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Health-related quality of life (HRQL) has been assessed in various lung transplantation (LT) investigations but never analyzed systematically across multiple studies. We addressed this knowledge gap through a systematic literature review. We searched the PubMed, CINAHL, and PsychInfo databases for publications from 1/1/1983-12/31/2011. We performed a thematic analysis of published studies of HRQL in LT. Using a comparative, consensus-based approach, we identified themes that consistently emerged from the data, classifying each study according to primary and secondary thematic categories as well as by study design. Of 749 publications initially identified, 73 remained after exclusions. Seven core themes emerged: 1) Determinants of HRQL; 2) Psychosocial factors in HRQL; 3) Pre- and post-transplant HRQL comparisons; 4) Long-term longitudinal HRQL studies; 5) HRQL effects of therapies and interventions; 6) HRQL instrument validation and methodology; 7) HRQL prediction of clinical outcomes. Overall, LT significantly and substantially improves HRQL, predominantly in domains related to physical health and functioning. The existing literature demonstrates substantial heterogeneity in methodology and approach; relatively few studies assessed HRQL longitudinally within the same persons. Opportunity for future study lies in validating existing and potential novel HRQL instruments and further elucidating the determinants of HRQL through longitudinal multidimensional investigation.
Lung transplantation (LT) aims not merely to extend recipient survival, but also to improve health-related quality of life (HRQL). It is well-appreciated that patients with advanced lung disease awaiting LT suffer from poor HRQL.1-11 While in-depth studies of survival are routine, analyses of HRQL outcomes following LT are relatively infrequent. Among other chronic diseases, HRQL is recognized as a key patient-centered outcome (PCOs). Although this presumably true in LT as well, PCOs have not been an emphasized area of the research agenda to date and the literature on this subject thus remains fragmented.
An improved understanding of HRQL has important clinical and research implications. It could provide patients and clinicians with estimates of the magnitude and durability of improvements in HRQL that might be expected from LT, identify HRQL determinants that may be targets for intervention, and lay the foundation needed to incorporate HRQL into clinical decision-making.
In this systematic review, we aimed to analyze studies of HRQL in LT in order to distill the unifying themes embedded within the existing biomedical literature. In characterizing the current state of knowledge, we also sought to identify knowledge gaps that provide opportunity for future study.
We queried the PubMed, CIHNAL, and PsychINFO databases using the search terms “(health-related) quality of life” “utility/ies”, and “lung transplant/ation”, limited to studies in adults (age≥18), and published from1/1/1983-12/31/2011. We identified 749 potentially relevant citations and, after exclusions, 73 publications were ultimately retained (one of these in abstract form only) (Figure 1).
We utilized thematic analysis, a qualitative mode of scientific inquiry that systematically analyzes textual data12. A central aspect of thematic analysis is its inductive and iterative nature, which is not bound to any philosophic tradition or theoretical paradigm.12 Study content was iteratively reviewed and analyzed by three investigators (J.S, J.C.,H.C.).12 First, a provisional list of recurring themes was developed by each investigator. These were compared and discussed. Themes deemed similar or overlapping were merged; those encompassing conceptually distinct themes were split. A master thematic list was coded; definitions for each theme were developed to ensure consistency among investigators (Table 1). Using the listed themes, each investigator independently assigned a primary thematic code to each study. For some studies, a secondary code also was assigned. Investigators reconvened to compare coding assignments; discrepancies in coding were resolved by consensus ultimately resulting in the 73 studies being categorized according to the overarching themes that emerged (Table 1).
Among 73 publications, 7 themes emerged (Table 1): 1) Determinants of HRQL; 2) Psychosocial factors in HRQL; 3) Pre- and post-transplant HRQL comparisons; 4) Longitudinal studies of HRQL in the post-transplant period; 5) HRQL in relation to therapies or other interventions; 6) HRQL instrument validation and methodology; 7) HRQL prediction of clinical outcomes. For 40 studies a secondary thematic category was assigned.
The majority of studies (primary theme, n=24; secondary theme, n=4) assessed determinants of HRQL. Exclusive of psychosocial factors (categorized separately), bronchiolitis obliterans syndrome (BOS) and transplant type were the determinants most commonly addressed. Others included: pre-transplant diagnosis, immunosuppressant adverse effects, dyspnea, allograft function, pain, and acute rejection. Notably, few studies employed multivariate adjustment,13-23 making confounding difficult to assess.
Studies consistently observed that BOS is strongly associated with poorer HRQL.13, 20, 21, 23-28 This was consistent across HRQL instruments, including both respiratory-specific measures (St. George's Respiratory Questionnaire [SGRQ])24, 26 and generic measures (Quality of Life Profile for Chronic Diseases13, 12- or 36-item Short Form [SF-12 or SF-36]25,26, Nottingham Health Profile [NHP]17, 27, 28) and utilities (Standard gamble)21. The impact of BOS was greatest in HRQL domains relating to physical functioning, energy, and mobility. Several of these studies included overlapping cohort participants; most were cross-sectional, comparing patients with and without BOS. Only two studies (total n=51) assessed change in HRQL longitudinally as BOS developed.27, 28
Six studies evaluating transplant type yielded mixed results. The findings of single-, bilateral- and heart-lung transplantation comparisons, although equivocal, suggested better outcomes among bilateral- and heart-lung recipients compared to single LT. Two demonstrated higher health-utilities (5-Dimensional EuroQOL [EQ-5D] or Standard Gamble) among bilateral and heart-lung recipients.21, 29 Underscoring the heterogeneity of findings, one study observed that single-LT recipients reported greater pain and worse HRQL than recipients of bilateral-LT18, whereas another reported the opposite22 (both used the SF-36). The only study employing a respiratory-specific instrument (SGRQ) demonstrated non-statistically significantly better HRQL in bilateral-LT versus single-LT.7 In studies among various organ recipients (one including lung, kidney and liver recipients30 and another lung, heart and liver recipients14), LT recipients manifested the greatest magnitude post-transplant improvement in HRQL in most domains of the SF-36.30
While few studies examined the impact of pre-LT diagnosis on HRQL, four suggested that cystic fibrosis, compared to other diagnoses, is associated with better post- vs. pre-LT HRQL..4, 22, 26, 31, 32 Other less-studied factors that may impact post-LT HRQL include side-effects related to immunosuppression26, 33, dyspnea20, 34, energy/mobility23, 27, 28, pain18, 20, 35, rejection13, 20, exercise tolerance36, infections,13 and olfactory performance19.
Psychosocial factors emerged as the primary theme in eight studies and a secondary theme in nine others. Most of these focused on depression or anxiety symptoms, observing that many patients manifested symptoms both before and after LT.16, 37-39 Symptoms were more likely post-LT when pre-LT depression or anxiety were present6, 16 These studies employed a broad range of psychosocial measures, including the Hospital Anxiety Depression Scale (n=10), Beck Depression Inventory (n=5), Zung Self-Rating Depression Scale (n=8), and State Trait Anxiety Inventory (n=11).
Psychosocial factors other than depression and anxiety have also been investigated40-46. These included symptoms of post-traumatic stress disorder44, burden on relationships37, adjustment to illness,41 feeling of responsibility to donors and caregivers42, low self-esteem38, decreased sexual drive38, and perceived threat of risk of graft rejection48. Few of these studies, however, analyzed such factors beyond identifying an association between them and HRQL or describing the extent of the attribute observed. A notable exception was a longitudinal study of 105 patients in which greater optimism, social support, and perceived positive relationships predicted higher HRQL, while avoidant coping strategies predicted poorer HRQL.46 Similar cross-sectional relationships have also been observed in two other studies.46, 47, 49
Thirty-four studies (primary theme, n=20; secondary theme, n=14) compared HRQL in relation to LT status (i.e., pre- vs. post-LT). Many (n=13) compared wait-listed patients to others that had undergone LT 11, 19, 22, 29, 37, 38, 45, 50, 51; others (n=14) did employ a true longitudinal design, assessing the same patients before and after LT. 17, 30, 31, 39, 52-56 Of these, eleven studied cohorts of relatively modest size (n=22-66).3, 4, 6, 30, 39, 52, 54-58 A larger 5-year prospective cohort study obtained repeated measures of HRQL before and after LT in 88 patients who survived the first post-LT year.53 Of the 88, 48 contributed data at 5-years post-LT. Notably, it is unclear whether this study represented an overlapping cohort from an earlier report.52 Another study (abstract only) assessed health-utilities in 207 patients before and after LT.31 A single study determined that HRQL pre-LT was not predictive of post-LT mortality.17
Importantly, the HRQL instruments employed varied greatly. The SF-36 was the most frequently employed generic instrument.3, 6, 9, 11, 22, 30, 37, 38, 50, 52-54, 59 Other generic instruments included the Nottingham Health Profile (NHP)1, 4, 5, 17, 28, 55, 57, 58, 60 and health-utility indices, including the EQ-5D1, 29, 61, Standard Gamble1, 4, 21, 56, 62, Health Utilities Index (HUI)39, 51, 61, Index of Well Being5, 17, 27, 28, 32, 55, 58, 63, and Visual Analog Scale7, 20, 24, 38, 56, 64-66. The only frequently employed respiratory-specific instrument was the SGRQ.7, 11, 20, 24, 26, 34, 52, 56, 67
Despite instrument heterogeneity, the impact of LT on HRQL was consistently demonstrated to be both significant and substantial. The largest changes were typically observed in physical health and functioning domains. As expected, improvements in these domains paralleled improvements in forced expiratory volume in 1-second and walk distance11, 54, 59, 68. Despite large improvements, residual HRQL impairments remained post-LT in comparison to normative population values. These impairments tended to affect physical health and functioning domains9, 15, 20, 26, 30, 42, 50, 51, 54, 64, 69-71. Further, improvements in HRQL were not uniform and sometimes spared other domains..3, 4, 9, 11, 30, 38 For example, pain was unchanged or possibly worsened soon after transplant11, 15, 30, 37, 52, 55, although it was observed to improve over time39, 52. In contrast to physical health, changes in emotional well-being and mental health domains were heterogeneous, frequently demonstrating small or non-significant improvements2, 3, 6, 9, 11, 22, 42, 52, 53, 59, 72,52, 54, 68. Post-transplant scores in these domains were comparable with normative population values 9, 14, 15, 20, 26, 42, 50, 53, 54, 64, 70, 71. In studies of depression and anxiety, depression appeared to decrease post-LT, whereas an effect on anxiety was not observed19, 39. In an atypical study design combining archival data with a contemporary cross-sectional analysis, pre-transplant psychopathology (anxiety, depression) was associated with poorer HRQL (SF-36), disturbed sleep, and poorer mental health.6
A small number of relatively recent studies report long-term HRQL assessed longitudinally (primary theme n=4, secondary theme n=11). HRQL tends to improve substantially within the first 6-months post-LT and continues to do so through the first year.46, 52 Thereafter, the trajectory of HRQL is less clear. In some studies, HRQL stabilized after the first post-transplant year 5, 53, 58, whereas in others, it declined7, 55, 71. Nonetheless, in those studies observing a decline, the impairment never reached levels observed before transplant. Declines were associated with the onset of BOS and comorbid illnesses.23, 24, 27, 53, 55, 58, 63, 71
A limited number of studies with a relatively small cumulative subject pool studied HRQL in patients surviving greater than three years post-LT.7, 23, 24, 27, 53, 55, 63, 67, 71, 73 Survivorship bias due to losses to follow-up makes interpreting these data difficult. Additionally, results from these studies vary depending on the analytic approach used.73 Only 175 of such “long-term” survivors have been included in the entire body of this literature.24, 53, 55, 63, 71 Two additional studies evaluated long-term survivors within larger cohorts, but the data are presented in ways that make it difficult to extract information on this subset. 7, 23
Nine studies evaluated therapies or interventions. Six of these involved behavioral interventions.43, 65, 67, 72, 74, 75 Four studies employed randomized designs (RCT.)51, 67, 74, 76 One RCT assessed the impact of incorporating utilities (HUI-measure) into the post-transplant care of 213 subjects.51 Small improvements in patient-clinician communication and patient management were observed but improved health status (EQ-5D) was not. A separate RCT of 30 subjects studied a hand-held, computer-based device used to record, review, and report health data. Use of this device improved measures of self-care and HRQL (SF-36).74 A small RCT (reported in letter form) evaluated the impact of citalopram on HRQL.76 Non-randomized, uncontrolled studies have also evaluated pulmonary rehabilitation72, pet companionship43, and complementary and alternative medicine65 post-LT.
Relatively few studies (primary theme n=7, secondary theme n=1) evaluated the psychometric performance and validity of HRQL instruments LT populations. The SF-36 and SGRQ demonstrated good internal consistency and discriminant validity.11, 41 Santana et al. evaluated HUI Mark-3 utility construct validity by comparing clinician-based predictions with observed correlations.51 They showed that the instrument performed largely in the expected manner. Other investigators have evaluated preference-based utilities.31, 77 Using the Standard Gamble, utilities are associated with “transplant-readiness” and improve post-LT. Interestingly, LT candidates can accurately estimate utilities post-LT, except in the setting of advanced BOS.
Only one study evaluated HRQL through qualitative methods.40 Descriptions of life post-LT were provided based on a collection of patient narratives. The study uncovered important factors not captured in the quantitative literature, such as mixed feelings of both gratitude and guilt for the donor and their family, “sacrificing” extra-pulmonary organ function (i.e., renal) to maintain allograft function, and a responsibility to make the most of a “second chance at life”.
A single study analyzed whether pre-transplant HRQL predicted survival both on the waiting list and after transplant. HRQL (Quality of Well-Being Scale [QWB]), was collected in 74 waitlisted subjects. Of these, 49 underwent LT. In the total cohort of waitlisted and transplanted subjects, subjects with upper median baseline QWB scores (higher HRQL) had significantly better survival than subjects with lower median scores. Although the statistical modeling included transplant status, other methodological limitations make it difficult to determine whether pre-transplant HRQL predicts survival post-transplant. Further, the survival models did not include covariates other than HRQL and transplant status raising the possibility of unmeasured confounding.78
This systematic review of 73 studies over three-decades of scholarship identifies important insights into HRQL relevant for clinicians and patients considering lung transplantation. Most importantly, the literature supports that LT results in clinically meaningful and significant improvements in HRQL for patients with advanced lung disease. This improvement is greatest in physical health and functioning domains. The largest improvement is observed within the first 6-months after LT, continuing up to one-year. After one-year, HRQL trajectories are less stable, being negatively affected by BOS and incident comorbidities. Although some heterogeneity exists, overall HRQL levels post-LT do not decline to pre-LT levels.
Nevertheless, LT recipients manifest substantial residual impairments in HRQL compared to population norms. Comparative data with other types of solid organ transplant, while limited, suggest that LT recipients may derive greater HRQL benefit. This benefit, however, is likely attributable to the extremely poor HRQL in pre-operative LT candidates.
While the insights provided in the existing literature are impressive, our search revealed limitations that provide opportunity for future research. First and foremost, despite its clinical primacy, HRQL remains understudied in the field of LT. Indeed, similar search criteria over the same time-period yielded 1131 articles published in cardiac transplantation, 1291 in liver, and 1689 in kidney. Poorer survival post-LT relative to other solid-organ transplants further underscores the importance of HRQL as a key clinical and research outcome. By accounting for HRQL, a substantial “net-benefit” could arguably be achieved from LT even when extended survival may not be clear. Indeed, just such a net-benefit was demonstrated in lung volume reduction surgery for emphysema.79 Notably, we employed a rather liberal approach in defining HRQL, including health utilities within our search. Health utility-based instruments quantitatively measure patient preferences for certain health states or outcomes. Health utilities, which capture degree of impairment, degree of bother, and willingness to undergo risk to reduce bother, offer an alternative means for measuring the health benefit of interventions80. Health-utilities are conceptually related to HRQL but are not wholly inter-changeable; in particular, the item content contained in utility-based instruments rarely reflect the multidimensional nature of HRQL. Had we excluded studies employing utilities, only 45 of 73 would have remained.
Analyzed thematically, it becomes clear that the available data are fragmented among investigations of a variety of clinical and psychosocial determinants with relatively sparse data on instrument validation. Other methodological limitations include incomplete or no multivariate adjustment, a focus on single risk factors studied in isolation, overlapping cohorts, survivorship effects, and small sample sizes. These limitations raise concerns for bias and unmeasured confounding.73, 81-83 Moreover, longitudinal studies are critically few in number; rarer still are those following subjects from before transplant to beyond the first post-transplant year.5, 53 Notably, no U.S. study of HRQL has been reported since 2005 overhaul of the system of U.S. organ allocation (Lung Allocation Score [LAS]),84 which increased the medical acuity of waitlisted patients.85 Therefore, prior studies of HRQL may no longer be generalizable to U.S. populations. Furthermore, studies have yet to measure psychosocial and physiologic factors concurrently before and after transplant. The knowledge gaps of the cumulative and relative effect of these factors on HRQL hinder the development of interventions designed to relieve disability and further improve HRQL.
Additionally, a thematic imbalance across these studies identifies areas ripe for future research. The majority of studies focused on individual determinants of HRQL. Studies of interventions and instrument validation/methodology were infrequently represented. Moreover, the heterogeneity of HRQL instruments employed further magnifies the underlying imbalance. Many instruments were not respiratory-specific and none were specific to LT. While this heterogeneity makes cross-study comparisons difficult, these data lay the groundwork for the development of a LT-specific instrument. Finally, we identified only one study that employed qualitative methods. This represents a significant shortcoming as qualitative methods are generally considered a prerequisite for adequate characterization of disease-specific HRQL constructs.
The limitations discussed above provide a roadmap to advance HRQL in LT. Existing limitations and gaps aligned with potential research solutions are summarized in Table 3. In particular, the path forward includes longitudinal studies (accounting for survivorship and important covariates) and investigations in understudied thematic areas. Future studies should use structured instruments (established or newly developed, all with appropriate validation for LT populations) as well as qualitative approaches. Additionally, since immunosuppressives used in LT have broad effects, studies should consider use of both respiratory-specific and generic instruments. Indeed, in HRQL assessment, respiratory-specific and generic measures are considered complementary rather than duplicative. Not only do generic instruments capture transplant-related co-morbidities and treatment side-effects, they also permit comparisons of HRQL across other types of solid-organ transplantation. On the other hand, respiratory-specific instruments are likely to be more sensitive in measuring the impact of respiratory factors such as BOS.75
Central to advancing the field is developing a shared understanding within the pulmonary transplant community of how HRQL in LT should be conceptually defined. Consensus definitions of primary graft dysfunction and bronchiolitis obliterans syndrome, for example, have led to important scientific progress. Such definitions, with professional society engagement, could direct research efforts by defining relevant domains of HRQL and identifying instruments that best assess them in LT. If existing instruments fail to meet the criteria identified, this would serve to underscore prioritization for funding necessary to develop novel instruments specific to LT. Consensus definitions could also guide instrument selection for future investigators, thereby reducing cross-study heterogeneity. Once common metrics are established, HRQL instruments could potentially be incorporated into existing LT registries. Such incorporation could address sample size limitations and aid efforts to understand the impact of lung transplant on HRQL, identify areas for intervention, and even inform organ allocation.
Despite advances in our understanding of HRQL in the field of LT, many important questions remain. The next decade promises additional understanding as we address these questions armed with new research methods and tools among a growing cohort of international researchers focused on this area of inquiry. This understanding is critically important for providing patients with evidence-based counseling, identifying areas for interventions aimed at maximizing the HRQL benefit from transplant, exploring efforts to incorporate patient-centered outcomes into clinical decision-making, and more broadly quantifying the “net”-benefit afforded by lung transplantation.
Grant support: Supported in part by NHLBI K23 HL111115, F32 HL107003-01 (J.S.), NHLBI K23 HL086585 (H.C.), and Novartis Pharmaceuticals (J.S.,P.B.)
*The majority of the work on this manuscript was completed while Dr. Chen was a member of the UC San Francisco Division of Pulmonary, Critical Care, Allergy and Sleep Medicine and the Cardiovascular Research Institute at UC San Francisco.
JPS and PDB have conflicts of interest to disclose as described by the American Journal of Transplantation. They hold an investigator initiated research agreement with Novartis Pharmaceuticals to study health-related quality of life in lung transplantation. No representative from Novartis was involved in any aspect of this manuscript.
The remaining authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.