Some lines of research yield breakthroughs before all ethical considerations have been fully worked out. That's where heart xenotransplantation (XTx) is today.
An emergency-use authorization in January of this year allowed a 57-year-old man with end-stage heart disease to successfully receive the heart of a genetically altered pig at the University of Maryland School of Medicine (UMSOM). The patient, Maryland resident David Bennett, lived for another 2 months.
The historic XTx procedure, celebrated as a scientific milestone, had its share of hitches along with the triumphs that raise questions about next steps for this kind of research.
Opinions differ, for example, on whether to continue with individual cases that lay groundwork for future trials, or to begin those trials right away.
The case also highlights certain clinical and ethical challenges unique to XTx in humans.
For example, traditional standards of equipoise, informed consent, selection of patients, and their long-term rights and responsibilities may be a poor fit.
And the unique potential hazards of XTx defy usual approaches to risk assessment. Animal organs for transplantation in humans may pose a risk of novel infection in the recipient by viruses that could, in theory, spread to the general population. Zoonotic diseases are actually common, but they vary widely in virulence and transmissibility, neither of which would be predictable in the post-XTx setting.
At UMSOM, the heart xenograft impressively cleared its first critical hurdle by avoiding hyperacute rejection, thanks largely to genetic manipulation of the donor pig. But as later discovered, the animal had also harbored a porcine cytomegalovirus (PCMV) that accompanied the heart during the transplantation procedure.
The latent virus had evaded an intensive donor-pig screening process for potential pathogens, as the published report of Bennett's case details. His care team was "surprised" that the PCMV wasn't detected earlier, said UMSOM's Bartley P. Griffith, MD, who performed the XTx surgery.
The pig had undergone "no fewer than four very recent tests," polymerase-chain-reaction (PCR) assays for PCMV, "and we missed it," the surgeon said at a forum conducted during the recent Heart Failure Society of America (HFSA) 2022 Annual Scientific Meeting, held outside Washington, DC.
"Float-off" DNA from the virus was detected in the patient's circulation and several organs, including the spleen, liver, kidneys, and lungs, Griffith said. "It was just DNA. There was no evidence within [Bennett] that the virus that infected his pig heart affected anything else in his body."
But the initially latent PCMV may still have been involved in the graft's ultimate failure. As recently described, on autopsy the heart showed a peculiar pattern of microvascular destruction and myocardial necrosis uncharacteristic of typical rejection. That process may have been triggered by PCMV that reactivated during Bennett's postoperative treatment, Griffith speculated.
That a virus, even one not usually considered a major risk to humans, escaped detection until after the surgery highlights the long-recognized potential for pig-to-human transmission of possible pathogens during XTx.
It also raises unresolved ethical questions regarding the conduct of XTx research that must be reconciled with patient rights and preservation of public safety, cardiologist Savitri Fedson, MD, observed during the panel discussion at the HFSA plenary session.
For example, she said, given that recipients of xenograft organs are at possible risk of zoonotic infection, "so too, potentially, are their close contacts, their work associates, and their medical teams."
That means society has a stake in mitigating infection risk from heart XTx that doesn't apply to standard heart allograft transplantation, said Fedson, who studies medical ethics at Baylor College of Medicine and DeBakey VA Medical Center, Houston, Texas.
Without a way to measure the potential of XTx for zoonotic infection, she said, "At what point of risk, or at what certainty of no risk, will it be acceptable and we be comfortable?"
Screening Lessons Learned
Potential infection transmission is always a concern even in standard allograft transplantation, "but in fact, transmission is very rare," Jay Fishman, MD, told theheart.org | Medscape cardiology.
"There are lots of infections that we share with animals, toxoplasmosis, for example. There's no magic to zoonotic infections," said Fishman, who directs the transplant infectious diseases and compromised host program at Massachusetts General Hospital, Boston, and wasn't part of the UMSOM case.
A porcine virus "was allowed to get into the human, but it did not, in fact, cause infection in that human," he said in reference to the Bennett case. "There was no evidence that the virus ever infected human cells."
Still, transmission of porcine endogenous retrovirus (PERV) type C has always been a potential caution in XTx involving pig organs. Part of the porcine genome, the retrovirus has been known to infect human cells. The donor pig in Bennett's case, however, had been cloned from a PERV-C-negative cell line, as described in the published report.
Pigs are widely used in commercial and laboratory settings throughout the world, but there has never been evidence of PERV transmission from pigs to humans, Griffith observed. "Basically, in most forms that we see, it's not very transmissible."
Fishman said PERV infection of humans in XTx "is a legitimate theoretical concern, but not one that's ever been demonstrated."
Going forward with XTx, "I think we can certainly do appropriate screening of the animals and then surveillance of the recipients," he said. "I don't think the threat to society in general is great. You never say never, but I think the potential zoonotic threats are manageable."
Based on the Bennett case, UMSOM's XTx program has made "radical changes" to its molecular and serologic testing protocols, especially those for PCMV. "We've gone through a lot of additional soul searching in terms of how to have a better screening," Griffith said. "We think we can detect it now."
"What Else Are They Missing?"
David Bennett's case is indeed a red flag on the potential risk of zoonotic infections from XTx procedures as they are performed now, Brendan Parent, JD, told theheart.org | Medscape Cardiology.
There are "strong arguments" suggesting that PCMV cannot transfer from porcine grafts to human tissue, Parent noted, but also suggestions that the virus was at least partly responsible for xenograft failure in Bennett's case. If the virus evaded the UMSOM team's screening process, "what else are they missing?"
Parent, from the departments of surgery and population health at New York University Grossman School of Medicine, New York City, studies transplantation and organ-procurement ethics and policy. He's affiliated with NYU Langone Health, which recently conducted porcine-heart transplants in two brain-dead recipients on ventilatory support.
"All the teams that have a stake in the game are viewing the risks through their own lens, through their own biases," Parent said. "And it is very difficult, I think, to get any kind of objective sense of whether the risks have been adequately addressed."
Moreover, a lot is riding on these first heart XTx attempts in humans, "which means the teams performing them have to be more than perfectly diligent —because any misstep can set the field back significantly. And this was a misstep," Parent said, referring to the Bennett case.
Connecting Patient Selection to Graft Failure
Griffith said the ganciclovir Bennett had on board should have "taken care of" any PCMV in his body. But as previously described, the patient had been in strikingly poor clinical condition going into the surgery. He had recently emerged from a crushing 40 days on veno-arterial extracorporeal membrane oxygenation (ECMO) support, for example, and his bone-marrow function was poor.
Ganciclovir made it worse. Using any drug toxic to bone marrow in Bennett "became quite an issue," Griffith said. "We reduced the ganciclovir therapy, even stopped it for a short period of time altogether."
With that, he said, "I think we let the cat out of the bag." Withdrawal of the antiviral apparently reactivated the latent PCMV, which in turn may have promoted graft failure, Griffith and his colleagues speculate.
"We could have done a much better job if he hadn't been so sick. Then maybe he would never have had a virus, because we could have treated it with robust therapies," Griffith said.
"We are looking for a second patient," but "we're certainly not going to take a bone-marrow-insufficient patient on the front end, ever again."
Patient Rights vs Responsibilities
"Multiple guidelines and international statements" on XTx recommend that the organ recipients be monitored throughout their lifetimes for signs of zoonotic infection, Fedson said during her plenary presentation. And they would have to continue reporting any symptoms or illnesses and consent to an autopsy.
So, she said, "we have a conundrum here." Our standards of clinical ethics, with foundations in the Nuremberg Code and Declaration of Helsinki, "hold that subjects involved in medical research have the right to withdraw at any time, for any reason." But that right conflicts with any mandate for lifelong surveillance because of the "unknown risks to them and their close contacts."
Unresolved, Fedson said, is whether the informed consent process for XTx recipients should exclude the right to withdraw from surveillance. "Or is the right to withdraw so inalienable that we are willing perhaps to sacrifice public safety for the benefit of one or two individuals?"
Based on the ethics discussions at the plenary session, Mark H. Drazner, MD, said there may have to be "special rules" for XTx recipients, particularly regarding any right to withdraw. The patients, in order to have the surgery, may have to "agree to lifelong monitoring," Drazner, University of Texas Southwestern Medical Center, Dallas, told theheart.org | Medscape Cardiology.
"We Made an Exception"
Whether or not the right to withdraw is preserved, the field may well require selection of XTx recipients believed likely to comply with immunosuppressive therapy and surveillance demands based on past behavior.
The UMSOM team knowingly accepted a patient with a noteworthy history of poor compliance, although its long-term relevance is unclear because Bennett did not survive to hospital discharge. Still, his referring cardiologist in Hagerstown, Maryland, told the clinicians that Bennett "was the worst patient he'd ever had in terms of follow-up." For example, "He'd come in when he was sick and not be seen again."
Such behavior would likely exclude Bennett from eligibility for a standard heart allograft at UMSOM, Griffith said. But "we felt that importance of the experimental transplant meant that members of the team would be willing to follow-up, even drive to his house, to make sure he was taking his meds. So, we made an exception."
When recipients of a human heart allograft choose to stop immunosuppressive therapy, "the harm is just to themselves," Fedson observed for theheart.org | Medscape Cardiology. But the risks of a zoonotic infection spreading beyond the patient are unknown. And, "we don't know whether it's going to be the next SARS, or the next Ebola," she said, citing two familiar zoonotic diseases.
The possibility of such noncompliance is "a huge deal," Parent said. Candidate selection should consider compliance history, but more comprehensive measures should be in place to help ensure surveillance, long-term immunosuppressive therapy, and clinical follow-up. "That includes, obviously, a ton of education to make it clear to the patient how incredibly crucial this is."
Next Steps for Research
More progress should be made on unresolved ethics issues before heart XTx moves to large clinical trials, Drazner said. "The last thing you want is a large trial, ethical issues are raised on the back end, and then it hurts the advancement of the field."
One approach, he added, might be to convene a national panel of experts on XTx research ethics to provide guidance on these key issues.
Given the inability to quantify the risks objectively, Parent said, one approach might be to assemble a panel of stakeholders from different corners of society to explore acceptable ways forward "democratically," whether that's by "granting more emergency authorizations or moving to clinical trials and, eventually, potentially even clinical translation."
Such a panel could include not only regulators, researchers, and industry, but also "transplant recipients, patients on the waiting list, family members, religious leaders, epidemiologists, infectious disease specialists, and immunologists," he proposed. "That should be happening as soon as possible."
Trials or More One-Offs?
"The single biggest challenge now is how to translate what we have learned in nonhuman primates to humans," surgeon and UMSOM XTx program director Muhammad M. Mohiuddin, MBBS, said at the plenary panel discussion.
But US regulators are requiring the center to continue XTx research in animals. They need to be convinced, he said, that people and nonhuman primates are different and to "give us permission to test out a few humans just like we did with Mr Bennett, to figure out how we can move forward."
There are limits on what else can be learned from XTx in nonhuman primates, Griffith agreed. Individual cases can inform the design of future trials in potentially critical ways.
Were large trials to proceeded without the benefit of lessons from the Bennett case — for example, that a virus can evade the donor animal screening process — the results could be "disastrous." Griffith said. "What would that have said about the whole field? Whereas maybe one small adjustment could have made a huge difference."
It's troubling, Drazner offered, that PCMV wasn't detected before Bennett's surgery. "I personally think there still is a lot more that needs to be understood before we're ready to do this in any type of large-scale clinical trial."
Fishman said the UMSOM experience and recent porcine heart and kidney decedent studies "were very useful steps," but they didn't address issues such as infection risk that usually take longer to emerge.
"I don't think we're in the era of one-off studies going forward. I think what the future holds is multi-patient, FDA-approved clinical trials." In such a trial with a well-defined protocol, Fishman said, "I think you would not just have better control, I think you'd learn more."
Fedson proposed that such procedures be performed next in smaller-scale studies modeled after phase-1 drug trials, which patients join primarily for the advancement of knowledge knowing that they may not personally benefit.
Regardless of their form, future XTx trials may require a rethink of informed consent, because the risks are so poorly understood. It may be, Fedson said, "that with xenotransplantation, the standard that we typically require for informed consent is simply not possible."
Perhaps Bennett's case can be instructive there, as well. Griffith related his patient's last words to him before his death after withdrawal of life support on March 8. Bennett, on hearing for the last time that he could not receive a human heart, said "Well, then, learn something."
"I thought that was pretty insightful," Drazner noted. "It made me think he really did understand what he was getting into, and that he felt he could contribute to the advancement of science."
For future XTx procedures, "at a minimum, I'd want to make sure the patient gets that concept down," he said. "One could say that is a pretty good surrogate for true informed consent at some level."
Griffith discloses consulting for Abiomed. Fedson, Drazner, and Fishman have reported no relevant financial relationships. Parent discloses receiving research support from the Applebaum Foundation and United Therapeutics. Mohiuddin discloses receiving research support from United Therapeutics.
Heart Failure Society of America Annual Scientific Meeting 2022. Cardiac Xenotransplantation: Where We Are and Where We Are Going. Presented October 3.
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Cite this: Ethical Quandaries With Pig-Heart Transplants at the Crossroads - Medscape - Oct 25, 2022.