Xenotransplantation: Infection control on the cutting edge
Research presses ahead amid fears of lighting the fuse of a new retrovirus
[Editor’s note: The many infection control issues raised by xenotransplantation (animal-to-human transplants) are the subject of a special report in this issue of Hospital Infection Control. While the emerging science takes the field to the literal cutting edge, many infection control issues are still arising in the ever-expanding arena of allografts human-to-human transplants. Look for an exploration of those issues in our January issue in the second part of this special report.]
Striking a precarious balance between risk and reward, animal and man, federal health officials are calling on infection control professionals to play a critical role in a new medical frontier xenotransplantation. Such animal-to-human transplants have great potential medical benefit, but pose a real risk of unleashing new infectious agents.
To address the infection control challenges of xenotransplants, the Centers for Disease Control and Prevention, the Food and Drug Administration, and the National Institutes of Health have combined under the aegis of the U.S. Public Health Service in Washington, DC, to issue draft guidelines aimed at lowering the risks while permitting clinical trials to continue and expand.1 The guidelines which are open for comment through Dec. 22, 1996 assign infection control practitioners and hospital epidemiologists key responsibilities for surveillance and control efforts to protect both transplant patients and health care workers who may be exposed to new pathogens. Duties include deciding on appropriate isolation precautions, establishing patient surveillance, drawing baseline blood from health care workers, and creating a xenotransplant nosocomial exposure log to document any incidents that may ultimately lead to infection. By the same token, immunosuppressed xenotransplant recipients may be vulnerable to a broad range of nosocomial infections in the post-procedure period.
’We are living science fiction,” says Patricia Grant, RN, BSN, CIC, infection control coordinator at Parkland Memorial Hospital in Dallas, after reviewing the guidelines. ’I am not advanced enough in my own practice to weigh all of the checks and balances the ifs, ands, or buts, and huge gray areas. But from an implementation standpoint, I could see where it could really get out of control. I’m not going to say I don’t think it’s worth the risk. I am not the person who is going to benefit from this procedure.”
As opposed to use of non-living animal tissues such as pig heart valves, xenotransplantation involves the transplant of organs, tissues, and cellular materials directly from living animals primarily baboons and pigs into humans. Though the first modern clinical trials in the United States were done in the 1960s, a new wave of xenotransplantation is beginning, due in part to the development of more powerful immunosuppressive drugs and biotechnological advances that make new procedures possible. Such procedures are becoming an increasingly realistic alternative to overcome the chronic shortage of human organs. As opposed to whole organs, the transplant of animal tissues also may provide unique treatment benefits under special protocols like the much-publicized attempt last year to bolster an AIDS patient’s immune system with an engraftment of baboon bone marrow.
Ironically, the specter of HIV is being raised in another regard as a retrovirus that very likely crossed species lines from animal to man with devastating effect. Indeed, there is broad agreement in the emerging science that the procedures carry an unknown risk of unleashing a new pathogen either a mutation between species, or more likely, a virus that is harbored benignly in an animal host. A more recent example than HIV is hantavirus, which causes no disease in its rodent host but can cause a pulmonary syndrome in infected humans that leads to fatality rates in the 50% range. Such a transfer of a zoonotic virus has not previously been linked to a xenotransplant, but the threat of such an occurrence is being taken seriously.
A dangerous proposition
A respected AIDS researcher and expert in primate viruses, who was a dissenting voice on the FDA committee that approved the aforementioned baboon bone marrow transplant, says the risks are far too great to proceed with xenotransplantation procedures that would draw living tissue and organs from baboons and other primates.2,3 In addition to baboons’ HIV-resistant bone marrow, such primates are seen as possible ’bridge” candidates for transplant patients awaiting human organs because their strong genetic correlation to humans minimizes some of the possibility of rejection in the recipient.
Overwhelming current evidence, however, suggests that HIV began as an immunodeficiency virus in African monkeys, thus creating a bizarre scenario where the very government agencies that have been heavily involved in battling AIDS are now opening the door to recreate conditions similar to its origins, says Jonathan Allan, DVM, a virologist and baboon researcher at the Southwest Foundation for Biomedical Research in San Antonio.
’There should be a ban on the use of non-human primates. We have enough information to know that this is a dangerous proposition,” he says. ’Even to use a few people is actually jeopardizing the public health of the population. You introduce a new retrovirus into the human population and it gets beyond the recipient, into his or her contacts, and the blood supply is at risk.”
While acknowledging the validity of Allan’s concerns with surprising candor his research is referenced in the guidelines federal health officials say the extensive animal screening, patient surveillance, and infection control measures outlined in the draft will allow medical science to move ahead in a critical area with minimal risk to public health.4 At a symposium on the subject last year, the National Institute of Medicine (IOM) in Washington, DC, also recommended issuing national guidelines, establishing preventive measures, and proceeding cautiously with procedures.5
’There was fairly broad agreement that the risk was not zero,” says Amy Patterson, MD, senior medical officer in the FDA division of cellular and gene therapy. ’The guideline represents an effort to try and strike a very difficult balance between an unknown, as yet unquantifiable risk in terms of infectious agents that may emerge with very present initial signs of clinical benefit.”
While the analogy of opening Pandora’s box can be applied in the sense that the guidelines will encourage broader clinical trials, they also standardize federal oversight of the procedures to some degree. Rather than case-by-case oversight by the FDA, the guidelines for the first time outline the rigorous animal controls and the broad level of clinical expertise that must be brought to bear to conduct any type of xenotransplantation a need that has been underscored by some of the protocols submitted to the FDA.
’We have had people call up or even send in protocols where they are proposing to use animals obtained, for instance, at the local slaughterhouse,” Patterson notes. ’They would like to be able to call up the local farmer and get a pig on order, simply brought to the surgical suite or an adjacent room where they could remove the organ and then put it in the patient.”
To improve surveillance as procedures expand, the CDC is developing retrovirus diagnostic assays as part of a planned national registry and database on xenograft recipients, says Louisa Chapman, MD, medical epidemiologist in the CDC retroviruses diseases branch. The approach will include screening the source animal and recipient prior to the procedure, and then following the recipient periodically after the transplant. The CDC and participating labs will look for evidence of xenogeneic retroviral infections using both established assays for known pathogens and newly developed ’generic” retroviral tests to pick up signs of an unknown agent.
Possible silent infection’ poses concern
’What is really a concern in terms of public health are infections which could potentially infect someone silently’ and be transmissible for a long period of time before clinical disease is evident in the initially infected host,” she tells Hospital Infection Control. ’That is the kind of infection that could readily spread through the population in the way that AIDS did.”
Indeed, such ’long fuses” are characteristic of retroviruses, notes Allan, reminding that under such conditions it may take 100 infections before disease is found in one person five or 10 years later.
’If you transmit an unknown agent, how are you going to look for it?” he says. ’The CDC is developing these assays that they are starting to tout that can pick up generic retroviruses. I don’t have much faith in those assays when they haven’t been tested and there is no way to test them until you have an outbreak. To use that as a reason to go forward is a real mistake in my opinion.”
Though the FDA has announced it will be issuing more detailed clinical guidelines, Allan also questions why the PHS guidelines did not include a list of the known viruses baboons harbor so that they could be earmarked for testing and exclusion from programs.
’That means under life-and-death circumstances being played out at the local level, one could see a scenario where perhaps a baboon would be used that has several known infectious agents that could be infectious in humans,” he says. ’The baboon carries endogenous retroviruses. They are in every cell type in the baboon and we know those viruses infect human cells. It’s a no-brainer.”
Preferable pigs
Given such concerns, the infectious disease physician in the baboon marrow case concedes that exclusive use of swine would be ultimately preferable in xenotransplants, though infectious disease risks would remain even then.
’I think the risk of transmission will be substantially less not zero by any means using animals such as pigs that are going to be more easily raised in a controlled system where you can breed out specific organisms,” says Marian Michaels, MD, MPH, assistant professor of pediatrics and surgery at the Universtiy of Pittsburgh School of Medicine and a member of the IOM xenotransplantation committee. ’People are working very hard to go towards that, but at this point in time the ability to cross those barriers is just easier with a non-human primate than it is with the swine.”
In that regard, Michaels has researched and published extensive infectious disease evaluations for xenotransplants that address known infectious agents in swine and baboons.6
’I have a very keen respect for the hazards of infectious disease transmission with biologics,” she says.
While there are less likely to be ethical questions raised about using swine rather than baboons, there also is the general perception that xenografts with swine will be inherently safer because humans have domesticated and consumed the animals for centuries. But such conditions are not the same as placing living animal tissue in a severely immune-suppressed human host, and regardless, there is still some question about what unknown pathogens pigs may harbor.
’Most of us feel comfortable saying based on no data that the risk [in swine] is lower,” says Jay Fishman, MD, clinical director of transplantation infectious disease at Massachusetts General Hospital in Boston. ’The caveat is that we don’t know anything about unknown pathogens, retroviruses, and endogenous viruses of various types because they haven’t been studied in swine very well.”
Fishman is currently conducting swine-to-swine allografts and swine-to-primate xenografts to study the pathogenesis of infections in the immunocompromised host.7 Having compiled a list of 27 pathogens that currently should exclude swine from xenotransplant use, he argues for continuing animal research in order to develop DNA probes and other tools to better identify pathogens in animal sources. Such an approach would be better than trying to measure immune response after infection in human recipients, he notes.
’We should be developing the technology in animals before we take it to humans,” he says. ’I think the real risk in using swine as donors if they are carefully screened to the best of our ability is probably very low. But the way one answers these questions as a clinician is not, would you give this to your mother-in-law, but to your mother or your child? Saying that would I do this the answer is, not now.”
Genie out of the bottle
But even an outright moratorium on U.S. xenotransplant programs would not eliminate the risk of the emergence of a new virus globally, as hundreds of xenotransplants are thought to have been conducted in Russia, China, and Eastern Europe in this decade. According to the IOM, anecdotal reports indicate the xenotransplants were used for the treatment of diabetes using pancreatic tissue from pigs, cows, and rabbits, but ’the magnitude and possible efficacy of these efforts are not known because of poor patient documentation, follow-up, and publication.”5
Facing such uncontrolled conditions in an increasingly small world, it is preferable to establish the appropriate animal screening and infection control protocols rather than try to hold back the tide of scientific inquiry, notes a member of the IOM committee, Stephen Morse, PhD, associate professor of epidemiology at Columbia University in New York.
’One of the arguments I would make for the PHS guidelines is that if we don’t take leadership and develop a system that will minimize risk to the extent that it can be managed, people in other countries will not be constrained,” he says. ’They are going to do it and have done it in the past. If it’s going to be done, it should be done right or least as well as it can be done. I think it is going to be very hard to have a moratorium. My feeling is that the risks are worth taking if they are carefully chosen, because there are benefits in the long run that are likely to outweigh the risk.”
Such discussions of unknown risk are reminiscent of the early days of the space program, Chapman says, when elaborate screening and decontamination of crews and vehicles were enacted lest microorganisms from space begin an earthly epidemic.
’In retrospect, it is easy to say they probably weren’t necessary concerns, but I don’t think anyone can say they were not reasonable and appropriate concerns at the time,” she says. ’I think we are very much at a similar point in transplantation where we are talking about in a sense having two worlds, two species come together in a way that they haven’t come together before.”
The eloquence of that analogy is lost on Allan, who argues that the public health service is bowing to pressure from the transplant community, biotechnology companies, and AIDS activist groups in allowing xenotransplants to proceed with baboons.
’The AIDS epidemic is not Mars,” he says. ’There is historical evidence of what can happen when you put a monkey virus in a human. We already have it.”
References
1. Department of Health and Human Services. Draft Public Health Service guideline on infectious disease issues in xenotransplantation. Fed Reg Sept. 23, 1996; 49,919-49,932.
2. Allan JS. Xenotransplantation and possible emerging infectious diseases. Molecular Diagnosis 1996; 1:1-7.
3. Allan JS. Xenotransplantation at a crossroads: Prevention versus progress. Nature Medicine. 1996; 2:18-21.
4. Chapman LE, Folks TM, Salomon DR, et al. Xenotransplantation and xenogeneic infections. New Engl J Med 1995; 333:1,498-1,501.
5. Institute of Medicine Committee on Xenograft Transplantation. Xenotransplantation: Science, Ethics and Public Policy. Washington, DC: National Academy Press; 1996.
6. Michaels MG. Xenotransplant-associated zoonoses: Strategies for prevention. Transplantation 1994; 57:1-7.
7. Fishman JA. Miniature swine as organ donors for man: Strategies for prevention of xenotransplant-associated infections. Xenotransplantation 1994; 1:47-57.
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