- Email: [email protected]
Outcomes in Pediatric Lung Transplant Recipients Receiving Adult Allografts
GENERAL THORACIC
Outcomes in Pediatric Lung Transplant Recipients Receiving Adult Allografts Don Hayes, Jr, MD, MS, Patrick I. McConnell, MD, Mark Galantowicz, MD, Bryan A. Whitson, MD, PhD, Joseph D. Tobias, MD, and Sylvester M. Black, MD, PhD Departments of Pediatrics, Internal Medicine, Surgery, and Anesthesiology, Ohio State University College of Medicine; and Section of Pulmonary Medicine, Department of Cardiothoracic Surgery, and Department of Anesthesiology and Pain Medicine, Nationwide Children’s Hospital, Columbus, Ohio
Background. Clinical practice in the United States has no restrictions in allocating lungs from adult donors to pediatric recipients. Methods. The United Network for Organ Sharing database was queried from 1987 to 2013 for pediatric lung transplant recipients (aged less than 18 years) to assess survival using continuous donor age in years and two donor age groups, ‡ 18 years and > 30 years, for analysis. Results. Of 930 pediatric lung transplants, basic survival analysis identified a mortality hazard when adult lung allografts were transplanted into pediatric recipients; however, multivariate Cox models demonstrated that continuous donor age (hazard ratio [HR] 1.004, 95% confidence interval [CI]: 0.992–1.015, p [ 0.524) as well as both categoric age groups, donor 18 years or older (HR 0.967, 95% CI: 0.714–1.309, p [ 0.827) and donor older than 30 years (HR 1.168, 95% CI: 0.815–1.673, p [ 0.398), did not
significantly influence the risk for death. Moreover, propensity score matching analysis confirmed a lack of association of mortality risk with donor age ‡ 18 years (HR 1.129, 95% CI: 0.696–1.831, p [ 0.623) and donor age > 30 years (HR 1.050, 95% CI: 0.569–1.937, p [ 0.876). Bronchiolitis obliterans syndrome (BOS) was found to be a significant predictor of mortality in univariate analysis (HR 2.033, 95% CI: 1.639–2.521, p < 0.001), but the hazard of BOS did not vary across donor age categories. Conclusions. Adult donor lung allografts appear not to negatively affect survival in pediatric lung transplant recipients when considering confounders, and do not influence survival through an increased hazard for the development of BOS.
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younger recipients [4]. We sought to assess the influence of donor allograft age on outcomes of pediatric lung transplant recipients using an available database in the United States. We hypothesized that lung allografts from adult donors affected clinical outcomes in children undergoing lung transplantation.
ung transplantation is an accepted indication for treating end-stage lung disease in children. Recently, an analysis of the International Society for Heart and Lung Transplantation (ISHLT) registry reported that survival after pediatric lung transplantation had improved by era comparing the years 1988 to 1999 and 2000 to June 2011, with a median survival improving from 3.3 to 5.8 years, respectively [1]. Moreover, median survival conditional on surviving at least 1 year for children after lung transplantation improved from 7.2 to 8.7 years, respectively [1]. With an aging population, patients on organ transplant waiting lists are tending to be older, while donors are also growing older [2]. According to analysis of the ISHLT registry, donor age for recipients aged 11 to 17 years did not appear to be associated with death after transplant [1]. In a single-center experience, donor age of more than 16 years was associated with negative influence on survival in pediatric lung transplantation [3]. The impact of older donor age on transplantation varies by organ, with limited data examining the effect of age between donor and recipients after pediatric lung transplantation. In the adult population, a recent study found that old donor lungs negatively impacted survival of
Accepted for publication Dec 5, 2014. Address correspondence to Dr Hayes, Ohio State University, Nationwide Children’s Hospital, 700 Children’s Dr, Columbus, OH 43205; e-mail: [email protected].
Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier
(Ann Thorac Surg 2015;99:1184–92) Ó 2015 by The Society of Thoracic Surgeons
Material and Methods Data Collection We retrospectively evaluated data from lung transplant recipients who were registered in the Organ Procurement and Transplant Network (OPTN) standard transplant analysis and research database administered by the United Network for Organ Sharing (UNOS) since 1987 [5]. The study was approved by Ohio State University Wexner Medical Center Institutional Review Board with a waiver of the need for individual consent (IRB#2012H0306). The UNOS/OPTN thoracic database was queried for all lung transplants from October 1987 to September 2013.
Statistical Methods All analyses were performed using Stata/MP, version 13.1 (StataCorp, College Station, TX). For all analyses, a p value less than 0.05 was considered statistically significant. Descriptive statistics for continuous variables are 0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2014.12.008
presented as means and standard deviations, and descriptive statistics for categoric variables are presented as proportions. To assess the effects of donor lung age for children less than 18 years of age after lung transplantation, we examined continuous measure of donor age and two arbitrarily chosen categorical groups for donor age cutoffs: 18 years or older and more than 30 years. Survival duration was analyzed from the date of the transplant until the date of death or censoring. Univariate Cox proportional hazards models were fitted separately using a continuous measure of donor age in years; and two categoric measures of donor age, the first equaling 1 if the donor was aged 18 years or more and 0 otherwise, and the second equaling 1 if the donor was aged more than 30 years and 0 otherwise. Kaplan-Meier survival curves were completed separately for survival differences between both age cutoffs. Cox proportional hazards regression models were used to assess the relationship between donor age and the hazard of mortality after transplant. For each measure of donor age, a multivariate Cox proportional hazards model was then fitted, and was adjusted for a series of characteristics including donor and recipient age and sex, diagnosis, age, creatinine, body mass index (BMI), oversized donor (donor BMI > 120% of recipient BMI), and ischemic time. The time metric was days of survival until death or censoring. Bronchiolitis obliterans syndrome (BOS) was considered as a potential mediator of the relationship between donor age and patient survival. The development of BOS was assessed at follow-up visits scheduled for 6 months after lung transplantation and every subsequent anniversary of the transplantation date. A patient was considered to have BOS if a “yes” answer was recorded to the question regarding “bronchiolitis obliterans syndrome” at any follow-up visit after lung transplantation in which BOS status was known. Differences in BOS onset across donor age categories were assessed descriptively
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using c2 tests, and the relationship of BOS to survival was assessed using a univariate Cox proportional hazards model, as previously described. Additionally, multivariate Cox proportional hazards models were fitted with days from lung transplantation until BOS diagnosis or censoring at the last follow-up as the time metric. These models included the same donor age measures and covariates as the multivariate Cox models assessing recipient survival. Finally, BOS was added to the multivariate Cox model of patient survival to assess whether this variable explained any effect of donor age on mortality hazard. Propensity score matching was completed to estimate mortality hazard risk by matching children with older donors to children with younger donors who had a similar predicted probability of receiving a lung allograft from an older donor. The propensity of receiving an adult lung allograft in children undergoing lung transplantation was calculated as a logit function of the covariates included in the multivariate Cox analysis of patient survival (not including BOS). The matching algorithm used nearest-neighbor matching without replacement on the logit of the propensity score, with a caliper width equal to 0.2 standard deviations of the logit of the propensity score. Cox proportional hazards regression stratified on the matched pairs was used to estimate a hazard ratio (HR) of adult donor age in children after lung transplantation.
Results Study Population Figure 1 presents inclusion and exclusion criteria. Of all 136,498 organ transplant candidates, 930 children (less than 18 years of age) who received a first-time single or double lung transplant were included in the study. Exclusion criteria included cases with no lung transplant Fig 1. Patient inclusion and exclusion criteria for survival analysis, multivariate Cox analysis, and propensity score matching.
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date, retransplant, duplicated entry, and noncadaveric donor. The limitation of the analysis to single or double lung transplants from cadaveric donors resulted in excluding 12 children receiving lobar transplants. Further exclusion included identical waiting list entry and exit dates for survival analysis, known donor age, missing covariate data for multivariate survival analysis, and unmatched controls for propensity score matching. Tables 1 and 2 summarize the patient characteristics of pediatric lung transplant recipients for both age cutoff groups used in our analysis. There was a trend toward a male recipient predominance in the 18 years or older donor age group but not in the more than 30 years old donor age group. A male donor predominance was found in both donor age groups. As anticipated for both donor age groups, pediatric lung transplant recipients were significantly older and had significantly higher BMI as compared with recipients receiving lungs from younger donors. Yet, older donors were significantly more likely than younger donors to have BMI exceeding recipient BMI by more than 20% (p < 0.001). No significant differences were observed across donor age categories in the proportion of recipients diagnosed with BOS after lung transplantation.
Univariate and Kaplan-Meier Survival Analysis In all, 924 patients were included in the univariate Cox analysis and 923 patients in the Kaplan-Meier survival analysis (age of one donor was not available). A continuous measure of donor age found a significant risk for death (HR 1.008, 95% confidence interval [CI]: 1.001–1.015, p ¼ 0.030) as did the categoric analysis for both donor age 18 years or more (Table 3, Fig 2) and donor age more than 30 years (Table 3, Fig 3). There were no covariates that were protective, whereas higher recipient BMI (HR 1.025, 95% CI: 1.003–1.048, p ¼ 0.028) was associated with significantly greater mortality risk. Two covariates, cytomegalovirus mismatch and Epstein-Barr virus mismatch, were not significantly associated with survival and had a very high proportion of missing data, leading them to be excluded from the multivariate analyses. Bronchiolitis obliterans syndrome (BOS) (HR 2.033, 95% CI: 1.639– 2.521, p < 0.001) was significantly associated with increased mortality hazard.
Multivariate Survival Analysis A total of 593 patients was included in the multivariate survival analysis. Table 4 demonstrates the Cox proportional hazards model with patient survival as the time metric. The continuous measure of donor age and the categoric donor age groups of 18 years or older and more than 30 years were not associated with increased risk of death. As with the univariate Cox analysis, no variables were protective. Supplemental multivariate models were fitted with time until BOS diagnosis or censoring as the time metric. The latter models revealed that time to BOS was not influenced by the continuous measure of donor age (HR 0.998, 95% CI: 0.981–1.015, p ¼ 0.814), the categoric measure of donor age 18 years or more (HR 0.875, 95% CI: 0.564–1.357, p ¼ 0.550), or the categoric measure
Ann Thorac Surg 2015;99:1184–92
of donor age more than 30 years (HR 0.987, 95% CI: 0.571– 1.706, p ¼ 0.963). The lack of a significant association between donor age and BOS hazard indicated that BOS did not mediate the relationship between donor age and survival. This finding was confirmed by adding BOS to the multivariate models of recipient survival, whereupon HR of continuous donor age (HR 0.991, 95% CI: 0.978– 1.005, p ¼ 0.206), donor age 18 years or more (HR 0.794, 95% CI: 0.566–1.114, p ¼ 0.183), and donor age more than 30 years (HR 0.929, 95% CI: 0.613–1.408, p ¼ 0.728) remained statistically insignificant.
Propensity Score Matching Totals of 254 patients and 146 patients were included in the propensity score matching analysis for the donor age groups of 18 years or more and more than 30 years, respectively. All covariates from Table 4 (ie, excluding BOS, cytomegalovirus mismatch, and Epstein-Barr virus mismatch) were included in the model of propensity of receiving an adult (donor aged 18 years or more or donor aged more than 30 years, respectively) lung allograft. Neither donor age of 18 years or more (HR 1.129, 95% CI: 0.696–1.831, p ¼ 0.623) nor age more than 30 years (HR 1.050, 95% CI: 0.569–1.937, p ¼ 0.876) was associated with increased risk of death for pediatric lung transplant recipients.
Comment The most important finding revealed by the basic statistics from the current study was a reduction in survival among children less than 18 years of age receiving adult donor lungs, but further analysis adjusting the estimated effect of donor age for several covariates did not confirm an associated mortality risk based on donor age. In adult lung transplantation, the medical literature is slowly expanding with regard to the effects of donor age on clinical outcomes [4, 6–10]. The majority of this literature is reporting that older donor lungs can influence outcomes in the adult lung transplant population. The matching of donor and recipient ages may potentially enhance survival for the younger adult population [4]. To date, with the only published data regarding donor lung age in children, Cano and coworkers [3] found that survival rates for patients whose donors were more than 16 years of age were 33.3%, 25%, 12.5%, and 12.5% at 1, 3, 5, and 10 years, respectively; whereas recipients who had donors less than 16 years of age had survival rates of 76%, 66.8%, 56.4%, and 49.3% at these respective times. Recently, Baldwin and colleagues [6] demonstrated that adult recipients of lungs from pediatric age donors had higher rates of 1-year graft failure. The reasons for this finding could not be addressed by their study, although the investigators speculated structural differences were likely important factors. We would also add that immunologic variations between adult and pediatric lungs are likely factors in donor-recipient lung interactions after transplantation. With an increasing number of patients listed for lung transplantation in the United States, methods are needed to expand the donor pool and to optimize long-term
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Table 1. Characteristics of Adolescent Lung Transplant Recipient for Donor Age Groups 18 Years or More and Less Than 18 Years Donor Age 18 Years (n ¼ 203)
All (n ¼ 930)a
a
Donor age data available for 929 cases.
n (%)
Mean (SD)
n (%)
Mean (SD)
390 (41.94) 481 (51.72)
. .
97 (47.78) 79 (38.92)
. .
292 (40.22) 401 (55.23)
. .
743 (79.89) 57 (6.13) 130 (13.98)
. . .
165 (81.28) 10 (4.93) 28 (13.79)
. . .
577 (79.48) 47 (6.47) 102 (14.05)
. . .
580 (62.37) 186 (20.00) 164 (17.63)
. . .
127 (62.56) 36 (17.73) 40 (19.70)
. . .
453 (62.40) 150 (20.66) 123 (16.94)
. . .
104 489 69 48 220 213
(11.18) (52.58) (7.42) (5.16) (23.66) (28.48)
. . . . . .
20 136 16 2 29 47
(9.85) (67.00) (7.88) (0.99) (14.29) (30.52)
. . . . . .
84 353 53 46 190 166
(11.57) (48.62) (7.30) (6.34) (26.17) (27.99)
. . . . . .
130 57 147 84
(31.10) (13.64) (35.17) (20.10)
. . . .
23 11 35 29
(23.47) (11.22) (35.71) (29.59)
. . . .
107 46 112 55
(33.44) (14.38) (35.00) (17.19)
. . . .
. . . . 10.96 (5.73) 0.59 (1.04) 17.20 (4.04) . 5.31 (1.48)
0 1 27 36
. . . . 15.28 (1.84) 0.67 (0.91) 18.42 (3.96) . 5.41 (1.65)
43 22 73 88
t test
c2 0.054 <0.001 0.708
0.504
<0.001
0.536 0.034
<0.001 43 23 100 124
(14.83) (7.93) (34.48) (42.76) . . . 322 (45.87) .
(0) (1.56) (42.19) (56.25) . . . 122 (67.40) .
(19.03) (9.73) (32.30) (38.94) . . . 200 (38.39) .
. . . . 9.77 (5.86) 0.57 (1.08) 16.87 (4.00) . 5.28 (1.43)
<0.001 0.249 <0.001 <0.001 0.302
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BMI ¼ body mass index.
Mean (SD)
HAYES ET AL OUTCOMES OF PEDIATRIC LUNG RECIPIENTS
Male recipient Male donor Race of recipient White Black Other Race of donor White Black Other Diagnosis Primary pulmonary hypertension Cystic fibrosis Idiopathic pulmonary fibrosis Congenital heart disease Other Bronchiolitis obliterans syndrome Cytomegalovirus matching Donor negative, recipient negative Donor negative, recipient positive Donor positive, recipient negative Donor positive, recipient positive Epstein-Barr virus matching Donor negative, recipient negative Donor negative, recipient positive Donor positive, recipient negative Donor positive, recipient positive Age, years Creatinine, mg/dL Body mass index, kg/m2 Donor BMI >120% of recipient BMI Ischemia time, hours
n (%)
p Value
GENERAL THORACIC
Variable
Donor Age <18 Years (n ¼ 726)
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Donor Age >30 Years (n ¼ 103)
All (n ¼ 930)a Variable
a
Data on donor age available for 929 cases.
BMI ¼ body mass index.
n (%)
Mean (SD)
n (%)
Mean (SD)
n (%)
Mean (SD)
390 (41.94) 481 (51.72)
. .
46 (44.66) 23 (22.33)
. .
343 (41.53) 457 (55.33)
. .
743 (79.89) 57 (6.13) 130 (13.98)
. . .
84 (81.55) 6 (5.83) 13 (12.62)
. . .
658 (79.66) 51 (6.17) 117 (14.16)
. . .
580 (62.37) 186 (20.00) 164 (17.63)
. . .
68 (66.02) 17 (16.50) 18 (17.48)
. . .
512 (61.99) 169 (20.46) 145 (17.55)
. . .
104 489 69 48 220 213
(11.18) (52.58) (7.42) (5.16) (23.66) (28.48)
. . . . . .
10 72 6 0 15 25
(9.71) (69.90) (5.83) (0) (14.56) (32.05)
. . . . . .
94 417 63 48 204 188
(11.38) (50.48) (7.63) (5.81) (24.70) (28.10)
. . . . . .
130 57 147 84
(31.10) (13.64) (35.17) (20.10)
. . . .
9 8 17 13
(19.15) (17.02) (36.17) (27.66)
. . . .
121 49 130 71
(32.61) (13.21) (35.04) (19.14)
. . . .
. . . . 10.96 (5.73) 0.59 (1.04) 17.20 (4.04) . 5.31 (1.48)
0 0 10 23
. . . . 15.31 (1.87) 0.73 (1.25) 18.56 (4.47) . 5.50 (1.68)
43 23 90 101
p Value t test
c2 0.543 <0.001 0.898
0.620
0.002
0.465 0.221
0.002 43 23 100 124
(14.83) (7.93) (34.48) (42.76) . . . 322 (45.87) .
(0) (0) (30.30) (69.70) . . . 65 (67.71) .
(16.73) (8.95) (35.02) (39.30) . . . 257 (42.41) .
. . . . 10.43 (5.81) 0.57 (1.01) 17.04 (3.96) . 5.29 (1.45)
<0.001 0.182 <0.001 <0.001 0.177
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Male recipient Male donor Race of recipient White Black Other Race of donor White Black Other Diagnosis Primary pulmonary hypertension Cystic fibrosis Idiopathic pulmonary fibrosis Congenital heart disease Other Bronchiolitis obliterans syndrome Cytomegalovirus matching Donor negative, recipient negative Donor negative, recipient positive Donor positive, recipient negative Donor positive, recipient positive Epstein-Barr virus matching Donor negative, recipient negative Donor negative, recipient positive Donor positive, recipient negative Donor positive, recipient positive Age, years Creatinine, mg/dL Body mass index, kg/m2 Donor BMI >120% of recipient BMI Ischemia time, hours
Donor Age 30 Years (n ¼ 826)
HAYES ET AL OUTCOMES OF PEDIATRIC LUNG RECIPIENTS
Table 2. Characteristics of Adolescent Lung Transplant Recipient for Donor Age Groups More Than 30 Years and 30 Years or Less
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Table 3. Univariate Survival Analysis for Continuous Measure of Donor Age and Two Categoric Measures of Donor Age, 18 Years or More and More Than 30 Years (n ¼ 924) Variable
n
Donor age, continuous Donor age 18 years, binary Donor age >30 years, binary Male recipient Male donor Race of recipient White Black Other Race of donor White Black Other Diagnosis Primary pulmonary hypertension Cystic fibrosis Idiopathic pulmonary fibrosis Congenital heart disease Other Bronchiolitis obliterans syndrome Cytomegalovirus matching Donor negative, recipient negative Donor negative, recipient positive Donor positive, recipient negative Donor positive, recipient positive Epstein-Barr virus matching Donor negative, recipient negative Donor negative, recipient positive Donor positive, recipient negative Donor positive, recipient positive Age, years Creatinine, mg/dL Body mass index, kg/m2 Donor BMI >120% of recipient BMI Ischemia time, hours BMI ¼ body mass index; ratio.
HR
(95% CI)
p Value
923 1.008 (1.001–1.015) 923 1.269 (1.024–1.572)
0.030 0.029
923 1.333 (1.012–1.755)
0.041
924 0.840 (0.698–1.011) 924 0.958 (0.799–1.147) 924 ref. 1.348 (0.929–1.956) 1.094 (0.838–1.426) 924 ref. 1.061 (0.838–1.342) 0.991 (0.769–1.277) 924 ref.
0.065 0.638
0.116 0.509
0.625 0.944
1.204 (0.890–1.631) 1.201 (0.777–1.858)
0.229 0.409
1.410 (0.872–2.281) 0.959 (0.683–1.346) 748 2.033 (1.639–2.521)
0.161 0.809 <0.001
417 ref. 0.848 (0.516–1.393)
0.516
1.051 (0.735–1.505)
0.784
0.996 (0.643–1.543)
0.985
Fig 2. Kaplan-Meier survival functions of the pediatric lung transplant recipient for donor age groups (n ¼ 923) 18 years and more (blue line) and less than 18 years (red line).
the recent finding that lung allografts from donors 50 years of age or more negatively affect survival of adult recipients less than 60 years of age [4], there is clearly a threshold that exists and should be implemented for the younger population, including children. In the models of the current study, BOS was associated with patient survival in univariate Cox models. Nevertheless, children who received older donor lungs as defined either by continuous age or categorically (18 years or older and more than 30 years) did not exhibit increased hazard of BOS development in multivariate survival analysis of time to diagnosis. With a limited understanding of BOS and no therapeutic options, further research is needed, especially with children for whom we
288 ref. 2.245 (0.754–6.688)
0.146
2.381 (0.999–5.672)
0.050
2.327 (0.983–5.508)
0.055
1.011 1.024 1.025 1.058
(0.995–1.028) (0.945–1.109) (1.003–1.048) (0.853–1.312)
0.183 0.562 0.028 0.609
869 1.031 (0.967–1.099)
0.349
924 780 896 698
CI ¼ confidence interval;
HR hazard
outcomes. With the number of older donors increasing [2], this is a patient population that will increase the number of donor lungs, but research is needed to determine best possible methods for allocation of organs. With
Fig 3. Kaplan-Meier survival functions of the pediatric lung transplant recipient for donor age groups (n ¼ 923) more than 30 years (blue line) and 30 years or less (red line).
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Binary Donor Age 18 Years
Continuous Donor Age Variable Donor age, continuous Donor age 18 years, binary Donor age >30 years, binary Male recipient Male donor Race of recipient White Black Other Race of donor White Black Other Diagnosis Primary pulmonary hypertension Cystic fibrosis Idiopathic pulmonary fibrosis Congenital heart disease Other Age, years Creatinine, mg/dL Body mass index, kg/m2 Donor BMI >120% of recipient BMI Ischemia time, hours BMI ¼ body mass index;
HR
(95% CI)
1.004
(0.992–1.015)
p Value
Binary Donor Age >30 Years
HR
(95% CI)
p Value
0.967
(0.714–1.309)
0.827
HR
(95% CI)
p Value
0.524
0.831 0.831
(0.647–1.068) (0.647–1.067)
0.148 0.147
0.839 0.808
(0.652–1.080) (0.633–1.032)
0.173 0.087
1.168 0.829 0.837
(0.815–1.673) (0.645–1.065) (0.651–1.076)
0.398 0.142 0.165
ref. 2.615 1.047
(1.554–4.401) (0.732–1.496)
<0.001 0.803
ref. 2.658 1.056
(1.582–4.467) (0.739–1.509)
<0.001 0.764
ref. 2.601 1.054
(1.545–4.378) (0.738–1.506)
<0.001 0.772
ref. 0.894 0.788
(0.640–1.249) (0.569–1.092)
0.511 0.152
ref. 0.887 0.776
(0.635–1.238) (0.562–1.073)
0.481 0.125
ref. 0.896 0.791
(0.641–1.252) (0.571–1.095)
0.520 0.158
ref. 1.542 1.777 1.524 1.372 1.018 1.042 1.024 1.018 1.009
(0.972–2.446) (0.931–3.391) (0.679–3.419) (0.812–2.319) (0.978–1.058) (0.954–1.138) (0.990–1.059) (0.768–1.349) (0.928–1.097)
0.066 0.081 0.307 0.237 0.400 0.365 0.163 0.902 0.832
ref. 1.550 1.784 1.518 1.395 1.024 1.044 1.026 1.056 1.008
(0.977–2.457) (0.934–3.406) (0.676–3.409) (0.827–2.354) (0.986–1.063) (0.956–1.141) (0.992–1.060) (0.798–1.397) (0.928–1.096)
0.063 0.079 0.311 0.212 0.217 0.338 0.132 0.705 0.845
ref. 1.537 1.766 1.524 1.366 1.019 1.041 1.024 1.024 1.008
(0.969–2.438) (0.925–3.370) (0.679–3.420) (0.809–2.308) (0.983–1.058) (0.953–1.137) (0.991–1.059) (0.779–1.345) (0.927–1.095)
0.068 0.085 0.307 0.244 0.305 0.368 0.154 0.868 0.857
CI ¼ confidence interval;
HR hazard ratio;
HAYES ET AL OUTCOMES OF PEDIATRIC LUNG RECIPIENTS
Table 4. Multivariate Survival Analysis for Continuous Measure of Donor Age and Categoric Measures of Donor Age, 18 Years or More and More Than 30 Years (n ¼ 593)
Ref. ¼ reference. Ann Thorac Surg 2015;99:1184–92
have even less a grasp on BOS. Based on the results of the current study, donor-recipient age discrepancies do not impact long-term survival in children and thus should not influence lung allocation for a pediatric lung transplant candidate. Our study is limited by the retrospective collection of data from a large database that could potentially not include confounding variables, along with the potential risk for data entry errors. Furthermore, data available for pediatric recipients of lung transplantation in this database were substantially more limited than data available for adult lung transplantation recipients, with fewer than 1,000 pediatric patients eligible to be included in this analysis. Despite its limitations, our study draws results from a large, multi-institutional registry database of transplant recipients and thus reduces potential biases observed in single-institution observational studies. In conclusion, adult donor lungs appear not to negatively impact survival of pediatric lung transplant recipients when considering confounding variables. However, there is a significant mortality risk for the pediatric patient population associated with BOS. With the results of the current study and the existing medical literature that older donor lungs limit outcomes for adult lung transplant recipients, the methods for allocation of donor lungs in the United States may need to be revisited. The authors would like to acknowledge Dmitry Tumin for his statistical expertise in the data analysis.
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References 1. Benden C, Edwards LB, Kucheryavaya AY, et al, for the International Society for Heart and Lung Transplantation. The registry of the International Society for Heart and Lung Transplantation: sixteenth official pediatric lung and heartlung transplantation report—2013; focus theme: age. J Heart Lung Transplant 2013;32:989–97. 2. Organ Procurement and Transplantation Network and Scientific Registry of Transplant Recipients. OPTN/SRTR 2010 annual data report, 2011. Available at: http://srtr.transplant. hrsa.gov/annual_reports/2011/default.aspx. Accessed June 1, 2014. 3. Cano JR, Cerezo F, Algar FJ, et al. Prognostic factors influencing survival rates in children following lung transplantation. Transplant Proc 2008;40:3070–2. 4. Hayes D Jr, Black SM, Tobias JD, Higgins RS, Whitson BA. Influence of donor and recipient age in lung transplantation. J Heart Lung Transplant 2015;34(1):43–9. 5. United Network for Organ Sharing/Organ Procurement and Transplantation Network standard transplant analysis and research database. Available at: http://optn.transplant.hrsa. gov/data/about/optndatabase.asp. Accessed September 6, 2013. 6. Baldwin MR, Peterson ER, Easthausen I, et al. Donor age and early graft failure after lung transplantation: a cohort study. Am J Transplant 2013;13:2685–95. 7. Dezza MC, Parigi PC, Corno V, et al. Lung transplantation with grafts from elderly donors: a single-center experience. Transplant Proc 2010;42:1262–4. 8. Vadnerkar A, Toyoda Y, Crespo M, et al. Age-specific complications among lung transplant recipients 60 years and older. J Heart Lung Transplant 2011;30:273–81. 9. Bittle GJ, Sanchez PG, Kon ZN, et al. The use of lung donors older than 55 years: a review of the United Network of Organ Sharing database. J Heart Lung Transplant 2013;32:760–8. 10. Shigemura N, Horai T, Bhama JK, et al. Lung transplantation with lungs from older donors. recipient and surgical factors affect outcomes. Transplantation 2014;98(8):903–8.
INVITED COMMENTARY Lung transplantation in the pediatric age group is an uncommon but potentially lifesaving procedure [1]. Historically, the waiting list mortality in the pediatric age group has been much higher than in adults, although recent trends suggest that this is improving [2]. To address this challenge, several strategies have been pursued, such as lobar transplantation [3]. The use of adult donors, either with or without size reduction, remains a consideration. It has been more prominently used in Europe, where 43% of pediatric recipients received lungs from an adult donor, as opposed to 25% in North America [4]. In the United States, allocation of donor organs is based on a combination of donor and recipient age, geography, and Lung Allocation Score (for recipients 12 years or older). Periodic reassessment of the outcomes of this system is required to optimize outcomes and fairness. Benden and colleagues had previously reported, based on the International Society for Heart and Lung Transplantation Registry data, that donor age is not a predictor of death, in a univariable analysis treating donor age as
Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier
an ordinal variable [4]. By contrast, smaller studies have raised concerns regarding the use of adult donors for pediatric recipients. In this report, Hayes and colleagues [5] examine the United Network for Organ Sharing (UNOS) data for outcomes in pediatric recipients, focusing on donor age as a potential risk factor. Although donor age initially appeared to be a risk factor on univariable analysis, multivariable logistic regression models and propensity-matching models both suggest that no such link exists. Use of the UNOS dataset allowed a more robust conclusion with careful consideration of potentially linked covariates. Interestingly, donor age was also not predictive of the development of bronchiolitis obliterans syndrome. However, it should be noted that owing to missing data, the multivariable models and especially the propensity matching models are based on smaller numbers of patients than the univariable analysis. For practicing surgeons, this work suggests that more liberal use of older donors may be justified, given the ongoing concerns about wait-list mortality
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GENERAL THORACIC
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Outcomes in Pediatric Lung Transplant Recipients Receiving Adult Allografts Don Hayes, Jr, MD, MS, Patrick I. McConnell, MD, Mark Galantowicz, MD, Bryan A. Whitson, MD, PhD, Joseph D. Tobias, MD, and Sylvester M. Black, MD, PhD Departments of Pediatrics, Internal Medicine, Surgery, and Anesthesiology, Ohio State University College of Medicine; and Section of Pulmonary Medicine, Department of Cardiothoracic Surgery, and Department of Anesthesiology and Pain Medicine, Nationwide Children’s Hospital, Columbus, Ohio
Background. Clinical practice in the United States has no restrictions in allocating lungs from adult donors to pediatric recipients. Methods. The United Network for Organ Sharing database was queried from 1987 to 2013 for pediatric lung transplant recipients (aged less than 18 years) to assess survival using continuous donor age in years and two donor age groups, ‡ 18 years and > 30 years, for analysis. Results. Of 930 pediatric lung transplants, basic survival analysis identified a mortality hazard when adult lung allografts were transplanted into pediatric recipients; however, multivariate Cox models demonstrated that continuous donor age (hazard ratio [HR] 1.004, 95% confidence interval [CI]: 0.992–1.015, p [ 0.524) as well as both categoric age groups, donor 18 years or older (HR 0.967, 95% CI: 0.714–1.309, p [ 0.827) and donor older than 30 years (HR 1.168, 95% CI: 0.815–1.673, p [ 0.398), did not
significantly influence the risk for death. Moreover, propensity score matching analysis confirmed a lack of association of mortality risk with donor age ‡ 18 years (HR 1.129, 95% CI: 0.696–1.831, p [ 0.623) and donor age > 30 years (HR 1.050, 95% CI: 0.569–1.937, p [ 0.876). Bronchiolitis obliterans syndrome (BOS) was found to be a significant predictor of mortality in univariate analysis (HR 2.033, 95% CI: 1.639–2.521, p < 0.001), but the hazard of BOS did not vary across donor age categories. Conclusions. Adult donor lung allografts appear not to negatively affect survival in pediatric lung transplant recipients when considering confounders, and do not influence survival through an increased hazard for the development of BOS.
L
younger recipients [4]. We sought to assess the influence of donor allograft age on outcomes of pediatric lung transplant recipients using an available database in the United States. We hypothesized that lung allografts from adult donors affected clinical outcomes in children undergoing lung transplantation.
ung transplantation is an accepted indication for treating end-stage lung disease in children. Recently, an analysis of the International Society for Heart and Lung Transplantation (ISHLT) registry reported that survival after pediatric lung transplantation had improved by era comparing the years 1988 to 1999 and 2000 to June 2011, with a median survival improving from 3.3 to 5.8 years, respectively [1]. Moreover, median survival conditional on surviving at least 1 year for children after lung transplantation improved from 7.2 to 8.7 years, respectively [1]. With an aging population, patients on organ transplant waiting lists are tending to be older, while donors are also growing older [2]. According to analysis of the ISHLT registry, donor age for recipients aged 11 to 17 years did not appear to be associated with death after transplant [1]. In a single-center experience, donor age of more than 16 years was associated with negative influence on survival in pediatric lung transplantation [3]. The impact of older donor age on transplantation varies by organ, with limited data examining the effect of age between donor and recipients after pediatric lung transplantation. In the adult population, a recent study found that old donor lungs negatively impacted survival of
Accepted for publication Dec 5, 2014. Address correspondence to Dr Hayes, Ohio State University, Nationwide Children’s Hospital, 700 Children’s Dr, Columbus, OH 43205; e-mail: [email protected].
Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier
(Ann Thorac Surg 2015;99:1184–92) Ó 2015 by The Society of Thoracic Surgeons
Material and Methods Data Collection We retrospectively evaluated data from lung transplant recipients who were registered in the Organ Procurement and Transplant Network (OPTN) standard transplant analysis and research database administered by the United Network for Organ Sharing (UNOS) since 1987 [5]. The study was approved by Ohio State University Wexner Medical Center Institutional Review Board with a waiver of the need for individual consent (IRB#2012H0306). The UNOS/OPTN thoracic database was queried for all lung transplants from October 1987 to September 2013.
Statistical Methods All analyses were performed using Stata/MP, version 13.1 (StataCorp, College Station, TX). For all analyses, a p value less than 0.05 was considered statistically significant. Descriptive statistics for continuous variables are 0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2014.12.008
presented as means and standard deviations, and descriptive statistics for categoric variables are presented as proportions. To assess the effects of donor lung age for children less than 18 years of age after lung transplantation, we examined continuous measure of donor age and two arbitrarily chosen categorical groups for donor age cutoffs: 18 years or older and more than 30 years. Survival duration was analyzed from the date of the transplant until the date of death or censoring. Univariate Cox proportional hazards models were fitted separately using a continuous measure of donor age in years; and two categoric measures of donor age, the first equaling 1 if the donor was aged 18 years or more and 0 otherwise, and the second equaling 1 if the donor was aged more than 30 years and 0 otherwise. Kaplan-Meier survival curves were completed separately for survival differences between both age cutoffs. Cox proportional hazards regression models were used to assess the relationship between donor age and the hazard of mortality after transplant. For each measure of donor age, a multivariate Cox proportional hazards model was then fitted, and was adjusted for a series of characteristics including donor and recipient age and sex, diagnosis, age, creatinine, body mass index (BMI), oversized donor (donor BMI > 120% of recipient BMI), and ischemic time. The time metric was days of survival until death or censoring. Bronchiolitis obliterans syndrome (BOS) was considered as a potential mediator of the relationship between donor age and patient survival. The development of BOS was assessed at follow-up visits scheduled for 6 months after lung transplantation and every subsequent anniversary of the transplantation date. A patient was considered to have BOS if a “yes” answer was recorded to the question regarding “bronchiolitis obliterans syndrome” at any follow-up visit after lung transplantation in which BOS status was known. Differences in BOS onset across donor age categories were assessed descriptively
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using c2 tests, and the relationship of BOS to survival was assessed using a univariate Cox proportional hazards model, as previously described. Additionally, multivariate Cox proportional hazards models were fitted with days from lung transplantation until BOS diagnosis or censoring at the last follow-up as the time metric. These models included the same donor age measures and covariates as the multivariate Cox models assessing recipient survival. Finally, BOS was added to the multivariate Cox model of patient survival to assess whether this variable explained any effect of donor age on mortality hazard. Propensity score matching was completed to estimate mortality hazard risk by matching children with older donors to children with younger donors who had a similar predicted probability of receiving a lung allograft from an older donor. The propensity of receiving an adult lung allograft in children undergoing lung transplantation was calculated as a logit function of the covariates included in the multivariate Cox analysis of patient survival (not including BOS). The matching algorithm used nearest-neighbor matching without replacement on the logit of the propensity score, with a caliper width equal to 0.2 standard deviations of the logit of the propensity score. Cox proportional hazards regression stratified on the matched pairs was used to estimate a hazard ratio (HR) of adult donor age in children after lung transplantation.
Results Study Population Figure 1 presents inclusion and exclusion criteria. Of all 136,498 organ transplant candidates, 930 children (less than 18 years of age) who received a first-time single or double lung transplant were included in the study. Exclusion criteria included cases with no lung transplant Fig 1. Patient inclusion and exclusion criteria for survival analysis, multivariate Cox analysis, and propensity score matching.
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date, retransplant, duplicated entry, and noncadaveric donor. The limitation of the analysis to single or double lung transplants from cadaveric donors resulted in excluding 12 children receiving lobar transplants. Further exclusion included identical waiting list entry and exit dates for survival analysis, known donor age, missing covariate data for multivariate survival analysis, and unmatched controls for propensity score matching. Tables 1 and 2 summarize the patient characteristics of pediatric lung transplant recipients for both age cutoff groups used in our analysis. There was a trend toward a male recipient predominance in the 18 years or older donor age group but not in the more than 30 years old donor age group. A male donor predominance was found in both donor age groups. As anticipated for both donor age groups, pediatric lung transplant recipients were significantly older and had significantly higher BMI as compared with recipients receiving lungs from younger donors. Yet, older donors were significantly more likely than younger donors to have BMI exceeding recipient BMI by more than 20% (p < 0.001). No significant differences were observed across donor age categories in the proportion of recipients diagnosed with BOS after lung transplantation.
Univariate and Kaplan-Meier Survival Analysis In all, 924 patients were included in the univariate Cox analysis and 923 patients in the Kaplan-Meier survival analysis (age of one donor was not available). A continuous measure of donor age found a significant risk for death (HR 1.008, 95% confidence interval [CI]: 1.001–1.015, p ¼ 0.030) as did the categoric analysis for both donor age 18 years or more (Table 3, Fig 2) and donor age more than 30 years (Table 3, Fig 3). There were no covariates that were protective, whereas higher recipient BMI (HR 1.025, 95% CI: 1.003–1.048, p ¼ 0.028) was associated with significantly greater mortality risk. Two covariates, cytomegalovirus mismatch and Epstein-Barr virus mismatch, were not significantly associated with survival and had a very high proportion of missing data, leading them to be excluded from the multivariate analyses. Bronchiolitis obliterans syndrome (BOS) (HR 2.033, 95% CI: 1.639– 2.521, p < 0.001) was significantly associated with increased mortality hazard.
Multivariate Survival Analysis A total of 593 patients was included in the multivariate survival analysis. Table 4 demonstrates the Cox proportional hazards model with patient survival as the time metric. The continuous measure of donor age and the categoric donor age groups of 18 years or older and more than 30 years were not associated with increased risk of death. As with the univariate Cox analysis, no variables were protective. Supplemental multivariate models were fitted with time until BOS diagnosis or censoring as the time metric. The latter models revealed that time to BOS was not influenced by the continuous measure of donor age (HR 0.998, 95% CI: 0.981–1.015, p ¼ 0.814), the categoric measure of donor age 18 years or more (HR 0.875, 95% CI: 0.564–1.357, p ¼ 0.550), or the categoric measure
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of donor age more than 30 years (HR 0.987, 95% CI: 0.571– 1.706, p ¼ 0.963). The lack of a significant association between donor age and BOS hazard indicated that BOS did not mediate the relationship between donor age and survival. This finding was confirmed by adding BOS to the multivariate models of recipient survival, whereupon HR of continuous donor age (HR 0.991, 95% CI: 0.978– 1.005, p ¼ 0.206), donor age 18 years or more (HR 0.794, 95% CI: 0.566–1.114, p ¼ 0.183), and donor age more than 30 years (HR 0.929, 95% CI: 0.613–1.408, p ¼ 0.728) remained statistically insignificant.
Propensity Score Matching Totals of 254 patients and 146 patients were included in the propensity score matching analysis for the donor age groups of 18 years or more and more than 30 years, respectively. All covariates from Table 4 (ie, excluding BOS, cytomegalovirus mismatch, and Epstein-Barr virus mismatch) were included in the model of propensity of receiving an adult (donor aged 18 years or more or donor aged more than 30 years, respectively) lung allograft. Neither donor age of 18 years or more (HR 1.129, 95% CI: 0.696–1.831, p ¼ 0.623) nor age more than 30 years (HR 1.050, 95% CI: 0.569–1.937, p ¼ 0.876) was associated with increased risk of death for pediatric lung transplant recipients.
Comment The most important finding revealed by the basic statistics from the current study was a reduction in survival among children less than 18 years of age receiving adult donor lungs, but further analysis adjusting the estimated effect of donor age for several covariates did not confirm an associated mortality risk based on donor age. In adult lung transplantation, the medical literature is slowly expanding with regard to the effects of donor age on clinical outcomes [4, 6–10]. The majority of this literature is reporting that older donor lungs can influence outcomes in the adult lung transplant population. The matching of donor and recipient ages may potentially enhance survival for the younger adult population [4]. To date, with the only published data regarding donor lung age in children, Cano and coworkers [3] found that survival rates for patients whose donors were more than 16 years of age were 33.3%, 25%, 12.5%, and 12.5% at 1, 3, 5, and 10 years, respectively; whereas recipients who had donors less than 16 years of age had survival rates of 76%, 66.8%, 56.4%, and 49.3% at these respective times. Recently, Baldwin and colleagues [6] demonstrated that adult recipients of lungs from pediatric age donors had higher rates of 1-year graft failure. The reasons for this finding could not be addressed by their study, although the investigators speculated structural differences were likely important factors. We would also add that immunologic variations between adult and pediatric lungs are likely factors in donor-recipient lung interactions after transplantation. With an increasing number of patients listed for lung transplantation in the United States, methods are needed to expand the donor pool and to optimize long-term
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Table 1. Characteristics of Adolescent Lung Transplant Recipient for Donor Age Groups 18 Years or More and Less Than 18 Years Donor Age 18 Years (n ¼ 203)
All (n ¼ 930)a
a
Donor age data available for 929 cases.
n (%)
Mean (SD)
n (%)
Mean (SD)
390 (41.94) 481 (51.72)
. .
97 (47.78) 79 (38.92)
. .
292 (40.22) 401 (55.23)
. .
743 (79.89) 57 (6.13) 130 (13.98)
. . .
165 (81.28) 10 (4.93) 28 (13.79)
. . .
577 (79.48) 47 (6.47) 102 (14.05)
. . .
580 (62.37) 186 (20.00) 164 (17.63)
. . .
127 (62.56) 36 (17.73) 40 (19.70)
. . .
453 (62.40) 150 (20.66) 123 (16.94)
. . .
104 489 69 48 220 213
(11.18) (52.58) (7.42) (5.16) (23.66) (28.48)
. . . . . .
20 136 16 2 29 47
(9.85) (67.00) (7.88) (0.99) (14.29) (30.52)
. . . . . .
84 353 53 46 190 166
(11.57) (48.62) (7.30) (6.34) (26.17) (27.99)
. . . . . .
130 57 147 84
(31.10) (13.64) (35.17) (20.10)
. . . .
23 11 35 29
(23.47) (11.22) (35.71) (29.59)
. . . .
107 46 112 55
(33.44) (14.38) (35.00) (17.19)
. . . .
. . . . 10.96 (5.73) 0.59 (1.04) 17.20 (4.04) . 5.31 (1.48)
0 1 27 36
. . . . 15.28 (1.84) 0.67 (0.91) 18.42 (3.96) . 5.41 (1.65)
43 22 73 88
t test
c2 0.054 <0.001 0.708
0.504
<0.001
0.536 0.034
<0.001 43 23 100 124
(14.83) (7.93) (34.48) (42.76) . . . 322 (45.87) .
(0) (1.56) (42.19) (56.25) . . . 122 (67.40) .
(19.03) (9.73) (32.30) (38.94) . . . 200 (38.39) .
. . . . 9.77 (5.86) 0.57 (1.08) 16.87 (4.00) . 5.28 (1.43)
<0.001 0.249 <0.001 <0.001 0.302
1187
BMI ¼ body mass index.
Mean (SD)
HAYES ET AL OUTCOMES OF PEDIATRIC LUNG RECIPIENTS
Male recipient Male donor Race of recipient White Black Other Race of donor White Black Other Diagnosis Primary pulmonary hypertension Cystic fibrosis Idiopathic pulmonary fibrosis Congenital heart disease Other Bronchiolitis obliterans syndrome Cytomegalovirus matching Donor negative, recipient negative Donor negative, recipient positive Donor positive, recipient negative Donor positive, recipient positive Epstein-Barr virus matching Donor negative, recipient negative Donor negative, recipient positive Donor positive, recipient negative Donor positive, recipient positive Age, years Creatinine, mg/dL Body mass index, kg/m2 Donor BMI >120% of recipient BMI Ischemia time, hours
n (%)
p Value
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Variable
Donor Age <18 Years (n ¼ 726)
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Donor Age >30 Years (n ¼ 103)
All (n ¼ 930)a Variable
a
Data on donor age available for 929 cases.
BMI ¼ body mass index.
n (%)
Mean (SD)
n (%)
Mean (SD)
n (%)
Mean (SD)
390 (41.94) 481 (51.72)
. .
46 (44.66) 23 (22.33)
. .
343 (41.53) 457 (55.33)
. .
743 (79.89) 57 (6.13) 130 (13.98)
. . .
84 (81.55) 6 (5.83) 13 (12.62)
. . .
658 (79.66) 51 (6.17) 117 (14.16)
. . .
580 (62.37) 186 (20.00) 164 (17.63)
. . .
68 (66.02) 17 (16.50) 18 (17.48)
. . .
512 (61.99) 169 (20.46) 145 (17.55)
. . .
104 489 69 48 220 213
(11.18) (52.58) (7.42) (5.16) (23.66) (28.48)
. . . . . .
10 72 6 0 15 25
(9.71) (69.90) (5.83) (0) (14.56) (32.05)
. . . . . .
94 417 63 48 204 188
(11.38) (50.48) (7.63) (5.81) (24.70) (28.10)
. . . . . .
130 57 147 84
(31.10) (13.64) (35.17) (20.10)
. . . .
9 8 17 13
(19.15) (17.02) (36.17) (27.66)
. . . .
121 49 130 71
(32.61) (13.21) (35.04) (19.14)
. . . .
. . . . 10.96 (5.73) 0.59 (1.04) 17.20 (4.04) . 5.31 (1.48)
0 0 10 23
. . . . 15.31 (1.87) 0.73 (1.25) 18.56 (4.47) . 5.50 (1.68)
43 23 90 101
p Value t test
c2 0.543 <0.001 0.898
0.620
0.002
0.465 0.221
0.002 43 23 100 124
(14.83) (7.93) (34.48) (42.76) . . . 322 (45.87) .
(0) (0) (30.30) (69.70) . . . 65 (67.71) .
(16.73) (8.95) (35.02) (39.30) . . . 257 (42.41) .
. . . . 10.43 (5.81) 0.57 (1.01) 17.04 (3.96) . 5.29 (1.45)
<0.001 0.182 <0.001 <0.001 0.177
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Male recipient Male donor Race of recipient White Black Other Race of donor White Black Other Diagnosis Primary pulmonary hypertension Cystic fibrosis Idiopathic pulmonary fibrosis Congenital heart disease Other Bronchiolitis obliterans syndrome Cytomegalovirus matching Donor negative, recipient negative Donor negative, recipient positive Donor positive, recipient negative Donor positive, recipient positive Epstein-Barr virus matching Donor negative, recipient negative Donor negative, recipient positive Donor positive, recipient negative Donor positive, recipient positive Age, years Creatinine, mg/dL Body mass index, kg/m2 Donor BMI >120% of recipient BMI Ischemia time, hours
Donor Age 30 Years (n ¼ 826)
HAYES ET AL OUTCOMES OF PEDIATRIC LUNG RECIPIENTS
Table 2. Characteristics of Adolescent Lung Transplant Recipient for Donor Age Groups More Than 30 Years and 30 Years or Less
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Table 3. Univariate Survival Analysis for Continuous Measure of Donor Age and Two Categoric Measures of Donor Age, 18 Years or More and More Than 30 Years (n ¼ 924) Variable
n
Donor age, continuous Donor age 18 years, binary Donor age >30 years, binary Male recipient Male donor Race of recipient White Black Other Race of donor White Black Other Diagnosis Primary pulmonary hypertension Cystic fibrosis Idiopathic pulmonary fibrosis Congenital heart disease Other Bronchiolitis obliterans syndrome Cytomegalovirus matching Donor negative, recipient negative Donor negative, recipient positive Donor positive, recipient negative Donor positive, recipient positive Epstein-Barr virus matching Donor negative, recipient negative Donor negative, recipient positive Donor positive, recipient negative Donor positive, recipient positive Age, years Creatinine, mg/dL Body mass index, kg/m2 Donor BMI >120% of recipient BMI Ischemia time, hours BMI ¼ body mass index; ratio.
HR
(95% CI)
p Value
923 1.008 (1.001–1.015) 923 1.269 (1.024–1.572)
0.030 0.029
923 1.333 (1.012–1.755)
0.041
924 0.840 (0.698–1.011) 924 0.958 (0.799–1.147) 924 ref. 1.348 (0.929–1.956) 1.094 (0.838–1.426) 924 ref. 1.061 (0.838–1.342) 0.991 (0.769–1.277) 924 ref.
0.065 0.638
0.116 0.509
0.625 0.944
1.204 (0.890–1.631) 1.201 (0.777–1.858)
0.229 0.409
1.410 (0.872–2.281) 0.959 (0.683–1.346) 748 2.033 (1.639–2.521)
0.161 0.809 <0.001
417 ref. 0.848 (0.516–1.393)
0.516
1.051 (0.735–1.505)
0.784
0.996 (0.643–1.543)
0.985
Fig 2. Kaplan-Meier survival functions of the pediatric lung transplant recipient for donor age groups (n ¼ 923) 18 years and more (blue line) and less than 18 years (red line).
the recent finding that lung allografts from donors 50 years of age or more negatively affect survival of adult recipients less than 60 years of age [4], there is clearly a threshold that exists and should be implemented for the younger population, including children. In the models of the current study, BOS was associated with patient survival in univariate Cox models. Nevertheless, children who received older donor lungs as defined either by continuous age or categorically (18 years or older and more than 30 years) did not exhibit increased hazard of BOS development in multivariate survival analysis of time to diagnosis. With a limited understanding of BOS and no therapeutic options, further research is needed, especially with children for whom we
288 ref. 2.245 (0.754–6.688)
0.146
2.381 (0.999–5.672)
0.050
2.327 (0.983–5.508)
0.055
1.011 1.024 1.025 1.058
(0.995–1.028) (0.945–1.109) (1.003–1.048) (0.853–1.312)
0.183 0.562 0.028 0.609
869 1.031 (0.967–1.099)
0.349
924 780 896 698
CI ¼ confidence interval;
HR hazard
outcomes. With the number of older donors increasing [2], this is a patient population that will increase the number of donor lungs, but research is needed to determine best possible methods for allocation of organs. With
Fig 3. Kaplan-Meier survival functions of the pediatric lung transplant recipient for donor age groups (n ¼ 923) more than 30 years (blue line) and 30 years or less (red line).
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Binary Donor Age 18 Years
Continuous Donor Age Variable Donor age, continuous Donor age 18 years, binary Donor age >30 years, binary Male recipient Male donor Race of recipient White Black Other Race of donor White Black Other Diagnosis Primary pulmonary hypertension Cystic fibrosis Idiopathic pulmonary fibrosis Congenital heart disease Other Age, years Creatinine, mg/dL Body mass index, kg/m2 Donor BMI >120% of recipient BMI Ischemia time, hours BMI ¼ body mass index;
HR
(95% CI)
1.004
(0.992–1.015)
p Value
Binary Donor Age >30 Years
HR
(95% CI)
p Value
0.967
(0.714–1.309)
0.827
HR
(95% CI)
p Value
0.524
0.831 0.831
(0.647–1.068) (0.647–1.067)
0.148 0.147
0.839 0.808
(0.652–1.080) (0.633–1.032)
0.173 0.087
1.168 0.829 0.837
(0.815–1.673) (0.645–1.065) (0.651–1.076)
0.398 0.142 0.165
ref. 2.615 1.047
(1.554–4.401) (0.732–1.496)
<0.001 0.803
ref. 2.658 1.056
(1.582–4.467) (0.739–1.509)
<0.001 0.764
ref. 2.601 1.054
(1.545–4.378) (0.738–1.506)
<0.001 0.772
ref. 0.894 0.788
(0.640–1.249) (0.569–1.092)
0.511 0.152
ref. 0.887 0.776
(0.635–1.238) (0.562–1.073)
0.481 0.125
ref. 0.896 0.791
(0.641–1.252) (0.571–1.095)
0.520 0.158
ref. 1.542 1.777 1.524 1.372 1.018 1.042 1.024 1.018 1.009
(0.972–2.446) (0.931–3.391) (0.679–3.419) (0.812–2.319) (0.978–1.058) (0.954–1.138) (0.990–1.059) (0.768–1.349) (0.928–1.097)
0.066 0.081 0.307 0.237 0.400 0.365 0.163 0.902 0.832
ref. 1.550 1.784 1.518 1.395 1.024 1.044 1.026 1.056 1.008
(0.977–2.457) (0.934–3.406) (0.676–3.409) (0.827–2.354) (0.986–1.063) (0.956–1.141) (0.992–1.060) (0.798–1.397) (0.928–1.096)
0.063 0.079 0.311 0.212 0.217 0.338 0.132 0.705 0.845
ref. 1.537 1.766 1.524 1.366 1.019 1.041 1.024 1.024 1.008
(0.969–2.438) (0.925–3.370) (0.679–3.420) (0.809–2.308) (0.983–1.058) (0.953–1.137) (0.991–1.059) (0.779–1.345) (0.927–1.095)
0.068 0.085 0.307 0.244 0.305 0.368 0.154 0.868 0.857
CI ¼ confidence interval;
HR hazard ratio;
HAYES ET AL OUTCOMES OF PEDIATRIC LUNG RECIPIENTS
Table 4. Multivariate Survival Analysis for Continuous Measure of Donor Age and Categoric Measures of Donor Age, 18 Years or More and More Than 30 Years (n ¼ 593)
Ref. ¼ reference. Ann Thorac Surg 2015;99:1184–92
have even less a grasp on BOS. Based on the results of the current study, donor-recipient age discrepancies do not impact long-term survival in children and thus should not influence lung allocation for a pediatric lung transplant candidate. Our study is limited by the retrospective collection of data from a large database that could potentially not include confounding variables, along with the potential risk for data entry errors. Furthermore, data available for pediatric recipients of lung transplantation in this database were substantially more limited than data available for adult lung transplantation recipients, with fewer than 1,000 pediatric patients eligible to be included in this analysis. Despite its limitations, our study draws results from a large, multi-institutional registry database of transplant recipients and thus reduces potential biases observed in single-institution observational studies. In conclusion, adult donor lungs appear not to negatively impact survival of pediatric lung transplant recipients when considering confounding variables. However, there is a significant mortality risk for the pediatric patient population associated with BOS. With the results of the current study and the existing medical literature that older donor lungs limit outcomes for adult lung transplant recipients, the methods for allocation of donor lungs in the United States may need to be revisited. The authors would like to acknowledge Dmitry Tumin for his statistical expertise in the data analysis.
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References 1. Benden C, Edwards LB, Kucheryavaya AY, et al, for the International Society for Heart and Lung Transplantation. The registry of the International Society for Heart and Lung Transplantation: sixteenth official pediatric lung and heartlung transplantation report—2013; focus theme: age. J Heart Lung Transplant 2013;32:989–97. 2. Organ Procurement and Transplantation Network and Scientific Registry of Transplant Recipients. OPTN/SRTR 2010 annual data report, 2011. Available at: http://srtr.transplant. hrsa.gov/annual_reports/2011/default.aspx. Accessed June 1, 2014. 3. Cano JR, Cerezo F, Algar FJ, et al. Prognostic factors influencing survival rates in children following lung transplantation. Transplant Proc 2008;40:3070–2. 4. Hayes D Jr, Black SM, Tobias JD, Higgins RS, Whitson BA. Influence of donor and recipient age in lung transplantation. J Heart Lung Transplant 2015;34(1):43–9. 5. United Network for Organ Sharing/Organ Procurement and Transplantation Network standard transplant analysis and research database. Available at: http://optn.transplant.hrsa. gov/data/about/optndatabase.asp. Accessed September 6, 2013. 6. Baldwin MR, Peterson ER, Easthausen I, et al. Donor age and early graft failure after lung transplantation: a cohort study. Am J Transplant 2013;13:2685–95. 7. Dezza MC, Parigi PC, Corno V, et al. Lung transplantation with grafts from elderly donors: a single-center experience. Transplant Proc 2010;42:1262–4. 8. Vadnerkar A, Toyoda Y, Crespo M, et al. Age-specific complications among lung transplant recipients 60 years and older. J Heart Lung Transplant 2011;30:273–81. 9. Bittle GJ, Sanchez PG, Kon ZN, et al. The use of lung donors older than 55 years: a review of the United Network of Organ Sharing database. J Heart Lung Transplant 2013;32:760–8. 10. Shigemura N, Horai T, Bhama JK, et al. Lung transplantation with lungs from older donors. recipient and surgical factors affect outcomes. Transplantation 2014;98(8):903–8.
INVITED COMMENTARY Lung transplantation in the pediatric age group is an uncommon but potentially lifesaving procedure [1]. Historically, the waiting list mortality in the pediatric age group has been much higher than in adults, although recent trends suggest that this is improving [2]. To address this challenge, several strategies have been pursued, such as lobar transplantation [3]. The use of adult donors, either with or without size reduction, remains a consideration. It has been more prominently used in Europe, where 43% of pediatric recipients received lungs from an adult donor, as opposed to 25% in North America [4]. In the United States, allocation of donor organs is based on a combination of donor and recipient age, geography, and Lung Allocation Score (for recipients 12 years or older). Periodic reassessment of the outcomes of this system is required to optimize outcomes and fairness. Benden and colleagues had previously reported, based on the International Society for Heart and Lung Transplantation Registry data, that donor age is not a predictor of death, in a univariable analysis treating donor age as
Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier
an ordinal variable [4]. By contrast, smaller studies have raised concerns regarding the use of adult donors for pediatric recipients. In this report, Hayes and colleagues [5] examine the United Network for Organ Sharing (UNOS) data for outcomes in pediatric recipients, focusing on donor age as a potential risk factor. Although donor age initially appeared to be a risk factor on univariable analysis, multivariable logistic regression models and propensity-matching models both suggest that no such link exists. Use of the UNOS dataset allowed a more robust conclusion with careful consideration of potentially linked covariates. Interestingly, donor age was also not predictive of the development of bronchiolitis obliterans syndrome. However, it should be noted that owing to missing data, the multivariable models and especially the propensity matching models are based on smaller numbers of patients than the univariable analysis. For practicing surgeons, this work suggests that more liberal use of older donors may be justified, given the ongoing concerns about wait-list mortality
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GENERAL THORACIC
Ann Thorac Surg 2015;99:1184–92