Evaluating mortality risk in elderly lung transplant patients

Introduction

Background

Lung transplantation is a life-saving intervention that has transformed the prognosis for individuals suffering from end-stage lung diseases. Over the past few decades, significant advancements in surgical techniques, immunosuppressive therapies, and post-operative care have propelled the field of lung transplantation into a new era (1-4). As a result, survival rates following lung transplantation have steadily improved, offering hope to countless patients worldwide. The demand for lung transplantation has risen steadily over the years, partly due to an aging population and an increased incidence of lung diseases. In the United States alone, the number of lung transplantations performed annually has more than doubled since the 1990s, reaching over 2,000 procedures in recent years (5). This surge in demand is further fueled by an aging demographic, with elderly individuals now comprising a significant portion of lung transplant recipients. Current data reveal that lung transplantation has become increasingly successful, with 1-year survival rates exceeding 85% and 5-year survival rates reaching nearly 60% (5). These improvements have been driven by a combination of factors, including better organ preservation methods, improved surgical techniques, and advancements in immunosuppressive medications.

Rationale and knowledge gap

However, these overall figures may obscure important disparities in outcomes among different patient populations. Despite the progress made in lung transplantation, a critical knowledge gap persists, particularly concerning the unique challenges faced by elderly recipients. While much has been written about overall transplant success, there remains a paucity of data addressing the specific mortality risk for elderly patients undergoing lung transplantation (6-9). As the number of elderly transplant recipients continues to rise, it is imperative that we gain a deeper understanding of the factors influencing their post-transplant survival.

Objective

To address this critical gap in knowledge, the objective of this study is clear: we aim to rigorously evaluate the mortality risk in elderly lung transplant patients through a comprehensive retrospective analysis. Our investigation focuses on patients aged ≥70 years who underwent lung transplantation. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-742/rc).

Methods

Study design

Clinical data were retrospectively obtained from electronic health records and compiled into a dedicated database at Northwestern University Medical Center in Chicago, Illinois, USA. The study population included adult individuals who received lung transplants at Northwestern Memorial Hospital between January 2018 and December 2023. Patients who underwent combined organ transplants or re-transplantation procedures were excluded. Collected variables included demographic information, underlying health conditions, donor profiles, pre-transplant laboratory results, as well as intraoperative and postoperative clinical outcomes. Preoperative laboratory values were recorded from the most recent measurements obtained prior to transplantation. No adjustments were made for sex or body size in the analysis. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This research received approval from the Northwestern University Institutional Review Board (protocol numbers STU00207250 and STU00213616). Given the retrospective nature of the study, the requirement for informed consent was waived by the board.

Statistical analysis

Characteristics of recipients and donors, along with preoperative laboratory findings and both intraoperative and postoperative outcomes, were analyzed by stratifying lung transplant recipients into two age groups: ≥70 and <70 years. Age and laboratory measurements were expressed as means with standard deviations, while durations (e.g., days) were summarized using medians and interquartile ranges [Q1–Q3]. For comparisons of continuous variables between groups, either the Student’s t-test or Mann-Whitney U test was applied, depending on data distribution. Categorical variables, presented as counts and percentages, were compared using the Chi-squared test. Survival probabilities were calculated using the Kaplan-Meier method, and differences in survival were evaluated using the Wilcoxon rank-sum test. A P value less than 0.05 was considered statistically significant. All analyses were conducted using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical interface for R (The R Foundation for Statistical Computing, Vienna, Austria) (10).

ECMO indication criteria

Before undergoing lung transplantation, all intubated patients received care from a multidisciplinary team following the ARDS Network guidelines established by the National Heart, Lung, and Blood Institute (11). Criteria for considering extracorporeal membrane oxygenation (ECMO) included persistent hypoxemia with arterial oxygen pressure (PaO₂) below 55 mmHg, oxygen saturation under 88% by pulse oximetry, and arterial pH falling below 7.2. These thresholds applied despite lung-protective ventilation strategies—such as maintaining plateau pressures under 35 mmHg—alongside neuromuscular blockade and prone positioning, in alignment with guidance from the Extracorporeal Life Support Organization (12). The decision to initiate ECMO was determined through multidisciplinary collaboration involving pulmonologists, thoracic surgeons, ECMO specialists, and intensive care physicians, with decisions facilitated using teleconferencing lines All surgical procedures were carried out by thoracic surgeons with extensive experience. Cannulation was performed using ECMO circuits connected to either a Rotaflow^TM (Getinge, Gothenburg, Sweden), Cardiohelp^TM (Getinge, Gothenburg, Sweden), or CentriMag^TM (Abbott, Abbott Park, Illinois, USA) system.

Anticoagulation during venous-venous (VV)-ECMO support

Continuous anticoagulation was not administered to patients unless clinically indicated, such as in cases of deep vein thrombosis (DVT) or pulmonary embolism. Consistent with our prior study, bleeding parameters like activated clotting time and activated partial thromboplastin time were not routinely monitored. For patients not on continuous systemic anticoagulation, a prophylactic dose of 5,000 units of subcutaneous unfractionated heparin was given every 8 hours to prevent DVT. VV-ECMO flow rates were maintained between 3.0 and 3.5 L/min, following our recent publications, to minimize thrombotic events within the ECMO circuit (13,14).

Definition of complication

Primary graft dysfunction (PGD)

Patients exhibiting no signs of pulmonary edema on chest X-ray (CXR) were assigned a grade 0. For those not on invasive mechanical ventilation, grading was based on the PaO₂/fraction of inspired oxygen (FiO₂) ratio, applying criteria similar to those used for ventilated patients. When PaO₂ measurements were unavailable for calculating the ratio, the oxygen saturation to FiO₂ ratio was utilized instead. The grading scheme was as follows: grade 1 corresponded to a PaO₂/FiO₂ ratio above 300; grade 2 ranged from 200 to 300; and grade 3 was assigned to ratios below 200. The lowest PaO₂/FiO₂ ratio recorded within 72 hours post-lung transplantation was used for classification. Patients requiring ECMO due to bilateral pulmonary edema visible on CXR were classified as grade 3. Cases with continuous ECMO support but without pulmonary edema on CXR were excluded from the grading (15).

Chronic lung allograft dysfunction (CLAD)

CLAD is characterized by the International Society for Heart and Lung Transplantation (ISHLT) as a sustained reduction of 20% or more in forced expiratory volume in one second (FEV₁) compared to the post-transplant baseline. In 2019, ISHLT released a consensus statement detailing the terminology and clinical subtypes associated with CLAD (16). Patients with three or fewer total FEV₁ measurements, which prevented a CLAD diagnosis, were excluded from the study.

Acute kidney injury (AKI)

AKI was defined according to the Risk, Failure, Loss, and End-stage kidney disease criteria as established in previous studies (17).

Results

Patient demographics: age ≥70 vs. <70 years

The study included 337 individuals who received lung transplants during the observation period. Elderly lung transplant recipients comprised 16.0% of the cohort (n=54) and had significantly fewer bilateral lung transplantations (25.9% vs. 70.3%, P<0.001), lower Lung Allocation Score (LAS) (46.4±11.4 vs. 57.2±19.9, P=0.002), shorter wait days {8 [5–15] vs. 17 [7–43], P=0.001} and higher hemoglobin (12.4±2.4 vs. 11.4±2.6 g/dL, P=0.007) than their younger counterparts (Table 1). In the elderly group, ILD was significantly more (61.1% vs. 33.9%, P<0.001) likely to be the etiology of lung failure of recipients than the younger group. There was no significant difference between the two groups in the donor characteristics. Subgroup analyses stratified by transplant type (single vs. bilateral) among the elderly and younger groups were presented in Table S1.

Intra- and postoperative outcomes after lung transplantation: age ≥70 vs. <70 years

The elderly group had a shorter ischemic time {4.3 [3.7–5.3] vs. 5.2 [4.2–5.9] hours, P=0.004}, a lower rate of intraoperative veno-arterial (VA) ECMO use (44.4% vs. 66.4%, P=0.003), a shorter duration of VA-ECMO {0 [0–2.2] vs. 2.5 [0–3.1] hours, P<0.001}, and a lower volume of blood transfusion {0 [0–1] vs. 1 [0–3] units, P<0.001} (Table 2).

There was a significant difference in operative time when all procedures were viewed {4.9 [3.5–5.6] vs. 6.2 [5.1–8.0] hours, P<0.001}, but there was no significant difference when viewed by single {4.3 [3.3–5.3] vs. 4.6 [3.3–5.4] hours, P=0.80} or bilateral {6.2 [5.3–7.2] vs. 7.4 [5.8–8.3] hours, P=0.06} lung transplantation (Table S1).

Postoperatively, there was no significant difference in the incidence of complications after lung transplantation including AKI, stroke, bowel ischemia, digit ischemia, PGD, post-transplant ECMO use, and hospital stay (Table 2). However, the elderly group had shorter intensive care unit (ICU) stay {6 [4–10] vs. 8 [5–18] days, P=0.01}, and post-transplant ventilator use {2 [1–2] vs. 2 [1–4] days, P=0.006} (Table 2). The incidence of CLAD was not significant different between the elderly and younger groups (8.3% vs. 24.1%, P=0.05), suggesting comparable rates of long-term allograft dysfunction across age groups.

In the Kaplan-Meier analysis, the 1-year survival rate for the elderly group was 82.7%, which was lower than the 90.1% for the young group (P=0.30). The overall survival rate was also nearly equivalent (5-year survival rate: 49.1% vs. 59.0%, P=0.30) (Figure 1).

Figure 1 Kaplan-Meier analysis of overall survival after lung transplantation. Comparison of the survival rates among patients aged ≥70 years and younger.

Infection outcomes

The infection outcomes were shown in Table 3. The overall incidence of infections had no significant difference between the elderly and younger groups (74.1% vs. 68.9%, P=0.63). Respiratory infections occurred at similar rates between the two groups (61.1% vs. 58.0%, P=0.76), as did recurrent respiratory infections (13.0% vs. 19.8%, P=0.26). There was no significant difference in cytomegalovirus (CMV) infections (22.2% vs. 17.0%, P=0.44) and positive Aspergillus galactomannan antigen (31.5% vs. 22.3%, P=0.17) between the elderly group and the younger group. Additionally, blood culture positivity rates for bacterial infections (7.4% vs. 7.4%, P>0.99) were comparable between the two groups. Blood culture positivity rates for fungal infections tended to be less frequent in the elderly group, though the difference did not reach statistical significance (1.9% vs. 4.6%, P=0.71).

Rejection outcomes

Rejection outcomes demonstrated no significant difference in the incidence of acute cellular rejection (ACR) (35.2% vs. 28.3%, P=0.33) and antibody-mediated rejection (AMR) (9.3% vs. 4.9%, P=0.21) between the elderly and younger groups (Table 4). The median number of ACR {0 [0–1] vs. 0 [0–1], P=0.53} and AMR {0 [0–0] vs. 0 [0–0], P=0.21} episodes was also similar between the groups.

Predictors of mortality in patients aged ≥70 years and cut-off level of serum creatinine

Univariate logistic regression analysis of recipient, donor, and operative characteristics revealed only serum creatinine level [hazard ratio (HR): 10.9, 95% CI: 1.44–82.0, P=0.02] as predictive of mortality in the elderly group (Table 5). Youden index showed creatinine level over 0.85 mg/dL (Youden index: 0.27, sensitivity: 73.3%, specificity: 53.8%) is a risk factor for mortality (Table S2).

Discussion

In our comprehensive retrospective study, we found no statistically significant difference in survival rates between elderly and young lung transplant recipients. This result provides valuable insights into the outcomes of these distinct patient groups, which is similar result as prior study (18). The focus on elderly lung transplant recipients, a growing demographic, adds unique value to the existing body of knowledge. While previous research has explored transplant outcomes (7,8), few studies have delved deeply into the unique challenges and outcomes faced by elderly individuals. The prior study has recently reported a single-center analysis of lung transplant outcomes in recipients aged ≥70 years, and survival did not differ between elderly and younger groups after propensity matching. Our study fills a critical gap in the literature by dedicating attention to a rapidly growing and underserved demographic. The absence of a statistically significant difference in survival rates between elderly and young lung transplant recipients can be attributed to advancements in surgical techniques, improved immunosuppressive therapies, and more precise patient selection criteria. This underscores the potential for successful lung transplantation in elderly individuals when appropriate clinical strategies are applied. Furthermore, our results stress the need for individualized post-transplant care for both age groups to address specific risk factors effectively. With an aging population and a rising demand for lung transplants (5), this study holds clinical relevance. It provides critical insights for transplant clinicians who must make complex decisions about patient eligibility and post-transplant care.

Historically, age is one of the important factors for success of lung transplantation (6,7), however, age alone should not be the sole determinant; instead, it serves as a starting point for evaluation. At our institution, assessment of physical activity and functional status is very crucial. Potential candidates undergo rigorous evaluations, including exercise tolerance tests. The ability to perform daily activities and the presence of physical limitations are considered. Candidates who maintain a reasonable level of physical activity despite their respiratory condition may be more favorable candidates. Nutritional status is also evaluated, as malnutrition can negatively impact post-transplant outcomes. Candidates with nutritional deficiencies may need to receive dietary interventions and support to improve their health prior to transplantation. Psychosocial assessments are performed to gauge a candidate’s mental and emotional readiness for transplantation. Candidates should have a strong support system in place, including family or caregivers who can assist during the post-transplant recovery period.

The significantly lower rate of bilateral lung transplantation in elderly recipients (25.9% vs. 70.3%) likely reflects a multifactorial decision-making process, including the patient’s physiologic status, comorbidities, and perceived perioperative risk. Elderly patients often have higher surgical risk profiles, including reduced cardiac function, frailty, and impaired renal function, which may make single lung transplantation a more favorable option. While institutional policy does not strictly dictate single lung transplantation for older patients, clinical judgment often leans toward minimizing procedural burden in this age group. Moreover, elderly lung transplant recipients had significantly lower LAS and markedly less frequent preoperative ECMO use compared to their younger counterparts. This likely reflects a more selective evaluation and listing process for elderly recipients, who are generally screened stringently to identify those with better functional status and lower perioperative risk. Such selection bias means that our elderly cohort may represent a relatively healthier subgroup, which could partly explain their comparable survival outcomes despite advanced age.

Immune dysfunction associated with aging is an important aspect of vulnerability to infection in elderly lung transplant recipients (19). Infection-related complications not only contribute to early mortality but also increase the risk of long-term graft loss and CLAD (20). Our study demonstrated that the elderly lung recipients had no significant higher incidence of infections, which may lead to comparable survival rate in the elderly group. Additionally, ACR and AMR remain critical causes of early and late graft dysfunction after lung transplantation (21,22). In our selected elderly lung transplant recipients, the incidence of rejections such as ACR and AMR was comparable to the younger group, suggesting that AMR and ACR can be controlled with appropriate immunosuppressant management. We also observed no significant difference in the incidence of CLAD between elderly and younger recipients. This finding is clinically meaningful, as CLAD remains a leading cause of late graft failure and long-term morbidity after lung transplantation. The comparable rates suggest that, when appropriately selected, elderly patients may achieve not only short-term survival but also durable graft function comparable to their younger counterparts. This supports the expanding role of lung transplantation in elderly candidates, emphasizing that age alone should not be a barrier to listing, particularly when long-term graft outcomes are taken into consideration.

In this analysis, only creatinine level was a risk factor of mortality for the elderly group (HR: 10.9, 95% CI: 1.44–82.0, P=0.02). This finding is biologically plausible, as serum creatinine reflects renal function, which is an established marker of overall physiological reserve and end-organ dysfunction. Pre-existing kidney impairment has been associated with increased susceptibility to perioperative complications, impaired drug clearance (particularly of immunosuppressants), and higher rates of infection and multi-organ dysfunction after transplantation. Therefore, creatinine levels may capture aspects of a patient’s underlying frailty not fully reflected by other clinical parameters. Moreover, our recent evidence suggests that early complications such as PGD are significantly associated with AKI, which subsequently contributes to worsening chronic kidney disease over time (3). This underscores the prognostic importance of early renal dysfunction as a reflection of systemic vulnerability in lung transplant recipients.

One of the explanations of equivalent overall survival rate between patients aged ≥70 and <70 years might be less invasive procedure (about 75% were single lung transplantation) with short ICU and hospital stay. It’s important to note that the selection process for elderly lung transplant candidates is highly individualized in our center. Each patient’s unique circumstances, including their overall health, comorbidities, and support system, are carefully considered. The goal is to ensure that candidates have the best possible chance of a successful transplantation and post-transplant quality of life. The findings guide clinicians in offering equitable access to life-saving lung transplantations for all eligible candidates, regardless of age. From a patient perspective, this study offers hope and reassurance. Elderly individuals suffering from end-stage lung diseases may now have a more positive outlook on the possibility of receiving a lung transplantation. This can alleviate anxiety and uncertainty among patients and their families.

Despite its strengths, our study is not without limitations. The retrospective design carries inherent risks of selection bias and unmeasured confounders. The reliance on data from a single center may limit the generalizability of our findings to other institutions. Additionally, our analysis focused primarily on survival rates, while other important clinical endpoints and quality-of-life measures were outside the study’s scope. Future research should delve into these aspects for a more comprehensive understanding of transplant outcomes.

Conclusions

In conclusion, our study challenges conventional wisdom by revealing comparable survival rates between elderly, particularly aged ≥70 years, and young lung transplant recipients. The risk factor for mortality in the patients aged ≥70 years was preoperative creatinine level. This finding underscores the significant progress made in lung transplantation and calls for a reconsideration of transplant eligibility criteria. Ultimately, this study represents a significant step toward ensuring equitable access to life-saving lung transplantations for all eligible candidates, regardless of age with careful selection.

Acknowledgments

The authors would like to thank Ms. Elena Susan for her administrative assistance in the submission of this manuscript. A portion of this work was presented as a poster at the 44th Annual Meeting and Scientific Sessions of the ISHLT in 2024.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-742/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-742/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-742/prf

Funding: This work was supported by the National Institutes of Health (grant No. HL176632, to C.K.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-742/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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This research received approval from the Northwestern University Institutional Review Board (protocol numbers STU00207250 and STU00213616). Given the retrospective nature of the study, the requirement for informed consent was waived by the board.

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/.

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