Repeat Rejection Still a Problem After Pediatric Heart Transplant

A study of recurrent rejection after pediatric heart transplantation has provided mixed results, showing that while it is occurring less frequently, it continues to be a risk factor for graft loss.

Each rejection episode was associated with a 47% greater relative risk of losing the transplanted heart (HR 1.47; 95% CI 1.39-1.54), researchers led by Shahnawaz Amdani, MD (Cleveland Clinic Children’s Hospital, OH), report in a study published online recently in the Journal of the American College of Cardiology.

Risk factors for recurrent rejection included an older age at transplant, Black race, and having a positive cross match or a more severe first rejection episode, among others.

“The reason this is important is because then I can go back to my colleagues and say, ‘These are the patients that we need to follow more closely,’” Amdani told TCTMD, noting that noninvasive methods to detect early signs of rejection have emerged over the past decade or so. “You can actually do a blood test to identify rejection very early before it develops in the heart and try to reverse it. . . . Because once you have the rejection episode, as we showed in our paper, it's too late.”

Commenting for TCTMD, Matthew O’Connor, MD (Children’s Hospital of Philadelphia, PA), said it’s not that surprising that recurrent rejection is associated with a poorer prognosis, “but what I think was eye-opening for this study was just the magnitude of the effect in terms of outcomes relative to patients who haven't had a recurrent rejection.”

Moreover, the study “opened some interesting areas of investigation to look at some of the disparities that they identified between white and nonwhite transplant recipients,” he said, suggesting that differences in access to care could be to blame.

Pediatric Heart Transplant Society Database

Survival among pediatric heart transplant recipients of all ages has been increasing over recent decades, but at the same time, patients have become more complex—they’re typically younger, more likely to have congenital heart disease, and more likely to be on life support, Amdani said. These complicated patients may have been exposed to blood products during other procedures, and thus may be at greater risk of developing rejection after heart transplant, which remains a leading cause of graft loss.

The current study grew out of Amdani’s clinical experience of seeing patients who were developing multiple episodes of rejection and being asked by parents about what that means for their children’s hearts. The last study done on the topic, however, was published 20 years ago and used data from the 1990s.       

To provide an updated look, Amdani and his colleagues examined data spanning January 2000 to June 2020 from the Pediatric Heart Transplant Society (PHTS) database, which pulls from 56 international transplant centers. The study included 6,342 transplant recipients younger than 18 years (45% female) who were followed for a median of 3.9 years.

The PHTS defines acute rejection on the basis of clinical findings, echocardiography, or endomyocardial biopsy as an episode that results in the use of antirejection treatment or additional immunosuppressive therapy. Overall, 62% of patients had no rejection episodes, 21% had one, and 17% had two or more. Recurrent rejection was less likely in the second versus first half of the study period (P < 0.0001).

The proportion of patients who remained free of cardiac allograft vasculopathy—a narrowing or blockage of the blood vessels supplying the donor heart—at 5 years did not significantly vary based on the number of rejection episodes (95.3% to 96.6%), or by the type of recurrent rejection—ie, antibody-mediated rejection (AMR), acute cellular rejection (ACR), or mixed (ACR/AMR).

However, freedom from graft loss at 5 years was significantly lower for patients with recurrent rejection (70.1%) than for those with one or zero rejection episodes (81.9% and 87.2%, respectively); findings were similar at 10 years.

In addition, among patients with recurrent rejection, freedom from graft loss was lower in patients with mixed rejection or AMR (65.3% and 50.0%, respectively) than in those with ACR (81.8%; P = 0.015).

Risk factors for recurrent rejection assessed at the time of transplant or at the first rejection episodes included older age, female sex, Black race, transplant during the earlier era, a positive cross match, and IV steroid use.

Addressing Disparities in Care

Underscoring the racial disparity, which is consistent with the earlier study looking into recurrent rejection after pediatric heart transplant, Amdani et al report that Black children had significantly lower rates of freedom from cardiac allograft vasculopathy and graft loss compared with other children with recurrent rejection at both 5 and 10 years of follow-up.

“To me, in 2024, that's not acceptable. Disparities in outcomes based on the color of your skin in the absence of immune-mediated factors is not acceptable,” Amdani said. “And so we should work as a community towards reducing and ultimately eliminating these disparities, which is one of the central messages [of] this paper.”

He said the poorer outcomes in Black children are likely driven by multiple factors, noting that there is limited information on the socioeconomic status of patients in the database. A prior study from his group indicated that both implicit and explicit biases among pediatric heart transplant clinicians may be at play, and Amdani suggested that increasing the diversity of the pediatric transplant community, along with electronic health record (EHR) alerts, may help close some of the gaps.

Disparities in outcomes based on the color of your skin in the absence of immune-mediated factors is not acceptable. Shahnawaz Amdani

For O’Connor, “it just shows a lot of work that we need to do as physicians and other providers caring for these patients to improve the access to care, such that we're not having rejection being diagnosed in a delayed fashion; such that kids from all backgrounds, regardless of resources, can get the same access to care as those with extensive resources. And I think that's where we need to focus our efforts.”

Greater efforts to improve compliance with post-transplant medications may help, too, he said. “I think one area where we can address some of these disparities, not even including race, is to really involve support from social work, psychology, mental health, because those are the things that are going to help people take their medications and follow through with recommendations.”

In an accompanying editorial, Amanda McCormick, MD, and David Peng, MD (both from Michigan Medicine, Ann Arbor), stress the importance of addressing these gaps in care.

“We call upon the pediatric heart transplant community to continue their efforts to understand existing disparities in post-transplantation outcomes and care and, more importantly, to identify interventions that may mitigate these disparities,” they write. “Our collective goal remains improving the quality of life and survival for all children in need of heart transplantation, which cannot be achieved until these disparities are eliminated.”