Children who experience recurrent mixed or antibody-mediated rejection episodes of heart transplants face a higher risk of losing their graft, according to a new multi-institutional analysis. The study, based on the Pediatric Heart Transplant Society (PHTS) database, also found that, while recurrent rejection (RR) has decreased over time in pediatric populations, children experiencing RR in general are at “greatly” increased risk. The findings were published Monday online ahead of the November 26 issue of the Journal of the American College of Cardiology, in an article led by Shahnawaz Amdani, MD, from the Children’s Institute Department of Heart Vascular and Thoracic, Ohio. While some studies suggests that post heart transplant survival has improved over the last 4 decades for children of all ages — with advances in post-transplant clinical care and immunosuppressants in particular driving down pediatric rejection episodes — research evaluating the prevalence and impact of RR in pediatric heart transplant is sparse and more than two decades old, the authors said. Despite the decline in rejection, around 1 in 10 children undergoing heart transplant will experience it. Furthermore, RR it remains a leading cause of graft loss, they added, noting that the timing (early vs late) of rejection and presence or absence of hemodynamic compromise have all been recognized as affecting outcomes for these patients. The current study therefore aimed to describe demographic and clinical characteristics of children who experience RR, as well as freedom from recurrent rejection among a more contemporary population; 6,342 heart transplant recipients under 18 years of age who were treated from January 2000 to June 2020 in the PHTS. It also aimed evaluate the impact of RR on cardiac allograft vasculopathy (CAV) and graft loss. Patient characteristics At baseline, 1,035 of the patients had experienced 2 or more rejections, 1,386 had experienced 1 rejection, and 3,921 had suffered no rejections. The median duration of follow-up for the cohort was 3.9 years (interquartile range [IQR]: 1.3 - 7.5 years). The median time from transplant to first rejection episode was 0.24 years (IQR: 0.06- 1.54 years), and the median interval between first and second rejection episodes was 0.73 years (IQR: 0.21- 1.96 years). A higher proportion of those who had a transplant under the age of 1 had experience no rejections (35.1%) compared with those experiencing 1 rejection, or 2 upwards (25.4% vs. 17.4% respectively). Conversely, the biggest percentage of patients for the 2 or more rejections group received their transplants at the age of 11 to 19 years (39.8%) compared to 34.4% of the 1 rejection group, and 28.9% with no rejections. Sex weighting among the three groups was similar (with a slight increase in male patients), roughly 90% of each category were classed as “priority” at time of transplant rather than “routine,” and waitlist times were an average of 1.81 months in the 0 rejection group, 1.87 months in the 1 rejection group and 1.58 months in the 2 or more rejections group. Induction of therapy at transplant occurred in 81.4% of those with no rejections, 78.6% of the 1 rejection group and 74.6% of the 2 or more rejection group. Median creatinine levels ranged from 0.40 mg/dL (IQR: 0.30-0.61) for those with no rejections, to 0.49 mg/dL (IQR: 0.31-0.70) for those with 1 rejection, to 0.50 mg/dL (IQR: 0.40-0.74) for those with 2 or more rejections. Median bilirubin levels were 0.61 mg/dL (IQR: 0.40-1.20), 0.60 mg/dL (IQR: 0.40-1.20), and 0.70 mg/dL (IQR: 0.40-1.30). Graft rejection rises with RR episodes In general, the researchers found that RR risk decreased over time. “Compared with children undergoing HT in the early era, those undergoing HT in the current era were less likely to experience recurrent rejection (P < 0.0001),” they said. Risk factors for RR identified at time of transplant included increasing age (hazard ratio [HR]: 1.05 per 1 year increase; P <0.001), being female (HR: 1.14; P = 0.035), being Black (HR: 1.26; P = 0.002), undergoing an “earlier era” of transplant (HR: 2.06; P < 0.001), and a positive cross match (HR: 1.29; P = 0.013), said the researchers. RR risk was also higher for children with more severe first rejection episodes, the researchers said, adding that intravenous steroid use at the first rejection episode was a risk factor for RR (HR: 1.39; P <0.001). Freedom from CAV was similar for all groups, with over 95% of each avoiding CAV, and was similar regardless of the type of RR, either acute cellular rejection (ACR) and antibody-mediated rejection (AMR), the researchers said. However, freedom from graft loss was significantly lower for those experiencing RR to those with none or 1 episode (56.3% vs. 72.3% vs. 82.3%, respectively at 10 years; P <0.0001). The graft survival rate was lower still for those experienced RR due to “mixed” reasons – with episodes or both ACR and AMR – and recurrent AMR, compared with children experiencing recurrent ACR (65.3% vs 50% vs 81.8%; P = 0.015). In an accompanying editorial, Amanda D. McCormick, MD, David M. Peng, MD, from Michigan Medicine, MI, highlighted limitations with the current study, including that rejection is defined as an episode necessitating increased immunotherapy, as well as the “highly variable follow-up and treatment practices of the centers” in the PHTS. “PHTS has begun to address widespread practice variability by forming the Standardizing Care Committee. Given the rapidly evolving diagnostic and therapeutic options, this committee should focus on the development of standardized rejection surveillance, follow-up, and treatment protocols so that the community can better assess the impact of new interventions on outcomes,” they said. Racial differences In particular, the researchers and editorialists highlighted the increased risk of RR in Black children, who are at a subsequent higher risk of both graft loss and CAV. The researchers called for further studies on whether treatment differs by race and the interaction between socioeconomic status and post-transplant care. “Although medical advancements have led to a decrease in recurrent rejection rates, the significant impact of recurrent rejection on graft survival, particularly among Black children, underscores the need for continued vigilance, collaboration, standardization of practice, and equity-focused interventions,” the editorialists added. Sources: AMdani S, Kirklin JK, Cantor R, et al. Prevalence and Impact of Recurrent Rejection on Pediatric Heart Transplant Recipients: A PHTS Multi-Institutional Analysis. J Am Coll Cardiol 2024; 84: 2170-2182. McCormick AD, Peng DM. Hit Differently: Disparities Persist in Recurrent Rejection After Pediatric Heart Transplant. J Am Coll Cardiol 2024; 84: 2183-2184. Image Credit: Stock Source – stock.adobe.com