The underlying cause of David Bennett’s death on March 8, two months after he received the heart of a genetically altered pig, remains unknown and is only slightly less mysterious for what can likely be ruled out, suggests a progress report on the case from the director of the cardiac xenotransplantation program where the pioneering surgery took place.
Bennett died in “diastolic heart failure,” reported Muhammad M. Mohiuddin, MBBS, University of Maryland School of Medicine, Baltimore, “but the mechanism is still under investigation.”
Although the immediate cause could have been single or multiple, evidence so far does not point to immune rejection, nor does it support a role for a recently proposed suspect, infection by porcine cytomegalovirus (PCMV), Mohiuddin observed in front of a standing-room-only audience June 6 at the American Transplant Congress (ATC) in Boston. The congress is a joint meeting of the American Society of Transplant Surgeons (ASTS) and the American Society of Transplantation (AST).
Rocky Clinical Course
Early characterizations of the patient’s death focused more on his diminished, end-stage clinical condition at the time of the surgery than on immune rejection or other direct effects of the xenograft, or on the first-of-its-kind procedure itself.
The 57-year-old Bennett had presented to the University of Maryland team with nonischemic cardiomyopathy, on multiple inotropes, and requiring an intra-aortic balloon pump, Mohiuddin said in his ATC presentation. The patient had suffered multiple arrests and resuscitations, and by the time of surgery had been hospitalized for almost 2 months, including 40 days on veno-arterial extracorporeal membrane oxygenation (ECMO).
The transplant procedure itself went as planned until removal of the aortic cross clamp, which triggered a type-A aortic dissection. “We put a graft in the ascending aorta and a stent in the descending aorta. Even after 2 days, we found the dissection extending to the renal artery, so we had to go back and also put a stent in the renal artery,” Mohiuddin said.
Bennett also underwent two exploratory laparotomies in the first 10 days after transplantation, after CT imaging revealed signs of possible bowel inflammation and ischemia.
Further, he had to fight back a series of infections that led to major changes to his experimental drug regimen, which included immunosuppressants methylprednisolone and mycophenolate mofetil (MMF), the investigational anti-CD40 antibody KPL-404 (Kiniksa Pharmaceuticals), and the anti-inflammatories etanercept (Enbrel) and tocilizumab (Actemra).
One episode of sepsis, in particular, forced temporary withdrawal of MMF and a reduction in methylprednisolone dosage. It’s unknown whether the 30-day MMF suspension played a role in Bennett’s ultimate clinical deterioration and death, but it’s “highly possible,” Mohiuddin told theheart.org | Medscape Cardiology.
Realistically, Bennett’s death was likely “multifactorial,” Mohiuddin said. He was in such poor clinical condition going into the procedure, and afterward confronted so many clinical challenges, that “it’s very difficult to say that one thing caused it.”
That hasn’t lessened speculation that the patient’s heart failed secondary to immunologic rejection or PCMV infection, either in Bennett or the donor pig.
A Role for PCMV?
Weeks after 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. 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 Bennett’s case, preoperative screening of the pig donor missed signs of the virus.
Still, PCMV could potentially have contributed to 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 City, from the audience during the comment period after 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.”
Sachs asked Mohiuddin for confirmation that 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 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, 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, Mohiuddin replied.
Nor of Ongoing Rejection
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 Bennett’s novel immunosuppressant regimen, myocardial biopsy on postoperative days 34, 50, and 56 and necropsy showed “no signs of typical xenograft rejection,” 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.”
Bennett once again went on veno-arterial ECMO but died 10 days later. Once they had seen histologic evidence of fibrosis, Mohiuddin told theheart.org | Medscape Cardiology, the team believed the myocardial injury was irreversible. “That was the reason we gave up on recovery.”
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.”
Looking Ahead to Clinical Trials
Research involving humans is always subject to vagaries of human nature, including degree of adherence to prescribed therapy and — in xenotransplantation — precautions in place to mitigate any risks to public health. Such risks theoretically include transfer of porcine viruses or other pathogens to the patient and subsequent release into the general population.
Looking ahead to the possibility of clinical trials after this successful xenotransplantation experience, transplant nephrologist and epidemiologist Peter P. Reese, MD, PhD, University of Pennsylvania, Philadelphia, raised the potentially controversial issue in discussion following Mohiuddin’s presentation.
It’s known that Bennett had been repeatedly turned down for a conventional allograft transplant primarily because of his history of treatment noncompliance. Should such a record, Reese asked, be a relative contraindication to enrollment in any future xenotransplantation trials? Or does the field need a standardized gauge of a patient’s readiness, once discharged, to adhere not only to all medications — including those that fight infection — but also with rules established for public safety, such as routine contact reporting?
“It makes me wonder about choosing a noncompliant patient for these trials,” Reese said. “If we discharge a patient from the hospital who is at risk for a zoonotic infection that could spread if they basically refuse to cooperate with us or with public health authorities, it really could have negative consequences for the reputation of the field.”
Mohiuddin agreed such concerns are valid. Bennett “and all his immediate contacts” signed consent forms acknowledging their willingness to be followed should he be discharged. Bennett himself “signed a consent to inform us if he has any other intimate contact with someone,” he said in an interview.
“But those are only on paper.” Had Bennett survived to be discharged, Mohuiddin said, “no one knows how he would have behaved.”
Mohiuddin said the research staff had prepared to monitor Bennett at his home if that’s what it took. “We were ready to follow him as long as we could. There was a surveillance plan in place.”
American Transplant Congress 2022. Clinical Xenotransplantation Updates. The Maryland Experience. Presented June 6, 2022.