Pediatr Transplantation 2015: 19: 133–135

© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Pediatric Transplantation DOI: 10.1111/petr.12427

Editorial

Adolescents with cystic fibrosis: Take the door, not the window In their manuscript, “High-risk age window for mortality in children with cystic fibrosis (CF) after lung transplantation,” Hayes et al. used Organ Procurement and Transplantation Network (OPTN) in retrospect, this word is redundant in this context data to assess the relationship between attained age and outcome in children with CF who received lung transplants (1). In essence, by controlling for transplantation itself by including only postprocedure patients and adjusting for other transplant-associated covariates, the authors tested whether attained age in patients with CF is an independent risk factor for post-transplant mortality. Hayes et al. developed a piecewise-constant hazard rate model of post-transplant mortality and observed that attained age between 16 and 20 yielded a higher hazard rate than other age groups. With 16–20 as a reference age group, groups with attained ages ≤15, >20 to ≤25, and >25 had unadjusted hazard ratios of 0.880, 0.472, and 0.512, respectively. The finding for a lower hazard ratio persists for the 21- to 25-yr-old group after adjustment for other covariates available in the OPTN database, with the final model including age at transplant, donor and recipient sex, and donor race. The authors conclude that there is a “high-risk” window of attained age for mortality after lung transplant that is independent of age at transplant as well as other factors known to influence post-transplant outcome. They suggest that this window may partially explain previous work in CF that demonstrated decreasing survival benefit with increasing age at lung transplant in children (2) and may help resolve the seeming discrepancy inferred from the observation of increasing survival benefit with increasing age at lung transplant in adults (3, 4). They also conclude that their findings support a survival benefit in adults with CF undergoing transplant. The authors suggest that poor adolescent adherence and challenges related to

transition to adult care are potential underlying causes for increased hazard of mortality in the 16- to 20-yr-old window. The analysis includes some assumptions that are not explicitly discussed in the manuscript. First, that the mortality hazard following lung transplantation is constant. Hosenpud et al. found rapidly decreasing hazard ratios in the immediate post-transplant period and employed a time-dependent non-proportional hazards model to analyze survival (5). Their study found that once beyond the high-risk early post-transplant period, CF patients aged from one to 49 yr undergoing lung transplantation had improved survival relative to patients on the waiting list. In contrast, using an arbitrary updated covariate for post-transplantation survival, Liou et al. found that the hazard of death following transplantation was unchanging for patients 17 yr of age and younger at the time of transplant (2). Rather than directly testing for the possibility of varying hazards depending on time since transplantation, Hayes et al. employed piecewise-constant rate hazard modeling to estimate hazard ratios for five-yr increments of age, which reduces but does not eliminate the potential effects of non-constant post-transplantation hazard ratios. Thus, the observation may be somewhat biased toward increased mortality hazard in the age window with the largest numbers of pediatric lung transplant recipients (the median age of transplant was not reported but is likely to be in the mid-teens). Nonetheless, this bias was further addressed by including age at transplant in their final model. A second assumption is that the age distribution of children with CF undergoing lung transplant is unchanged during the 20-yr window included in this study. The median age of survival of children with CF has increased significantly during this period (6), so this assumption likely leads to a bias toward older patients getting transplanted during the more recent 133

Editorial

era which, as recent ISHLT registry analyses demonstrate (7), would suggest they are likely to have better early post-transplant survival. More patients in the older age window receiving transplants during the recent era would tend to reduce the mortality hazard in that group. The conclusion regarding a high-risk window of attained age seems reasonable based on the analysis presented; however, the analysis cannot be used to explain differences in survival benefit between children and adults undergoing lung transplantation. Previous analyses compared survivorship between transplant recipients and patients still waiting for transplant (2–5). The analysis of Hayes et al. estimated hazard ratios among patients grouped by attained age exclusively after transplantation. Thus, drawing conclusions regarding survival benefit would require assuming a constant piecewise mortality hazard for patients with CF awaiting transplant during the relevant age windows. The finding that there is a high-risk window of attained age independent of age at transplant and time from transplant suggests that the higher hazard rate might, or even should be, observable in non-transplanted patients. Although adolescents with CF have the highest year-to-year declines in lung function declines of any age (8), an increased mortality hazard has not been observed in this age group. While one might expect that more rapid declines in lung function would expose such an increased mortality hazard in CF patients with severe lung disease awaiting transplant, this remains an area of debate (9, 10). The authors reference work supporting the concept that adolescents with CF also face significant challenges with non-adherence; however, there is some evidence that transition from pediatric to adult CF care may not be associated with significant worsening in lung function (11). Whether problems associated with poor adherence or with transition between pediatric and adult CF care centers underlie, accompany, or follow the observed lung function losses in the high-risk age group is simply not known. The study takes a novel approach to the evaluation of poorer outcomes in adolescent lung transplant recipients, but in the end, we are left with the usual suspects: non-adherence and transition to adult care. Although a recent paper which drew much the same conclusions in pediatric kidney transplant recipients speculated on a growth-related “hyperfiltration injury” as a potential cause for renal graft dysfunction (12), no similar hypothesis in lung transplant recipients is readily apparent—perhaps until now. The authors close by calling for further study 134

to identify risk factors for poor outcome in the adolescent age window, presumably by determining the causes for non-adherence. Their urging to further study raises the natural question, “What form should a study take?” Existing data in the Cystic Fibrosis Foundation Patient Registry or other large data sets involving patients with CF poorly address the issues of adherence and transition difficulties. However, one implication of the findings of Hayes et al. is that pediatric patients with an attained age of 16–20 post-transplantation may represent a group especially sensitive to the effects of poor adherence and difficult transitions in care. Thus, performance of a carefully planned, prospective observational study focused on this group may be better suited to find risk factors for, and etiologies of, non-adherence than a study involving all patients with CF. Unfortunately, notwithstanding the potential usefulness of a highly sensitive patient group, there are many barriers to success for such a study. There is no gold standard measure that reliably measures adherence to all domains of health care (for example, medication event monitoring systems are an expensive and imperfect surrogate). Correlation of non-adherence to patient outcome will require a sufficiently sized study population to control for confounders. Even if all patients were included, the current rate of pediatric lung transplant would be unlikely to provide sufficient power for such a study without prolonged enrollment which would introduce additional statistical and logistic issues. Even a study involving all adolescent solid organ transplant recipients would be challenging to construct. Finally, at least some and possibly most of the factors responsible lie in the psychosocial realm, with limited availability of validated objective measures to cover all of the possible socioeconomic, psychiatric, and behavioral risk factors contributing to non-adherence. So perhaps a different approach is warranted, more akin to quality improvement than randomized clinical trial or even prospective observation. Perhaps the study to be carried out should be one that identifies and implements best practices to address potential psychosocial causes of nonadherence (identification and removal of barriers to adherence, development of effective medication dose reminder strategies, screening for and treatment of underlying psychiatric disease, and addressing of economic limitations in access to care) and assesses patient outcomes in comparison with patients who do not receive structured intervention. Although such a study may learn little about the underlying risk factors for non-

Editorial

adherence, it may open the door to improved outcomes in pediatric transplantation and possibly in the general population of patients with CF. Authors’ contributions Each author contributed equally to reviewing the subject of the editorial, drafting and revising the manuscript, and approving the submitted version.

Stuart C. Sweet, MD, PhD1 and Theodore G. Liou, MD2 1 Department of Pediatrics, Washington University, St. Louis, MO, USA 2 Departments of Internal Medicine and Pediatrics, University of Utah, Salt Lake City, UT, USA E-mail: [email protected]

References 1. HAYES D Jr, MCCOY KS, WHITSON BA, MANSOUR HM, TOBIAS JD. High-risk age window for mortality in children with cystic fibrosis after lung transplantation. Pediatr Transplant 2015: 19: 206–210. 2. LIOU TG, ADLER FR, COX DR, CAHILL BC. Lung transplantation and survival in children with cystic fibrosis. N Engl J Med 2007: 357: 2143–2152. 3. LIOU TG, ADLER FR, HUANG D. Use of lung transplantation survival models to refine patient selection in cystic fibrosis. Am J Respir Crit Care Med 2005: 171: 1053–1059.

4. THABUT G, CHRISTIE JD, MAL H, et al. Survival benefit of lung transplant for cystic fibrosis since lung allocation score implementation. Am J Respir Crit Care Med 2013: 187: 1335–1340. 5. HOSENPUD JD, BENNETT LE, KECK BM, EDWARDS EB, NOVICK RJ. Effect of diagnosis on survival benefit of lung transplantation for end-stage lung disease. Lancet 1998: 351: 24–27. 6. MACKENZIE T, GIFFORD AH, SABADOSA KA, et al. Longevity of patients with cystic fibrosis in 2000 to 2010 and beyond: Survival analysis of the cystic fibrosis foundation patient registry. Ann Intern Med 2014: 161: 233–241. 7. BENDEN C, GOLDFARB SB, EDWARDS LB, 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. J Heart Lung Transplant 2014: 33: 1025–1033. 8. LIOU TG, ELKIN EP, PASTA DJ, et al. Year-to-year changes in lung function in individuals with cystic fibrosis. J Cyst Fibros 2010: 9: 250–256. 9. ROSENBLUTH DB, WILSON K, FERKOL T, SCHUSTER DP. Lung function decline in cystic fibrosis patients and timing for lung transplantation referral. Chest 2004: 126: 412–419. 10. LIOU TG, ADLER FR, CAHILL BC. Testing lung function decline to time lung transplantation. Chest 2005: 128: 472–473. 11. TUCHMAN L, SCHWARTZ M. Health outcomes associated with transition from pediatric to adult cystic fibrosis care. Pediatrics 2013: 132: 847–853. 12. Van ARENDONK KJ, JAMES NT, BOYARSKY BJ, et al. Age at graft loss after pediatric kidney transplantation: Exploring the high-risk age window. Clin J Am Soc Nephrol 2013: 8: 1019– 1026.

135

Copyright of Pediatric Transplantation is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.

Adolescents with cystic fibrosis: take the door, not the window.

Adolescents with cystic fibrosis: take the door, not the window. - PDF Download Free
61KB Sizes 0 Downloads 8 Views