.9 to 27 years). Indications for LT-included pulmonary fibrosis (n = 4), BOS (n = 3), interstitial pneumonitis related to graft-versus-host disease (GVHD) (n = 1), and primary pulmonary hypertension (n = 1). Median survival was 49 months (range, 2 weeks to 87 months), and 1 patient remains alive at more than 3 years after LT. Survival at 1 year and 5 years after LT was 89% and 37%, respectively. In the medical literature between 1992 and July 2013, we identified 20 articles describing 61 cases of LT after HCT from various centers in the United States, Europe, and Asia. Twenty-six of the 61 cases (43%) involved patients age