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Updates in Lung Transplantation and Research Opportunities

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By Jen Alexander-Brett MD PhD, Siddhartha Kapnadak MD, and Amy Skiba

The practice of lung transplantation is evolving with recent developments including the emergence of new molecular diagnostics for acute rejection, changes in the definition and management of chronic rejection, and the very recent adoption of the Composite Allocation Score for prioritizing transplant candidates. Continued engagement of transplant patients in research will be critical to evaluating the benefit, cost-effectiveness, and equity of ongoing changes in clinical practice. Furthermore, as long-term lung transplant survival continues to lag other organs, advances in early detection and treatment of chronic rejection remain substantial unmet needs for improving patient outcomes.

While lung transplantation is an important treatment option for advanced lung disease, the number of patients in need far exceeds available donors. Donor allocation has evolved to support the overarching goals of improving transplant access for those most in need, avoiding futile transplants, and reducing the impact of geography. The U.S. lung allocation score (LAS) was implemented in 2005, prioritizing candidates based on projected 1-year waiting list mortality and likelihood of 1-year post-transplant survival, with the former weighted double. The LAS reduced waiting list mortality without impacting one-year post-transplant survival despite average recipients being older and sicker in the post-LAS era. Despite its benefits, the LAS did not address the impact of geography on allocation, historically prioritizing organs by Donor Service Area (DSA)’s, which were heterogenous in size, population, and donor availability, resulting in geographical disparities in waiting list outcomes. In 2017 the primary allocation unit was changed to a 250-nautical mile radius surrounding the donor hospital. However, several new concerns became apparent including potential to reduce efficiency (e.g., travel distances, costs), and the arbitrary nature of the 250-mile primary allocation zone by which sicker but slightly more distant candidates may be ineligible for organs. Moreover, several studies demonstrated that candidates who are allo-sensitized (with pre-transplant anti-human leukocyte antigen antibodies), of shorter stature, and blood group O have reduced donor access impacting waiting list survival.

To address these issues, a new lung Composite Allocation Score (CAS) took effect on March 9, 2023, prioritizing candidates based on:

1. Pre-transplant medical urgency

2. Projected post-transplant survival

3. Biological disadvantages (blood type, sensitization, height)

4. “Patient access” issues (points awarded for previous organ donors and age < 18)

5. Efficiency of donor organ transport to a given (nationwide) recipient.

In addition to removal of rigid geographic boundaries, the CAS utilizes five (rather than one)-year post-transplant survival and pre/ post-transplant survival are weighted 1:1. These are important distinctions that prioritize longer-term outcomes after transplant. The CAS is projected to reduce waiting list mortality particularly among sicker candidates, with no change in 2-year post-transplant survival.

The “continuous distribution” framework is the first in organ transplantation and this novel approach brings numerous research opportunities to the lung transplant community, as described here.

First, a likely shift in demographics will require further understanding on multiple fronts, with the CAS projected to increase transplant rates in sicker and younger candidates, while reducing the proportion of transplants for chronic obstructive pulmonary disease and increasing waiting time for less urgent candidates. While transplant rates are projected to increase in candidates with blood group O and shorter stature, it is unclear if/how the changes may impact populations with reduced healthcare access including those with non-white race or socioeconomic barriers.

Second, the overall median distance from donor to recipient is projected to increase particularly for the sickest recipients. It will be important to understand the impact on ischemia times and risk of primary graft dysfunction, as well as optimal organ management strategies in the current era marked by increasing use of ex-vivo lung perfusion and other preservation systems. Costs, resource utilization, and optimal donor selection practices in the CAS era will also need further elucidation. Finally, although projections do not show decreases in transplant rates among lower volume transplant centers, it is unclear how center volume will interact with potential changes in transplant demographics and donor acceptance practices in the coming years. It’s also unclear how these factors may impact practices and transplant outcomes.

Following lung transplantation, serial surveillance biopsies are typically obtained within the first year and represent the gold standard method for detecting acute rejection. Bronchoscopy with biopsy is not without risk, and recently developed molecular diagnostic tests including donor-derived cell-free DNA (cfDNA) or gene expression 8 June 2023Research News Quarterly profiling (GEP) assays performed on peripheral blood are a welcome supplemental diagnostic tool for allograft injury. Cell-free DNA assays are based upon detection of the small quantity of circulating donor-derived extracellular (cell-free) DNA released from the allograft in the setting of cellular damage. Blood samples are subject to highly sensitive next-generation sequencing to yield the fraction of cell-free DNA derived from the allograft. Based on analysis of patient cohorts in multiple solid organ transplant populations, threshold percentages of donor-derived cfDNA have been validated as a measure of allograft injury that correlates with acute rejection on tissue biopsy. The demonstrated utility of these supplemental methods for surveillance in patients at increased risk for biopsy have prompted recent Medicare coverage of testing and subsequent widespread uptake among transplant programs across the country. However, additional research is needed to guide interpretation of these less invasive methods when other forms of lung injury are present, particularly in the presence of infection, antibody mediated rejection and early chronic rejection. Furthermore, these tests are based on expensive and specialized methods. Therefore, technological advancements, as well as cost-benefit analyses, will be needed to support insurance coverage. Most importantly, analysis of the impact on overall rates of chronic rejection and survival post-lung transplant will better define the role of molecular diagnostics in transplant program surveillance protocols going forward.

Chronic rejection stubbornly remains the greatest barrier to longterm survival post lung transplant, with a current median survival rate of 6.0 years. Historically, the clinical diagnosis bronchiolitis obliterans syndrome (BOS), with obstructive physiology and the obliterative bronchiolitis pathological correlate, were considered the hallmarks of chronic rejection. While that pattern remains dominant, other forms of chronic rejection are now recognized. An example is restrictive allograft syndrome (RAS), which is characterized by restrictive physiology, radiographic infiltrates and histopathology with features of alveolar damage and parenchymal fibroelastosis. Collectively, these entities along with mixed or undefined forms of chronic injury are now included under the umbrella term chronic lung allograft dysfunction (CLAD). The definition of CLAD is made regardless of subtype and based on a persistent (≥ 3 months) decline in FEV1 of ≥ 20%, with 4 stages encompassing a range of FEV1 from 80% to less than 35%.

There remain limited options for management of CLAD, with typical practice including addition of macrolide antibiotics, extracorporeal photopheresis (ECP), or otherwise intensifying immunosuppression. A multicenter Medicare sponsored clinical trial investigating the efficacy of ECP in lung transplant patients with CLAD has completed enrollment and programs are currently awaiting the results and subsequent decisions regarding future patient access. There have also been limited studies investigating the addition of antifibrotics or mesenchymal stem cell-based therapies in treatment of CLAD.

Research focused on interventions for CLAD going forward will likely need to consider heterogeneity of the process and anticipate potential differences in response within BOS and RAS subtypes. Currently, they are distinguished based on a combination of physiological impairment, radiographic features and the exclusion of other contributing processes. Future research protocols would benefit greatly from the availability of molecular diagnostics specific to CLAD, particularly if diagnosis could be made prior to onset of physiological impairment and with the ability to distinguish between the major subtypes BOS and RAS.

Given the numerous research questions to be addressed in lung transplantation, as a research community, how can we best partner with our patients to achieve the necessary advances in access, diagnostic capabilities, and outcomes? The Lung Transplant Foundation strives to help connect patients with researchers through dissemination of information about ongoing clinical trials and tissue specimen biorepositories to support basic-translational research into conditions for which these patients are referred for lung transplantation. These efforts continue to be especially critical for rare diseases, where the genetic basis is unknown and animal models are lacking. With respect to patient participation in clinical trials, many find the protocols or interventions difficult to understand, and it can be challenging to access more information. Likewise, patient education regarding chronic rejection is highly variable and improved understanding of the diagnosis and treatment options could facilitate better participation. Accordingly, the Lung Transplant Foundation is working on a one-page report for clinical trials that may be shared with patients and clinicians to facilitate recruitment into trials for CLAD. The Foundation also recently participated in an FDA Patient-Focused Drug Development meeting on the topic of BOS, which was summarized in a Voice of the Patient Report.

Together, clinicians and patients can be empowered to improve outcomes in lung transplantation. The practice changes and advancements described above, along with ongoing clinical trials in CLAD, as well as the development of precision diagnostics and advancement of basic research into the fundamental pathophysiology that drives chronic rejection, all hold promise for better future outcomes.

The ATS Research News Quarterly is a new publication that features updates and announcements from all of the research programs that the ATS monitors, including the National Institute of Health (NIH), Centers for Disease Control and Prevention (CDC), the VA Research program, the Agency for Healthcare Research and Quality (AHRQ) and the Environmental Protection Agency (EPA).

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