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 . 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
Existing Research Limitations and Future Directions
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.