A persistent variant telomere sequence in a human pedigree.

The telomere sequence, TTAGGG, is conserved across all vertebrates and plays an essential role in suppressing the DNA damage response by binding a set of proteins termed shelterin. Changes in the telomere sequence impair shelterin binding, initiate a DNA damage response, and are toxic to cells. Here we identify a family with a variant in the telomere template sequence of telomerase, the enzyme responsible for telomere elongation, that led to a non-canonical telomere sequence. The variant is inherited across at least one generation and one family member reports no significant medical concerns despite ~9% of their telomeres converting to the novel sequence. The variant template disrupts telomerase repeat addition processivity and decreased the binding of the telomere-binding protein POT1. Despite these disruptions, the sequence is readily incorporated into cellular chromosomes. Incorporation of a variant sequence prevents POT1-mediated inhibition of telomerase suggesting that incorporation of a variant sequence may influence telomere addition. These findings demonstrate that telomeres can tolerate substantial degeneracy while remaining functional and provide insights as to how incorporation of a non-canonical telomere sequence might alter telomere length dynamics.

Incidence of Acute Cellular Rejection After Granulocyte Colony-Stimulating Factor in Lung Transplant Recipients.

BackgroundNeutropenia is a common complication in lung transplant recipients (LTRs). Filgrastim may be used to treat neutropenia in LTRs, but its consequences on acute cellular rejection (ACR) remain controversial. Objective: The purpose was to examine the association between filgrastim and incidence of ACR 6 months after filgrastim administration in LTRs. Secondary outcomes included burden of ACR, infections, chronic lung allograft dysfunction (CLAD), and survival. Methods: This was a matched cohort study of patients transplanted between January 2010 and October 2019. LTRs who received filgrastim for neutropenia were compared to a cohort who did not. LTRs were matched on transplant indication, sex, age, and time post-transplant and multivariable logistic regression models were used to evaluate the likelihood of ACR. Results: 212 patients were included in the analysis (106 in each group). 50 patients (47.2%) in the filgrastim group experienced ACR compared to 37 patients (34.9%) in the no filgrastim group (P = .070). In multivariable analysis, filgrastim use was not associated with ACR at 6 months (OR 1.409, 95% CI 0.772-2.571). Time to first ACR was shorter (P = .049) and 6-month ACR score was higher in the filgrastim group (.49 vs .33, P = .047). LTRs in the filgrastim group had higher incidence of bacterial pneumonia and 1-year mortality. Conclusions: Although not associated with increased likelihood of ACR at 6 months, our study found that filgrastim is associated with increased ACR burden and decreased time to ACR. This study can help inform clinicians of ACR risk after filgrastim use in LTRs.

Design of Lung Transplant Go (LTGO): A randomized controlled trial evaluating the efficacy of a telerehabilitation behavioral exercise intervention to improve physical activity, physical function, and blood pressure control after lung transplantation.

Background: Lung transplantation is an established treatment option for persons with advanced lung disease. After transplantation, lung function typically returns to near normal levels, however exercise capacity remains low due to chronic deconditioning, limited physical function, and inactive lifestyles which undermine the intended benefits of the highly selective, resource-intensive transplant procedure. Pulmonary rehabilitation is recommended to improve fitness and activity tolerance, however due to multiple barriers, lung transplant recipients either never participate, or fail to complete, pulmonary rehabilitation programs. Purpose: To describe the design of Lung Transplant Go (LTGO), a trial modified for the remote environment based on recommendations to preserve trial integrity during COVID. The aims are to evaluate a behavioral exercise intervention to improve physical function, physical activity, and blood pressure control in lung transplant recipients conducted safely and effectively using a telerehabilitation (telerehab) platform, and to explore the role of potential mediators and moderators of the relationship between LTGO and outcomes. Methods: Single-site, 2-group randomized controlled trial with lung transplant recipients randomized 1:1 to either the LTGO intervention (a 2-phased, supervised, telerehab behavioral exercise program), or to enhanced usual care (activity tracking and monthly newsletters). All study activities, including intervention delivery, recruitment, consenting, assessment, and data collection, will be performed remotely. Conclusion: If efficacious, this fully scalable and replicable telerehab intervention could be efficiently translated to reach large numbers of lung recipients to improve and sustain self-management of exercise habits by overcoming barriers to participation in existing, in-person pulmonary rehabilitation programs.

Intraoperative Support for Primary Bilateral Lung Transplantation: A Propensity-Matched Analysis.

BACKGROUND: Single-center studies support benefits of venoarterial extracorporeal membrane oxygenation (VA-ECMO) as a method of intraoperative support. Propensity-matched data from a large cohort, however, are currently lacking. Therefore, our goal was to compare outcomes of intraoperative VA-ECMO and cardiopulmonary bypass (CPB) during bilateral lung transplantation (LTx) with a propensity analysis. METHODS: We performed a retrospective analysis of 795 consecutive primary adult LTx patients (June 1, 2011-December 26, 2020) using no intraoperative support (n = 210), VA-ECMO (n = 150), or CPB (n = 197). Exclusion criteria included LTx on venovenous-ECMO, single/redo LTx, ex vivo lung perfusion, and concomitant solid-organ transplantation or cardiac procedure. Propensity analysis was performed comparing patients who underwent intraoperative CPB or VA-ECMO. RESULTS: The propensity CPB group required more blood products at 72 hours (P = .02) and longer intensive care unit length of stay (P < .001) and ventilator dependence days (P < .001). There were no differences in cerebrovascular accident (P = 1), reintubation (P = .4), dialysis (P = .068), in-hospital mortality (P = .33), and 1-year (P = .67) and 3-year (P = .32) survival. The CPB group had a higher incidence of grade 3 primary graft dysfunction at 72 hours (P < .001). Neither support strategy was a predictor of 1- and 3-year mortality in our multivariable model (VA-ECMO, P = .72 and P = .57; CPB, P = .45 and P = .91, respectively). CONCLUSIONS: Intraoperative VA-ECMO during lung transplantation was associated with fewer postoperative blood transfusions, shorter length of mechanical ventilation, and lower incidence of a grade 3 primary graft dysfunction at 72 hours. Although there were some differences in the postoperative course between the VA-ECMO and CPB groups, support type was not associated with differences in survival.

Oxygenated right ventricular assist device with a percutaneous dual-lumen cannula as a bridge to lung transplantation.

Background: Oxygenated right ventricular assist device (oxyRVAD) placement has become more streamlined with the introduction of the dual-lumen pulmonary artery cannula. Peripherally cannulated oxyRVAD may provide oxygenation support with right heart support as an alternative to venoarterial extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation. Methods: A single-institution, retrospective analysis was performed on patients placed on oxyRVAD with a dual-lumen pulmonary artery cannula with the intention of bridging to lung transplantation in 2019. Results: Four patients with idiopathic pulmonary fibrosis were placed on oxyRVAD as a bridge to transplantation. Two patients were extubated and ambulated while waiting for a lung offer, and two patients required conversion to venoarteriovenous ECMO (VAV ECMO) from oxyRVAD. The median waiting time for extracorporeal life support (ECLS) was 42 h. All patients underwent double lung transplantation. Two patients stayed on oxyRVAD, and one patient was placed on venovenous ECMO (VV ECMO) after transplantation. Primary graft dysfunction score at 72 h after transplantation was grade 1 in three patients and grade 3 in one patient. Conclusions: Peripherally cannulated oxyRVAD with percutaneous dual-lumen venous cannula could be an ambulatory bridge for lung transplantation. It is unknown whether oxyRVAD is feasible as a long-term bridge to lung transplantation.

Risk factors of bronchial dehiscence after primary lung transplantation.

BACKGROUND: Although the incidence of bronchial dehiscence following lung transplantation has decreased significantly due to improvements in perioperative managements and surgical techniques, it remains a devastating postoperative complication associated with high morbidity and mortality. METHODS: We retrospectively reviewed 811 lung transplantation performed at our institution between January 2011 and December 2020. Bronchial dehiscence was confirmed with flexible bronchoscopy, computed tomography (CT) scan, or clinical findings grade using International Society for Heart and Lung Transplantation recommendations. RESULTS: Bronchial dehiscence was diagnosed in 38 patients (4.7%). The overall survival rates of the patients with bronchial dehiscence were significantly worse than those of the patients without bronchial dehiscence (p = .003). Multivariate analysis identified use of our basiliximab induction protocol (odds ratio = 3.03, p = .008) as an independent predictive factor of postoperative airway dehiscence in our multivariable model, along with total ventilator duration (odds ratio = 1.02, p = .002). CONCLUSIONS: Based on our analysis, patients that underwent our basiliximab induction protocol for lung transplantation experienced a higher rate of postoperative bronchial dehiscence when compared with patients who receive alemtuzumab induction. We believe this may be associated with a higher steroid exposure in this population. Additional studies are necessary to further characterize the relationship between different induction protocols and bronchial dehiscence following transplantation.

Prospective Evaluation of Coronavirus Disease 2019 (COVID-19) Vaccine Responses Across a Broad Spectrum of Immunocompromising Conditions: the COVID-19 Vaccination in the Immunocompromised Study (COVICS).

BACKGROUND: We studied humoral responses after coronavirus disease 2019 (COVID-19) vaccination across varying causes of immunodeficiency. METHODS: Prospective study of fully vaccinated immunocompromised adults (solid organ transplant [SOT], hematologic malignancy, solid cancers, autoimmune conditions, human immunodeficiency virus [HIV]) versus nonimmunocompromised healthcare workers (HCWs). The primary outcome was the proportion with a reactive test (seropositive) for immunoglobulin G to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain. Secondary outcomes were comparisons of antibody levels and their correlation with pseudovirus neutralization titers. Stepwise logistic regression was used to identify factors associated with seropositivity. RESULTS: A total of 1271 participants enrolled: 1099 immunocompromised and 172 HCW. Compared with HCW (92.4% seropositive), seropositivity was lower among participants with SOT (30.7%), hematological malignancies (50.0%), autoimmune conditions (79.1%), solid tumors (78.7%), and HIV (79.8%) (P < .01). Factors associated with poor seropositivity included age, greater immunosuppression, time since vaccination, anti-CD20 monoclonal antibodies, and vaccination with BNT162b2 (Pfizer) or adenovirus vector vaccines versus messenger RNA (mRNA)-1273 (Moderna). mRNA-1273 was associated with higher antibody levels than BNT162b2 or adenovirus vector vaccines after adjusting for time since vaccination, age, and underlying condition. Antibody levels were strongly correlated with pseudovirus neutralization titers (Spearman r = 0.89, P < .0001), but in seropositive participants with intermediate antibody levels, neutralization titers were significantly lower in immunocompromised individuals versus HCW. CONCLUSIONS: Antibody responses to COVID-19 vaccines were lowest among SOT and anti-CD20 monoclonal recipients, and recipients of vaccines other than mRNA-1273. Among those with intermediate antibody levels, pseudovirus neutralization titers were lower in immunocompromised patients than HCWs. Additional SARS-CoV-2 preventive approaches are needed for immunocompromised persons, which may need to be tailored to the cause of immunodeficiency.

Rate of recipient-derived alveolar macrophage development and major histocompatibility complex cross-decoration after lung transplantation in humans.

Alveolar macrophages (AM) play critical roles in lung tissue homeostasis, host defense, and modulating lung injury. The rate of AM turnover (donor AM replacement by circulating monocytes) after transplantation has been incompletely characterized. Furthermore, the anatomic pattern of recipient-derived lung macrophages repopulation has not been reported, nor has their ability to accumulate and present donor major histocompatibility complex (a process we refer to as MHC cross-decoration). We longitudinally characterized the myeloid content of bronchoalveolar lavage (BAL) and biopsy specimens of lung transplant recipients and found a biphasic rate in AM turnover in the allograft, with a rapid turnover perioperatively, accelerated by both the type of induction immunosuppression and the presence of primary graft dysfunction. We found that recipient myeloid cells with cell surface AM phenotype repopulated the lung in a disorganized pattern, comprised mainly of large clusters of cells. Finally, we show that recipient AM take up and present donor peptide-MHC complexes yet are not able to independently induce an in vitro alloreactive response by circulating recipient T cells.

Outcomes following lung re-transplantation in patients with cystic fibrosis.

PURPOSE: We examined cystic fibrosis (CF) patients and compared their clinical status at the time of primary versus double lung re-transplantation (re-DLTx) in order to better understand lung retransplant practice patterns. METHODS: We performed a retrospective analysis of the UNOS Database identifying CF patients ≥18 years old undergoing re-DLTx (5/4/2005 and 12/4/2020). Baseline and clinical variables at the primary and re-DLTx were compared utilizing the paired student t-test. Graft survival was defined as time from surgery to retransplant and analyzed using Kaplan-Meier estimates. RESULTS: 277 CF patients who underwent re-DLTx experienced a significantly worse 5-year survival when compared to the primary DLTx cohort (47.9% vs 58.8%, p = 0.00012). The following differences were observed comparing CF re-DLTx group to their primary DLTx: higher LAS score at the time of listing (50.66 vs 42.15, p < 0.001) and transplant (62.19 vs 48.20, p < 0.001), and increase LAS from the time of listing to transplant (+12.22 vs +7.23, p = 0.002). While serum albumin and total bilirubin were similar, CF patients had a higher creatinine (1.05 vs 0.74, p < 0.001), dialysis (4.4% vs 0.6%, p < 0.001), ECMO bridge to transplant rates (7.6% vs 4.0%, p < 0.001), and higher oxygen requirements (5.95 vs 3.93, p < 0.001) at the time of listing for a re-DLTx. CONCLUSION: Compared to their initial transplant, CF patients experience significant clinical decline in renal, cardiac, and pulmonary function at the time of lung retransplantation. This may indicate that an earlier evaluation and rehabilitation process may be necessary to identify patients earlier for lung retransplantation prior significant clinical decline.

Lung transplantation for idiopathic pulmonary fibrosis enriches for individuals with telomere-mediated disease.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the most common indication for lung transplantation in North America and variants in telomere-maintenance genes are the most common identifiable cause of IPF. We reasoned that younger IPF patients are more likely to undergo lung transplantation and we hypothesized that lung transplant recipients would be enriched for individuals with telomere-mediated disease due to the earlier onset and more severe disease in these patients. METHODS: Individuals with IPF who underwent lung transplantation or were evaluated in an interstitial lung disease specialty clinic who did not undergo lung transplantation were examined. Genetic evaluation was completed via whole genome sequencing (WGS) of 426 individuals and targeted sequencing for 5 individuals. Rare variants in genes previously associated with IPF were classified using the American College of Medical Genetics guidelines. Telomere length from WGS data was measured using TelSeq software. Patient characteristics were collected via medical record review. RESULTS: Of 431 individuals, 149 underwent lung transplantation for IPF. The median age of diagnosis of transplanted vs non-transplanted individuals was significantly younger (60 years vs 70 years, respectively, p<0.0001). IPF lung transplant recipients (IPF-LTRs) were twice as likely to have telomere-related rare variants compared to non-transplanted individuals (24% vs 12%, respectively, p=0.0013). IPF-LTRs had shorter telomeres than non-transplanted IPF patients (p=0.0028) and >85% had telomeres below the age-adjusted mean. Post-transplant survival and CLAD were similar amongst IPF-LTRs with rare variants in telomere-maintenance genes compared to those without, as well as in those with short telomeres versus longer telomeres. CONCLUSIONS: There is an enrichment for telomere-maintenance gene variants and short telomeres among IPF-LTRs. However, transplant outcomes of survival and CLAD do not differ by gene variants or telomere length within IPF-LTRs. Our findings support individual with telomere-mediated disease should not be excluded from lung transplantation and focusing research efforts on therapies directed toward individuals with short-telomere mediated disease.

Considerations for assessing physical function and physical activity in clinical trials during the COVID-19 pandemic.

The coronavirus disease-2019 (COVID-19) pandemic has changed the conduct of clinical trials. For studies with physical function and physical activity outcomes that require in-person participation, thoughtful approaches in transitioning to the remote research environment are critical. Here, we share our experiences in transitioning from in-person to remote assessments of physical function and activity during the pandemic and highlight key considerations for success. Details on the development of the remote assessment protocol, integration of a two-way video platform, and implementation of remote assessments are addressed. In particular, procedural challenges and considerations in transitioning and conducting remote assessments will be discussed in terms of efforts to maintain participant safety, maximize study efficiency, and sustain trial integrity. Plans for triangulation and analysis are also discussed. Although the role of telehealth platforms and research activities in remote settings are still growing, our experiences suggest that adopting remote assessment strategies are useful and convenient in assessing study outcomes during, and possibly even beyond, the current pandemic. Trial register and number: ClinicalTrials.gov [NCT03728257].

Extracorporeal Membrane Oxygenation for Primary Graft Dysfunction After Lung Transplantation.

Extracorporeal membrane oxygenation (ECMO) is used as the last resort for primary graft dysfunction (PGD). The aim of this study is to explore the predictors and outcomes for early mortality in postlung transplant patients who required ECMO for PGD. Between January 2006 and December 2015, 1,049 cases of lung transplantation were performed at our center. Ninety-six patients required ECMO support after lung transplantation, 52 patients (54%) had PGD. Seven patients (13.5%) required venoarterial ECMO due to concomitant hemodynamical instability, and the others required venovenous ECMO. The patients were on ECMO for 5.00 ± 10.6 days. Forty-four patients (84.6%) were successfully decannulated. The 90 day, 1 year, and 5 year survival of patients who required ECMO for PGD after lung transplantation were 67.3%, 50.0%, and 31.5%, respectively. Cox regression indicated that when the patient was placed on ECMO later than 48 hours after transplantation, the patient could have higher in-house mortality (hazard ratio, 2.79; 95% CI, 1.21-6.43) and also higher 3 year mortality (hazard ratio, 2.30; 95% CI, 1.13-4.68) regardless of the patients' preoperative conditions or complexity of lung transplantation. Earlier recognition of PGD and initiation of ECMO may be beneficial in this population.

Lung transplantation for the treatment of irreversible acute respiratory distress syndrome.

BACKGROUND: Despite advances in critical care for acute respiratory distress syndrome (ARDS), some survivors in the acute phase are unable to wean from extracorporeal membrane oxygenation (ECMO) or mechanical ventilation. To date, little is known regarding whether lung transplantation confers a survival benefit for irreversible ARDS. METHODS: This retrospective study was conducted using the United Network for Organ Sharing database (May 2005-December 2018). Patients with restrictive lung disease were divided into two groups: patients with and without ARDS. Propensity score matching identified recipients without ARDS for the control group. RESULTS: A total of 63 patients with ARDS were waitlisted for lung transplantation, while 39 received a lung transplant after a median waitlist duration of 8 days. Seventy-eight patients were matched as controls. In the ARDS group, the median age was 30 years, and the median lung allocation score was 88.4. Among the 39 recipients, 30 (76.9%) received ECMO support prior to transplantation. Lung transplantation for ARDS and restrictive lung disease showed similar 90-day (87.2% vs. 88.5%, p = .80), 1-year (82.1% vs. 85.9%, p = .52), and 3-year (69.2% vs. 65.4%, p = .94) survival rates. CONCLUSIONS: Lung transplantation provides acceptable outcomes in selected patients with irreversible ARDS.

Dabigatran reversal with idarucizumab prior to lung transplantation.

BACKGROUND: When the transplant candidates are receiving oral anticoagulation therapy before transplantation, it is crucial to have an urgent reversal strategy to prevent hemorrhagic complications perioperatively. The aim of this study was to present the experience with idarucizumab to reverse the anticoagulant activity of dabigatran prior to lung transplantation. METHODS: A single-center retrospective study was performed to analyze the clinical outcomes of idarucizumab use before lung transplantation. RESULTS: Between July 2016 and June 2019, six patients were on dabigatran at the time of transplantation. Out of the six patients, four patients received idarucizumab. These four recipients received a median of 3 units (range 0-4 units) of packed red blood cells (pRBCs) and 450 ml (range 250-1500 ml) of intraoperative salvage of shed blood (cell saver blood) during the lung transplant. The two patients who were not administered idarucizumab received 5 units and 13 units of pRBCs and 900 ml and 3600 ml of cell saver blood, respectively. There was no grade 3 primary graft dysfunction (PGD) at 72 hours after transplantation or in-hospital mortality in idarucizumab group. In the group without idarucizumab, there was one case of grade 3 PGD without any in-hospital mortality. CONCLUSION: Dabigatran reversal with idarucizumab provides reasonable hemostasis during lung transplantation.

Bilateral sequential lung transplantation in Jehovah's Witnesses.

The ethical concerns of refusing lifesaving treatments after receiving an already limited resource such as a solid organ transplantation in a Jehovah's Witness patient have been discussed in the literature. Many of these studies have concluded that with a multidisciplinary approach, solid organ transplantation is possible in the setting of Jehovah's Witness patients. To date, there are no reported cases of bilateral sequential lung transplantation in the literature. We report two successful cases of bilateral sequential lung transplantation in Jehovah's Witness patients with excellent long-term follow-up.

Trends in Lung Transplantation Practices Across the United States During the COVID-19 Pandemic.

BACKGROUND: The purpose of this study is to examine the effects of the coronavirus disease 2019 (COVID-19) pandemic on adult lung transplants and report practice changes in the United States. METHODS: A retrospective analysis of a public dataset from the United Network for Organ Sharing was performed regarding adult lung transplantation (January 19, 2020-June 30, 2020). Data were stratified into 3 periods: pre-COVID-19 (January 19, 2020-March 14, 2020), first COVID-19 era (March 15, 2020-May 8, 2020), and second COVID-19 era (May 9, 2020-June 30, 2020). Weekly changes in waitlist inactivations (COVID-19 precautions or not), waitlist additions, transplant volume, and donor recovery were examined across eras and changes across era were correlated. RESULTS: During the first COVID-19 era, 301 patients were added to the waitlist, representing a 40% decrease when compared to the prior 8-week period. This was followed by a significant increase in listing during the second COVID-19 era (t = 2.16, P = 0.032). Waitlist inactivations decreased in the second COVID-19 era from the first COVID-19 era (t = 3.60, P < 0.001). There was no difference in waitlist inactivations between the pre-COVID era and the second COVID-19 era (P = 0.10). Weekly volume was not associated with trends in COVID-19 cases across any era, but was negatively associated with waitlist inactivations due to COVID-19 precautions entering the first COVID-19 era (r = -0.73, P = 0.04) and second COVID-19 era (r = -0.89, P = 0.003). CONCLUSIONS: Due to the COVID-19 pandemic, the United States experienced a decrease in lung transplant volume. While overall volume has returned to normal, additional studies are needed to identify areas of improvement to better prepare for future pandemics.

Type-1 immunity and endogenous immune regulators predominate in the airway transcriptome during chronic lung allograft dysfunction.

Chronic lung allograft dysfunction (CLAD) remains the major complication limiting long-term survival among lung transplant recipients (LTRs). Limited understanding of CLAD immunopathogenesis and a paucity of biomarkers remain substantial barriers for earlier detection and therapeutic interventions for CLAD. We hypothesized the airway transcriptome would reflect key immunologic changes in disease. We compared airway brush-derived transcriptomic signatures in CLAD (n = 24) versus non-CLAD (n = 21) LTRs. A targeted assessment of the proteome using concomitant bronchoalveolar lavage (BAL) fluid for 24 cytokines/chemokines and alloimmune T cell responses was performed to validate the airway transcriptome. We observed an airway transcriptomic signature of differential genes expressed (DGEs) in CLAD marked by Type-1 immunity and striking upregulation of two endogenous immune regulators: indoleamine 2, 3 dioxygenase 1 (IDO-1) and tumor necrosis factor receptor superfamily 6B (TNFRSF6B). Advanced CLAD staging was associated with a more intense airway transcriptome signature. In a validation cohort using the identified signature, we found an area under the curve (AUC) of 0.77 for CLAD LTRs. Targeted proteomic analyses revealed a predominant Type-1 profile with detection of IFN-γ, TNF-α, and IL-1ß as dominant CLAD cytokines, correlating with the airway transcriptome. The airway transcriptome provides novel insights into CLAD immunopathogenesis and biomarkers that may impact diagnosis of CLAD.

Donor-specific antibody characteristics, including persistence and complement-binding capacity, increase risk for chronic lung allograft dysfunction.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is the major complication limiting long-term survival in lung transplant recipients (LTRs), with those developing donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) previously found to have increased risk for CLAD. However, as DSA responses vary in timing of development, specificity, breadth, persistence, and complement-binding capacity, we hypothesized that these characteristics would impact CLAD and survival outcomes. METHODS: We retrospectively analyzed DSA characteristics and outcomes in a single-center cohort of 582 LTRs who had serum samples collected prospectively from 2010 to 2016. Luminex-based single antigen bead assays were performed to assess DSA. RESULTS: DSAs were detected in 247 LTRs (42%), of which 124 (21.3%) were de novo DSAs and 53 (9.1%) were complement-binding (C1q+). CLAD developed in 208 LTRs (35.7%) during the follow-up period, with 67.8% determined as bronchiolitis obliterans syndrome phenotype and 32.2% as restrictive allograft syndrome phenotype. We found a shorter time to CLAD in LTRs with persistent DSAs (p = 0.04) and HLA-DQ-specific DSAs (p = 0.03). LTRs who developed C1q+ DSAs had significantly shorter time to CLAD (p < 0.001), with 100% of C1q+ DSAs being persistent and no differences between CLAD phenotypes. CLAD-free survival was significantly reduced in LTRs who developed C1q+ DSAs (p = 0.001), HLA-DQ-specific DSAs (p = 0.03), and multiple DSAs (p = 0.02). CONCLUSIONS: Together, our findings demonstrate that DSA characteristics of persistence, HLA-DQ specificity, and C1q+ DSAs are associated with shorter time to CLAD. Additionally, C1q+, HLA-DQ-specific, and multiple DSAs are associated with decreased CLAD-free survival. These characteristics may improve DSA risk stratification for deleterious outcomes in LTRs.

Access to Lung Transplantation in the United States: The Potential Impact of Access to a High-volume Center.

BACKGROUND: Health disparities plague our healthcare system. Utilizing a novel approach, we sought to assess the effects of geographic disparities on access to lung transplantation (LT) in the United States. METHODS: A total of 13 743 LT adult recipients in the United Network for Organ Sharing Database were identified between May 2005 and December 2014 with a zip code status. Geographic access was defined by global spherical distance from patient zip code centroid to transplant center. Measures analyzed included the association among socioeconomic status (SES), distance to a transplant center, and center switching behavior. RESULTS: Median distance traveled was 62.9 miles. There was an inverse relationship between Diez Roux SES and median distance traveled (90 versus 80.1 versus 60.5 versus 30, P < 0.001). There was no association found between 5-y survival and distance traveled (P = 0.099). However, traveling >158.7 miles was associated with worse survival (hazard ration 1.1; 95% confidence interval, 1.0-1.2; P = 0.005). Over 80% of patients exhibiting center switching were transplanted at a high-volume center than their home institution. Those more likely to switch to a high-volume center were those with an associates/bachelor (P < 0.005) or graduate-level degree (P < 0.05). Recipients with high-volume home institutions had the lowest probability of switching to an alternative center (odds ratio, 0.009; P < 0.001). There was no difference in survival when comparing those transplanted at their home institution versus those who sought transplantation at an alternative institution (55.3% versus 55.0%, P = 0.41). CONCLUSIONS: Although there was no association among SES, distance traveled, and survival, access to LT services varies among populations in the United States.