Health-related quality of life in long-term survivors of paediatric liver transplantation

Abstract

BACKGROUND:

Long-term survival after paediatric liver transplantation is now the rule rather than the exception. Improving long-term outcomes after transplantation must consider not only the quantity but also the quality of life years restored.

OBJECTIVES:

To characterize health-related quality of life (HRQOL) of LT recipients ≥15 years after paediatric LT.

METHODS:

Recipients of a paediatric LT performed before December 1996 in a single institution with continuous follow-up at either the paediatric or adult partner centre were identified. Patients with severe developmental or neurological impairment were excluded. HRQOL was assessed using the Pediatric Quality of Life Inventory 4.0, the Medical Outcomes Study Short Form-36 version 2 and the Pediatric Liver Transplant Quality of Life Tool.

RESULTS:

A total of 27 (67% male) subjects (mean age 24.3±6.7 years [median 23.2 years; range 16.6 to 40.3 years]) participated. The median age at transplant was 1.7 years (range 0.5 to 17.0 years). Seven (26%) participants underwent retransplantation. Seventeen (63%) participants were engaged in full-time work/study. Mean Short Form-36 version 2 scores included physical (49.6±11.1) and mental (45.3±12.5) subscale scores. The mean score for the disease-specific quality of life tool for paediatric liver transplant recipients (the Pediatric Liver Transplant Quality of Life Tool) was 64.70±15.2. The physical health of the young adults strongly correlated with level of involvement in work/study (r=0.803; P<0.05).

CONCLUSIONS:

The self-reported HRQOL of participants <18 years of age was comparable with a standardized healthy population. In contrast, participants between 18 and 25 years of age had HRQOL scores that were more similar to a group with chronic illness. Participants engaged in full-time work/study experienced enhanced physical health.

In 2015, liver transplantation (LT) is the established standard of care for infants, children and adults with end-stage liver disease, as well as other primary indications including paediatric acute liver failure, liver tumours and liver-based metabolic conditions (1). With a 10-year patient survival rate of >80% (2), focus by the health care teams involved in the care of this patient population has appropriately shifted to enhancing understanding of medical, psychosocial and physical post-transplantation complications (3), as well as health-related quality of life (HRQOL) (4,5). Quality of life (QOL) is defined by the WHO as “individuals’ perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns” (6). HRQOL is a quantitative or qualitative self-assessment measuring an individual’s physical, functional, social and psychological dimensions of life (7).

Despite excellent long-term patient survival rates, only 32% of 10-year survivors achieved an ‘ideal’ outcome following paediatric LT (ie, still alive with first graft on immunosuppression monotherapy, normal laboratory test results, unimpaired linear growth and absence of the most common post-transplantation medical comorbidities) (2). Most studies conducted to date report that HRQOL generally improves after LT compared with pre-LT; however, follow-up times have mainly been short term (8–12). Paediatric LT recipients have been found to self-report HRQOLs that are lower in comparison with a healthy population (8,9,11–15), but comparable with children with other chronic illnesses such as diabetes and asthma (1). Clearly, attention to strategies to improve HRQOL in this population is warranted.

Dommergues et al (16) found the QOL status of 116 paediatric LT recipients reaching adulthood to be comparable with healthy population controls, although most of these recipients exhibited psychological disturbances many years after LT (ie, expressed anxiety about long-term graft survival and recurrence of disease, negative thoughts, limitation of freedom and feelings of loneliness). In another study evaluating the health status of 37 young adults two decades after paediatric LT, validated generic tools revealed lower physical HRQOL, measurable transplant-related disability and lower health utility (17). A study performed in the United Kingdom involving 15-year survivors of paediatric LT identified normal social adaptation and functioning, as well as normal HRQOL; however, neither formal nor validated QOL tools were administered (18). The development and availability of well-validated, age-appropriate and disease-specific tools would enhance exploration and understanding of HRQOL trends across all domains, as well as facilitate novel surveillance, diagnostic or interventional long-term care techniques toward the overarching goal of optimizing durable and holistic outcomes for this population (4). To date, the published literature regarding HRQOL outcomes in long-term survivors of paediatric LT is limited. The present study aimed to use validated and age-appropriate tools to describe HRQOL experienced by 15-year survivors of paediatric LT, including comparison with standardized scores of both the general population as well as individuals with selected chronic illnesses.

METHODS

A prospective study was performed to examine the HRQOL in >15-year survivors of paediatric LT performed at a single institution. Patient inclusion criteria were all recipients of a first isolated LT performed before December 31, 1996 at The Hospital for Sick Children (HSC; Toronto, Ontario) who were alive with follow-up at either HSC or Toronto General Hospital and were able to complete self-reported questionnaires. Patient exclusion criteria included non-English primary language, and severe developmental or neurological impairment precluding the ability to complete HRQOL assessment with the proposed instruments. Information regarding patient demographics, transplant type and contact information was collected through the Organ Transplant Tracking Record and electronic patient charts. The Research Ethics Boards of both institutions approved the study.

Telephone and/or clinic conversations were used to approach eligible patients for the study. Individuals who agreed to participate were mailed a package containing an information letter, an implied consent form, three separate questionnaires and a Fed-Ex return envelope. The study questionnaires administered to each participant included three HRQOL questionnaires and a general patient information questionnaire.

Survey instruments

The Pediatric Quality of Life Inventory^TM generic core scales (PedsQL4.0) is a 23-item questionnaire that has been validated in paediatric and young adult populations (19–21). Standardized data exist for healthy individuals as well as individuals with chronic disease conditions including asthma, diabetes, attention deficit hyper-activity disorder and depression. HRQOL is assessed in four domains – physical, emotional, social and school/work – and converted into a score ranging from 0 to 100 (19). Summary scores included the physical summary score (composed of the mean physical scores) and the psychosocial summary score (incorporated the emotional, social and school/work scores). Three scales were used, according to patient age – the teen report (for participants 13 to 18 years of age), the young adult report (for those 19 to 25 years of age) and the adult report (for those >25 years of age).

The Short Form-36 Health Survey version 2 (SF-36v2) is the most widely used assessment tool for HRQOL in the adult literature. The SF-36v2 was administered to participants >18 years of age. Scores out of 100 were converted using the t score-based scoring technique built into the SF-36 software (22). This technique compares scores with a United States general population mean (± SD) of 50±10. Scores were assessed in two overall component scores (mental and physical) comprising physical function, role physical, bodily pain, general health, vitality, social function, role emotional and mental health subdomains.

The Pediatric Liver Transplant Quality of Life tool (PeLTQL) is a novel disease-specific HRQOL instrument developed and validated for paediatric LT recipients (23). This tool has an emerging role in the armamentarium of tools for the clinical care teams because it is a nonstigmatizing way to screen for mental health issues in patients eight to 18 years of age (23). The PeLTQL was administered to study participants <18 years of age. This 26-item disease-specific questionnaire provides both a total score as well as three subscores for future health, coping and adjustment, and social-emotional domains. A higher score indicates better HRQOL.

One additional study-specific questionnaire (the demographics questionnaire) included questions regarding frequency of hospital and doctor visits, quantity and adherence to medications, involvement in work or study, level of education and living situation.

Statistical analyses

PedsQL and SF-36v2 scores (summary and domain) were compared with standardized healthy and chronic illness population means via independent-sample t tests using Stata/MP version 11 (StataCorp, USA). Scoring data were categorized into teenage, young adult and adult groups to facilitate comparison. Two-sided P values (P<0.05 and P<0.01) were used to assess statistical significance. Pearson’s bivariate correlations (two-tailed) were subsequently conducted between the domains that revealed significantly different scores than the population norm scores in the PedsQL and variables from the demographics questionnaire. Correlation analyses were conducted using SPSS (IBM Corporation, USA) version 20.0. An alpha of 0.05 was used for correlation tests.

RESULTS

As of May 31, 2012, the HSC electronic patient charts contained data for 347 children who had undergone an initial isolated LT. Patients not included in the study were those with <15 years of follow-up (n=211), those who died before 15 years of follow-up (n=60), those who transferred care outside of the greater Toronto area (n=23) and those lost to follow-up (n=4). Three patients with severe developmental impairment were excluded. In addition, death during the study (n=1), retransplantation during the study (n=1), and a ‘no approach’ suggestion by a nurse coordinator (n=1) led to the identification of 43 patients who were contacted for study. Of these, 27 individuals (67% male) agreed to participate and returned questionnaires, yielding an overall participation rate of 63%, similar to previous studies (1,17). Table 1 summarizes the characteristics of the study participants. Eight (30%) paediatric participants were followed at HSC, while 19 (70%) participants were followed at the adult partner program. One female participant had a successful single pregnancy post-LT. Thirteen participants (48%) were engaged in full- or part-time work compared with a provincial employment rate of 61% (24). Ten adult participants >25 years of age (91%) had completed a college or university education, compared with a national postsecondary qualification attainment of 63% (24).

TABLE 1.

Characteristics of study cohort of 27 15-year survivors of liver transplantation

Patient characteristic	Participants (n=27)	Male participants (n=18)	Female participants (n=9)
Age at time of study, mean ± SD (median)	24.3±6.7 (23.2)	25.7±6.6 (25.9)	21.6±6.3 (17.7)
Age at transplantation, years, mean ± SD (median)	4.5±5.4 (1.7)	5.0±5.6 (1.9)	3.4±5.1 (1.6)
Time since first liver transplantation, years, mean ± SD (median)	19.8±3.2 (19.7)	20.7±3.0 (20.8)	18.2±3.0 (16.9)
Primary diagnosis	–	–	–
Biliary atresia	15 (55.6)	10 (55.6)	5 (55.6)
Metabolic	4 (14.8)	3 (16.7)	1 (11.1)
Acute liver failure – indeterminate/viral	2 (7.4)	1 (5.6)	1 (11.1)
Tumour	2 (7.4)	2 (11.1)	0 (0)
Primary sclerosing cholangitis	2 (7.4)	2 (11.1)	0 (0)
Other	2 (7.4)	0 (0)	2 (22.2)
Liver retransplantation	7 (25.9)	4 (22.2)	3 (33.3)
1	4 (14.8)	2 (11.1)	2 (22.2)
2	3 (11.1)	2 (11.1)	1 (11.1)
Professional life
Full-time work/study	17 (63.0)	12 (66.7)	5 (55.6)
Part-time work/study	4 (14.8)	2 (11.1)	2 (22.2)
Not working or studying	6 (22.2)	4 (22.2)	2 (22.2)
Classmate/colleague attitude, n	26	18	8
Unaware of condition	13 (50.0)	9 (50.0)	4 (50.0)
Understanding of condition	12 (46.2)	8 (44.4)	4 (50.0)
They could do more to help out	1 (3.8)	1 (5.6)	0
Their attitude causes personal stress	0	0	0
Living situation	–	–	–
<25-year-old living with parent(s) or guardian(s)	15 (93.8)	9 (100.0)	6 (85.7)
>25-year-old living with parent(s) or guardian(s)	6 (54.5)	5 (55.6)	1 (50.0)
Highest level of school completed, n	26	18	8
Grade 10	6 (23.1)	4 (22.2)	2 (25.0)
Grade 12	6 (23.1)	2 (11.1)	4 (50.0)
College	11 (42.3)	10 (55.6)	1 (12.5)
University	3 (11.5)	2 (11.1)	1 (12.5)
Health characteristics
Total number of current medications	–	–	–
0	1 (3.7)	1 (5.6)	0
1–2	14 (51.9)	10 (55.6)	4 (44.4)
3–4	5 (18.5)	4 (22.2)	1 (11.1)
≥5	7 (25.9)	3 (16.7)	4 (44.4)
Current immunosuppression type	–	–	–
Calcineurininhibitor – cyclosporine	15 (55.6)	11 (61.1)	4 (44.4)
Calcineurininhibitor – tacrolimus	10 (37.0)	6 (33.3)	4 (44.4)
Anti-proliferative -mycophenolatemofetil	7 (25.9)	5 (27.8)	2 (22.2)
Steroid – prednisone	6 (22.2)	4 (22.2)	2 (22.2)
mTOR inhibitor – sirolimus	1 (3.7)	0	1 (11.1)
Frequency of missing transplant medications, n	26	17	9
More than once per week	5 (19.2)	4 (23.5)	1 (11.1)
Once per week	5 (19.2)	3 (17.6)	2 (22.2)
Once per month	4 (15.4)	3 (17.6)	1 (11.1)
Less than once per month	12 (46.2)	7 (41.2)	5 (55.6)
Hospital admissions in the past 12 months	–	–	–
None	15 (55.6)	9 (50.0)	6 (66.6)
1–2	11 (40.7)	9 (50.0)	2 (22.2)
≥3	1 (3.7)	0	1 (11.1)
Frequency of liver clinic visits	–	–	–
Once per year or less	22 (81.5)	14 (77.8)	8 (88.9)
Twice per year	1 (3.7)	0	1 (11.1)
Three times per year	3 (11.1)	3 (16.7)	0
Every month	1 (3.7)	1 (5.6)	0

Data presented as n (%) unless otherwise indicated. mTOR Mammalian target of rapamycin

The teen PedsQL (for participants 13 to 18 years of age) was completed by eight participants. Their social functioning score (92.5±7.6) was significantly higher than both the standardized healthy population (85.0±16.7, P=0.03) and the chronic illness group (76.4±21.6, P=0.0005) (Figure 1). Total scores for teenage study participants (82.2±10.4) were more similar to the healthy population (83.2±12.5) than the chronic illness group (74.16±15.4)(20).

Figure 1).

Pediatric Quality of Life Inventory results for teenage participants (13 to 18 years of age), n=8. *P<0.05. PH Physical health summary score; PSH Psychosocial health summary score; EF Emotional functioning; SF Social functioning; SCF School functioning; TS Total score

Young adults (n=8) had a significantly impaired PedsQL social functioning domain (70.6±16.1) and physical domain summary (69.9±18.7) scores compared with healthy young adults (social functioning 85.5±11.9, P=0.04; physical summary score 86.3±10.6, P=0.04) (Figure 2). The total PedsQL score for young adults (70.0±14.1) was more similar to that of the chronic illness group (70.3±11.3) (21).

Figure 2).

Pediatric Quality of Life Inventory results for adolescent participants (18 to 25 years of age); n=8. *P<0.05. PH Physical health summary score; PSH Psychosocial health summary score; EF Emotional functioning; SF Social functioning; SCF School functioning; TS Total score

The SF-36v2 was completed by 20 participants (Table 2). LT recipients had significantly lower general health scores (45.3±9.85) compared with the healthy population (50±10; P=0.047). The mean total PeLTQL score among the seven participants was 64.7±15.2. The three subdomain scores included the future health domain (66.7±13.9), the coping and adjustment domain (55.8±20.1) and the social-emotional domain (70.6±16.3). Pearson’s bivariate correlation identified a strong positive correlation between involvement in work or study and PedsQL physical health (r=0.734, n=27; P<0.001).

TABLE 2.

Short Form-36 Health Survey version 2 results for participants ≥18 years of age

Short Form-36 Health Survey version 2	Long-term survivors (n=20)
Age, years	26.8±6.00
Physical component score	49.55±11.11
Mental component score	45.34±12.48
Physical function	49.77±10.45
Role-physical	47.55±9.94
Bodily pain	50.20±11.23
General health	45.31±9.85*
Vitality	49.44±10.83
Social function	44.85±11.55
Role-emotional	45.58±11.98
Mental health	46.63±10.99

Data presented as mean ± SD scores. Mean scores were assessed according to the norm-based scoring technique, in which scores are compared with a sample population mean score of 50±10.

^*P<0.05

DISCUSSION

The present study demonstrates that long-term survivors of paediatric LT <18 years of age (teenagers) have HRQOL that is comparable with a standardized healthy population, while those between 18 and 25 years of age (young adults) had HRQOL more similar to that of a standardized chronic illness population, with physical health and social functioning being most affected. Physical health scores in all groups strongly correlated with degree of involvement in work or study.

The PedsQL scores revealed better social functioning among the teenage group of paediatric LT than both the general healthy and self-reported chronic illness populations. The social-functioning domain serves as a measure of how well one socializes relative to other individuals their age. Sundaram et al (13) previously theorized that paediatric LT recipients may experience post-traumatic growth (13), defined as a ‘significant beneficial change in cognitive and emotional life that may have behavioural implications’ (25). Through facing adversity, these children may have altered self-perceptions and a greater appreciation of life (13). It is possible that the enhanced psychosocial support provided after LT from family, communities and team expertise contributes to the improved social functioning domain in the teenage group of survivors of paediatric LT.

The impaired social and physical functioning domains in young adults after paediatric LT resulted in an overall HRQOL similar to a population with a self-reported chronic illness. The reduced physical domain summary scores is not a novel trend in survivors of LT. Mohammad et al (17) determined that survivors of paediatric LT had lower physical HRQOL as measured by the PedsQL, but no notable differences as measured by the SF36 physical component score. The PedsQL physical domain score captures eight items surrounding physical ability, physical pain and overall energy, whereas the SF36v2 evaluates 21 items surrounding physical function, role physical, bodily pain and general health. Reduced HRQOL within the physical domain has been theorized to be related to the side effects of immunosuppression (1). Additional research is needed to further explore the side effects of life-saving immunosuppression on HRQOL. Furthermore, immunosuppression withdrawal may be achievable in the foreseeable future (26).

All age groups demonstrated a positive correlation between higher physical scores and more involvement in work or study, a trend previously found in other studies (8,27,28). It is clear that those engaged in full-time work or study experience better physical health, but whether better physical health is the cause or the outcome of full-time work is not known. Perhaps individuals that participate in full-time work or study have less time to worry about their physical health or have learned to live with their condition. Conversely, those with poor physical health may be unable to participate in full-time work or study (27). This inability to participate may affect academic progress and cognitive development. A recent longitudinal study in children ≥2 years after LT found an increased risk for lasting cognitive and academic deficits (29). Further investigation with longer developmental follow-up and inclusion of physical function as a risk factor may be able to shed light on a causal direction of this association.

We acknowledge that there are several limitations existing within the present study. First, as with any clinical research study involving surveys completed by participants, the present study was subject to response bias. In addition, the study cohort of 27 patients within one single paediatric LT centre in Canada was small. Finally, the present study examined participants who underwent LT before December 1996; therefore, the study participants experienced early immunosuppressive protocols and medical management that was different from patients transplanted in the past decade. One would anticipate that current transplant procedures would yield better patient survival rates and subsequent long-term QOL. Future studies with multicentre participation and the availability of a disease-specific HRQOL tool for paediatric LT recipients (23) as well as adult LT recipients (30) may help future studies to overcome these limitations.

The importance of information gained from the present study will help to better define expectations and guide the clinical course after LT to patients and their families. Improving long-term patient and graft survival rates for paediatric LT recipients has created a growing number of adolescent and adult patients with a unique set of physical, mental and social challenges. Children are distinctly different from adult LT recipients because they differ with regard to primary disease, process of care, surgical complications and infections (9). Continued focus on the complex interaction between psychosocial, emotional, biological and physical spheres in adolescent LT recipients is likely to have a positive impact on their ongoing care (13). Identifying individuals at a higher risk for impaired HRQOL will assist transplant teams to target early interventions and multidisciplinary approaches to further improve long-term outcomes (30). The availability of valid, disease-specific HRQOL tools will complement the broad armamentarium of currently available generic instruments in the management of the unique needs of teenage, young adult and adult LT recipients (4).

CONCLUSION

The present study showed that HRQOL in teenage long-term paediatric LT survivors was comparable with a healthy population. In contrast, the young adult survivors of paediatric LT proved to be more vulnerable and had HRQOL that was more comparable with a group of patients with a chronic illness, with physical health and social functioning being most affected. Physical health scores in all groups were strongly correlated with the degree of work or study involvement.