ISHLT consensus document on lung transplantation in patients with connective tissue disease: Part I: Epidemiology, assessment of extrapulmonary conditions, candidate evaluation, selection criteria, and pathology statements.

Patients with connective tissue disease (CTD) and advanced lung disease are often considered suboptimal candidates for lung transplantation (LTx) due to their underlying medical complexity and potential surgical risk. There is substantial variability across LTx centers regarding the evaluation and listing of these patients. The International Society for Heart and Lung Transplantation-supported consensus document on lung transplantation in patients with CTD standardization aims to clarify definitions of each disease state included under the term CTD, to describe the extrapulmonary manifestations of each disease requiring consideration before transplantation, and to outline the absolute contraindications to transplantation allowing risk stratification during the evaluation and selection of candidates for LTx.

Perspectives on donor lung allocation from both sides of the Atlantic: The United States.

Donor lung allocation in the United States focuses on decreasing waitlist mortality and improving recipient outcomes. The implementation of allocation policy to match deceased donor lungs to waitlisted patients occurs through a unique partnership between government and private organizations, namely the Organ Procurement and Transplantation Network under the Department of Health and Human Services and the United Network for Organ Sharing. In 2005, the donor lung allocation algorithm shifted toward the prioritization of medical urgency of waitlisted patients instead of time accrued on the waitlist. This led to the Lung Allocation Score, which weighs over a dozen clinical variables to predict a 1-year estimate of survival benefit, and is used to prioritize waitlisted patients. In 2017, the use of local allocation boundaries was eliminated in favor of a 250 nautical mile radius from the donor hospital as the first unit of distance used in allocation. The next upcoming iteration of donor allocation policy is expected to use a continuous distribution algorithm where all geographic boundaries are eliminated. There are additional opportunities to improve donor lung allocation, such as for patients with high antibody titers with access to a limited number of donors.

Design and rationale of a multi-center, pragmatic, open-label randomized trial of antimicrobial therapy - the study of clinical efficacy of antimicrobial therapy strategy using pragmatic design in Idiopathic Pulmonary Fibrosis (CleanUP-IPF) clinical trial.

Compelling data have linked disease progression in patients with idiopathic pulmonary fibrosis (IPF) with lung dysbiosis and the resulting dysregulated local and systemic immune response. Moreover, prior therapeutic trials have suggested improved outcomes in these patients treated with either sulfamethoxazole/ trimethoprim or doxycycline. These trials have been limited by methodological concerns. This trial addresses the primary hypothesis that long-term treatment with antimicrobial therapy increases the time-to-event endpoint of respiratory hospitalization or all-cause mortality compared to usual care treatment in patients with IPF. We invoke numerous innovative features to achieve this goal, including: 1) utilizing a pragmatic randomized trial design; 2) collecting targeted biological samples to allow future exploration of 'personalized' therapy; and 3) developing a strong partnership between the NHLBI, a broad range of investigators, industry, and philanthropic organizations. The trial will randomize approximately 500 individuals in a 1:1 ratio to either antimicrobial therapy or usual care. The site principal investigator will declare their preferred initial antimicrobial treatment strategy (trimethoprim 160 mg/ sulfamethoxazole 800 mg twice a day plus folic acid 5 mg daily or doxycycline 100 mg once daily if body weight is < 50 kg or 100 mg twice daily if ≥50 kg) for the participant prior to randomization. Participants randomized to antimicrobial therapy will receive a voucher to help cover the additional prescription drug costs. Additionally, those participants will have 4-5 scheduled blood draws over the initial 24 months of therapy for safety monitoring. Blood sampling for DNA sequencing and genome wide transcriptomics will be collected before therapy. Blood sampling for transcriptomics and oral and fecal swabs for determination of the microbiome communities will be collected before and after study completion. As a pragmatic study, participants in both treatment arms will have limited in-person visits with the enrolling clinical center. Visits are limited to assessments of lung function and other clinical parameters at time points prior to randomization and at months 12, 24, and 36. All participants will be followed until the study completion for the assessment of clinical endpoints related to hospitalization and mortality events. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02759120.

Sensitization in Transplantation: Assessment of Risk (STAR) 2017 Working Group Meeting Report.

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.

Medication Nonadherence After Lung Transplantation in Adult Recipients.

BACKGROUND: Our objective was to identify potential avenues for resource allocation and patient advocacy to improve outcomes by evaluating the association between recipient sociodemographic and patient characteristics and medication nonadherence after lung transplantation. METHODS: States US adult, lung-only transplantations per the United Network for Organ Sharing database were analyzed from October 1996 through December 2006, based on the period during which nonadherence information was recorded. Generalized linear models were used to determine the association of demographic, disease, and transplantation center characteristics with early nonadherence (defined as within the first year after transplantation) as well as late nonadherence (years 2 to 4 after transplantation). Outcomes comparing adherent and nonadherent patients were also evaluated. RESULTS: Patients (n = 7,284) were included for analysis. Early and late nonadherence rates were 3.1% and 10.6%, respectively. Factors associated with early nonadherence were Medicaid insurance compared with private insurance (adjusted odds ratio [AOR] 2.45, 95% confidence interval [CI]: 1.16 to 5.15), and black race (AOR 2.38, 95% CI: 1.08 to 5.25). Medicaid insurance and black race were also associated with late nonadherence (AOR 2.38, 95% CI: 1.51 to 3.73 and OR 1.73, 95% CI: 1.04 to 2.89, respectively), as were age 18 to 20 years (AOR 3.41, 95% CI: 1.29 to 8.99) and grade school or lower education (AOR 1.88, 95% CI: 1.05 to 3.35). Early and late nonadherence were both associated with significantly shorter unadjusted survival (p < 0.001). CONCLUSIONS: Identifying patients at risk of nonadherence may enable resource allocation and patient advocacy to improve outcomes.

Determining eligibility for lung transplantation: A nationwide assessment of the cutoff glomerular filtration rate.

BACKGROUND: Historical concerns about lung transplantation in patients with a glomerular filtration rate (GFR) ≤ 50 ml/min/1.73 m(2) have not been validated. We hypothesize that a pre-transplant GFR ≤ 50 ml/min/1.73 m(2) represents a high mortality risk, especially in the setting of acute GFR decline. In addition, we explore the potential for improved risk stratification using a statistically derivable alternative cutoff. METHODS: Adult, primary, lung recipients in the United Network for Organ Sharing database were analyzed (October 1987 to December 2011). Recursive partitioning identified the GFR value that provides maximal separation in 1-year mortality. Survival over/under the cutoffs was compared using stratified log-rank, Cox, and Kaplan-Meier methods, before and after 1:2 propensity score matching. RESULTS: Median GFR at time of transplant for 19,425 study patients was 94.2 ml/min/1.73 m(2) (quartile 1-quartile, 2 76.9-105.9 ml/min/1.73 m(2)). Recursive partitioning identified a GFR of 40.2 ml/min/1.73 m(2) as the ideal inflection point for predicting 1-year survival. Cutoffs demonstrated statistically significant effects on survival after 840 patients with a GFR ≤ 50 ml/min/1.73 m(2) (hazard ratio, 1.28; 95% confidence interval, 1.15-1.43) and 401 patients with a GFR ≤ 40.2 ml/min/1.73 m(2) (hazard ratio, 1.57; 95% confidence interval, 1.36-1.83) were matched with high GFR controls (p < 0.001). In 13,509 patients with available GFR at the time of listing and transplant, a pre-transplant GFR decline of ≥ 50% from baseline was associated with worse survival (p < 0.001). CONCLUSIONS: A pre-transplant GFR ≤ 50 ml/min/1.73 m(2) is associated with decreased survival. However, patients with GFR between 40 and 50 ml/min/1.73 m(2) do not suffer excessive post-transplant mortality and should not be automatically excluded from listing. Notably, outcomes are worse in patients with poor renal function and concomitant pre-transplant GFR decline. Strategies should be devised to detect and manage interval renal deterioration before lung transplantation.

Assessment of different threshold preoperative glomerular filtration rates as markers of outcomes in lung transplantation.

BACKGROUND: The evidence behind the widely used pre-lung transplant glomerular filtration rate (GFR) cutoff of 50 mL/min per 1.73 m2 is limited. This study reviews data from a large cohort to assess outcomes associated with this historical cutoff and to estimate other possible cutoffs that might be appropriate in lung transplantation. METHODS: We conducted a retrospective cohort analysis of lung recipients at a single center. Recursive partitioning and receiver operating characteristics analysis were used to estimate other potential GFR cutoffs with 1-year mortality as the outcome. Postoperative outcomes around the various cutoffs, including survival, acute kidney injury, and dialysis, were assessed using χ2, Kaplan-Meier, and Cox regression methods. RESULTS: A total of 794 lung recipients met study inclusion criteria. Compared with 778 patients with GFR 50 mL/min per 1.73 m2 or greater at time of transplant, 16 patients with GFR below this cutoff were older and more likely to have restrictive disease. One-year mortality below the cutoff was 31.3% compared with 15.1% above the cutoff (p=0.021). Recursive partitioning estimated potential GFR cutoff values between 46 and 61 mL/min per 1.73 m2. Patients with GFR below these cutoffs were at significantly higher risk for adverse outcomes (p<0.05). Receiver operating characteristics analysis was less successful at identifying meaningful cutoff values with areas under the curve approximately 0.5. CONCLUSIONS: Study results support the practice of requiring candidate GFR 50 mL/min per 1.73 m2 or greater for lung transplantation. Future work should focus on reproducing the analysis in a larger cohort of patients including more individuals with low GFR.

Lung transplantation at Duke University.

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