1 Background
Based on the International Society for Heart and Lung Transplantation (ISHLT) data, the ratio of recipients aged ≥ 66 years has increased up to 19% in 2017 [
1]. In the US, reports showed that the percent of recipients aged ≥ 65 years increased to over 30% in 2019 [
2]. Recent guidelines have characterized age over 65 years as a relative contraindication, but a steady increase in the threshold at which age is taken into consideration for lung transplantation has been observed [
3].
Several risk factors for mortality in recipients aged ≥ 65 years have been reported on the basis of the large multinational LT registry [
4]. End-stage lung disease with concurrent cardiac abnormalities, including coronary artery disease (CAD) and cardiac valve disease, is common in the aged population. Coronary angiography-confirmed CAD, regardless of treatment with either drugs, percutaneous coronary intervention (PCI), or coronary artery bypass graft (CABG), is not an absolute contraindication for lung transplantation [
5]. Cardiovascular-related deaths account for 11.6% of the deaths in lung transplant recipients within the first month of LT [
6], and the use of immunosuppressive therapy post-LT may accelerate the progression of atherosclerosis. Cases with concurrent or consecutive LT and cardiac surgery have been reported; however, the effect of the therapeutic strategy of CAD on LT is not adequately established. Furthermore, data are extremely lacking on LT recipients who are elderly and have cardiac diseases.
We have previously reported the outcomes of LT programs between 2015 and 2018 in China [
7]. The number of LT recipients who are aged ≥ 65 years has increased dramatically in recent years; in particular, we have performed LT in five elderly patients suffering from respiratory failure caused by COVID-19-related pulmonary fibrosis [
8]. Our center maintains the largest LT program in China, with a transplant volume of approximately 150 cases/year [
9]. In this study, we presented data of lung transplant recipients aged ≥ 65 years at our center over the past 5 years to determine the survival outcomes, risk of death, and early comorbidities.
2 Methods
2.1 Study population
This retrospective cohort study recruited patients who underwent lung transplantation from January 2016 to October 2020 at our center. A total of 166 recipients aged ≥ 65 years were identified, and the study included 55 recipients who were ≥ 70 years old and 111 recipients aged between 65 (included) and 70 (not included) years. The ratio of patients aged ≥ 65 years in all recipients from 2016 to 2020 was about 24%.
The Institutional Ethics Committees of Wuxi People’s Hospital approved the study, including our retrospective review, non-interventional design, and data analysis. All patients in our study were anonymous. The research was conducted in accordance with the 2000 Declaration of Helsinki and the Declaration of Istanbul 2008. The Institutional Ethics Committee approved the transplantation procedures, and transplanted organs were obtained from volunteer donations. No lungs were obtained from executed prisoners. A written informed consent on the transplantation procedure was obtained from patients and next of kin. The transplanted organs were obtained from volunteer donations, and the next of kin voluntarily provided a written informed consent.
2.2 Data collection and clinical characteristics
Patient pre-operative demographics, donor’s data, operative data, post-operative clinical features, and clinical events during the follow-up period were collected through a medical record database in our center and national lung transplantation registry database. Data collection protocol is demonstrated in supplementary methods. We collected data from recipients who had cardiovascular abnormalities (CAD and valve disease) for pre-LT evaluation, and these patients were defined as the group of patients with cardiac abnormalities.
2.3 Statistics
Demographic data related to donors, recipients, and transplants were presented as numbers and percentages for categorical variables. Continuous variables were expressed as the mean ± SD if they exhibited a normal distribution or as median (interquartile range (IQR)) if they displayed a skewed distribution. Continuous and categorical variables were compared using Student’s t-test or the Mann–Whitney U test, Chi-square, or Fisher’s exact test as appropriate. In identifying the prognostic effect of age group and cardiac abnormality on survival, cumulative survival as a function of time was investigated using Kaplan–Meier analysis and compared by log-rank tests. Univariate and multivariate Cox proportional-hazard regression models were used to test the correlation between exposure variables and post-lung transplantation survival. Regression analysis results are presented as hazard ratios (HR) and 95% confidence interval (CI). The modifications and interactions of subgroups were inspected by likelihood ration tests. Data calculations and comparisons were performed using SPSS version 25 (SPSS Inc., Chicago, IL, USA). Furthermore, R (The R Foundation) and EmpowerStats (X&Y Solutions, Inc., Boston, MA) were used to plot and model. A P value less than 0.05 was considered significant.
3 Results
3.1 Pre-operative characteristics
Among the entire study cohort of 166 lung transplant recipients aged ≥ 65 years, subgroups of patients aged 65–70 years (111 recipients, group 65–70) and ≥ 70 years (55 recipients, group ≥ 70) were included (Tab.1). A high percentage of recipients aged ≥ 70 years were residents in Jiangsu Province, where our center is located, considering the medical insurance coverage for LT. Group D restrictive lung disease was the main indication of LT in recipients aged ≥ 65 years, and chronic obstructive pulmonary disease (COPD) was the second most indicated underlying condition for LT. The cardiac function, as graded by the NYHA system, showed that most recipients were Grade III–IV before LT. The majority of subjects were hospitalized at the time of transplantation (97.3% and 92.8%).
For candidates with CAD, CT angiography and cardiac ultrasound were still performed when the patient was evaluated for LT and treated with drug therapy or PCI. Among patients who had a history of cardiac disease during admission to our center, six (3.6%) had PCI and stent implantation pre-LT, and one received a concomitant CABG. We also found a significantly higher percentage of coronary artery abnormalities in group ≥ 70 compared with group 65–70 (30.9% vs. 14.4% in group 65–70,
P = 0.014); furthermore, we found valvular structural abnormalities in both groups, ranging from 8.1% to 16.4%, which included medium-to-severe valve stenosis or regurgitation. Only data from transthoracic ultrasound were available because of limitations in time and facilities. Recipients aged ≥ 65 years had a high mean pulmonary artery pressure level (58.2 ± 19.1 mmHg in group 65–70 vs. 54.9 ± 11.2 mmHg in group ≥ 70). ECMO bridging to LT was performed in 5.4% (group 65–70) and 7.3% (group ≥ 70) of patients. All bridging cases were recipients that had underlying pulmonary fibrosis, and the rate was higher than the rate reported in the other registry [
4]. Comorbidities, such as cardiac disease and hypertension, were more common in group ≥ 70 recipients. A high percentage of pulmonary infection that required hospitalization in group ≥ 70 patients was also observed. Furthermore, no significant differences in the rate of pre-LT cerebral vascular disease, diabetes, pre-transplant pulmonary embolism, or CMV/EB antibody tests were observed among the groups.
3.2 Perioperative course
In China, more lungs were donated, but donors often have a long intubation time before organ retrieval, which causes a low utilization rate [
10]. Most donations were brain death donors, who had an average intubation time of 7.6 days (group 65–70) and 5.5 days (group ≥ 70) before organ retrieval (Tab.2). The average cold ischemic time was 434.6 min in group 65–70 and 395.9 min in group ≥ 70, which were both over 6.5 h. Single lung transplantation was performed most often in both groups, and we performed more single left lateral lung transplantation in group ≥ 70 patients, which may be due to patients primarily having pulmonary fibrosis. The strategies for the selection of the LT type were different between the two age groups and were affected by the indication and cardiopulmonary function. Intraoperative ECMO support was used in 73% of the recipients in group 65–70 and 65.5% of recipients in group ≥ 70, and ECMO support for single lateral lung transplantation was performed in 91.7% of the recipients in group ≥ 70. The median ICU stay post-LT was 5 days (group 65–70) and 4 days (group ≥ 70). Post-LT infections occurred in over 90% of patients in both groups, and the rate of fungal infections was as high as 58.2% in group ≥ 70 (Tab.3). Significantly higher occurrence rates of acute rejection, cardiac arrhythmia, and pleural effusion were observed in group ≥ 70 compared with group 65–70. In particular, we still observed residual or new-onset cardiac valvular abnormalities post-LT in 20.7% of the recipients in group 65–70 and 34.5% in group ≥ 70 during the follow-up, although the difference did not reach statistical significance.
3.3 Outcome and survival
Using the Cox proportional-hazards regression model with cubic spline functions and smooth curve fitting, we observed that the correlation between age and death is nonlinear (Fig. S1). Kaplan–Meier estimates of the 30-day, 3-month, and 1- and 3-year survival by age groups are shown in Table S1, and the survival curves are shown in Fig.1. The most common cause of death post-lung transplantation was infection (47.4% vs. 44.4%), followed by multi-organ dysfunction and fatal hemorrhage (Tab.3). We further compared the survival curves between patients with and without cardiac abnormality and the NYHA grading, and the result showed a significantly higher mortality risk in recipients with a cardiac abnormality (P = 0.0093, Fig.1) and a NYHA Grade of IV (P < 0.0001, Fig.1).
3.4 Multivariate and subgroup analyses using the Cox proportional-hazard regression model
In univariable analysis, assessed clinical characteristics were found to be significantly associated with mortality (Table S2). In adjusting for covariates, patients with cardiac abnormality have 93% increased risk of mortality based on an unadjusted model. After adjustment for age, the risk was 82%, and the difference was statistically significant; furthermore, when adjusted for other demographic variables, an even higher risk was demonstrated (Tab.4). We conducted stratified analysis and interaction tests in pre-defined subgroups to comprehensively understand other potential influencing factors related to cardiac disease and risk of post-lung transplantation mortality (Tab.5). Interaction analysis detected that age and cardiac abnormality played an interactive role in post-lung transplantation mortality (P for interaction = 0.0013). The results were not statistically significant for diagnosis and transplantation type, which were the key factors when considering the transplantation strategy, thereby minimizing the risk of mortality.
Discrepancy between the hemodynamic characteristics and post-LT event risk was observed between pulmonary fibrosis recipients and COPD recipients, which need optimizing the transplantation strategy. A bilateral lung transplantation was preferred for all indicated patients without cardiac abnormalities and in patients without the need for ECMO support. In general, we performed a single lateral lung transplantation with V-V or V-A ECMO for patients with pulmonary fibrosis with cardiac abnormalities or who had the need for ECMO support after considering lung function and pulmonary hypertension; otherwise, for COPD patients, bilateral lung transplantation with V-V ECMO was performed on patients without significant cardiac abnormalities, whereas a V-A ECMO-supported single lateral lung transplantation was preferred for patients with cardiac abnormalities (Fig.2). A statistically higher incidence of mortality events was observed in recipients with moderate-to-severe primary graft dysfunction (PGD), cardiac arrhythmia, reintubation, and acute kidney injury (Figs. S2 and S3). More events of cardiac arrhythmia, pulmonary embolism, and acute kidney injury were found in recipients with cardiac abnormalities (Table S3). A nomogram with C-statistic of 0.77 for predicting survival in recipients ≥ 65 years was further constructed on the basis of the data set with an internal validation (Fig. S4).
4 Discussion
We conducted this analysis of survival outcomes and risk factors for mortality in LT recipients aged ≥ 65 years in the largest LT center in China during the past 5 years. Since 2015, China has announced that voluntary organ donation after death is the sole source of transplantation, and the “green channel of human organ transportation” was established in 2016. We have transplanted more recipients with extreme ages and critical conditions. We published the initial results of LT outcomes in the China Lung Transplantation Registry from 2015 to 2018 [
7]. When survival was stratified by age groups, we observed that patients aged 66+ years had an inferior survival probability compared with younger recipients, as reported by other studies [
11]. Compared with those reports from Western LT centers with long waiting lists, the utilization rate of donor lungs in China remains low [
10]. Meanwhile, we had a high proportion of critical patients aged ≥ 65 years who were reluctant to consider LT as their treatment of choice when their lung disease progressed to a late stage. When the patients were referred for LT, they always had multiple comorbidities, and they were not tolerant to full evaluation, including a 6-min walking distance, lung function, and coronary angiography by catheterization.
In our center, we have a protocol to evaluate candidates aged ≥ 65 years, and this protocol includes a CTA for cardiac and pulmonary vascular evaluation [
12]. We did not perform routine coronary angiography by left-heart catheterization in patients aged ≥ 65 years in our center if they had already been treated with drugs and/or stents implanted in cardiac centers before they were referred for LT. However, if the candidates showed moderate or severe cardiac vascular abnormalities on CT angiography when the patients were evaluated for LT and if the patients had symptoms demonstrating an unstable cardiac status, we performed repeated PCI to determine whether further revascularization should be considered and if a LT should be performed. The cardiac function, pulmonary hypertension, pre-LT steroid use, and admission for pulmonary infection are crucial factors when considering the LT type and need for ECMO support.
Although various studies included recipients with various ages, indications, and extents of cardiac disease, cardiac disease did not compromise the survival of LT recipients. Pre-LT catheterization intervention, CABG, or concomitant CABG with LT were all feasible [
13]; however, these interventions increased the post-LT complications or readmission rate because of cardiac reasons [
14]. Chaikriangkai
et al. also found that preoperative CAD did not increase the mortality risk but suggested that subsequent nonfatal cardiovascular events were increased [
15]. Further studies warned of the risks of performing concomitant CABG in patients over the age of 65 years [
16]. In our study, recipients who had cardiac abnormalities had inferior survival rates post-LT. Without optimizing surgical plan, recipients with cardiac abnormalities, who have a high risk of cardiac- or vascular-related events, were associated with a higher mortality. The intraoperative V-A ECMO has been used to support heart and lung function during LT; however, prolonged V-A ECMO post-LT may also increase the workload of the left heart. Its effect on the survival of recipients with advanced age and pre-LT cardiac abnormalities has not been clarified, and optimizing the post-LT care in these recipients remains to be further investigated.
In the current study, we collected preliminary data on cardiac structural abnormalities in elderly patients, and these cardiac structural abnormalities were not specified in previous reports. The high incidence of cardiac valvular stenosis or regurgitation in elderly patients also increased the risk of cardiac dysfunction and death. Transcatheter valve repair or replacement techniques helped more critical patients who were not tolerant of open-heart surgery and improved their quality of life, and these techniques have been adopted as new bridging methods in LT patients with cardiac valve abnormalities, which have been explained in recent case reports [
17]. We also observed valvular abnormalities during the follow-up post LT, and these abnormalities might be related to alterations in cardiopulmonary hemodynamics or aging. We did not obtain further data to evaluate valvular diseases, and no intervention was further performed for these groups of patients. Our research revealed that for LT candidates aged ≥ 65 years, more cardiac-related factors should be taken into consideration for pre-LT, as wells as coronary artery angiography. Pre-LT cardiac structural abnormalities, electrophysiological condition evaluations, and optimized perioperative management strategies for these patients remain to be further illustrated in future prospective studies.
In China, we have a higher proportion of patients with pulmonary fibrosis who had ECMO bridging before LT than in the ISHLT report; thus, perioperative strategies have great challenges. Our results provide several important observations regarding the outcomes of lung transplantation in recipients aged ≥ 65 years. Bilateral transplantation is associated with improved long-term survival, whereas single lung transplantation confers a survival benefit within the first year of transplantation [
18,
19]. In addition, we provide evidence that the benefit of the transplantation type might be related to indications and comorbidities. Recipients with pulmonary fibrosis were in critical status with cardiac dysfunction, which might not be tolerant to long surgery durations and may have hemodynamic instability. These patients had single lateral LTs, particularly on the left side. For COPD patients without the need for ECMO, a bilateral lung transplantation was preferred. Post-LT severe pulmonary infection, such as multi-drug resistant bacteria (MDR)-related infection, has been recognized as a great risk factor for long-term outcomes. An increased risk of MDR infection was related to factors such as idiopathic pulmonary fibrosis, pre-transplant colonization and infections, and comorbidities [
20]. The aged population receiving multiple drugs and immunosuppression therapy and undergoing invasive procedures was vulnerable to infection events.
Furthermore, a large proportion of recipients are supported by intraoperative and prolonged ECMO, and complications related to ECMO in elderly patients should be considered. Apart from infection, thrombosis, and hemorrhage, which have been previously discussed, neurological complications in aged LT recipients are rarely reported. Common neurological complications related to ECMO include hypoxic-ischemic brain injury, intracranial hemorrhage, cerebral edema, and brain death [
21]. We observed that 51.4% of recipients aged 65–70 years and 41.8% of recipients aged ≥ 70 years had post-LT neurological complications in our cohort. Cerebral infarction, hemorrhage, and epilepsy had high occurrence rates, followed by delirium, depression, or anxiety. Influencing factors, including surgery, drug interactions, patient metabolism, ECMO-related factors (including rapid correction of hypercarbia and coagulation disturbance), ICU stay, and the nutritional status of patients, might contribute to adverse events. However, we still lack sufficient data to illustrate the impact of these events on recipients’ post-LT survival because of limited methods of neurologic assessment and neuromonitoring.
However, this study, similar to many other studies, is limited in its statistical power because of being a single-center cohort with a relative infrequency of events. The majority of our cohort had restrictive lung disease, as it is the main indication for LT in recipients aged ≥ 65 years. Our findings may reflect the contributions of patients with interstitial lung disease to a greater extent compared with other diseases. Our outcomes may not be broadly applicable, as factors such as surgical strategy and team experience vary in different centers. In illustrating post-LT complications, more diagnostic tools might be needed to supplement the routine monitoring protocol, such as gastroesophageal reflux disease-related manometry and pH monitoring. Outcome-related results, not only survival but also quality of life, should also be measured in detail to reflect the benefit of LT in the aged population.
5 Conclusions
Our experience from the largest aged LT cohort from the eastern population supported that LT can be performed in candidates with advanced chronological age and provided life-extending benefits to these patients. This analysis may help the global transplant community to expand recipient access despite a growing number of older recipients. Therefore, evaluation and treatment protocol are of great importance for recipients aged ≥ 65 years to improve post-transplant survival in future adaptations of organ allocation.
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