Beating the odds: long-term survival after lung transplantation

In a recent issue of Journal of Thoracic Disease, Miggins and colleagues report recipient and donor factors identified in the United Network for Organ Sharing (UNOS) database that are associated with long-term survival beyond 20 years of lung transplant conditional to one-year survival (1). Specifically, these authors analyzed data on over 6,000 patients and found younger recipient age, female-to-female gender matching, minimal human leukocyte antigen (HLA) mismatch, waitlist time >1 year, donor cause of death: head trauma, and bilateral lung transplant as independent predictors for 20-year survival. On the contrary, a pre-transplant diagnosis of chronic obstructive pulmonary disease/emphysema in the recipient, recipient blood groups O & AB, decreased glomerular filtration rate (GFR) in the recipient and donor, and donor smoking history were associated with a decreased likelihood of 20-year survival.

The identification and prevention of donor- and recipient-related predisposing factors to chronic lung allograft dysfunction (CLAD) are critical to the attainment of improved long-term survival outcomes in lung transplant recipients. Interestingly, there was no association between recipient body mass index (BMI), donor-recipient size matching and long-term survival which contradicts findings from recent International Society for Heart and Lung Transplantation (ISHLT) reports on recipient and donor characteristics (2,3). In these studies, increasing BMI and donor-recipient size mismatch were associated with decreased survival; undersized lungs were associated with a decreased survival for all end-stage lung disease diagnoses except interstitial lung disease. Since these reports examined 5-year survival outcomes, it is likely these variables have a transient impact on survival and fail to impact multi-decade survival outcomes.

Concurrent with prior reports, a long-term survival benefit was observed with bilateral (BLTs) over single lung transplants (SLTs) (2,4). Compared to SLT recipients, those who underwent BLTs were 30% less likely to suffer mortality within 20 years of their transplant. BLTs have been found to decrease the risk of acute cellular rejection, bronchiolitis obliterans (a predominant manifestation of CLAD), and improve long-term survival for lung transplant recipients (4). The relatively increased utilization of BLT over the last decade is likely reflective of this survival benefit.

Female patients undergoing lung transplantation demonstrate relatively improved survival outcomes (2). In the current analysis, female donor-recipient gender matching was notably associated with an increased likelihood of 20-year survival. The same trend was not observed with male donor-recipient gender matching. If gender matching alone was the driver of this survival benefit, the same trend would be expected with all allografts from gender-matched donors. It is unclear what biologic and immunologic characteristics in women confer this survival advantage. While it is plausible that the Y-chromosome derived antigens elicit an antibody response that compromises long-term allograft function with male-female donor-recipient gender mismatching, there are certainly more questions to be answered.

Although, not examined in the current analysis, outcomes of donor-recipient racial matching is an area of interest in thoracic organ transplantation. Using UNOS data, Allen et al. reported superior short-term survival outcomes among racially matched donor-recipient pairs undergoing lung and heart transplantation (5). These findings highlight the need for focused investigation into relevant gender- and racial-based hormonal, biologic and immunologic factors that may influence long-term survival outcomes of lung transplant recipients. Identifying these characteristics could create potential avenues for intervention that would help mitigate the existing challenge in the long-term survivorship of lung transplant patients.

Beyond gender matching, this paper highlights the potential benefits of more closely matching donors and recipients based on their HLA. Unfortunately, matching on several donor-recipient characteristics including HLA has not been feasible in the face of a limited donor pool. Potential solutions to the existing shortage in the donor pool are the increased utilization of extended criteria donors (ECD) and ex-vivo lung perfusion (EVLP) in carefully selected patients, while increasing public awareness surrounding organ donation (6). Recent studies have described comparable short- and medium-term survival with ECD and EVLP as compared to standard protocol lung transplantation (7,8). It is left to be seen how these grafts will compare to standard protocol grafts in terms of multi-decade survival outcomes. Notably, this study found no association between advanced donor age on 20-year survival after lung transplantation, which augurs well in view of the limited donor organ pool.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Thoracic Disease. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1018/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Miggins JJ, Reul RM Jr, Barrett S, et al. Twenty-year survival following lung transplantation. J Thorac Dis 2023;15:2997-3012. [Crossref] [PubMed]
2. Chambers DC, Perch M, Zuckermann A, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-eighth adult lung transplantation report - 2021; Focus on recipient characteristics. J Heart Lung Transplant 2021;40:1060-72. [Crossref] [PubMed]
3. Chambers DC, Cherikh WS, Harhay MO, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-sixth adult lung and heart-lung transplantation Report-2019; Focus theme: Donor and recipient size match. J Heart Lung Transplant 2019;38:1042-55. [Crossref] [PubMed]
4. Kulkarni HS, Cherikh WS, Chambers DC, et al. Bronchiolitis obliterans syndrome-free survival after lung transplantation: An International Society for Heart and Lung Transplantation Thoracic Transplant Registry analysis. J Heart Lung Transplant 2019;38:5-16. [Crossref] [PubMed]
5. Allen JG, Weiss ES, Merlo CA, et al. Impact of donor-recipient race matching on survival after lung transplantation: analysis of over 11,000 patients. J Heart Lung Transplant 2009;28:1063-71. [Crossref] [PubMed]
6. Neizer H, Singh GB, Gupta S, et al. Addressing donor-organ shortages using extended criteria in lung transplantation. Ann Cardiothorac Surg 2020;9:49-50. [Crossref] [PubMed]
7. Christie IG, Chan EG, Ryan JP, et al. National Trends in Extended Criteria Donor Utilization and Outcomes for Lung Transplantation. Ann Thorac Surg 2021;111:421-6. [Crossref] [PubMed]
8. Chakos A, Ferret P, Muston B, et al. Ex-vivo lung perfusion versus standard protocol lung transplantation-mid-term survival and meta-analysis. Ann Cardiothorac Surg 2020;9:1-9. [Crossref] [PubMed]