The NHLBI Lung Transplant Consortium 2025 Steering Committee Report: Strategies to Maximize the Use of the Consortium for Advancing Lung Transplantation

Abstract

The Lung Transplant Consortium (LTC) sponsored by the National Heart, Lung, and Blood Institute (NHLBI) is a 20-center collaboration among lung transplant programs in North America conducting both smaller multicenter projects and one consortium-wide prospective observational cohort study called the Prospective Multicenter Research on Donor and Recipient Management Strategies to Improve Lung Transplant Outcomes (PROMISE) Lung Study – for more information about the LTC, visit their website: https://lungtransplantconsortium.org/. The LTC conducted a meeting in April 2025 to strategize how to maximize the benefits of the PROMISE study to advance the field of lung transplant. This paper summarizes the key themes that emerged from the meeting: leveraging PROMISE data elements, including biomarkers, imaging, and PROs; clinical syndrome and consensus definitions; variation in management and management strategies; and future interventional trials leveraging the PROMISE consortium. The PROMISE study will serve as the platform for establishing best practices in lung transplant, inform the validity of newly identified syndromes, and support analysis of patient-reported outcomes, image data, and biosamples. The PROMISE study and LTC create a critically needed research platform and multicenter collaborative structure that may be adapted to conduct future multicenter clinical trials that will advance lung transplant medicine.

Introduction

The National Heart, Lung, and Blood Institute (NHLBI) created the Lung Transplant Consortium (LTC) to serve as a research platform for observational and mechanistic studies in lung transplant.^1–3 The LTC aims to better understand how lung transplant selection and clinical management strategies influence donor lung utilization, lung allograft function, and patient-centered outcomes in order to improve patient management and survival after lung transplantation.

The LTC comprises 20 North American lung transplant centers, organized into seven clinical centers (LTC-CCs), each with a funded study and supported by a data coordinating center (LTC-DCC), led by a multi-investigator team with expertise in clinical transplant medicine, epidemiology, and biostatistics housed at Duke Clinical Research Institute and at University of Pennsylvania. The LTC developed the Prospective Multicenter Research on Donor and Recipient Management Strategies to Improve Lung Transplant Outcomes (PROMISE) study, a consortium-wide common protocol to collect detailed clinical data, blood samples, and patient-reported outcomes (PROs) in a planned population of up to 2,600 lung transplant candidates and recipients.⁴ Data and specimen collection in the PROMISE study are designed to support future studies that will address unmet needs across the spectrum of lung transplant research. Study design was led by the LTC-DCC in close collaboration with the National Institutes of Health (NIH) and the LTC Steering Committee, which includes medical and surgical representatives from each LTC-CC, principal investigators from the LTC-DCC, and NIH-appointed independent committee co-chairs.

The LTC conducted a virtual steering committee meeting on April 11, 2025, to strategize how to maximize the benefits of the PROMISE study. The meeting included four breakout sessions: 1) leveraging PROMISE data elements, including biomarkers, imaging, and PROs; 2) clinical syndrome and consensus definitions; 3) variation in management and management strategies; and 4) future interventional trials. In addition to the steering committee members, site PIs and co-investigators from the PROMISE study were invited to participate in the sessions. A participant list is included in the Appendix. This paper describes the key themes and ideas that emerged from these discussions.

Breakout Session 1: Leveraging PROMISE Data Elements: Biomarkers, Imaging, and PROs

Participants highlighted the importance of donor biomarkers, imaging, and PROs in predicting and redefining outcomes such as primary graft dysfunction (PGD) and acute lung allograft dysfunction (ALAD).

Group members discussed using PROMISE data to assess the validity of the new ALAD consensus definition and the opportunity to develop multi-component syndromic definitions, with the goal of moving toward more precise endotype classifications. The PROMISE study could also serve as a rich platform for cross-validation of previously identified biomarkers (such as protein markers or cell-free DNA). For example, biomarkers and/or tissue biopsies could help quantify the severity of lung injury beyond standard measures of lung function decline.

The group also highlighted opportunities to collaborate by using imaging data to evaluate differences in donor acceptance practices across centers, as well as variations in size-matching protocols between donors and recipients. The planned routine collection of donor CT scans in the PROMISE study will facilitate these efforts. They also noted synergy of the PROMISE study with individual UO1 LTC studies, including the specific opportunity to link PROMISE donor blood samples to explore potential associations with PGD.

Looking ahead, the group proposed future studies that could have transformative impacts, such as those using PRO data to evaluate long-term quality of life in lung transplant recipients, particularly in diseases such as chronic obstructive pulmonary disease (COPD) where the survival benefit of transplant is less clear. This work could help identify which patients benefit most from lung transplantation. Additionally, the group expressed interest in studying outcomes in patients who undergo lung transplantation due to acute lung failure without prior lung disease to assess whether their post-transplant quality of life is comparable to that of patients who undergo transplantation for other indications.

Breakout Session 2: Clinical Syndromes and Consensus Definitions

Among the participants in this group, there was broad consensus that syndromic definitions should be driven by data rather than expert consensus alone to build more robust, evidence-based frameworks. The collection of granular clinical data in PROMISE presents an opportunity for refining the definitions and validating the incidence of syndromes such as ALAD, baseline lung allograft dysfunction (BLAD), chronic lung allograft dysfunction (CLAD), and PGD.

Further discussion focused on moving beyond these syndromic definitions toward biologically driven endotypes. Although PROMISE may not yield enough longitudinal data to study CLAD in the short term, many participants will be followed for at least four years. Additionally, collaborations with other established cohorts such as the Lung Transplant Outcomes Group (LTOG) and the Clinical Trials in Organ Transplant (CTOT) could help develop more precise definitions and eventually link early syndromes such as PGD, ALAD, or BLAD to CLAD and later mortality.^5,6 There was also interest in assessing how patient characteristics and clinical outcomes have changed with respect to syndromic definitions by era (for example, the increasing use of extracorporeal membrane oxygenation [ECMO] over time).

The group also identified opportunities for genetic phenotyping and polygenic risk scoring, particularly to explore non-pulmonary outcomes that are highly relevant in lung transplant patients, such as renal dysfunction. These efforts are facilitated by the collection of donor and recipient blood samples in the PROMISE study from which genomic DNA can be extracted. Furthermore, the LTC is ideal to study donor management with the latest transplant technologies, such as machine perfusion for organ support. Improving decision-making around recipient transplant eligibility was also highlighted as a priority.

Additionally, the group emphasized the importance of the singular data element structure in the PROMISE study that cuts across 20 different transplant centers. In particular, the PROMISE study includes infrastructure for data extraction, processing, and reintegration to enable large-scale analyses. The group felt that the infrastructure created for the LTC is an outstanding framework for moving toward interventional studies in lung transplant, either in building on natural variations in clinical practice (Topic 3) or in executing future clinical trials (Topic 4).

Breakout Session 3: Variation in Management and Management Strategies

This group focused on leveraging the strengths of the PROMISE platform, particularly its large sample size and standardized data collection protocols, to study variation in management and determine best practices to address questions that are not likely to be addressed through randomized controlled trials due to potential ethical or feasibility barriers. Discussion centered around identifying sources of site-level variability that could be analyzed to determine impact on transplant outcomes.

Within the perioperative domain, the group identified several key center-specific factors, including differences in injury severity at the time of transplant, risk tolerance, and practices around sensitization, ex vivo lung perfusion (EVLP), ECMO, and donation after circulatory death (DCD). The group noted that some centers manage sensitized patients or utilize EVLP and ECMO more aggressively than others. In addition, potential differences in outcomes with DCD warrant further exploration.

In the post-transplant phase, the group highlighted variability in practices such as immunosuppression targets and especially the density and intensity of surveillance protocols. They pointed to inconsistencies across sites in how often bronchoscopic biopsies are performed in the first-year post-transplant, as well as variation in cytomegalovirus monitoring, donor-specific antibody surveillance, and pulmonary function testing. This heterogeneity is a valuable opportunity to study associations between these practices and patient outcomes, with the potential to inform future iterations of PROMISE and clinical trials in lung transplantation.

The group noted that most of the key data elements necessary to study these sources of variability were already being captured in the PROMISE case report forms. The PROMISE dataset could also be leveraged to support further studies addressing additional relevant ancillary questions, such as referral patterns leading into listing or treatment. In addition, as transplant programs treat sicker patients, there is growing interest in how length of stay and outcomes are evolving. Participants stressed the need to identify which risk factors are modifiable and which conditions are more tolerable versus too high-risk for transplant. To help address these complexities, participants suggested innovative observational study designs, including propensity matching and inverse probability weighting, especially to study populations not listed or denied due to sensitization. Other game-changing concepts included modeling a tiered system for transplant centers based on demonstrated competency (similar to trauma center designations) and better matching needs with specific center capabilities. Overall, the group emphasized the existing variability in practice in quasi-experimental study designs to identify strategies that could improve outcomes.

Breakout Session 4: Future Interventional Trials Leveraging the PROMISE Consortium

This group discussed potential of the consortium to facilitate clinical trials, starting with reflections on past experiences from previous trials in lung transplant, which often required longer times to meet enrollment. Collaborative experience in the execution of the PROMISE protocol across the 20 LTC centers will provide valuable experience, which will enable future randomized clinical trials.

Novel trial designs and pragmatic approaches were discussed. The example of the Clinical Efficacy of Antimicrobial Therapy Strategy Using Pragmatic Design in Idiopathic Pulmonary Fibrosis (CleanUP-IPF) study, a pragmatic trial that repurposed existing low-risk, low-cost antibiotics, was cited to demonstrate that well-designed, less complex trials can be viable and impactful in the rare disease space.⁷ The group encouraged similar approaches in lung transplant and explored optimal outcomes for initial PROMISE-related trials, agreeing that early efforts should focus on well-validated outcomes, such as PGD and acute rejection. In contrast, CLAD was considered less feasible as an outcome due to its long time-to-event nature, making it more suitable for dedicated long-term studies.

The group recognized the need to pursue diverse funding strategies and/or pragmatic trial designs to navigate these constraints. In addition, creative partnerships with industry sponsors that develop medications for other indications such as bronchiolitis obliterans syndrome in the context of graft-versus-host disease offer an opportunity for the lung transplant community.⁸

Finally, the discussion turned toward creative trial designs that could enhance feasibility and power. These included prognostic and predictive enrichment strategies to reduce required sample sizes, target trial emulation using large multi-center datasets, and implement synthetic control arms, as explored in idiopathic pulmonary fibrosis studies.⁹ Overall, the group emphasized innovative design, recognizing that while traditional randomized trials remain valuable, a more flexible and strategic approach is necessary to launch impactful clinical trials.

Conclusion

The LTC, with the strong support of NIH/NHLBI, is an ambitious 20 center collaboration of lung transplant programs in North America. Analysis of data collected through the PROMISE study will serve as a platform for establishing best practices in lung transplant. The LTC studies will inform the validity of lung transplant syndromes and extend those concepts through analysis of PROs, image data, and biosamples. The PROMISE study and LTC create a critically needed research platform and multicenter collaborative experience, which can be easily adapted to conduct future multicenter clinical trials that will advance the practice of lung transplant medicine.

Table 1.

LTC 2025 State of the Art Breakout Session Topics

Breakout Session Title	Key Points
#1 Leveraging PROMISE data elements: biomarkers, imaging, and PROs	• Donor biomarkers, imaging, and PROs are crucial in predicting primary graft dysfunction and acute lung allograft dysfunction. • The PROMISE dataset can be used to refine the consensus definition of acute lung allograft dysfunction and can incorporate endotype classification.
	• Proposed studies could use PROs to evaluate long-term quality of life in transplant recipients, particularly those with chronic obstructive pulmonary disease or acute lung failure.
	• Synergies should be built across data sources (biomarkers, imaging, and PROs) to guide future lung transplant research.
#2 Clinical syndrome and consensus definitions	• Validation and refinement of syndrome definitions are major opportunities for PROMISE. • There is a desire to refine broad clinical syndrome definitions by using biologically driven classifications.
	• Alignment of PROMISE with complementary cohorts (e.g. the Lung Transplant Outcomes Group and Clinical Trials in Organ Transplant) could help link early syndromes to long-term outcomes.
	• There was significant interest in assessing changes in patient characteristics and clinical outcomes by era (for example, with the increased use of extracorporeal membrane oxygenation before, during, and after transplant).
#3 Variation in management and management strategies	• Perioperative variability, including differences in injury severity, risk tolerance, and use of sensitization protocols, should be studied. • Post-transplant variability, including variations in immunosuppression targets and surveillance intensity (e.g., biopsy frequency, cytomegalovirus monitoring, donor-specific antibody surveillance, and pulmonary function testing), should be studied.
	• Referral patterns are underrepresented but important for understanding access, equity, and pre-transplant risk.
	• Proposed innovations include advanced observational designs (e.g., propensity matching, inverse probability weighting) to study high-risk or non-listed patients and modeling of a tiered system for transplant centers.
#4 Future interventional trials leveraging the PROMISE consortium	• The Lung Transplant Consortium (LTC) infrastructure is well-suited to support future trials to target well-validated, early lung transplant outcomes, such as primary graft dysfunction and acute rejection.
	• Creative academic, foundation, industry, and federal partnerships are needed to support interventional trials in lung transplant
	• Traditional randomized trials remain important, but success in future trials will depend on adopting more flexible, innovative, and strategic designs leveraging concepts such as adaptive trial design or synthetic controls

Abbreviations: PRO, patient-reported outcomes; PROMISE, Prospective Multicenter Research on Donor and Recipient Management Strategies to Improve Lung Transplant Outcomes.

Abbreviations:

ALAD

acute lung allograft dysfunction

BLAD

baseline lung allograft dysfunction

CC

clinical center

CLAD

chronic lung allograft dysfunction

CleanUP-IPF

Clinical Efficacy of Antimicrobial Therapy Strategy Using Pragmatic Design in Idiopathic Pulmonary Fibrosis

COPD

chronic obstructive pulmonary disease

CTOT

Clinical Trials in Organ Transplant

DCC

data coordinating center

DCD

donation after circulatory death

ECMO

extracorporeal membrane oxygenation

EVLP

ex vivo lung perfusion

LTC

Lung Transplant Consortium

LTOG

Lung Transplant Outcomes Group

NHLBI

National Heart, Lung, and Blood Institute

NIH

National Institutes of Health

PGD

primary graft dysfunction

PRO

patient-reported outcome

PROMISE

Prospective Multicenter Research on Donor and Recipient Management Strategies to Improve Lung Transplant Outcomes