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The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

Outcomes of adolescent recipients after lung transplantation: An analysis of the International Society for Heart and Lung Transplantation Registry

Published:February 17, 2017DOI:https://doi.org/10.1016/j.healun.2017.02.017

      Background

      Recipient adolescent age for non-lung solid-organ transplantation is associated with higher rates of rejection, graft loss and mortality. Although there have been no studies specifically examining adolescent outcomes after lung transplantation (LTx), limited data from the International Society of Heart and Lung Transplantation (ISHLT) Registry suggest that a similar association may exist. Recently, adolescence has been defined as 10 to 24 years of age, taking into account the biologic and sociologic transitions that occur during this age interval.

      Methods

      The ISHLT Registry was used to examine the survival outcomes of LTx recipients 10 to 24 years of age between 2005 and 2013. Given the developmental changes that occur in adolescence, survival outcomes for the tertiles of adolescence (10 to 14, 15 to 19 and 20 to 24 years old) were also examined.

      Results

      Adolescents made up 9% (n = 2,319) of the 24,730 LTxs undertaken during the study period. Kaplan–Meier survival estimates at 3 years showed lower adolescent survival (65%) when compared with younger children (73%, p = 0.006) and adults 25 to 34 (75%, p < 0.00001) and 35 to 49 (71%, p < 0.00001) years of age, without a significant survival difference compared with those 50 to 65 years old. Critically, 15- to 19-year-old recipients had the poorest outcomes, with reduced 1-year survival (82%) compared with those 10 to 14 years old (88%, p = 0.02), and reduced 3-year survival (59%) compared with those 10 to 14 (73%, p < 0.00001) and 20 to 24 (66%, p < 0.0001) years old.

      Conclusions

      Adolescent LTx recipients have poorer overall survival when compared with younger children and adults, with those 15 to 19 years old having the highest risk of death. This survival disparity among age groups likely reflects the difficult period of adolescence and its biologic and social transitions, which may influence both immunologic function and adherence.

      Keywords

      Analyses of renal, heart and liver transplant cohorts have demonstrated an association between adolescent age at transplant and poorer outcomes compared with older and younger recipients, with higher rates of acute and chronic rejection, graft loss and mortality.
      • Bell L.E.
      • Bartosh S.M.
      • Davis C.L.
      • et al.
      adolescent transition to adult care in solid organ transplantation: a consensus conference report.
      • Keith D.S.
      • Cantarovich M.
      • Paraskevas S.
      • et al.
      Recipient age and risk of chronic allograft nephropathy in primary deceased donor kidney transplant.
      • LaRosa C.
      • Baluarte H.J.
      • Meyers K.E.
      Outcomes in pediatric solid-organ transplantation.
      • Foster B.J.
      • Dahhou M.
      • Zhang X.
      • et al.
      High risk of graft failure in emerging adult heart transplant recipients.
      • Foster B.J.
      • Dahhou M.
      • Zhang X.
      • et al.
      High risk of liver allograft failure during late adolescence and young adulthood.
      • Foster B.J.
      • Dahhou M.
      • Zhang X.
      • et al.
      Association between age and graft failure rates in young kidney transplant recipients.
      The reasons for these poorer outcomes remain undefined and they occur despite the adolescent recipients’ young age and relative lack of co-morbidities. Adolescence is a period fraught with inherent challenges in both chronically ill and healthy individuals. It is a time of transition from childhood, with the parent as the primary caregiver, to independent individual who must negotiate social situations and make decisions about education and family. It has been hypothesized that the impact of adolescence and the challenges of this transition, coupled with the increased potential for non-adherence and a vigorous immune system, may contribute to the poorer outcomes generally reported.
      • Dharnidharka V.R.
      • Lamb K.E.
      • Zheng J.
      • et al.
      Across all solid organs, adolescent age recipients have worse transplant organ survival than younger age children: a US national registry analysis.
      • Foster B.J.
      • Dahhou M.
      • Zhang X.
      • et al.
      Change in mortality risk over time in young kidney transplant recipients.
      • Arnett J.J.
      Emerging adulthood. A theory of development from the late teens through the twenties.
      • Hsu D.T.
      Biological and psychological differences in the child and adolescent transplant recipient.
      Although we typically define adolescence in terms of age, historical definitions have varied. The World Health Organization has defined adolescence as being 10–19 years of age

      WHO. The second decade: improving adolescent health and development. 2001.

      ; the United Nations suggests 15–24 years of age

      United Nations. Secretary-General’s Report to the General Assembly. A/40/256, paragraph 19;1985

      ; and society, which utilizes the term “teenager,” defines adolescence as the age range 13–19 years. Societal changes in much of the developed world have led to the broadening of the timeline over which the transition to adulthood occurs, thus increasing the age at which “adult” roles and responsibilities are adopted and prolonging the traditional end of adolescence. This, coupled with increasing evidence that brain maturation occurs well into the third decade has led to the development of the composite term “young person.”
      • Sawyer S.M.
      • Afifi R.A.
      • Bearinger L.H.
      • et al.
      Adolescence: a foundation for future health.
      This term spans the period between 10 and 24 years of age, and encompasses both the transition from childhood to adolescence and the period of emerging adulthood.
      Lung transplantation (LTx) is a particularly challenging therapy for recipients, often requiring complex medication, dietary and physical therapy regimens, as well as rigorous medical and investigational follow-up to maintain graft function and survival. Although there are no specific studies examining adolescent outcomes after LTx, the International Society for Heart and Lung Transplantation (ISHLT)
      • Benden C.
      • Goldfarb S.B.
      • Edwards L.B.
      • et al.
      The Registry of the International Society for Heart and Lung Transplantation: seventeenth official pediatric lung and heart–lung transplantation report—2014; Focus theme: retransplantation.
      and Organ Procurement Transplantation Network data
      • Hayes Jr, D.
      • Glanville A.R.
      • McGiffin D.
      • et al.
      Age-related survival disparity associated with lung transplantation in cystic fibrosis: an analysis of the Registry of the International Society for Heart and Lung Transplantation.
      suggest that poorer outcomes occur in adolescent LTx recipients.
      LTx registry data and studies have tended to separate pediatric (<18 years) from adult (≥18 years) outcomes. This renders much of adolescence invisible by dividing adolescent recipients among pediatric and adult populations. Given the suggestion that adolescents have the worst outcomes in non-lung solid-organ transplant groups, we examined the outcomes of adolescents 10–24 years old and compared them with both younger and older LTx recipients.

      Methods

       Cohort

      All LTx recipients reported to the ISHLT Registry, an international longitudinal voluntary database, between January 1, 2005 and June 30, 2013 (n = 27,684) were considered for inclusion. The period selected as the beginning date corresponded to a change in data collection for the ISHLT Registry, whereas the end date allowed for accrual of at least 1 year of follow-up data. Data were censored at death or retransplant. Individuals undergoing retransplantation were entered as 2 separate cases. The final cohort consisted of 24,118 LTx recipients between the ages of 0 and 65 years who underwent 24,730 LTx procedures (Figure 1).
      Figure 1
      Figure 1Study cohort, excluded patients and cohort division based on recipient age at transplantation (yo = years old).

       Defining age groups

      The study cohort was divided into 3 groups, based on recipient age at transplant: (1) children (0–9 years); (2) adolescents (10–24 years); and (3) adults (≥25 years).
      Acknowledging the variations in development that occur during adolescence, data were also reported from the 3 tertiles of adolescence, 10–14, 15–19 and 20–24 years of age. Adults were also divided into 3 groups based on age, 25–34, 35–49 and 50–65 years of age (Figure 1).

       Defining baseline donor, recipient and transplant factors and survival analysis

      The ISHLT Registry collects pre-transplant baseline data, post-transplant data from the time of hospital discharge, and data from yearly follow-ups. Variables of interest were selected on the basis of clinical relevance and grouped according to recipient (pre-transplant), donor and transplant/procedural factors (see Table S1 in Supplementary Material available online at www.jhltonline.org/).
      Descriptive statistics were used to describe the baseline and clinical characteristics of all age groups and were presented as mean and standard deviation for continuous variables and as count and percentage for categorical variables. Categorical variables among groups were compared using the chi-square test whereas continuous variables were compared using the Kruskal–Wallis test. Testing was performed across all ages and separately for the 3 adolescent groups. Variables included in the univariate analysis are listed in the Supplementary Material online. Missing values are reported but were not included in the descriptive statistics.
      Survival analysis was performed for all patients with follow-up submitted to the ISHLT Registry and was stratified by age group using the Kaplan–Meier method. Survival rate curves were compared using the log-rank test. For pairwise comparisons, the Scheffé method was used to adjust for multiple comparisons. Comparisons of survival rates at specified time-points post-transplant were compared using a cloglog transformation test.
      Cox proportional hazards regression was used to assess the relationship between recipient age and post-transplant survival. We tested model assumptions and performed regression diagnostics. A backward selection method was used to determine the risk factors to retain in the model. The results of the Cox models are reported as hazard ratio (HR) with the corresponding p-value and 95% confidence interval (CI). A risk factor with HR <1 indicates that the event being analyzed was less likely to occur when the factor was present (categorical) or at that value (continuous) compared with baseline.
      Continuous risk factors were fit using a restricted cubic spline to allow for the most flexible fit of the functional form. To reduce bias associated with data not missing at random, a multiple imputation approach was used to handle missing information. This method produced a set of imputed values for each missing value, based on the other characteristics of the recipient, donor and transplant. The results of each imputed data set were combined to produce a final set of estimates and associated HR estimates and p-values. HR and 95% CI data for categorical variables are displayed in forest plots and tables. Continuous factors were fit using a restricted cubic spline and the HR were displayed graphically.

      Results

       Comparing adolescents with adults

      Adolescents 10–24 years old at the time of transplant made up 9% (n = 2,319) of the cohort. The majority of adolescents (88%) were transplanted in middle to late adolescence, aged 15–24 years (Figure 1).

       Recipient factors

      Cystic fibrosis (CF) was the main indication for transplantation in adolescent recipients (75% vs 13%; p < 0.001), whereas the majority of adults were transplanted for emphysema and interstitial lung disease (ILD). Compared with the adult groups, more females were transplanted in adolescence.
      Adolescent recipients were more likely to be in hospital or the intensive care unit (ICU) (32%, vs adults at 16%; p < 0.0001), mechanically ventilated (11%, vs adults at 6%, p < 0.0001) and/or requiring extracorporeal membrane oxygenation (ECMO) support (5%, vs adults at 2%; p < 0.0001) at the time of transplant (Table 1).
      Table 1Recipient Factors
      NChildren: 0-9 years (N = 192)NAdolescents: 10-24 years (N = 2,319)NAdults: 25-65 years (N = 22,219)p-value: 10-24 years vs 25-65 years
      Patient characteristics
       Female192100 (52%)2,3181,325 (57%)22,2199,585 (43%)<0.0001
      Underlying disease
       Cystic fibrosis18640 (22%)2,2621,696 (75%)21,7562,833 (13%)<0.0001
       Emphysema (COPD/ATD)1 (1%)14 (1%)7,809 (36%)
       ILD35 (19%)90 (4%)6,957 (32%)
       PAH27 (14%)117 (5%)554 (3%)
       OB16 (9%)66 (3%)236 (1%)
       Other67 (35%)279 (12%)3,367 (15%)
      Pre-transplant condition
       ECMO1342 (1%)1,05252 (5%)11,529191 (2%)<0.0001
       Mechanical ventilation13456 (42%)1,046119 (11%)11,500727 (6%)<0.0001
       In ICU12950 (39%)981158 (16%)11,157915 (8%)<0.0001
       Hospitalized (but not in ICU)26 (20%)157 (16%)890 (8%)
       Outpatient53 (41%)666 (68%)9,352 (84%)
       Pan-resistant infection1278 (6%)918200 (22%)10,630362 (3%)<0.0001

       Donor factors

      Adolescent recipients had younger donors with more consistent age matching, likely reflecting donor–recipient size matching; they received organs from donors who were shorter and lighter than those received by adults (Table 2). Donors of organs received by adolescent recipients were less likely have a smoking history of >20 pack-years, with a trend toward a lower incidence of donor diabetes (Table 2).
      Table 2Donor and Transplant Factors
      NChildren: 0 to 9 years (N = 192)NAdolescents: 10-24 years (N = 2,319)NAdults: 25-65 years (N = 22,219)p-value: 10-24 years vs 25-65 years
      Donor characteristics
       Donor age1923 [0–21]2,30731 [10–57]22,15140 [16–62]<0.0001
       Donor height (cm)164101 [59–146]1,727168 [145–184]18,131172 [157–188]<0.0001
       Donor weight (kg)16515 [6–44]1,73266 [36–97]18,14874 [52–102]<0.0001
      Donor BMI16115.9 [12.6–22.2]1,71623.5 [16.7–33.3]18,06124.6 [19.1–34]<0.0001
       Donor smoking1340 (0%)1,091136 (13%)11,8761,857 (16%)0.005
       Donor diabetes1263 (2%)90648 (5%)21,489730 (7%)0.06
      Procedural characteristics
       Bilateral transplant191191 (99.5%)2,3172,247 (97%)22,20416,047 (72%)<0.0001
       DCD1362 (1%)1,18852 (4%)13,258583 (4%)0.97
       Retransplant1927 (4%)2,319181 (8%)22,2191,009 (5%)<0.0001
       Ischemic time (hours)1295.8 [3.7–8]1,1655.6 [3.1–9]13,0555 [2.6–8.3]<0.0001
      Transplant characteristics
       CMV mismatch13045 (35%)1,014312 (31%)11,2212,653 (24%)<0.0001
       EBV mismatch10837 (34%)958217 (23%)10,252833 (8%)<0.0001
       Most recent PRA (%)970 [0–29]8290 [0–24]10,1160 [0–43]0.0019
      BMI, body mass index; CMV, cytomegalovirus; DCD, donation after circulatory death; EBV, Epstein–Barr virus; PRA, panel-reactive antibodies.

       Transplant/procedural factors

      The vast majority (97%) of adolescent recipients received a bilateral LTx, whereas 30% of the adult cohort received a single LTx (p < 0.001). Few transplants (4%) in any age group involved organs from a donation after circulatory death (DCD). Overall, few retransplants were performed, although the rate was higher in adolescent recipients compared with adults (8%, vs adults at 5%; p < 0.0001; Table 2).
      There was no difference in HLA matching (p = 0.74), although panel-reactive antibody (PRA) distribution was higher in the adult cohort (p = 0.002). Adolescent patients were more likely to be cytomegalovirus (CMV) and Epstein–Barr virus (EBV) mismatches (recipient IgG negative / donor IgG positive) (Table 2). They were also more likely to have pre-transplant evidence of a pan-resistant bacterial infection, possibly a reflection of the high proportion of recipients with CF. Ischemic time was, on average, 0.6 hour longer in the adolescent group (p < 0.0001; Table 1, Table 2).

       Adolescent tertiles

      Within the adolescent tertiles, there was a difference in recipient and donor age, height, weight and body mass index (BMI). Younger recipients (10–14 years old) received younger donors (median age 16 years old), likely reflecting the influence of size matching. In those aged 15–19 and 20–24 years, median donor age was ≥10 years older than the upper limit of the age group, with those 15–19 years old receiving organs from donors with a median age of 29 years and those 20–24 years old receiving organs from donors with a median age of 36 years (Table 3).
      Table 3Adolescent Tertiles
      NEarly adolescence: 10`14 years (n = 285)NMid-adolescence: 15`19 years (n = 775)NLate adolescence: 20`24 years (n = 1,259)p-value
      Patient characteristics
       Female285172 (60%)775469 (60%)1,258684 (54%)0.01
      Underlying disease
       Cystic fibrosis281177 (63%)757561 (74%)1,224958 (78%)<0.0001
       Emphysema (COPD/ATD)3 (1%)2 (0.5%)9 (1%)
       ILD26 (9%)27 (3%)37 (3%)
       PAH20 (7%)51 (7%)46 (4%)
       OB22 (8%)20 (2.5%)24 (2%)
       Other33 (12%)96 (13%)150 (12%)
      Pre-transplant condition
       ECMO13810 (7%)36320 (6%)55122 (4%)0.24
       Mechanical ventilation13515 (11%)36045 (13%)55159 (11%)0.70
       In ICU11618 (16%)34058 (17%)52582 (16%)0.02
       Hospitalized28 (24%)61 (18%)68 (13%)
       Outpatient70 (60%)221 (65%)375 (71%)
       Pan-resistant infection11219 (17%)32072 (23%)486109 (22%)0.42
      Donor characteristics
       Donor age28416 [6–53]77529 [10–56]1,24836 [15–58]<0.0001
       Donor height (cm)209160 [122–178]572165 [145–183]946169 [155–185]<0.0001
       Donor weight (kg)21356 [22–85]57365 [35–91]94670 [50–100]<0.0001
       Donor BMI20822 [13.9–33.3]56523.2 [16.6–32.4]94324.1 [18.5–33.5]<0.0001
       Donor smoking13912 (9%)37236 (10%)58088 (15%)0.015
       Donor diabetes1122 (2%)31513 (4%)47933 (7%)0.05
      Procedural Characteristics
       Bilateral transplant284277 (97.5%)774752 (97%)12591,218 (97%)0.90
       DCD1464 (3%)39110 (3%)64538 (6%)0.02
       Retransplant28510 (3%)77558 (7%)1259113 (9%)0.007
       Ischemic time (hours)1315.5 [3.3–8.6]4105.5 [3.1–9.5]6245.6 [3.1–9]0.66
      Transplant Characteristics
       CMV mismatch12332 (26%)355104 (29%)536176 (33%)0.25
       EBV mismatch11734 (29%)34284 (25%)49499 (20%)
       Most recent PRA (%)870 [0–13]2770 [0–24]4650 [0–27]0.25
      ATD, α1-anti-trypsin deficiency; BMI, body mass index; CMV, cytomegalovirus; COPD, chronic obstructive pulmonary disease; DCD, donation after circulatory death; ECMO, extracorporeal membrane oxygenation; EBV, Epstein–Barr virus; ICU, intensive-care unit; ILD, interstitial lung disease; OB, obliterative bronchiolitis; PAH, pulmonary arterial hypertension; PRA, panel-reactive antibodies.
      The majority of adolescents were transplanted for CF (75%). In the youngest cohort (10–14 years), a greater proportion were transplanted for other underlying diseases, such as ILD, obliterative bronchiolitis (OB) and pulmonary arterial hypertension (PAH) (Table 3). Although more adolescent females were transplanted in all age groups, they formed a greater proportion of the cohorts 10–14 and 15–19 years old. There was no difference in the incidence of CMV/EBV mismatch or pan-resistant bacterial infection, although older recipients were more likely to have a history of cigarette smoking (Table 3).
      Most adolescent recipients received bilateral LTx and there was no difference in PRA, HLA matching or ischemic time. A greater number of DCD transplants occurred in the 20–24-year cohort (p = 0.02; Table 3). Older recipients were more likely to have had a previous transplant and/or receive a donor with a history of cigarette smoking or diabetes. Although adolescents were overall more likely to be hospitalized and/or in the ICU at the time of transplant, this was particularly true of the younger cohorts (10–14 [40%] vs 15–19 [35%] vs 20–24 [29%] years of age; p = 0.03). There was no difference in the use of mechanical ventilation or ECMO before transplantation (Table 3). Overall, patients in these tertiles had similar underlying disease distribution and transplant characteristics (Table 3).

       Comparison to 25–34-year cohort

      Adolescent recipients had many similarities to the 25–34-year cohort wherein the greatest proportion of transplants were undertaken for CF and were predominantly bilateral LTx. Compared with adolescent recipients, those 25–34 years old received organs from older donors (adolescents: 31 years; 25–34 years: 37 years; p < 0.0001), who were taller and heavier. There was no significant difference in PRA, CMV mismatch, DCD, retransplant or ischemic time. There was no difference in the use of ECMO, mechanical ventilation or incidence of hospitalization and/or ICU admission pre-transplant. Adolescents were more likely to be EBV mismatches and have pan-resistant infection (see Table S2 in Supplementary Material online).

       Survival outcomes

       Overall survival

      A difference in survival was evident between all cohorts, with adolescents and 50–65-year-olds demonstrating the poorest post-transplant survival compared with the other age categories. Adolescents demonstrated an up to 10% lower graft survival at 3 years compared with the other age groups (Figure 2).
      Figure 2
      Figure 2Survival stratified by age group. Adolescent survival at 1 year (84%) was decreased compared with the 25–34-year cohort (86%, p = 0.005). At 3 years, adolescent survival (65%) was significantly poorer compared with younger children (73%, p = 0.006) and with the 25–34-year (75%, p < 0.00001) and 35–49-year (71%, p < 0.00001) cohorts.
      Adolescent survival at 1 year (84%) was better than that of the 50–65-year cohort (81%; p = 0.0009), and similar to that of younger children (83%; p = 0.84) and the 35–49-year cohort (84%; p = 0.69). Adolescent survival was reduced compared with the 25–34-year age group (86%; p = 0.005).
      At 3 years this difference was magnified. Adolescent survival (65%) was similar to the oldest cohort, 50 to 65 years (66%; p = 0.14), but significantly poorer than that of younger children (73%; p = 0.006) and the 25–34-year (75%; p < 0.00001) and 35–49-year (71%; p < 0.00001) age groups.
      When examining survival conditional on survival to 1 year, adolescent 3-year survival (77%) improved, but was significantly reduced when compared with younger children (88%; p = 0.01) and adults 25–34 (87%; p < 0.00001), 35–49 (85%; p < 0.00001) and 50–65 (81%; p < 0.0001) years old (Figure 3).
      Figure 3
      Figure 3Survival stratified by age group, conditional on survival to 1 year. Adolescent 3-year survival (77%) was significantly reduced when compared with the 0–9-year (88%, p = 0.01), 25–34-year (87%, p < 0.00001), 35–49-year (85%, p < 0.00001) and 50–65-year (81%, p < 0.0001) cohorts.

       Survival outcomes of adolescent tertiles

      Of the 3 tertiles of adolescence, the 15–19-year cohort had poorer outcomes compared with both the younger adolescents 10–14 years old (p = 0.006) and older adolescents 20–24 years old (p = 0.04). Survival was reduced at 1 year compared with the 10- to 14-year group (82% vs 88%; p = 0.02) and at 3 years compared with the 10- to 14-year (59% vs 73%; p < 0.00001) and 20–25-year cohort (59% vs 65%; p < 0.00001) (Figure 4). This difference persisted when analyzed conditional on 1-year survival.
      Figure 4
      Figure 4Survival stratified by adolescent age group. The 15–19-year cohort had the worst outcomes, compared younger adolescents aged 10–14 years (p = 0.006) and older adolescents aged 20–24 years (p = 0.04).

       Comparison to 25–34-year-old cohort

      Despite demographic, transplant and immunologic similarities, the 25–34-year age cohort demonstrated the best survival when compared with all other cohorts at all time-points, with 1-year survival of 86% and 3-year survival of 75%, which was >10% better than the adolescent (10–24-year) group (Figure 2).

       Impact of diagnosis of CF

      Survival analysis suggested that the CF group did better than their non-CF counterparts at both 1 year (CF: 86%; non-CF: 79%; p < 0.0001) and 3 years (CF: 66%; non-CF: 61%; p = 0.002). This difference did not persist conditional on 1-year survival for the overall cohort (p = 0.62).

       Multivariate analysis

      Multivariate analysis examined the effect of age on mortality in those with CF, using a reference group of 35–49-year-olds with a non-CF diagnosis. A survival difference was noted between the age groups even after adjustment for age × diagnosis interaction and other risk factors (Figure 5, see also Figure S1 in Supplementary Material online for details of factors used in the model). The risk of mortality for those with CF was highest in relation to the reference group in the 15–19-year cohort (HR = 1.38), with increased risk of mortality also evident in the 20–24-year cohort (HR = 1.15). In addition, this increased risk of mortality in the 15–19-year cohort persisted in those with a non-CF diagnosis (HR = 1.34). Compared with non-CF patients in the same age group, there was a statistically significant difference in mortality for 10–14-year-old CF patients (HR = 1.67, p = 0.02). The HRs were not statistically significant for either 15–19-year-olds (HR = 1.03, p = 0.8) or 20–24-year-olds (HR = 0.98, p = 0.8).
      Figure 5
      Figure 5Multivariate analysis of post-transplant mortality. CF: cystic fibrosis; reference group: 35–49 years old with a non-CF diagnosis. The risk of mortality was evident in the 15–19-year cohort with (HR = 1.38) or without (HR = 1.34) CF, and 20–24-year chort with CF (HR = 1.15) compared with the reference group (p = 0.02).

      Discussion

      Adolescence is a time of transition, fraught with social and societal challenges in both chronically ill and healthy individuals. An adolescent age at transplantation has been associated with poorer short- and long-term outcomes in solid-organ transplant groups, with higher rates of acute rejection and shorter median graft half-lives when compared with younger children and older adults.
      • Keith D.S.
      • Cantarovich M.
      • Paraskevas S.
      • et al.
      Recipient age and risk of chronic allograft nephropathy in primary deceased donor kidney transplant.
      • LaRosa C.
      • Baluarte H.J.
      • Meyers K.E.
      Outcomes in pediatric solid-organ transplantation.
      • Foster B.J.
      • Dahhou M.
      • Zhang X.
      • et al.
      Association between age and graft failure rates in young kidney transplant recipients.
      • Dharnidharka V.R.
      • Lamb K.E.
      • Zheng J.
      • et al.
      Across all solid organs, adolescent age recipients have worse transplant organ survival than younger age children: a US national registry analysis.
      • Foster B.J.
      • Dahhou M.
      • Zhang X.
      • et al.
      Change in mortality risk over time in young kidney transplant recipients.
      • Benden C.
      • Goldfarb S.B.
      • Edwards L.B.
      • et al.
      The Registry of the International Society for Heart and Lung Transplantation: seventeenth official pediatric lung and heart–lung transplantation report—2014; Focus theme: retransplantation.
      • Hayes Jr, D.
      • Glanville A.R.
      • McGiffin D.
      • et al.
      Age-related survival disparity associated with lung transplantation in cystic fibrosis: an analysis of the Registry of the International Society for Heart and Lung Transplantation.
      Although this disparity in survival between young and adult transplant recipients has been acknowledged, studies have tended to confine their examination to the pediatric age group (i.e., those aged <18 years) and have not taken into account the more contemporary definitions of adolescence or the impact of emerging adulthood. This analysis of the ISHLT Registry shows that adolescent recipients aged 10–24 years had significantly poorer survival when compared with children and adults, despite their young age, fewer comorbidities and more favorable donor and transplant characteristics. Among the adolescents, the 15–19-year-old recipients had the highest risk of death, an outcome not apparent when the pediatric and adult registries are examined in isolation.
      The underlying cause of the increased risk of mortality in adolescence is likely multifactorial and at least in part biologically driven. Not only is the transition from childhood to adulthood characterized by behavioral, social and cognitive developments,
      • Kaufman M.
      • Shemesh E.
      • Benton T.
      The adolescent transplant recipient.
      but there are likely changes in metabolism and immune responses.
      • Dhanireddy K.K.
      • Maniscalco J.
      • Kirk A.D.
      Is tolerance induction the answer to adolescent non-adherence?.
      These factors, coupled with the normal developmental changes of adolescence that affect an individual’s ability to self-monitor and self-care, the shift of care responsibilities, and the tendencies for increased risk-taking and widely varying emotions, create the “perfect storm,” which contributes to the poor outcomes seen.
      The impact of adolescence and its transitions are supported by evidence from Foster et al who showed that the incidence of graft failure in renal, heart and liver transplant recipients peaks between 17 and 21 years of age, regardless of age of transplant.
      • Foster B.J.
      • Dahhou M.
      • Zhang X.
      • et al.
      High risk of graft failure in emerging adult heart transplant recipients.
      • Foster B.J.
      • Dahhou M.
      • Zhang X.
      • et al.
      High risk of liver allograft failure during late adolescence and young adulthood.
      • Foster B.J.
      • Dahhou M.
      • Zhang X.
      • et al.
      Association between age and graft failure rates in young kidney transplant recipients.
      • Foster B.J.
      Heightened graft failure risk during emerging adulthood and transition to adult care.
      This may be the basis of the poorest outcomes noted in the 15–19-year cohort. Unlike those transplanted in childhood (<10 years), who will have a prolonged period of sustained stability before entering the “high-risk” period, 15–19-year-old recipients enter this “high-risk” period at the time of transplant. In turn, this likely impacts graft survival and contributes to the reduction in 3-year survival observed.
      There are several factors that may contribute to this period of “high-risk.” The perils of adolescence are well recognized in both the healthy and chronically ill. Late adolescence (age 18–24 years) is the time of greatest risk for healthy individuals, who, when compared with those age 12–17 years, have twice the mortality, 3 times the suicide risk and increased rates of high-risk drinking and substance abuse.
      Australian Institute of Health and Welfare
      Young Australians: their health and wellbeing 2007.
      Australian Bureau of Statistics (ABS)
      Australian social trends 2008: risk taking by young people.
      In other chronic diseases, similarly poor outcomes are demonstrated in adolescence; for instance, in Type 1 diabetes, metabolic control deteriorates with increased non-adherence and risk taking behavior
      • Silverstein J.
      • Klingensmith G.
      • Copeland K.
      • et al.
      Care of children and adolescents with type 1 diabetes: a statement of the American Diabetes Association.
      and, in asthma, this period is characterized by inadequate disease management and increased exacerbation risk.
      • Rhee H.
      • Belyea M.J.
      • Ciurzynski S.
      • et al.
      Barriers to asthma self-management in adolescents: relationships to psychosocial factors.
      The ISHLT Registry does not collect data on the timing of transition of care from pediatric to adult centers. In most centers, this transition tends to occur somewhere between the ages of 15 and 20 years. There is clear data from studies of renal, liver and heart transplantation that points to a significant increase in morbidity, graft loss and death in the years that follow this transition of care.
      • Bell L.E.
      • Bartosh S.M.
      • Davis C.L.
      • et al.
      adolescent transition to adult care in solid organ transplantation: a consensus conference report.
      • Annunziato R.A.
      • Emre S.
      • Shneider B.
      • et al.
      Adherence and medical outcomes in pediatric liver transplant recipients who transition to adult services.
      • Harden P.N.
      • Walsh G.
      • Bandler N.
      • et al.
      Bridging the gap: an integrated paediatric to adult clinical service for young adults with kidney failure.
      • Koshy S.M.
      • Hebert D.
      • Lam K.
      • et al.
      Renal allograft loss during transition to adult healthcare services among pediatric renal transplant patients.
      • Wray J.
      • Sugarman H.
      • Davis L.
      • et al.
      Adolescence and transition to adult services: are these risky times for heart and/or lung recipients?.
      Reported non-adherence rates after transplantation are also highest in adolescent cohorts,
      • Bullington P.
      • Pawola L.
      • Walker R.
      • et al.
      Identification of medication non-adherence factors in adolescent transplant patients: the patient׳s viewpoint.
      • Dew M.A.
      • Dabbs A.D.
      • Myaskovsky L.
      • et al.
      Meta-analysis of medical regimen adherence outcomes in pediatric solid organ transplantation.
      and transition from pediatric to adult care is characterized by a further deterioration in adherence,
      • Bell L.E.
      • Bartosh S.M.
      • Davis C.L.
      • et al.
      adolescent transition to adult care in solid organ transplantation: a consensus conference report.
      • Annunziato R.A.
      • Emre S.
      • Shneider B.
      • et al.
      Adherence and medical outcomes in pediatric liver transplant recipients who transition to adult services.
      a factor likely to further add to the risk of the adolescent period.
      A strong association exists between non-adherence and psychosocial variables in adolescents. Factors such as depression and anxiety, disease severity, poor health-related quality of life, a poor physician–patient relationship and lack of parental monitoring and involvement have all been shown to impact adolescent adherence after transplantation.
      • Fredericks E.M.
      • Lopez M.J.
      • Magee J.C.
      • et al.
      Psychological functioning, nonadherence and health outcomes after pediatric liver transplantation.
      • Kahana S.Y.
      • Frazier T.W.
      • Drotar D.
      Preliminary quantitative investigation of predictors of treatment non-adherence in pediatric transplantation: a brief report.
      • Simons L.E.
      • McCormick M.L.
      • Devine K.
      • et al.
      Medication barriers predict adolescent transplant recipients׳ adherence and clinical outcomes at 18-month follow-up.
      These factors tend to be exacerbated in middle to late adolescence (15–24 years), particularly as this is also the time that care responsibility tends to transition from the parent to the individual. We hypothesize that all these factors contribute to the “high-risk” window leading to the poorest outcomes in 15–19-year-olds and the decline in survival seen at 3 years.
      Despite being demographically similar to adolescents (10–24 years), survival outcomes for those 25–34 years of age were superior to all other cohorts and, in particular, exceeded that of adolescents by 10% at 3 years. This supports our hypothesis that there are factors specific to adolescence that lead to these poorer outcomes. Current Registry reporting confines data to pediatric (<18 years)
      • Benden C.
      • Goldfarb S.B.
      • Edwards L.B.
      • et al.
      The Registry of the International Society for Heart and Lung Transplantation: seventeenth official pediatric lung and heart–lung transplantation report—2014; Focus theme: retransplantation.
      and adult cohorts (≥18 years),
      • Yusen R.D.
      • Christie J.D.
      • Edwards L.B.
      • et al.
      The Registry of the International Society for Heart and Lung Transplantation: thirtieth adult lung and heart–lung transplant report—2013; Focus theme: age.
      obscuring the true impact of adolescence on survival by dividing the poor outcomes of 15–19-year-olds between pediatric and adult cohorts. In addition, it artificially lowers the excellent outcomes of the 25–34-year cohort by including them with the poorer performing adolescents.
      The limitations of this study are those integral to Registry studies, including its voluntary data contribution, North American inclusion bias, and the potential biases of data entry errors and missing data.
      • Yusen R.D.
      • Christie J.D.
      • Edwards L.B.
      • et al.
      The Registry of the International Society for Heart and Lung Transplantation: thirtieth adult lung and heart–lung transplant report—2013; Focus theme: age.
      • Benden C.
      • Edwards L.B.
      • Kucheryavaya A.Y.
      • et al.
      The Registry of the International Society for Heart and Lung Transplantation: sixteenth official pediatric lung and heart–lung transplantation report—2013; Focus theme: age.
      Although Registry data allow the identification of trends in mortality, we were unable to clearly elucidate causation and could not control for center type (pediatric or adult). In addition, we could not comment on differences in immunosuppression or induction regimens, nor in rates of primary graft dysfunction between the groups, which may have influenced long-term outcomes. Despite such limitations, our study draws from a large multi-institutional, international database of transplant recipients, avoiding many of the potential biases observed in single-institution, observational studies.
      The recognition of the poorer outcomes of adolescent LTx recipients, particularly the very poor outcomes of 15–19-year-olds, may urge us to further study potential causations, but this will likely be challenging. The very nature of adolescent lung transplantation and in particular the small numbers would make any prospective study difficult to sufficiently power without prolonged enrollment. In addition, the effects of non-adherence and other psychosocial variables on outcomes in this age group and the lack of validated objective measures to assess these factors would make a study difficult, if not impossible, to design. Therefore, rather than focus on the design of randomized, controlled trials or retrospective database analyses, novel research protocols examining qualitative themes may allow us to explore the differences seen in adolescent survival after transplantation. In addition, this recognition of a clear difference in outcomes calls for the development of modified programs and strategies with an aim not to merely identify the factors that lead to these poorer outcomes but to attempt to mitigate them by impacting on non-adherence and other behavioral, socioeconomic and psychiatric variables that are likely to influence outcomes.
      In conclusion, recipient age at the time of transplant influences outcomes. Adolescents aged 10–24 years have poorer survival than younger children and older adults, with 15–19-year-olds demonstrating the poorest outcomes among all the age cohorts. As adolescents will continue to be managed in both pediatric and adult facilities, it remains important that they be regarded as a distinct cohort and not as “big” children nor “small” adults, and that adolescent-specific management strategies are employed. We also strongly advocate for modification of Registry reporting and longitudinal data analysis to reflect the effect of age on transplant outcomes.

      Disclosure statement

      The authors have no conflicts of interest to disclose. We thank the ISHLT Registry and the contributing institutions for the provision of the data. This study was supported by a 2014 Early Career Grant from the ISHLT. We also acknowledge the Margaret Pratt Foundation for their ongoing support.

      Supplementary material

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