A role for PCMV?
Weeks after Mr. Bennett’s death, as previously reported, his surgeon announced at a public forum that PCMV had been identified in the transplanted heart and in tissues of the donor pig. Mr. Bennett’s circulation showed traces of the viral DNA but not of the virus itself.
The presence of PCMV in transplanted porcine hearts is a well-recognized potential hazard in animal models but is considered avoidable with proper screening. In Mr. Bennett’s case, preoperative screening of the pig donor missed signs of the virus.
Still, PCMV could potentially have contributed to Mr. Bennett’s death, acknowledged Bartley P. Griffith, MD, University of Maryland School of Medicine, who had announced the PCMV finding in an AST-sponsored April 20 webcast.
Preclinical evidence does suggest that PCMV can harm a xenograft organ, observed David H. Sachs, MD, Columbia University Medical Center, New York, from the audience during the comment period after Dr. Mohiuddin’s presentation.
“Each species has a CMV, and they’re quite species-specific,” observed the renowned surgeon and xenotransplantation immunologist. “We showed almost 10 years ago that if PCMV was in a pig kidney, it led to a much shortened survival of the pig kidney in a baboon. There was never any evidence, however, that the CMV infected the baboon or any baboon cells.”
Dr. Sachs asked Dr. Mohiuddin for confirmation that Mr. Bennett displayed no more than DNAemia, circulating cell-free PCMV DNA presumably shed from the porcine heart, but no sign of the virus itself outside of the heart’s porcine cells.
Cell-free DNA had shown up in Mr. Bennett’s circulation about 20 days after the surgery, with concentrations rising until at least day 50. Post-hoc polymerase chain reaction (PCR) testing disclosed PCMV only in the pig’s spleen and porcine cells of the transplanted heart, Dr. Mohiuddin noted.
“We have not found any evidence that the patient was infected by PCMV,” nor was there evidence of any disease related to PCMV, Dr. Mohiuddin replied.
Nor of ongoing rejection
Mr. Bennett’s new heart passed a critical test in the first post-implantation hours by avoiding acute rejection, a potentially disastrous outcome that three of the pig’s 10 gene edits had been designed to prevent.
Although chronic immune rejection was always a concern despite Mr. Bennett’s novel immunosuppressant regimen, myocardial biopsy on postoperative days 34, 50, and 56 and necropsy showed “no signs of typical xenograft rejection,” Dr. Mohiuddin said at the ATC presentation. But “there’s a chance of atypical rejection which we were not accustomed to.”
By day 50, his diastolic function showed echocardiographic signs of deterioration, and “we started seeing interstitial edema with some extravasation of red blood cells, which we thought would resolve over a period of time,” he said. Eventually, however, “we saw that turn into fibroblasts and scar tissue.”
Mr. Bennett once again went on veno-arterial ECMO but died 10 days later. Once they had seen histologic evidence of fibrosis, Dr. Mohiuddin told this news organization, the team believed the myocardial injury was irreversible. “That was the reason we gave up on recovery.”
Mr. Bennett’s xenotransplantation journey has taught the field a lot, he said. “By no means was this a failure; we consider this a huge success. You can do all the experiments in animal models, but you won’t find out the true mechanism of rejection unless you do these kinds of human experiments.”