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The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

Is Acute Rejection Truly Acute or an Exacerbation of an Underlying Disease?

      Purpose

      The current paradigm defines acute rejection (AR), a composite of acute cellular rejection or antibody-mediated rejection, as distinct acute events. Yet, affected patients often progress to chronic lung allograft dysfunction despite initiation of targeted therapy at diagnosis of the acute process. We hypothesize that AR is not an acute event, but rather, an exacerbation of an on-going early post-transplant disease. Herein, we leverage donor-derived cell-free DNA, a sensitive marker, to define post-transplant allograft injury pattern associated with AR.

      Methods

      141 prospectively enrolled lung transplant patients (NCT02423070) were grouped as acute rejection (“AR”) or no rejection (“NR”) as determined by adjudication. Allograft injury was measured by ddcfDNA via shotgun sequencing in 1557 prospectively collected plasma samples; medians and interquartile ranges (IQR) are reported

      Results

      Over the median 19.6 months follow-up, 87 episodes of AR were detected in 51 patients (34.7%) at a median 7.6 (IQR =2.4 - 12.7) months post-transplant. %ddcfDNA was high after transplant surgery and then decayed. “AR” showed slower decay. Their baseline ddcfDNA levels were higher than for "NR" well before AR diagnosis (FigA), starting from Day 7 post-transplant and reached 4X higher than for “NR” by 3 months post-transplant (0.88%, IQR=0.31% - 1.93% vs. 0.23%, IQR=0.13% - 1.59%). At AR diagnosis, ddcfDNA levels rose (1.95%, IQR=1.14% - 5.04%) and were ∼2 fold higher than the within subject high baseline levels (FigB), and ∼6X higher than for time-matched “NR”. ddcfDNA reduced after AR treatment but remained higher than for time-matched “NR” (0.52%, IQR=0.22% - 1.59% vs. 0.25%, IQR=0.08% - 0.57%, p<0.01).

      Conclusion

      Early after transplant, “AR” patients show higher levels of baseline allograft injury that persist and then rise with diagnosis of AR. If ongoing studies confirm these findings and identify mechanisms that predict elevated baseline injury and AR phenotype, treatment paradigms could be revised to improve allograft outcomes.