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J Thorac Cardiovasc Surg 2008;135:412-420
© 2008 The American Association for Thoracic Surgery
Cardiothoracic Transplantation |
a Division of Cardiothoracic Surgery, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, Calif
b Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Calif
c Department of Pathology and Laboratory Medicine–Immunogenetics Center, David Geffen School of Medicine at University of California, Los Angeles, Calif
Received for publication May 4, 2007; revisions received August 9, 2007; accepted for publication September 11, 2007. * Address for reprints: Abbas Ardehali, MD, Division of Cardiothoracic Surgery, CHS 62-186, UCLA Medical Center, 10833 Le Conte Ave, Los Angeles, CA 90095. (Email: aardehali{at}mednet.ucla.edu).
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Abstract |
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Methods: We reviewed the records of our lung transplant recipients from March 2000 to September 2006. During this interval, 50 patients were 65 years or older at the time of transplantation. Fifty patients younger than 65 years were matched to the older cohort by means of propensity analysis. The demographics and perioperative and postoperative characteristics and survival of the 2 groups were compared.
Results: Older patients were more likely to receive single-lung transplantation (older group: 76% vs younger group: 16%, P < .05) and nonstandard donor lungs (older group: 46% vs younger group: 28%, P = .06). The composite in-hospital morbidity rate was similar in the older and younger groups. There was no significant difference in the early oxygenation parameters, incidence of acute cellular rejection, or incidence of bronchiolitis obliterans syndrome between the 2 groups. The early survival of the older patients was 95.7% compared with 95.9% in the younger cohort (P = .73). The 1-year survival of the 2 groups was also similar (older group: 79.7% vs younger group: 91.2%, P = .16). The 3-year survival of the older and younger recipients was 73.6% and 74.2%, respectively (P = .64). There were 8 deaths in the older recipient group during the 1-month to 1-year posttransplantation interval, predominantly because of infections.
Conclusions: Lung transplantation can be performed in patients older than 65 years with acceptable clinical outcomes. The "increased" mortality of older patients between 1 month and 1 year after transplantation, predominantly from infectious causes, might be due to immunosenescence of older patients. This finding warrants adjustments in the immunosuppression protocol of older patients undergoing lung transplantation. The effect of offering lung transplantation to older patients on donor lung availability deserves further investigation.
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Introduction |
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Advanced recipient age has also emerged as an independent predictor of death after lung transplantation in the International Society for Heart and Lung Transplantation (ISHLT) registry.2
Despite these strong arguments, several reports in the past decade have demonstrated that older recipients can undergo kidney, liver, and heart transplantation and be treated with immunosuppressive therapy with acceptable outcomes.3-6 In 1993, Snell and colleagues7 reviewed their lung transplantation experience in elderly patients; the survival of 5 patients older than 60 years was similar to that of the younger cohort. More recently, Smith and associates8 reported their lung transplantation experience with 16 patients older than 65 years. The survival of this cohort was similar to that of a contemporaneous younger group. Although advanced age remains a contraindication in many transplantation centers, a survey of active US lung transplantation programs showed that 24% of programs do not consider age of greater than 60 years a contraindication to bilateral lung transplantation. In the case of single-lung transplantation, approximately 20% of active programs did not consider age of 65 years or older to be an absolute contraindication.9
Starting in 1999, we have not used advanced age as an absolute contraindication in the selection of lung transplant recipients. We have offered lung transplantation to select older patients (>65 years) who lack other comorbid conditions. The purpose of this report is to compare the outcome of lung transplantation in older recipients with that in a matched younger cohort. The primary end points were 30-day, 1-year, and 3-year survival. The secondary end points included early oxygenation parameters, composite in-hospital morbidity rates, and the incidence of acute rejection and bronchiolitis obliterans syndrome (BOS).
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Materials and Methods |
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LAS was available for all transplant recipients after the institution of the new allocation system in May 2005. For patients undergoing transplantation before May 2005, LAS was tabulated after chart review by using the United Network for Organ Sharing (UNOS) Web site LAS calculator (http://www.unos.org/resources/frm_LAS-Calculator). If diagnostic tests had been performed more than 6 months before transplantation, they were used as up-to-date information for the LAS calculation. Donor and recipient characteristics, operative variables, and posttransplantation characteristics were compiled for both the older recipients and their matched younger cohorts.
Recipient Selection Criteria
Lung transplant recipients younger than 65 years were selected according to the "International guidelines for the selection of lung transplant candidates."1 Since 1999, we have offered lung transplantation to a select a group of patients aged 65 years and older. Relative contraindications for listing patients aged 65 years and older were body mass index of less than 18 or greater than 30, presence of obstructive coronary artery disease, presence of peripheral or cerebrovascular disease, renal insufficiency (creatinine clearance, <50 mL/min), and debilitation. All recipients were informed of the nonstandard donor lung program and consented.
Clinical Management Protocol
Single-lung transplantation was performed according to the standard techniques.11 Cardiopulmonary bypass (CPB) was used only as dictated by the recipient's hemodynamics. All double-lung transplantations were performed during CPB. All patients (single- and double-lung transplant recipients) except one received modified reperfusion after transplantation. The details of this technique have been previously reported.12
All lung transplant recipients received induction immunosuppressive therapy. In older patients we used basiliximab (Novartis, East Hanover, NJ), whereas in the younger cohort we favored rabbit anti-thymocyte globulin (ATG) as the induction agent (Genzyme, Cambridge, Mass). The induction therapy was followed with tacrolimus, mycophenolate mofetil, and a steroid regimen. All patients underwent surveillance biopsies at weeks 1, 4, 8, 12, and 24 and as clinically indicated. All recipients were treated with broad antimicrobial therapy during the first posttransplantation week. Oral trimethoprim–sulfamethoxazole was administered biweekly for prophylaxis against Pneumocystis carinii infections. Cytomegalovirus (CMV)–positive recipients received intravenous ganciclovir (Roche, Nutley, NJ) during hospitalization and were transitioned to valganciclovir (Roche, Nutley, NJ) for the first year or longer if inflicted with CMV infection. CMV-negative recipients who received a CMV-positive donor were also treated with CytoGam (CSL Behring, King of Prussia, Pa). The latter group also received acyclovir (GlaxoSmithKline, Bridgewater, NJ) for herpes simplex viral prophylaxis. Pulmonary function tests were performed at least once every 3 months and at each clinic visit.
Definition of Terms
Recipient diagnoses were divided into 3 categories: obstructive pulmonary disease, restrictive pulmonary disease, and other. Obstructive pulmonary diseases included emphysema and 
1-antitrypsin deficiency. Restrictive lung diseases included interstitial pulmonary fibrosis (IPF), usual interstitial pneumonia, nonspecific interstitial pneumonia, allergic alveolitis, scleroderma, rheumatoid arthritis, polymyositis, and sarcoidosis. Other end-stage lung diseases included bronchiectasis, cystic fibrosis, IgA deficiency, lymphangioleiomyomatosis, primary pulmonary hypertension, and granulomatous lung disease.
Nonstandard donor lungs were defined as follows: presence of lobar infiltrate on chest roentgenographic analysis (atelectasis was ruled out by means of preoperative and intraoperative treatment/assessment), hypoxemia (partial pressure of oxygen in arterial blood [PaO
2] of <300 on a fraction of inspired oxygen [FIO
2] of 1.0 and a peak end-expiratory pressure of 5), age of donor greater than 55 years, and a smoking history of greater than 20 pack-years.13 Allograft ischemic time was defined as the time of donor aorta crossclamping to the time of lung reperfusion. In double-lung transplantation the reperfusion of both lungs was done after implantation of the second lung.
Blood gases were assessed at 6, 24, 48, and 72 hours after arrival in the intensive care unit. The PaO 2/FIO 2 oxygenation parameters were collected on all recipients. The worst blood gas value within 6 hours of the specified time point was used to determine the PaO 2/FIO 2 ratio. The in-hospital complications that were collected include atrial fibrillation requiring antiarrhythmic therapy, wound complication requiring surgical intervention, renal failure requiring dialysis, pulmonary embolus, gastrointestinal bleeding requiring diagnostic endoscopy, and cerebrovascular accident (transient or permanent neurologic deficit and consistent radiographic findings). To allow comparison, a composite in-hospital morbidity index was calculated for each group.
Acute cellular rejection was diagnosed by means of transbronchial lung biopsy and graded according to the ISHLT guidelines: grade 0 (no rejection), grade A1 (minimal), grade A2 (mild), grade A3 (moderate), and grade A4 (severe).14 BOS was assessed on a 5-stage scale, as defined by a modification of the ISHLT consensus statement.15 We defined the baseline as an average of the 2 best spirometric values obtained in the first 6 months after transplantation. If significant decreases in spirometric function were noted, then the patient's clinical record was evaluated to ensure no confounding factors, such as infection, acute rejection, airway complications, or underlying disease recurrence, were apparent. Biopsies for diagnosis of BOS were not routinely performed.
We had complete follow-up on all patients in this study. Cause of death was obtained either from the death note in the medical record or by means of autopsy report.
Statistical Analysis
Actuarial survival rates and freedom from BOS rates were plotted as Kaplan–Meier estimates and compared by using Cox regression models with robust variance estimators accounting for matched patient pairs. The 
2 or Fisher exact tests were used, as appropriate, to test whether associations existed between groups for categorical variables. Continuous characteristics were compared by using the Student t test. The Wilcoxon rank sum test was used to compare medians between groups. The data were presented as means and SDs of the mean, unless indicated otherwise. All analyses were performed with Stata software (version 9.0; StataCorp, College Station, Tex).
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Results |
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Figure 1). Before 2003, 7 (14%) of 50 of the total transplantations were performed in patients 65 years and older. Since 2003, 43 (25.7%) of 167 transplantations were performed in older patients.
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Table 1. The median donor age, donor sex, cause of death, and donor oxygenation parameters were similar when the older recipient group and the younger matched cohort were compared. Forty-six percent of donor lungs for the older recipients were classified as nonstandard lungs compared with 28% of donor lungs in the younger group (P = .06). Older donors were preferentially allocated to the older recipients. Sixty-one percent of older recipients of nonstandard lungs received lungs from donors older than 55 years compared with 29% of their matched younger cohorts. This difference reached statistical significance (P < .05).
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Tables 2 and 3, respectively. As expected, there was a difference in the median age of the 2 groups. The oldest patient to undergo lung transplantation during this period was 72 years old. There was no statistical difference in recipient sex, incidence of diabetes mellitus, preoperative mean pulmonary artery pressure, and waiting time between the 2 groups. As expected, the diagnoses and LASs were similar in both groups because the control younger recipients were matched to the older recipients based on these criteria. It is notable that the median waiting time for both groups was less than 3 months. Analysis of our data before and after implementation of the new allocation system in May 2005 revealed that the median waiting time for our transplantation population has decreased: before May 2005, the median waiting time was 107 days, whereas after May 2005, the median waiting time was 47 days (P < .05).
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There were no intraoperative deaths. The median durations of mechanical ventilation, intensive care unit stay, and hospital stay were also similar between the older group and the matched younger cohorts. As noted in the Materials and Methods section, the 2 groups were treated with different induction therapy protocols; the older recipients are treated with the anti–interleukin 2 receptor antibody, whereas most of the younger recipients received rabbit ATG.
The oxygenation parameters at 24, 48, and 72 hours were similar in the older versus younger recipient groups (
Figure 2). Notably, the composite in-hospital morbidity rate was also similar in both groups (Table 3); the older recipients did not have higher in-hospital complication rates. The incidence of acute rejection (grade A3 or higher) during the study period was also similar in both groups (Table 3).
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Figure 3). After 12 months, the prevalence of BOS in the older cohort reached a plateau, whereas it increased in the younger cohort. Overall, there was no statistically significant difference in the prevalence of BOS between patients older than 65 years versus those younger than 65 years. Furthermore, we could not detect a difference in survival from the time of diagnosis of BOS in older patients who received single-lung transplants versus the younger patients who received double-lung transplants (likely because of a small number of index cases in both groups).
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Figure 4). The 1-year survival in the older group was 79.7%, with 8 deaths during the 1-month to 1-year posttransplantation interval. The 1-year survival in the control cohort (<65 years) was 91.2%, with 3 deaths during the 1-month to 1-year posttransplantation period. There was not a statistically significant difference in the 1-year survival of the 2 groups (P = .16). The causes of death in the older group included infections (n = 6), cardiovascular issues (n = 1), and BOS (n = 1,
Table 4). The 3 deaths in the younger group during this interval were due to infections (n = 2) and unknown causes (n = 1). None of the deaths in the single-lung transplant recipients could be attributed to the remaining native lung. The survival curve of the older group reached a plateau at 18 months and has been stable up to 3 years. The 3-year survival of the older recipients was 73.6%, whereas that of the younger matched group was 74.2% (P = .64).
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Discussion |
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These observations are predicated on several programmatic guidelines that deserve special emphasis. First, the older recipients were selected by using strict previously noted criteria. We ensured that older recipients were otherwise healthy candidates, with at most 1 relative contraindication.
Second, we favor single-lung transplantation in older recipients. Older recipients have been known to have better outcomes with single-lung transplantation compared with double-lung transplantation.16,17
Third, the immunosuppression regimen was tailored in older recipients. The findings of this study need to be analyzed within the context of the above caveats. The similarity of clinical outcomes in the older versus younger recipients in our experience might be due to our clinical management protocols (donor and recipient selection and management), small sample size in this study, or both.
Nonstandard donor lungs were preferentially allocated to older recipients. Use of nonstandard donor lungs is associated with higher perioperative mortality.18 The similar early outcome of the older and younger groups, despite this allocation bias, might be due to (1) the small number of patients in both groups (type II error) or (2) bias in the selection of "quality" nonstandard donor lungs when needed for single-lung transplantations in older recipients, or (3) higher perioperative mortality of double-lung transplantation17 in the younger group might balance the early perioperative mortality in the older group because of nonstandard donor lung dysfunction.
Despite the similarities of the early- and medium-term survival of the older group and the matched younger cohort, there were 8 deaths in the older group in the 1-month to 1-year period after lung transplantation. The majority of these deaths were attributed to infectious causes. Although our immunosuppression regimen was tailored in the older recipient group (interleukin 2 receptor blockade instead of rabbit ATG for induction therapy), it remains a possibility that overimmunosuppression in the older recipients might have contributed to life-threatening infections. Immunosenescence is a well-recognized entity in older individuals.19,20 Potential mechanisms of age-based differences in posttransplantation immune response include replicative senescence, thymic involution, degeneration of the T-cell repertoire, alterations in T-suppressor activity, altered cytokine profiles, and reduced perforin production.21,22 Moreover, several studies have shown that the incidence of acute cellular rejection in elderly recipients of kidney, liver, heart, and lung transplants are lower compared with that seen in younger recipients.4-7 In this study the incidence of acute cellular rejection was similar in the elderly group and the matched younger cohort.
Based on the findings of this study, it is reasonable to alter/reduce the immunosuppression regimen in older lung transplant recipients. A reduction in the dose of calcineurin inhibitors can lead to a reduction in the renal side effects; adjustments in the dose of steroids can also decrease the associated metabolic complications. The potential benefits of such adjustments, provided that the incidence of acute rejection and BOS do not increase, are significant. A more robust recipient immune system can combat infections more vigorously.
This study does not support widespread application of lung transplantation to older recipients. In fact, larger databases, such as UNOS/ISHLT registry, might be the only reasonable basis on which to change the current guidelines. In a recent report 42 older lung transplant recipients were matched to a younger cohort, and their survival was compared. The medium-term and long-term survival of the older recipients was significantly lower, even after adjustment for the older group's expected higher age-related mortality.23 Another important issue in offering lung transplantation to older recipients is the effect on donor supply. Given the limited donor pool, expanding the recipient pool by offering lung transplantation to older recipients will ultimately deprive a younger recipient of a potential donor organ. One might address this ethical dilemma by (1) informing all older recipients about a nonstandard donor pool program preoperatively and (2) preferential offering of nonstandard donor lungs to older recipients. Despite the adoption of these policies, more than half of our older recipients received donor lungs from the standard pool. A consensus on the definition of the nonstandard donor and recipients and UNOS adoption of a policy of allocating nonstandard donor organs to nonstandard recipients might be a solution to this ethical dilemma. Until then, the effect of lung transplantation in older recipients on the donor pool and other younger patients on the waiting list is an important question and deserves further study.
This study has several limitations. First, this is a retrospective case-control analysis with all the inherent limitations of such a study.
Second, the index older cases were matched to the younger recipients based on their diagnoses, severity of disease (by using LAS as surrogate marker), and the era of transplantation. Another factor that is known to affect short-term outcome after lung transplantation is the type of transplantation.16,17 We did not match for the type of transplantation (single vs double) because there were insufficient double-lung transplant recipients in the older group and single-lung transplant recipients in the younger group. The findings of this study might not be applicable when comparing the outcome of the type of transplantation in older versus younger recipients.
Third, another limitation of this study is the relatively small number of cases in both groups, thus requiring larger differences in clinical outcomes to detect statistically significant differences (type II error).
Fourth, although strict criteria were used in the selection of both the older and younger recipients, the final approval for lung transplantation was dependant on the decision of the multidisciplinary lung transplant selection committee. There might be inherent bias against selection of older patients based on overall clinical fitness and extent of comorbidities.
Fifth, another limitation of this study is the short follow-up time. Longer follow-up analyses are needed to assess the safety and clinical outcome of lung transplantation in older recipients.
Finally, this study only compares the survival of older and younger lung transplant recipients. Lung transplantation might not only affect survival but also the quality of life. We have no objective information on the quality of life after lung transplantation in the older or younger recipients as part of this study. The real effect of lung transplantation can only be assessed when survival and quality-of-life data are analyzed together.
In summary, lung transplantation can be performed safely and with comparable short-term and medium-term survival in selected patients older than 65 years.
Posttransplantation-related infections represent the major cause of early mortality that might require adjustments in immunosuppression protocols. Multidisciplinary consensus is needed to determine the ethical standards in offering lung transplantation to the elderly given the critically short supply of donor organs.
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Footnotes |
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* SB and RM contributed equally to this work. 
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References |
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