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Culture-independent study of the lower respiratory tract after lung transplantation has enabled an understanding of the microbiome – that is, the collection of bacteria, fungi, and viruses, and their respective gene complement – in this niche. The lung has unique features as a microbial environment, with balanced entry from the upper respiratory tract, clearance, and local replication. There are many pressures impacting the microbiome after transplantation, including donor allograft factors, recipient host factors such as underlying disease and ongoing exposure to the microbe-rich upper respiratory tract, and transplantation-related immunosuppression, antimicrobials, and post-surgical changes. To date, we understand that the lung microbiome after transplant is dysbiotic; that is, it has higher biomass and altered composition compared to a healthy lung. Emerging data suggest that specific microbiome features may be linked to host responses, both immune and non-immune, and clinical outcomes such as chronic lung allograft dysfunction (CLAD), but many questions remain. The goal of this review is to put into context our burgeoning understanding of the lung microbiome in the post-lung transplant patient, the interactions between microbiome and host, the role the microbiome may play in post-transplant complications, and critical outstanding research questions.

Primary graft dysfunction (PGD) is a form of acute lung injury after transplantation characterized by hypoxemia and the development of alveolar infiltrates on chest radiograph that occurs within 72 hours of reperfusion. PGD is among the most common early complications following lung transplantation and significantly contributes to increased short-term morbidity and mortality. In addition, severe PGD has been associated with higher 90-day and 1-year mortality rates compared with absent or less severe PGD and is a significant risk factor for the subsequent development of chronic lung allograft dysfunction. The International Society for Heart and Lung Transplantation released updated consensus guidelines in 2017, defining grade 3 PGD, the most severe form, by the presence of alveolar infiltrates and a ratio of PaO2:FiO2 less than 200. Multiple donor-related, recipient-related, and perioperative risk factors for PGD have been identified, many of which are potentially modifiable. Consistently identified risk factors include donor tobacco and alcohol use; increased recipient body mass index; recipient history of pulmonary hypertension, sarcoidosis, or pulmonary fibrosis; single lung transplantation; and use of cardiopulmonary bypass, among others. Several cellular pathways have been implicated in the pathogenesis of PGD, thus presenting several possible therapeutic targets for preventing and treating PGD. Notably, use of ex vivo lung perfusion (EVLP) has become more widespread and offers a potential platform to safely investigate novel PGD treatments while expanding the lung donor pool. Even in the presence of significantly prolonged ischemic times, EVLP has not been associated with an increased risk for PGD.

Background Previous studies have reported similarities in long-term outcomes following lung transplantation for connective tissue disease-associated interstitial lung disease (CTD-ILD) and idiopathic pulmonary fibrosis (IPF). However, it is unknown whether CTD-ILD patients are at increased risk of primary graft dysfunction (PGD), delays in extubation, or longer index hospitalizations following transplant compared to IPF patients. Methods We performed a multicenter retrospective cohort study of CTD-ILD and IPF patients enrolled in the Lung Transplant Outcomes Group registry who underwent lung transplantation between 2012 and 2018. We utilized mixed effects logistic regression and stratified Cox proportional hazards regression to determine whether CTD-ILD was independently associated with increased risk for grade 3 PGD or delays in post-transplant extubation and hospital discharge compared to IPF. Results A total of 32.7% (33/101) of patients with CTD-ILD and 28.9% (145/501) of patients with IPF developed grade 3 PGD 48-72 hours after transplant. There were no significant differences in odds of grade 3 PGD among patients with CTD-ILD compared to those with IPF (adjusted OR 1.12, 95% CI 0.64-1.97, p = 0.69), nor was CTD-ILD independently associated with a longer post-transplant time to extubation (adjusted HR for first extubation 0.87, 95% CI 0.66-1.13, p = 0.30). However, CTD-ILD was independently associated with a longer post-transplant hospital length of stay (median 23 days [IQR 14-35 days] vs17 days [IQR 12-28 days], adjusted HR for hospital discharge 0.68, 95% CI 0.51-0.90, p = 0.008). Conclusion Patients with CTD-ILD experienced significantly longer postoperative hospitalizations compared to IPF patients without an increased risk of grade 3 PGD.

In November 2017, the donation service area (DSA) was removed as the primary unit of US donor lung allocation. Our primary objective was to evaluate the effect of this change on recipient characteristics, the use of pretransplant extracorporeal membrane oxygenation (ECMO), and on index hospitalization length of stay (LOS) and early posttransplant complications. We also assessed whether these outcomes differed in high and low competition centers, as defined by the Herfindahl-Hirschman Index. Following DSA removal, there was a 9-day decrease in median waitlist time (P = .001) and an increase in median lung allocation score (40 vs 42, P

Introduction: Lung transplantation remains an important treatment for patients with end stage lung disease. Chronic lung allograft dysfunction (CLAD) remains the greatest limiting factor for long term survival. As the diagnosis of CLAD is based on pulmonary function tests, significant lung injury is required before a diagnosis is feasible, likely when irreversible damage has already occurred. Therefore, research is ongoing for early CLAD recognition, with biomarkers making up a substantial amount of this research.Areas covered: The purpose of this review is to describe available biomarkers, focusing on those which aid in predicting CLAD and distinguishing between different CLAD phenotypes. We describe biomarkers presenting in bronchial alveolar lavage (BAL) as well as circulating in peripheral blood, both of which offer an appealing alternative to lung biopsy.Expert opinion: Development of CLAD involves complex, multiple immune and nonimmune mechanisms. Therefore, evaluation of potential CLAD biomarkers serves a dual purpose: clinically, the goal remains early detection and identification of patients at increased risk. Simultaneously, biomarkers offer insight into the different mechanisms involved in the pathophysiology of CLAD, leading to the development of possible interventions. The ultimate goal is the development of both preventive and early intervention strategies for CLAD to improve the overall survival of our lung transplant recipients.

Rationale: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation, but the immunologic mechanisms are poorly understood. Innate lymphoid cells (ILC) are a heterogeneous family of immune cells regulating pathologic inflammation and beneficial tissue repair. However, whether changes in donor-derived lung ILC populations are associated with PGD development has never been examined.Objectives: To determine whether PGD in chronic obstructive pulmonary disease or interstitial lung disease transplant recipients is associated with alterations in ILC subset composition within the allograft.Methods: We performed a single-center cohort study of lung transplantation patients with surgical biopsies of donor tissue taken before, and immediately after, allograft reperfusion. Donor immune cells from 18 patients were characterized phenotypically by flow cytometry for single-cell resolution of distinct ILC subsets. Changes in the percentage of ILC subsets with reperfusion or PGD (grade 3 within 72 h) were assessed.Measurements and Main Results: Allograft reperfusion resulted in significantly decreased frequencies of natural killer cells and a trend toward reduced ILC populations, regardless of diagnosis (interstitial lung disease or chronic obstructive pulmonary disease). Seven patients developed PGD (38.9%), and PGD development was associated with selective reduction of the ILC2 subset after reperfusion. Conversely, patients without PGD exhibited significantly higher ILC1 frequencies before reperfusion, accompanied by elevated ILC2 frequencies after allograft reperfusion.Conclusions: The composition of donor ILC subsets is altered after allograft reperfusion and is associated with PGD development, suggesting that ILCs may be involved in regulating lung injury in lung transplant recipients.

It is unknown whether some donor specific antibodies (DSA) can be crossed at the time of lung transplant without desensitization or augmented induction immunosuppression. This study assessed whether crossing low-level pre-transplant DSA (defined as mean fluorescence intensity (MFI) 1000-6000) without augmented immunosuppression is associated with worse retransplant-free or chronic lung allograft dysfunction (CLAD)-free survival. Of the 458 included recipients, low-level pre-transplant DSA was crossed in 39 (8.6%) patients. The median follow-up time was 2.2 years. There were 15 (38.5%) patients with Class I DSA and 24 (61.5%) with Class II DSA. There was no difference in adjusted overall retransplant-free survival between recipients where pre-transplant DSA was and was not crossed (HR: 0.98 (95% CI = 0.49-1.99), p = 0.96). There was also no difference in CLAD-free survival (HR: 0.71 (95% CI = 0.38-1.33), p = 0.28). There was no difference in Grade 3 PGD at 72 hours (OR: 1.13 (95% CI = 0.52-2.48), p = 0.75) or definite or probable AMR (HR: 2.22 (95% CI = 0.64-7.61), p = 0.21). Lung transplantation in the presence of low-level DSA without planned augmented immunosuppression is not associated with worse overall or CLAD-free survival among recipients with intermediate-term follow-up. This article is protected by copyright. All rights reserved.

Rationale: Sarcopenia is associated with disability and death. The optimal definition and clinical relevance of sarcopenia in lung transplantation remain unknown. Objectives: To assess the construct and predictive validity of sarcopenia definitions in lung transplant candidates. Methods: In a multicenter prospective cohort of 424 lung transplant candidates, we evaluated limited (muscle mass only) and expanded (muscle mass and quality) sarcopenia definitions from the European Working Group on Sarcopenia in Older People 2 (EWGSOP2), the Foundation for the National Institutes of Health (FNIH), and a cohort-specific distribution-based lowest quartile definition. We assessed construct validity using associations with conceptually related factors. We evaluated the relationship between sarcopenia and frailty using generalized additive models. We also evaluated associations between sarcopenia definitions and key pretransplant outcomes, including disability (quantified by the Lung Transplant Valued Life Activities scale [range, 0–3; higher scores = worse disability; minimally important difference, 0.3]) and waitlist delisting/death, by multivariate linear and Cox regression, respectively. Results: Sarcopenia prevalence ranged from 6% to13% by definition used. The limited EWGSOP2 definition demonstrated the highest construct validity, followed by the expanded EWGSOP2 definition and both limited and expanded FNIH and lowest quartile definitions. Sarcopenia exhibited a linear association with the risk of frailty. The EWGSOP2 and expanded lowest quartile definitions were associated with disability, ranging from 0.20 to 0.25 higher Lung Transplant Valued Life Activities scores. Sarcopenia was associated with increased risk of waitlist delisting or death by the limited and expanded lowest quartile definitions (hazard ratio [HR], 3.8; 95% confidence interval [CI], 1.4–9.9 and HR, 3.5; 95% CI, 1.1–11.0, respectively) and the EWGSOP2 limited definition (HR, 2.8; 95% CI, 0.9–8.6) but not with the three other candidate definitions. Conclusions: The prevalence and validity of sarcopenia vary by definition; the EWGSOP2 limited definition exhibited the broadest validity in lung transplant candidates. The linear relationship between low muscle mass and frailty highlights sarcopenia’s contribution to frailty and also questions the clinical utility of a sarcopenia cut-point in advanced lung disease. The associations between sarcopenia and important pretransplant outcomes support further investigation into using body composition for candidate risk stratification.

The care of lung transplant recipients with prolonged index hospitalizations can be ethically complex, with conflicts arising over whether the expected outcomes justify ongoing intensive interventions. There are limited data to guide these conversations. The objective of this study was to evaluate survival to discharge for lung transplant recipients based on length of stay (LOS). This was a retrospective cohort study of adult lung transplant recipients in the Scientific Registry of Transplant Recipients. For each day of the index hospitalization the mortality rate among patients who survived to that length of stay or longer was calculated. Post-discharge survival was compared in those with and without a prolonged hospitalization (defined as the 97th percentile [>90 days]). Among the 19 250 included recipients, the index hospitalization mortality was 5.4%. Posttransplant stroke and need for dialysis were the strongest predictors of index hospitalization mortality. No individual or combination of available risk factors, however, was associated with inpatient mortality consistently above 50%. Recipients with >90 day index hospitalization had a 28.8% subsequent inpatient mortality. Their 1, 3 and 5 year survival following discharge was 53%, 26%, and 16%. These data provide additional context to goals of care conversations for transplant recipients with prolonged index hospitalizations.

We evaluated the feasibility, safety, and efficacy of a mHealth-supported physical rehabilitation intervention to treat frailty in a pilot study of 18 lung transplant recipients. Frail recipients were defined by a short physical performance battery (SPPB score ≤7). The primary intervention modality was Aidcube, a customizable rehabilitation mHealth platform. Our primary aims included tolerability, feasibility, and acceptability of use of the platform, and secondary outcomes were changes in SPPB and in scores of physical activity, and disability measured using the Duke Activity Status Index (DASI) and Lung Transplant-Value Life Activities (LT-VLA). Notably, no adverse events were reported. Subjects reported the app was easy to use, usability improved over time, and the app enhanced motivation to engage in rehabilitation. Comments highlighted the complexities of immediate post-transplant rehabilitation, including functional decline, pain, tremor, and fatigue. At the end of the intervention, SPPB scores improved a median of 5 points from a baseline of 4. Physical activity and patient-reported disability also improved. The DASI improved from 4.5 to 19.8 and LT-VLA score improved from 2 to 0.59 at closeout. Overall, utilization of a mHealth rehabilitation platform was safe and well received. Remote rehabilitation was associated with improvements in frailty, physical activity and disability. Future studies should evaluate mHealth treatment modalities in larger-scale randomized trials of lung transplant recipients.

Many lung transplant candidates and recipients are older and frailer compared to previous eras. Older patients are at increased risk for pre- and post-transplant mortality, but this risk is not explained by numerical age alone. This manuscript represents the product of the American Society of Transplantation (AST) conference on frailty. Experts in the field reviewed the latest published research on assessment of elderly and frail lung transplant candidates. Physical frailty, often defined as slowness, weakness, low physical activity, shrinking, and exhaustion, and frailty evaluation is an important tool for evaluation of age-associated dysfunction. Another approach is assessment by cumulative deficits, and both types of frailty are common in lung transplant candidates. Frailty is associated with death or delisting before transplant, and may be associated with post-transplant mortality. Sarcopenia, cognitive dysfunction, depression, and nutrition are other important components for patient evaluation. Aging-associated inflammation, telomere dysfunction, and adaptive immune system senescence may also contribute to frailty. Developing tools for frailty assessment and interventions holds promise for improving patient outcomes before and after lung transplantation.

Cystic fibrosis (CF) is the indication for transplantation in approximately 15% of recipients worldwide, and Cystic Fibrosis Lung Transplant Recipients (CFLTRs) have excellent long-term outcomes. Yet, CFLTRs have unique comorbidities that require specialized care. The objective of this document is to provide recommendations to CF and lung transplant clinicians for the management of perioperative and underlying comorbidities of CFLTRs and the impact of transplantation on these comorbidities. The Cystic Fibrosis Foundation (CFF) organized a multidisciplinary committee to develop CF Lung Transplant Clinical Care Recommendations. Three workgroups were formed to develop focused questions. Following a literature search, consensus recommendations were developed by the committee members based on literature review, committee experience and iterative revisions, and in response to public comment. The committee formulated 32 recommendation statements in the topics related to infectious disease, endocrine, gastroenterology, pharmacology, mental health and family planning. Broadly, the committee recommends close coordination of care between the lung transplant team, the cystic fibrosis care center, and specialists in other disciplines with experience in the care of CF and lung transplant recipients. These consensus statements will help lung transplant providers care for CFLTRs in order to improve post-transplant outcomes in this population.

INTRODUCTION Donor‒recipient HLA-DR locus matching may be protective against bronchiolitis obliterans syndrome (BOS) in lung transplant recipients. It is unknown whether this benefit is more significant among sensitized (calculated panel reactive antibodies (CPRAs) of >0%) and highly sensitized (CPRAs of ≥80%) recipients who may be at a higher risk for BOS. METHODS This was a retrospective cohort study of adults in the Scientific Registry of Transplant Recipients who underwent lung transplantation between May 5, 2005 and May 31, 2019. Retransplant-free survival and BOS-free survival were compared among recipients with 0 vs ≥1 DR mismatches, grouped according to sensitization. RESULTS Among all 20,355 included recipients, 0 DR mismatch status was associated with improved retransplant-free survival (hazard ratio [HR] = 0.83, 95% CI = 0.74–0.93, p = 0.002) and BOS-free survival (HR = 0.86, 95% CI = 0.77–0.96, p = 0.007). Among sensitized recipients, 0 DR mismatch status was also associated with improved retransplant-free survival (HR = 0.79, 95% CI = 0.65–0.97, p = 0.02) and BOS-free survival (HR = 0.82, 95% CI = 0.67–1.00, p = 0.04). There was however no difference in retransplant-free or BOS-free survival between sensitized and non-sensitized recipients with 0 DR mismatches. Among highly sensitized recipients, 0 DR mismatch status was not associated with retransplant-free or BOS-free survival. Among sensitized and highly sensitized recipients, 0 DR mismatch status was not associated with reduced use of plasmapheresis or reduced biopsy-proven, treated acute cellular rejection compared with non-sensitized recipients. CONCLUSIONS HLA-DR matching is associated with a similar improvement in retransplant-free and BOS-free survival among non-sensitized and sensitized lung transplant recipients. DR matching does not confer a more substantial retransplant-free or BOS-free survival benefit to highly sensitized recipients than to non-sensitized recipients.

INTRODUCTION One-year post-transplant survival is a significant quality measure for solid organ transplant programs in the United States. It is not known whether the use of this metric is associated with changes in life-sustaining clinical practices that would delay mortality for solid organ recipients until just beyond the one-year time point. METHODS We compared trends in mortality in the time period immediately preceding the one-year post-transplant mark compared to the period immediately after using second-order Cox proportional hazard regression models. RESULTS Among recipients of heart, liver, and lung transplantation, mortality did not decrease significantly in the period immediately before day 365 or increase in the 14 days thereafter. There was an increased adjusted hazard of mortality in the 30 days following day 365 among lung transplant recipients (HR 1.33, 95% CI 1.03-1.72, P = .03) with a 0.76% absolute mortality rate (94 deaths) in month 12 following lung transplantation and a 1.14% absolute mortality rate in month 13 (113 deaths). CONCLUSION Although we did not find evidence that life-sustaining treatment is routinely continued until just beyond the one-year mark in heart and liver transplantation recipients, there was an unexpected increased risk of mortality in the 30 days following day 365 among lung transplant recipients.

Lung transplantation provides the prospect of improved survival and quality of life for patients with end stage lung and pulmonary vascular diseases. Given the severity of illness of such patients at the time of surgery, lung transplant recipients require particular attention in the immediate post-operative period to ensure optimal short-term and long-term outcomes. The management of such patients involves active involvement of a multidisciplinary team versed in common post-operative complications. This review provides an overview of such complications as they pertain to the practitioners caring for post-operative lung transplant recipients. Causes and treatment of conditions affecting early morbidity and mortality in lung transplant recipients will be detailed, including primary graft dysfunction, cardiovascular and surgical complications, and immunologic and infectious issues. Additionally, lung donor management issues and bridging the critically ill potential lung transplant recipient to transplantation will be discussed.

The lung allocation score system in the United States and several European countries gives more weight to risk of death without transplantation than to survival following transplantation. As a result, centers transplant sicker patients, leading to increased length of initial hospitalization. The care of patients who have accumulated functional deficits or additional organ dysfunction during their prolonged stay can be ethically complex. Disagreement occurs between the transplant team, patients and families, and non-transplant health care professionals over the burdens of ongoing intensive intervention. These cases highlight important ethical issues in organ transplantation, including the nature and requirements of transplant informed consent, the limits of physician prognostication, patient autonomy and decision-making capacity following transplant, obligations to organ donors and to other potential recipients, and the impact of program metrics on individualized recipient care. We outline general ethical principles for the care of lung transplant recipients with prolonged hospitalization and give regulatory, research, and patient-centered recommendations for these cases.

CT measurement of body composition may improve lung transplant candidate selection. We assessed whether skeletal muscle adipose deposition on abdominal and thigh CT scans was associated with 6 min walk distance (6MWD) and wait-list survival in lung transplant candidates. Each ½-SD decrease in abdominal muscle attenuation (indicating greater lipid content) was associated with 14 m decrease in 6MWD (95% CI −20 to −8) and 20% increased risk of death or delisting (95% CI 10% to 40%). Each ½-standard deviation decrease in thigh muscle attenuation was associated with 15 m decrease in 6MWD (95% CI −21 to −10). CT imaging may improve candidate risk stratification.

Objective Factors associated with favorable outcome after stereotactic radiosurgery (SRS) for dural arteriovenous fistulas (DAVFs) with cortical venous reflux (CVR) are not completely understood. The aim of this retrospective cohort study was to assess the outcomes after SRS for high-grade DAVFs and identify predictors. Methods We performed a retrospective review of consecutive patients with high-grade DAVFs, defined as the presence of CVR, who underwent SRS between 1989 and 2017. The primary outcome was defined as DAVF obliteration without a new permanent neurologic deficit. Predictors of outcomes were determined using multivariate logistic regression. Results The study cohort was composed of 41 high-grade DAVF patients with a mean age of 52 years. DAVF obliteration without a new permanent neurologic deficit was achieved in 62% of patients (13/21). The rates of complete obliteration and new permanent neurologic deficit were 63% (17/27) and 23% (7/30) of patients, respectively. No independent predictors of the primary outcome or angiographic obliteration were identified in the multivariate model. Presentation with a nonhemorrhagic neurologic deficit (NHND) was found to be an independent predictor of a new permanent neurologic deficit after SRS (odds ratio, 14.176; 95% confidence interval, 1.119–179.540; P = 0.041). Conclusions Obliteration without a new permanent neurologic deficit can be achieved in most appropriately selected patients with high-grade DAVFs after treatment with SRS. NHND at presentation is a risk factor for new permanent neurologic deficit after SRS.

The presence of preexisting (memory) or de novo donor-specific HLA antibodies (DSAs) is a known barrier to successful long-term organ transplantation. Yet, despite the fact that laboratory tools and our understanding of histocompatibility have advanced significantly in recent years, the criteria to define presence of a DSA and assign a level of risk for a given DSA vary markedly between centers. A collaborative effort between the American Society for Histocompatibility and Immunogenetics and the American Society of Transplantation provided the logistical support for generating a dedicated multidisciplinary working group, which included experts in histocompatibility as well as kidney, liver, heart, and lung transplantation. The goals were to perform a critical review of biologically driven, state-of-the-art, clinical diagnostics literature and to provide clinical practice recommendations based on expert assessment of quality and strength of evidence. The results of the Sensitization in Transplantation: Assessment of Risk (STAR) meeting are summarized here, providing recommendations on the definition and utilization of HLA diagnostic testing, and a framework for clinical assessment of risk for a memory or a primary alloimmune response. The definitions, recommendations, risk framework, and highlighted gaps in knowledge are intended to spur research that will inform the next STAR Working Group meeting in 2019.

BACKGROUND: Delirium significantly affects postoperative outcomes, but the incidence, risk factors and the long-term impact of delirium in lung transplant recipients have not been well studied. METHODS: We analyzed 155 lung transplant recipients enrolled in the Lung Transplant Outcomes Group (LTOG) cohort at a single center. We determined delirium incidence by structured chart review, identified risk factors for delirium, determined if plasma concentrations of two cerebral injury markers (neuron specific enolase [NSE] and glial fibrillary acidic protein [GFAP]) were associated with delirium, and determined the association of postoperative delirium with 1-year survival. RESULTS: Fifty-seven (36.8%) patients developed postoperative delirium. Independent risk factors for delirium included pre-transplant benzodiazepine prescription (relative risk [RR] 1.82; 95% confidence interval [CI]: 1.08, 3.07; p = 0.025), total ischemic time (RR 1.10 per 30 minute increase; 95% CI: 1.01, 1.21; p = 0.027), duration of time with intraoperative mean arterial pressure

Background Unplanned rehospitalizations (UR) within 30 days of discharge are common after lung transplantation. It is unknown whether UR represents preventable gaps in care or necessary interventions for complex patients. The objective of this study was to assess the incidence, causes, risk factors, and preventability of UR after initial discharge after lung transplantation. Methods This was a single-center prospective cohort study. Subjects completed a modified short physical performance battery to assess frailty at listing and at initial hospital discharge after transplantation and the State-Trait Anxiety Inventory at discharge. For each UR, a study staff member and the patient's admitting or attending clinician used an ordinal scale (0, not; 1, possibly; 2, definitely preventable) to rate readmission preventability. A total sum score of 2 or higher defined a preventable UR. Results Of the 90 enrolled patients, 30 (33.3%) had an UR. The single most common reasons were infection (7 [23.3%]) and atrial tachyarrhythmia (5 [16.7%]). Among the 30 URs, 9 (30.0%) were deemed preventable. Unplanned rehospitalization that happened before day 30 were more likely to be considered preventable than those between days 30 and 90 (30.0% versus 6.2%, P = 0.04). Discharge frailty, defined as short physical performance battery less than 6, was the only variable associated with UR on multivariable analysis (odds ratio, 3.4; 95% confidence interval, 1.1-11.8; P = 0.04). Conclusions Although clinicians do not rate the majority of UR after lung transplant as preventable, discharge frailty is associated with UR. Further research should identify whether modification of discharge frailty can reduce UR.

Primary graft dysfunction (PGD) is a form of acute lung injury that results from ischemia reperfusion injury (IRI) and is the major cause of early posttransplant morbidity and mortality. Patients who survive PGD have decreased quality of life, an increased risk of chronic lung allograft dysfunction, specifically bronchiolitis obliterans syndrome, and a significantly increased risk of death. In 2017, the International Society for Heart and Lung Transplantation released updated consensus statements on the PGD definition, most up-to-date PGD risk factors, mechanisms of PGD development, and the state-of-the-art for PGD therapeutics. Risk factor identification has led to the development of PGD predictive algorithms, although their clinical utility remains limited. Ongoing areas of controversy and discussion include further refinements to the PGD grading scheme to account for technologic advances such as extracorporeal membrane oxygenation and the increased utilization of high flow nasal cannula, the use of PGD as an outcome measure in clinical trials of ex vivo lung perfusion, enhancement of predictive algorithms incorporating biochemical risk factors, and the need for development of therapies targeted at improving PGD outcomes.

Primary graft dysfunction (PGD) is a form of acute lung injury that occurs after lung transplantation. The definition of PGD was standardized in 2005. Since that time, clinical practice has evolved, and this definition is increasingly used as a primary endpoint for clinical trials; therefore, validation is warranted.We sought to determine whether refinements to the 2005 consensus definition could further improve construct validity.Data from the Lung Transplant Outcomes Group multicenter cohort were used to compare variations on the PGD definition, including alternate oxygenation thresholds, inclusion of additional severity groups, and effects of procedure type and mechanical ventilation. Convergent and divergent validity were compared for mortality prediction and concurrent lung injury biomarker discrimination.A total of 1,179 subjects from 10 centers were enrolled from 2007 to 2012. Median length of follow-up was 4 years (interquartile range = 2.4-5.9). No mortality differences were noted between no PGD (grade 0) and mild PGD (grade 1). Significantly better mortality discrimination was evident for all definitions using later time points (48, 72, or 48-72 hours; P 0.001). Biomarker divergent discrimination was superior when collapsing grades 0 and 1. Additional severity grades, use of mechanical ventilation, and transplant procedure type had minimal or no effect on mortality or biomarker discrimination.The PGD consensus definition can be simplified by combining lower PGD grades. Construct validity of grading was present regardless of transplant procedure type or use of mechanical ventilation. Additional severity categories had minimal impact on mortality or biomarker discrimination.

Purpose Lung transplant recipients with pre-transplant donor specific antibodies (DSA) are often treated with augmented immunosuppression. It is unknown whether some DSA can be safely crossed without additional therapies. We implemented a protocol allowing transplant when crossing select low level DSA (defined as mean fluorescence intensity (MFI) 1000-5000) without planned augmented immunosuppression. Methods This was a single center retrospective cohort study between 4/1/2015-8/31/2020. All recipients received solumedrol and basiliximab induction without desensitization. Presence of low level pre-transplant DSA was recorded. All post-transplant DSA was monitored within 14 days of transplant and then at routine intervals. The primary study outcomes were overall survival, definite CLAD≥1-free survival, and definite antibody mediated rejection (AMR), all defined according to ISHLT consensus guidelines. Results Of the 453 recipients, 36 (7.9%) had a low-level pre-transplant DSA crossed at transplant (Table 1). 13 had Class I antibodies and 26 had Class II. The median historical DSA MFI was 1800 (IQR 1300-2400) and the median most recent MFI was 1200 (IQR 950-2000). Among recipients where pre-transplant DSA was crossed, 17 (47.2%) had persistent post-transplant DSA with a median peak MFI of 7400. Class II antibodies were more likely to be detected post-transplant than Class I (57.7% vs 15.4%, p=0.02). There was no statistical difference in definite AMR in recipients where pre-transplant DSA was and was not crossed (8.3% vs 3.1%, p=0.11). With a median follow-up time of 2.4 years, there were no differences in adjusted overall survival (HR=1.14, 95% CI=0.57-2.32, p=0.71) or CLAD≥1-free survival (HR=0.82, 95% CI=0.44-1.54, p=0.54). Conclusion Lung transplantation in the presence of low level DSA without planned augmented immunosuppression was not associated with worse overall or CLAD-free intermediate-term survival but may be associated with increased AMR.

Pulmonary hypertension from pulmonary arterial hypertension or parenchymal lung disease is associated with an increased risk for primary graft dysfunction after lung transplantation.We evaluated the clinical determinants of severe primary graft dysfunction in pulmonary hypertension and developed and validated a prognostic model.We conducted a retrospective cohort study of patients in the multicenter Lung Transplant Outcomes Group with pulmonary hypertension at transplant listing. Severe primary graft dysfunction was defined as PaIn the explanatory model of 826 patients with pulmonary hypertension, donor tobacco smoke exposure, higher recipient body mass index, female sex, listing mean pulmonary artery pressure, right atrial pressure and creatinine at transplant, cardiopulmonary bypass use, transfusion volume, and reperfusion fraction of inspired oxygen were associated with primary graft dysfunction. Donor obesity was associated with a lower risk for primary graft dysfunction. Using a 20% threshold for elevated risk, the prognostic model had good negative predictive value in both derivation and validation cohorts (89.1% [95% confidence interval, 85.3-92.8] and 83.3% [95% confidence interval, 78.5-88.2], respectively), but low positive predictive value.Several recipient, donor, and operative characteristics were associated with severe primary graft dysfunction in patients with pulmonary hypertension, including several risk factors not identified in the overall transplant population. A prognostic model with donor and recipient clinical risk factors alone had low positive predictive value, but high negative predictive value, to rule out high risk for primary graft dysfunction.

Background Extracellular microvesicles (EVs) are being increasingly studied for their diagnostic potential. We investigated the feasibility of studying the kinetics and tissue-specific profiles of pulmonary EVs in the context of ex vivo lung perfusion (EVLP) used for salvaging marginal lungs for transplantation. Methods Perfusate from six marginal donor lungs placed on EVLP was collected at the following time points: 0, 10, and 60 minutes after and after perfusate exchange with Steen Solution; 120 and 180 minutes. Three lungs were successfully recovered for transplantation (transplant group), and three were not recoverable (nontransplant group). Perfusate EVs were isolated using methods of size exclusion chromatography, ultrafiltration, and ultracentrifugation. EVs were analyzed on NanoSight nanoparticle detector for quantity, size distribution, and surface expression of pulmonary tissue-specific markers. EV cargoes were profiled using mass spectrometry, reverse transcription polymerase chain reaction (RT-PCR), and Western blot analysis. Results Time course analysis showed EV presence by 10-minute time point. EV median size was smaller in the transplant group (165 nm versus 212 nm, p = 0.04). EV cargo analysis on Western blot analysis, RT-PCR, and NanoSight showed contribution from monocytes (CD14), endothelium (platelet endothelial cell adhesion molecule 1), and pulmonary parenchyma (epithelial cell adhesion molecule) into the perfusate total EV pool. Mass spectrometry showed differences in the EV protein cargoes of the transplant group versus the nontransplant group. Conclusions EVLP system provides a platform to understand the kinetics of pulmonary EVs in an isolated fashion. Donor lung recovery may be associated with changes in EV size distribution and proteomic profiles. Pulmonary tissue-specific EV profiling using the EVLP system may provide insights into EV contribution to pulmonary pathologic processes.

Primary graft dysfunction (PGD) is a principal cause of early morbidity and mortality after lung transplantation, but its pathogenic mechanisms are not fully clarified. To date, studies using standard clinical assays have not linked microbial factors to PGD. We previously used comprehensive metagenomic methods to characterize viruses in lung allografts >1 mo after transplant and found that levels of Anellovirus, mainly torque teno viruses (TTVs), were significantly higher than in nontransplanted healthy controls. We used quantitative polymerase chain reaction to analyze TTV and shotgun metagenomics to characterize full viral communities in acellular bronchoalveolar lavage from donor organs and postreperfusion allografts in PGD and non-PGD lung transplant recipient pairs. Unexpectedly, TTV DNA levels were elevated 100-fold in donor lungs compared with healthy adults (p = 0.0026). Although absolute TTV levels did not differ by PGD status, PGD cases showed a smaller increase in TTV levels from before to after transplant than did control recipients (p = 0.041). Metagenomic sequencing revealed mainly TTV and bacteriophages of respiratory tract bacteria, but no viral taxa distinguished PGD cases from controls. These findings suggest that conditions associated with brain death promote TTV replication and that greater immune activation or tissue injury associated with PGD may restrict TTV abundance in the lung.

Obesity is a risk factor for primary graft dysfunction (PGD), a form of lung injury resulting from ischemia-reperfusion after lung transplantation, but the impact of ischemia-reperfusion on adipose tissue is unknown. We evaluated differential gene expression in thoracic visceral adipose tissue (VAT) before and after lung reperfusion. Total RNA was isolated from thoracic VAT sampled from six subjects enrolled in the Lung Transplant Body Composition study before and after allograft reperfusion and quantified using the Human Gene 2.0 ST array. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed enrichment for genes involved in complement and coagulation cascades and Jak-STAT signaling pathways. Overall, 72 genes were upregulated and 56 genes were downregulated in the postreperfusion time compared with baseline. Long pentraxin-3, a gene and plasma protein previously associated with PGD, was the most upregulated gene (19.5-fold increase, p = 0.04). Fibronectin leucine-rich transmembrane protein-3, a gene associated with cell adhesion and receptor signaling, was the most downregulated gene (4.3-fold decrease, p = 0.04). Ischemia-reperfusion has a demonstrable impact on gene expression in visceral adipose tissue in our pilot study of nonobese, non-PGD lung transplant recipients. Future evaluation will focus on differential adipose tissue gene expression and the development of PGD after transplant.

Purpose ECMO is increasingly used for bridging and salvage therapies in lung transplantation, with favorable short-term results. Mid- to long-term outcomes of ECMO use for bridging and salvage are incompletely understood, as is effect on PGD risk; therefore, we sought to define the effects of these strategies on mortality and PGD. Methods The Lung Transplant Outcomes Group study is a multi-center prospective cohort study designed to identify risk factors for PGD and mortality. Patients were enrolled from August 2011 to June 2018. The effect of pre-operative (bridging) and post-operative (salvage) ECMO on Grade 3 PGD incidence and long-term survival were assessed using time-to-event analyses adjusted for center. Results 1,537 subjects were enrolled with a 17.0% incidence of PGD on day 3 and an 18.9% mortality overall. PGD was associated with mortality (p=0.0001, Fig. 1a). ECMO bridging and salvage strategies increased over time (Fig. 1b). 138 (9%) subjects had bridging ECMO and 275 (17.9%) had salvage ECMO. PGD was associated with bridging strategies (p=0.001). PGD incidence in bridged patients (50.7%) exceeded non-bridged (42.2%). Bridging was not associated with mortality overall (p=0.70, Fig. 1c); however, if PGD developed after transplant using a bridging strategy, there was a significant increase in mortality (HR 1.8 [1.3; 2.61]; p=0.0007). About 45% of patients bridged with ECMO required salvage after transplant. ECMO use for salvage was highly associated with mortality (HR 2.1 [1.6; 2.8]; p Conclusion Use of the ISHLT Revised definition identifies Grade 3 PGD as highly associated with mortality in the ECMO bridging and salvage era. ECMO use is increasing for both bridging and salvage strategies. ECMO bridging strategies do not seem to increase mortality in lung transplant patients unless Grade 3 PGD subsequently develops. ECMO salvage after transplant is associated with increased risk of mortality; however, it is likely used only in the severest cases, thus indication bias is likely present.

Tacrolimus exhibits unpredictable pharmacokinetics (PKs) after lung transplant, partly explained by cytochrome P450 (CYP)-enzyme polymorphisms. However, whether exposure variability during the immediate postoperative period affects outcomes is unknown, and pharmacogenetic dosing may be limited by residual PK variability. We estimated adjusted associations between early postoperative tacrolimus concentrations and acute kidney injury (AKI) and acute cellular rejection (ACR), and identified clinical and pharmacogenetic factors that explain postoperative tacrolimus concentration variability in 484 lung transplant patients. Increasing tacrolimus concentration was associated with higher AKI risk (hazard ratio (HR) 1.54; 95% confidence interval (CI) 1.20-1.96 per 5-mg/dL); and increasing AKI severity (odds ratio 1.29; 95% CI 1.04-1.60 per 5-mg/dL), but not ACR (HR 1.02; 95% CI 0.73-1.42). A model with clinical and pharmacogenetic factors explained 42% of concentration variance compared with 19% for pharmacogenetic factors only. Early tacrolimus exposure was independently associated with AKI after lung transplantation, but not ACR. Clinical factors accounted for substantial residual tacrolimus concentration variability not explained by CYP-enzyme polymorphisms.

Rationale: The oropharyngeal microbiome is a primary source of lung microbiota, contributes to lower respiratory infection, and is also a driver of oral health. Objectives: We sought to understand oropharyngeal microbial communities in advanced lung disease, community dynamics after lung transplantation, and ecological features of dysbiosis. Methods: Oropharyngeal wash samples were obtained from individuals with end-stage disease awaiting transplantation (n = 22) and longitudinally from individuals at 6 weeks, 3 months, and 6 months after transplantation (n = 33), along with healthy control subjects (n = 14). Bacterial 16S and fungal internal transcribed spacer rRNA regions were deep-sequenced, and bacterial community respiratory patterns were imputed from taxonomic composition. Results: Healthy subjects’ oropharyngeal microbiomes showed a gradient of community types reflecting relative enrichment of strictly anaerobic, aerobic, or facultative anaerobic bacteria. Patients with end-stage lung disease showed severe dysbiosis by both taxonomic composition and respiration phenotypes, with reduced richness and diversity, increased facultative and decreased aerobic bacteria, and absence of communities characterized by obligate aerobes. In patients at 6 weeks and 3 months post-transplant, richness and diversity were intermediate between healthy and pretransplant subjects, with near-normal distribution of community types. However, by 6 months post-transplant, oropharyngeal wash resembled the low-diversity facultative-dominated profile of pretransplant subjects. Community ecotype correlated with Candida abundance. Conclusions: End-stage lung disease is associated with marked upper respiratory tract dysbiosis involving both community structure and respiratory metabolism profiles of constituent bacteria. Dynamic changes occur after lung transplantation, with partial normalization early but later appearance of severe dysbiosis similar to pretransplant patients. Aberrant oropharyngeal communities may predispose to abnormal lung microbiota and infection risk both in advanced lung disease and after transplantation.

Background Prior studies of post-lung transplant acute kidney injury (AKI) have not accounted for confounding effects of primary graft dysfunction (PGD). We sought to test the impact of PGD on AKI risk factors and on the association of AKI with mortality. Methods We included patients transplanted at the University of Pennsylvania from 2005-12, defined AKI using consensus criteria during transplant hospitalization, and defined PGD as grade 3 at 48-72 hours. We used multivariable logistic regression to test the impact of PGD on AKI risk factors and Cox models to test association of AKI with one-year mortality adjusting for PGD and other confounders. Results Of 299 patients, 188 (62.9%) developed AKI with 142 (75%) cases occurring by postoperative day 4. In multivariable models, PGD was strongly associated with AKI (OR 3.76, 95% CI 1.72-8.19, P = .001) but minimally changed associations of other risk factors with AKI. Both AKI (HR 3.64, 95% CI 1.68-7.88, P = .001) and PGD (HR 2.55, 95% CI 1.40-4.64, P = .002) were independently associated with one-year mortality. Conclusions Post-lung transplant AKI risk factors and association of AKI with mortality were independent of PGD. AKI may therefore be a target for improving lung transplant mortality rather than simply an epiphenomenon of PGD.

Background Primary graft dysfunction (PGD) is the leading cause of early mortality after lung transplantation. Anti-collagen type-V (col(V)) immunity has been observed in animal models of ischemia-reperfusion injury (IRI) and in PGD. We hypothesized that collagen type-V is an innate danger signal contributing to PGD pathogenesis. Methods Anti-col(V) antibody production was detected by flow cytometric assay following cultures of murine CD19+ splenic cells with col.(V). Responding murine B cells were phenotyped using surface markers. RNA-Seq analysis was performed on murine CD19+ cells. Levels of anti-col(V) antibodies were measured in 188 recipients from the Lung Transplant Outcomes Group (LTOG) after transplantation. Results Col(V) induced rapid production of anti-col(V) antibodies from murine CD19+ B cells. Subtype analysis demonstrated innate B-1 B cells bound col.(V). Col(V) induced a specific transcriptional signature in CD19+ B cells with similarities to, yet distinct from, B cell receptor (BCR) stimulation. Rapid de novo production of anti-col(V) Abs was associated with an increased incidence of clinical PGD after lung transplant. Conclusions This study demonstrated that col.(V) is an rapidly recognized by B cells and has specific transcriptional signature. In lung transplants recipients the rapid seroconversion to anti-col(V) Ab is linked to increased risk of grade 3 PGD.

Frailty is a state of decreased physiologic reserve associated with poor outcomes before and after lung transplantation. Obesity, particularly central obesity characterized by excess proinflammatory visceral adipose tissue (VAT), is associated with incident frailty in middle-aged and older adults. The association between VAT and frailty in advanced lung disease, however, is unknown. In two, nonoverlapping multicenter cohorts of adults listed for lung transplantation, we measured VAT area on bioelectrical impedance assay (BIA) in one cohort and cross-sectional VAT and subcutaneous adipose tissue (SAT) areas on abdominal computed tomography (CT) in the other. We identified a nonlinear relationship between greater VAT by BIA and frailty. In fully adjusted piecewise regression models, every 20 cm(2) increase in VAT area was associated with 50% increased odds of frailty in subjects with high VAT (95% CI 1.2–1.9, P < .001), and 10% decreased odds of frailty (95% CI 0.7–1.04, P = .12) in subjects with low VAT. Compared to frail subjects with low VAT, those with high VAT were more likely to have low grip strength and less likely to have weight loss, suggesting that mechanisms of frailty may differ by VAT. Further investigation of mechanisms linking VAT and frailty may identify new targets for prevention and treatment.

BackgroundObesity is associated with an increased risk of primary graft dysfunction (PGD) after lung transplantation. The contribution of specific adipose tissue depots is unknown.MethodsWe performed a prospective cohort study of adult lung transplant recipients at 4 U.S. transplant centers. We measured cross-sectional areas of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) on chest and abdominal computed tomography (CT) scans and indexed each measurement to height.2 We used logistic regression to examine the associations of adipose indices and adipose classes with grade 3 PGD at 48 or 72 hours, and Cox proportional hazards models to examine survival. We used latent class analyses to identify the patterns of adipose distribution. We examined the associations of adipose indices with plasma biomarkers of obesity and PGD.ResultsA total of 262 and 117 subjects had available chest CT scans and underwent protocol abdominal CT scans, respectively. In the adjusted models, a greater abdominal SAT index was associated with an increased risk of PGD (odds ratio 1.9, 95% CI 1.02-3.4, p = 0.04) but not with survival time. VAT indices were not associated with PGD risk or survival time. A greater abdominal SAT index correlated with greater pre- and post-transplant leptin (r = 0.61, p < 0.001, and r = 0.44, p < 0.001), pre-transplant IL-1RA (r = 0.25, p = 0.04), and post-transplant ICAM-1 (r = 0.25, p = 0.04). We identified 3 latent patterns of adiposity. The class defined by high thoracic and abdominal SAT had the greatest risk of PGD.ConclusionsSubcutaneous, but not visceral, adiposity is associated with an increased risk of PGD after lung transplantation.

In the United States, an algorithm known as the "match-run" creates an ordered ranking of potential recipients for available lung allografts. A potential recipient's match-run position, or "sequence number," is available to the transplant center when contacted with a lung offer. Lung offers with higher sequence numbers may be interpreted as a crowd-sourced evaluation of poor organ quality, though the association between the sequence number at which a lung is accepted and its recipient's post-transplant outcomes is unclear.We sought to evaluate the primary reasons provided when a lung offer was refused by a transplant center, transplant center and donor/organ factors associated with a higher sequence number at acceptance, and the association of the sequence number at acceptance with post-transplant mortality and graft failure.Match-run outcomes for lung offers that occurred in the United States from May 2007 through June 2014 were merged with recipient follow-up data through December 2017. Associations between the sequence number at the time of acceptance and selected transplant center and donor characteristics were estimated using multivariable logistic and multinomial regression models. The associations between the final sequence number and recipient survival and graft survival were estimated using multivariable time-to-event models.Of 10,981 lung offer acceptances, nearly 70% were accepted by one of the top 10 ranked candidates. Higher median annual center volume and potential indicators of organ quality (e.g., abnormal chest radiograph or bronchoscopy) were associated with a higher sequence number at acceptance. There was weak evidence for a small positive relationship between the sequence number at acceptance and both mortality and graft failure. For example, the unadjusted and adjusted hazard ratios for death associated with the log-sequence number at acceptance were 1.019 (95% confidence interval, 1.001-1.038) and 1.011 (95% confidence interval, 0.989-1.033), respectively. On the absolute scale, using the multivariable model, a 10-fold increase in the sequence number translated into a 0.8% absolute decline in the predicted 5-year survival.Acceptance of a donor lung offer at a later point in the match-run was associated with measurable indicators of organ quality, but not with clinically meaningful differences in post-transplant mortality or graft failure.

Purpose Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Prior studies highlight the role of donor smoking in poor post-transplant outcomes. We therefore aimed to identify clinical risk factors for PGD after lung transplantation, more accurately assess the impact of donor smoking, and develop an accurate, generalizable PGD prediction model. Methods We performed a 10-center prospective cohort study of patients in the Lung Transplant Outcomes Group from 2012-2018. PGD was defined as grade 3 PGD at 48 or 72 hours after lung reperfusion. We defined donor smoking history by clinical documentation, UNOS-reported donor smoking, or donor cotinine >9 mg/ml from urine collected at organ procurement. Building on our prior PGD prediction models, multivariable logistic regression was used to identify PGD risk factors and develop regularized predictive models with a simple user interface (R shiny). Results Of 1180 patients, 26% developed PGD and 633 (53%) received an organ from a previously smoking donor. The PGD predictive model included novel predictors of center and donor distance plus recipient age, lung allocation score (LAS), body mass index, pulmonary artery pressure, sex, and indication for transplant; donor age, sex, mechanism of death, and donor distance; and interaction terms for LAS and donor distance. The interface allows for real-time assessment of PGD risk for any donor/recipient combination. The predictive model offers decision making benefit in the PGD risk range of 0.15-0.5. Donor smoking was associated with increased risk of PGD but not patient mortality (Figure 1). Conclusion We developed a clinically applicable PGD predictive algorithm based on modern lung transplant practices to aid in transplant decision making, post-transplant care, and to facilitate development of enriched PGD treatment trials. Donor smoking is a risk factor for PGD development but is not associated with increased mortality, potentially because of a lower risk phenotype of PGD occurring in smoking donor recipients.

Purpose Post-transplant frailty is a risk factor for poorer health-related quality of life, rehospitalization, and death. We aimed to evaluate the feasibility, safety, and efficacy of a remote mHealth-supported physical activity pilot intervention to treat frailty in lung transplant recipients following discharge from their index hospitalization. Methods We screened lung transplant recipients for frailty at the time of discharge at the University of Pennsylvania and UC San Francisco. Frailty was defined as a Short Physical Performance Battery (SPPB) score ≤7 and pre-frail as 8-9 (range 0-12, higher scores reflect less frailty). The primary intervention modality was Aidcube, a customizable app-based platform for home-based pulmonary rehabilitation providing personalized exercise prescriptions, for 8 weeks post-discharge. The primary aims included tolerability, feasibility, and acceptability of use of the mHealth platform. Additional outcome measures were changes in SPPB score and in scores of physical activity and disability measured using the DASI and LT-VLA. Results No adverse events were reported across the 18 study subjects throughout the 152 subject-week study time. Several themes emerged from weekly subject feedback. Subjects reported that the app was easy to use and that usability improved over time. Subjects also found that app use enhanced motivation to engage in post-transplant rehabilitation. Comments also highlighted the complexities of rehabilitation after lung transplant surgery, including level of functional decline, pain, tremor, and fatigue. At the end of the intervention, SPPB scores improved a median of 5 points (IQR 4, 7; p Conclusion Utilization of a personalized, app-based rehabilitation platform with participant-specific exercise prescriptions was safe and well received by post-lung transplant recipients. Remote rehabilitation was associated with improvements in frailty, physical activity and disability. Future studies should further evaluate mHealth treatment modalities in larger-scale randomized trials of lung transplant recipients.

RationaleFrailty is associated with morbidity and mortality in abdominal organ transplantation but has not been examined in lung transplantation.ObjectivesTo examine the construct and predictive validity of frailty phenotypes in lung transplant candidates.MethodsIn 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 resultsOf 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.ConclusionsFrailty is prevalent among lung transplant candidates and is independently associated with greater disability and an increased risk of delisting or death.

Background Thalamic deep brain stimulation (DBS) has largely replaced radiofrequency thalamotomy as the treatment of choice for disabling, medication-refractory essential tremor. Recently, the development of transcranial, high-intensity focused ultrasound has renewed interest in thalamic lesioning. The purpose of this study is to compare functional outcomes and quality of life in essential tremor patients treated with either bilateral Vim DBS or unilateral procedures (focused ultrasound or DBS). We hypothesized that all three would effectively treat the dominant hand and positively impact functional outcomes and quality of life as measured with the Clinical Rating Scale for Tremor and the Quality of Life in Essential Tremor Questionnaire. Methods This is a retrospective study of medication-refractory essential tremor patients treated at the University of Virginia with bilateral Vim DBS (n = 57), unilateral Vim DBS (n = 13), or unilateral focused ultrasound Vim thalamotomy (n = 15). Tremor was rated for all patients before and after treatment, using the Clinical Rating Scale for Tremor and Quality of Life in Essential Tremor Questionnaire. Results Patients undergoing bilateral DBS treatment had more baseline tremor and worse quality of life scores. Patients had significant improvements in tremor symptoms and quality of life with all three treatments. Both DBS procedures improved axial tremor. No difference was seen in the degree of improvement in upper extremity tremor score, disability, or overall quality of life between bilateral and either unilateral procedure. Conclusions Bilateral thalamic DBS improves overall tremor more than unilateral DBS or focused ultrasound treatment; however, unilateral treatments are equally effective in treating contralateral hand tremor. Despite the greater overall tremor reduction with bilateral DBS, there is no difference in disability or quality of life comparing bilateral versus unilateral treatments. © 2015 International Parkinson and Movement Disorder Society

This report details the successful use of bilateral lung transplantation for the management of severe postoperative bleomycin-associated lung injury. This case highlights that the extremely favorable prognosis of advanced testicular germ cell tumors after systemic chemotherapy (>90% cure rate) should not preclude lung transplant consideration in all cases, despite current guidance that considers an advanced malignancy to be a contraindication for lung transplant listing.

Purpose Rates of deep vein thrombosis (DVT) range from 20-60% in patients undergoing extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome. Data on the rates of DVT in lung transplant recipients bridged with ECMO is limited. The objective of this study was to report incidence and outcomes, including use of anticoagulation and subsequent bleeding rates, of DVT in ECMO-bridged transplant recipients. Methods This was a single center retrospective cohort study of all adult ECMO-bridged lung transplant recipients from 5/1/15 to 9/30/19. Recipients underwent routine ultrasound screening for upper extremity (UE) and lower extremity (LE) DVT following ECMO decannulation. Results Of the 45 ECMO-bridged recipients, 3 died before ECMO decannulation and 4 did not have screening ultrasounds, leaving 38 patients in the cohort. The majority (81.5%) were bridged using venovenous ECMO and most (63%) were decannulated immediately following transplant (Table 1). Among remaining recipients, mean time to decannulation was 4 days. Among recipients with adequate studies, the incidence of LE DVT was 26.4% and the incidence of UE DVT was 63.6%. Neither total time on ECMO, cannula size, nor need for femoral vein cannulation was associated with LE or UE DVT. All of the recipients with LE DVT but two, were anticoagulated. Three needed an inferior vena cava filter placed. Of recipients with UE DVT only, 43.75% were anticoagulated. Among all anticoagulated recipients, five (31.25%) had significant bleeding during their initial hospitalization requiring cessation of anticoagulation. Conclusion DVTs are common in patients bridged to lung transplantation with ECMO, particularly in the upper extremity. Bleeding poses further challenges for systemic anticoagulation in this high risk population. Additional studies are needed to identify risk factors for both LE DVT and for bleeding to help guide decisions for systemic anticoagulation in this population.