Association of Donors With US Public Health Service Risk Criteria and Outcomes After Adult vs Pediatric Cardiac Transplant

Key Points

Question  Do differences exist in use and outcomes of donors with US Public Health Services (PHS) risk criteria among pediatric vs adult heart transplant recipients in the recent era?

Findings  In this cohort study using data from the United Network for Organ Sharing database, a 3-fold greater proportion of adults receive a PHS risk criteria graft compared with children in the past decade. However, patient survival was similar in children and adults despite donor risk status.

Meaning  These findings suggest that despite similar patient survival, donors with PHS risk criteria are underused in the current era.

Importance  The United Network for Organ Sharing (UNOS) evaluates donor risk for acute transmission of HIV, hepatitis B, or hepatitis C based on US Public Health Services (PHS)–specific criteria. However, recent data regarding use and outcomes of those donors with PHS risk criteria among pediatric and adult heart transplant recipients are lacking.

Objective  To compare use and outcomes of graft from donors with PHS risk criteria vs those with a standard-risk donor (SRD) in children vs adults in a contemporary cohort.

Design, Setting, and Participants  This cohort was a nationwide analysis of heart transplants in the US that used data from the UNOS database. Participants were children (<18 years old) and adults (≥18 years old) who received a heart transplant from January 1, 2010, to December 31, 2021.

Exposures  UNOS-defined donor risk status.

Main Outcomes and Measures  Trend analysis compared changes in PHS risk criteria use among children and adults. Patient survival was analyzed using Kaplan-Meier curves with log rank and Cox proportional hazards to compare PHS risk-criteria outcomes vs SRD-criteria outcomes in children and adult heart transplant recipients. Additional analysis was performed among adults who received a PHS–risk criteria graft that was previously declined for pediatric recipients.

Results  Of 5115 pediatric transplant recipients (donor without PHS risk median [IQR] age, 5 [0-13] years and donor with PHS risk median [IQR] age, 8 [0-14] years) and 30 289 adult heart transplant recipients (donor without PHS risk median [IQR] age, 56 [46-63] years and donor with PHS risk median [IQR] age, 57 [47-63] years), PHS risk criteria comprised 8% in children vs 25% in adults. PHS criteria are being increasingly used over the past decade with the proportion of recipients transplanted with PHS risk-criteria donors being approximately 3 times greater among adult recipients than children recipients. Pediatric recipients of a PHS risk-criteria donor had greater pretransplant ventilatory support, whereas adult recipients of a PHS risk-criteria donor had greater pretransplant extracorporeal membrane oxygenation use. Patient survival was similar between pediatric recipients of PHS risk-criteria grafts vs SRD-criteria grafts and slightly higher among adult recipients of PHS risk-criteria grafts vs SRD-criteria grafts. The 1778 adult recipients who received a PHS criteria-risk donor that was previously declined for pediatric recipients had similar patient survival recipients compared with SRD-criteria donors (HR, 0.92; 95% CI, 0.81-1.03; P = .18).

Conclusions and Relevance  In the current era, a 3-fold greater proportion of adult recipients receive a PHS risk-criteria graft compared with children despite similar posttransplant patient survival. The ongoing organ donor shortage underscores the need for consideration of PHS risk criteria where these donors remain underused.

Heart transplant is a life-saving treatment for patients with end-stage heart failure. Long-term survival after heart transplant is 92% at 1 year and 82% at 5 years in children, while in adults the survival is 92% at 1 year and 80% at 5 years.¹ Each year, about 400 to 500 pediatric heart transplants and 3000 adult heart transplants are performed in the US.^2,3 Overall heart transplant wait list mortality for children in the US is 17%, although it may range up to 30% in small-volume centers and among children with additional complexity, including infants with congenital heart disease and those requiring extracorporeal membrane oxygenation (ECMO) or ventilator support.^4,5 Wait list mortality among adults is lower than for children at approximately 8%.¹ The ongoing organ donor shortage limits the number of heart transplants that can be performed and, thus, affects pretransplant wait list mortality.

In 1994, the United Network for Organ Sharing (UNOS) added the label for donors considered to have risk factors for viral transmission for any organ donor who met specific criteria, as outlined in the eTable in the Supplement.⁶ This definition was modified in 2013 and criteria were subsequently relaxed in 2020 in an effort to reduce the proportion of donors qualifying for PHS risk.⁷ Use of donor grafts with US Public Health Services (PHS)–specific risk criteria are lower compared with standard-risk donors (SRDs) without PHS risk criteria but may represent an opportunity to increase graft use and reduce wait list times. However, recent data on outcomes in PHS criteria-risk heart transplant recipients are limited, and differences between adult and pediatric use of PHS–risk criteria grafts may exist.^8,9

Our study addresses this knowledge gap among current practice patterns for donor acceptance by providing a recent overview of PHS risk-criteria heart transplant use among both children and adults over the most recent decade through 2021. The primary aim of this study is to compare the rate of PHS risk-criteria graft use in heart transplant in children and adults, and determine whether differences occur in posttransplant outcomes among those who received PHS risk-criteria grafts vs SRD criteria grafts. A secondary aim will evaluate the trend in PHS risk criteria use over time in children and adults.

Data from UNOS Standard Transplant Analysis and Research files were used to identify all patients who underwent primary heart transplant from January 1, 2010, to December 31, 2021. Those undergoing multiorgan transplant or retransplant were excluded. UNOS is a nonprofit organization that collects data on every organ transplant since 1987 in the US. Information collected in UNOS includes detailed pretransplant and posttransplant demographic and clinical information for recipients, such as age, race, sex, primary diagnosis, severity status, and follow-up information regarding mortality. The recipient population was divided into pediatric (<18 years old at the time of heart transplant) and adult (≥18 years old at the time of heart transplant) populations, and demographic differences between those that receive PHS risk-criteria grafts and SRD-criteria grafts were evaluated within each subgroup. PHS risk criteria was identified based on appropriate entry into the UNOS database using the 1994 PHS guidelines that were revised in UNOS in 2021.⁷ For ease of classification of adult heart transplant listing status with the recent change in 2018, we grouped adult listing status as 1A if they were status 1 to 3, status 1B if they were status 4, and status 2 if they were status 5 to 7. All patient information was deidentified, so institutional review board review and informed consent were waived. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.

The primary end point of the study was measured from time of transplant until death (censored at last follow-up). The primary outcome was whether differences in freedom from death after heart transplant occurred based on donor-risk status among pediatric and adult heart transplant recipients. The secondary objective was to determine whether a significant change in PHS risk criteria has occurred over the past decade among pediatric and adult heart transplant recipients.

Transplant recipient demographics were compared among PHS vs SRD among pediatric and adult heart transplant recipients using t test and χ² test. Nonparametric test for trend across time was used to evaluate trends in PHS risk criteria during the study period. Patient survival analysis was performed using Kaplan-Meier curves for outcome analysis after heart transplant. Survival between groups was compared using the Mantel-Haenszel log-rank test. Cox proportional hazard regression analysis was used to calculate hazard ratios (HRs) with 95% CIs. Bivariate analysis was performed assessing the association of recipient factors with the total cost and likelihood of superiority first. Significant variables (P < .05) were then included in multivariable analysis. Using this method, 10 or less variables were used instead of all available variables in the multivariable models to reduce the risk of overfitting the data. P values were 2-tailed and values less than .05 was considered clinically significant. Proportional hazards assumption was assessed through visual inspection of the log-log plot of the cumulative hazard function and the empirical vs predicted survival curves. Model fit of Cox proportional hazard regression model was assessed by visual inspection using the plot of the cumulative hazards of the Cox-Snell residuals using Nelson-Aalen estimator. A subgroup analysis was performed comparing outcomes among adults who received a PHS risk-criteria graft that had been declined for a pediatric recipient and those outcomes with adults who received an SRD criteria graft using the above described survival analysis methods. For trend analysis of PHS risk criteria use among children and adults, a nonparametric test for trend across year during the study was performed. Analyses were performed using Stata (StataCorp), version 15.1.

A total of 5115 pediatric heart transplants and 30 289 adult heart transplants occurred in the US between January 1, 2010, to December 31, 2021. Of these, 424 children (8.3%) and 7644 adults (25.2%) received a heart from a PHS risk-criteria donor during the study period. Overall, there were 14 113 PHS risk-criteria donors during the study period with 12 812 pediatric recipient offers and 514 508 adult recipient offers, of which 96.4% were ultimately declined for children and 98.4% were declined for adults. Among both children and adults, there was an increasing trend in use of PHS risk-criteria donors. The proportion of recipients transplanted with PHS risk-criteria donors was approximately 3 times more among adults compared with children during the study period (Figure 1).

Pretransplant patient characteristics of children who received a transplant from a PHS risk-criteria donor were similar to those who received a transplant from an SRD criteria donor (Table 1). Specifically, there was no significant difference in age, sex, race, underlying heart disease, listing status, or patient acuity (including use of ventricular assist device, ECMO, inotropes), with the exception of higher rates of mechanical ventilation among PHS risk-criteria pediatric recipients. In contrast, there were notable differences among PHS risk-criteria donors and SRD criteria donors among adult recipients. Although age and presence of congenital heart disease was similar among adults regardless of donor risk status, adults who received a PHS risk-criteria graft were more often male, White, and more often supported with ECMO at time of transplant. Adults who received a transplant from a PHS risk-criteria donor had higher transplant urgency listing status at the time of transplant but were less often supported with inotropic support at time of transplant.

Patient survival was similar between PHS risk criteria and SRD criteria in both pediatric and adult heart transplant recipients. Among children, Kaplan-Meier curves and log-rank analyses demonstrated no significant difference in patient survival between the 2 groups over the 10-year study period (Figure 2). The 1-year, 3-year, and 5-year survival among PHS risk criteria vs SRD criteria in children was 92% vs 93%, 86% vs 88%, and 80% vs 84%, respectively. Cox proportional hazard regression demonstrated similar outcomes among children, even after adjusting for differences in patient-level factors (adjusted HR, 1.14; 95% CI, 0.90-1.45; P = .28) as shown in Table 2. No children who received a PHS risk-criteria donor died of viral causes.

In adult recipients, there was slightly superior survival among PHS criteria-risk donors compared with SRD-criteria donors (Figure 2). The 1-year, 3-year, and 5-year survival among PHS risk criteria vs SRD criteria in adults was 92% vs 90%, 86% vs 85%, and 80% vs 79%, respectively. Cox proportional hazard regression demonstrated slightly superior posttransplant survival outcomes among adults receiving a PHS–risk criteria donor compared with an SRD-criteria donor after adjusting for patient-level factors (adjusted HR, 0.92; 95% CI, 0.87-0.98; P = .01). Death from viral cause was rare but slightly higher among PHS–criteria risk donor recipients than SRD–donor criteria adult recipients (0.25% vs 0.21%, respectively).

During the study period, there were 1778 PHS risk-criteria grafts that were accepted for adult recipients after being declined by pediatric potential recipients, with 57% of those pediatric refusals attributed to concerns about donor quality or social history. The median age of these potential pediatric recipients who declined the PHS risk-criteria graft that were ultimately transplanted into adults was 15 (IQR, 13-17) years compared with the median age of the adults who received these PHS risk-criteria hearts was 56 (IQR, 45-63) years. Among the 1778 adults who received a heart transplant from a PHS risk-criteria graft that was declined for a pediatric recipient, patient survival was similar to that of adults who received an SRD criteria graft (HR, 0.92; 95% CI, 0.81-1.03, P = .18; eFigure in the Supplement).

To date, to our knowledge, our study represents the most contemporary evaluation of outcomes of PHS risk-criteria heart transplant grafts in the current era. PHS risk criteria are being increasingly used over the past decade, although use in adults remains 3-fold higher than in children. Posttransplant survival in children and adults are similar regardless of donor-risk status, even after adjusting for patient-level factors. The ongoing organ donor shortage underscores the need for further consideration of PHS risk criteria to decrease wait list mortality, particularly among children where PHS risk criteria seems to be underused.

The high discard rate of pediatric donor hearts presents a major challenge for children awaiting heart transplant with 44% of available pediatric donor hearts being discarded in the US.¹⁰ A recent survey that was conducted as part of the International Society of Heart and Lung Transplantation donor consensus statement demonstrated significant variation in willingness to accept heart offers from PHS risk criteria in children.¹¹ There are several behavioral factors influencing transplant team decisions in donor offer scenarios for pediatric heart transplant.¹² Specifically, given the lower volume in pediatric heart transplant and regulatory concerns, pediatric health care professionals are more risk adverse and less likely to accept marginal donors. Programmatic factors also appear to influence this decision-making, with lower transplant volumes and overarching concerns about program scrutiny with any adverse outcomes after transplant. Thus, increasing the donor pool by accepting those donors deemed as being increased risk for infectious disease transmission may provide an important opportunity to increase transplant volume to allow more buffer for taking on potentially higher-risk transplants without risk of regular scrutiny.

Prior work evaluating PHS risk-criteria outcomes among children in an earlier era from 2004 to 2012 in the US demonstrated similar survival, hospital length of stay, and episodes of early rejection compared with SRD criteria outcomes.⁸ Another study⁹ in adults who received a heart transplant during a similar period also demonstrated similar 1-year and 5-year survival, as well as similar episodes of rejection, regardless of donor-risk status. A follow-up study during this same time period demonstrated minimal risk of infection transmission from PHS risk-criteria donors.¹³ However, more recent data on PHS risk criteria use among pediatric or adult heart transplant recipients are limited. Our study addresses this knowledge gap among current practice patterns for donor acceptance by providing a recent overview of PHS risk-criteria heart transplant use among both children and adults over the most recent decade through 2021. In our study, over the past decade there was a 3-fold higher use of PHS risk-criteria donors among adults compared with children, with nearly one-third of all adult transplant recipients coming from a PHS risk-criteria donor compared with less than 10% in children. It should be noted that during the study period from 2010 to 2021, there were several revisions to the criteria for donors deemed to have risk factors for viral transmission to allow a less stringent criteria and, thus, flagging less donors as having PHS criteria risk. This may have affected the rates of acceptance of PHS grafts during our study, but reassuringly there was not a change in posttransplant survival at each time point of these criteria modifications.

Among adults, there was a significant increase in PHS risk criteria use around 2014, which correlates with timing of Federal Drug Administration approval for the initial hepatitis C treatments for adults. The lack of approved pediatric hepatitis treatments may explain the absence of a similar uptick in PHS risk criteria acceptance for children at the same 2014 inflection point seen for adults. Additionally, there may be health care professional concerns regarding long-term complications of receiving a PHS risk-criteria graft in a child with a longer life expectancy compared with adults, who on average are older than 60 years at time of transplant. However, the risk of late infectious complications from an viral transmissible disease must be balanced against the risk of wait list mortality, which in many children is exceedingly high. These are ongoing challenges that our pediatric transplant community faces in light of ongoing donor shortages. However, with our data demonstrating extremely low risk of viral-related death in conjunction with recent adult data demonstrating treatability of hepatitis C in heart transplant recipients with evolving therapies for these virally transmissible diseases and equivalent overall patient survival,¹⁴ these potential therapies should also be considered when considering a donor with PHS risk criteria in children. It also must be noted that death from viral causes is not further delineated in our data set, and thus we cannot accurately assess whether these causes of death were related to hepatitis or nondonor-derived infections, such as COVID-19, or non-PHS donor–derived infections, such as cytomegalovirus and Epstein-Barr virus.

It is notable that use of PHS criteria-risk donor hearts decreased in 2021 among both children and adults. This may be explained by the recent change in the definition of PHS risk criteria that was less restrictive and, thus, qualified fewer hearts as PHS risk criteria.⁷ Specific changes in these criteria include decreasing the risk period from 12 months to 30 days prior to organ offer, as well as removing hemodilution and hemodialysis as criteria for increased disease transmission risk factors. However, it is also noted that there were fewer heart transplants during the most recent years in children and adults during the COVID-19 pandemic, and thus, there may have been some deferrals of PHS risk criteria that had concomitant COVID-19 concerns during that time as well.¹⁵

Notably, there were 1778 hearts from PHS risk criteria that were declined for pediatric recipients with a median age of 15 years that were ultimately accepted by an adult with the median age of 56 years. Of those hearts, nearly 60% were declined for pediatric recipients due to concerns about donor quality or social history. Despite improvements in medical and surgical therapies for patients with advanced heart failure awaiting heart transplant, there remains an unacceptably high wait list mortality, ranging from 16% wait list mortality in children with cardiomyopathy to 24% in children with congenital heart disease.¹⁶ In conjunction with high wait list mortality among children awaiting heart transplant, wait times for children in the most recent era remain prolonged up with median wait times of 108 days in youngest patients. Increasing use of PHS risk criteria knowing that patient survival is equivocal to SRD criteria may provide an important opportunity to decrease wait list time and wait list mortality. Additionally, with improvements in safe sex practices, needle exchange centers, and medical treatment for HIV and hepatitis C, the overall risk profile of the groups may be lower in the current era.

Limitations of this study include lack of granularity about some donor and recipient characteristics due to the retrospective nature of database analyses. Factors that resulted in donors being classified as having risk factors for viral transmission among children and adults may be different, but these data are not available for this study. Specifically, donor hepatitis C nucleic acid amplification testing status was not available for review in this data set. Additionally, posttransplant complications that occurred outside of the hospitalization may not be captured in this database, including infectious complications. It is notable that there were several revisions to the criteria of PHS criteria risk during the study period as outlined in the eTable in the Supplement, and these changes may have influenced the practice of accepting PHS risk-criteria donors and warrants ongoing evaluation of posttransplant outcomes after the most recent PHS risk criteria revision in 2020.

To date, to our knowledge, our study represents the most contemporary evaluation of outcomes of PHS risk-criteria heart transplant grafts in the current era. PHS risk-criteria grafts are being increasingly used over the past decade, and a 3-fold greater proportion of adults receive a PHS risk-criteria graft compared with children, despite similar posttransplant patient survival. The ongoing organ donor shortage underscores the need for consideration of PHS risk-criteria grafts where these donors remain underused.

Accepted for Publication: July 18, 2022.

Published Online: September 21, 2022. doi:10.1001/jamacardio.2022.3070

Corresponding Author: Danielle S. Burstein, MD, The Children’s Hospital of Philadelphia, 34th Street & Civic Center Boulevard, Philadelphia, PA 19103 (bursteind@chop.edu).

Author Contributions: Dr Burstein had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Burstein, Lindenfeld, Schlendorf, O’Connor, Menachem.

Acquisition, analysis, or interpretation of data: Burstein, Rossano, Lindenfeld, Do, Godown, Maeda, Edelson, Lin, Mazurek, Scholl, Menachem.

Drafting of the manuscript: Burstein, Menachem.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Burstein, Edelson, Menachem.

Obtained funding: Burstein.

Administrative, technical, or material support: Burstein, Rossano, Schlendorf, Do, Scholl.

Supervision: Burstein, Rossano, Lindenfeld, O’Connor, Maeda, Menachem.

Conflict of Interest Disclosures: Dr Rossano reported consultant fees from Abiomed, Myokardia, Bayer, Merck, and Cytokinetics, outside the submitted work. Dr Menachem reported consultant fees from Abbott Vascular, Zoll, and Abiomed, outside the submitted work. No other disclosures were reported.