By Stan Deresinski, MD, FACP, FIDSA
Clinical Professor of Medicine, Stanford University
SYNOPSIS: The first recipient of a transplanted pig heart died with evidence of infection with a porcine cytomegalovirus.
SOURCE: Regalado A. The gene-edited pig heart given to a dying patient was infected with a pig virus. MIT Technology Review. May 4, 2022. https://www.technologyreview.com/2022/05/04/1051725/xenotransplant-patient-died-received-heart-infected-with-pig-virus/?utm_source=Nature+Briefing&utm_campaign=3b02233ccc-briefing-dy-20220505&utm_medium=email&utm_term=0_c9dfd39373-3b02233ccc-46537826
On Jan. 7, 2022, a 57-year-old man, David Bennett Sr., with end-stage cardiac disease received a cardiac xenotransplant at the University of Maryland Medical Center. The donor was a pig with 10 genetic modifications.1,2 Among these were two human complement inhibitor genes (DAF and CD46), two immunomodulatory genes (CD47 and HO1), and deletion of a growth hormone receptor gene designed to prevent cardiac hypertrophy that had been seen in baboon recipients of pig hearts. There were deletions of genes encoding cell surface carbohydrate antigens, including blood cell antigens, making them suitable for universal donation.
The patient initially did well and, on day 34, an endomyocardial biopsy showed no evidence of rejection. However, as part of routine screening, next-generation sequencing of a plasma sample obtained on day 20 was marginally positive for the presence of porcine cytomegalovirus (PCMV). He developed fever and edema on day 45 (March 8) and, despite administration of cidofovir and intravenous immune globulin (IVIG), his illness rapidly progressed, and he died.
COMMENTARY
Although pig kidneys had previously been transplanted into humans on a few occasions, this was the first such transplantation of a pig heart. As noted, multiple genetic modifications had been implemented that were designed to, among other things, reduce the likelihood of organ rejection. There apparently was no evidence of rejection in this patient who was, of course, also receiving immunosuppressive therapy.
Despite its name, PCMV apparently is more closely related to human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7) than it is to human cytomegalovirus, and it is not known to be able to infect human cells. PCMV infection of porcine hearts transplanted into baboons is associated with reduced survival time of the transplant, and this was thought to be related to production of inflammatory cytokines as well as a pro-thrombotic effect in association with viral replication in the transplanted organ.3 This has led the clinicians involved in the human case to speculate that the observed illness, with fever and apparent capillary leak, was the result of a cytokine storm.
Pigs are uniformly infected with a variety of chromosomally integrated porcine endogenous retroviruses (PERV), but, although some of these viruses are capable of infecting human cells, there has been no evidence of transmission by transplantation of, e.g., pig islet cells. In addition to PCMV, other viruses affecting pigs to which attention should be paid are porcine circoviruses (PCV1-3), porcine lymphotropic herpesviruses (PLHV1-3), porcine reproductive and respiratory syndrome virus (PRRSV), Nipah virus (NIV), and hepatitis E virus (HEV).3 Of note is that university officials indicated that the donor pig had been screened for PCMV but “the tests pick up only active infections, not latent ones in which the virus may hide quietly in the pig’s body.”2
REFERENCES
- [No authors listed]. First pig-to-human heart. Nat Biotechnol 2022;40:145.
- Porcine cytomegalovirus - USA: (Maryland) human infection, porcine cardiac xenotransplant, fatal. ProMED-mail May 5, 2022. http://www.promedmail.org
- Denner J. Reduction of the survival time of pig xenotransplants by porcine cytomegalovirus. Virol J 2018;15:171.
The first recipient of a transplanted pig heart died with evidence of infection with a porcine cytomegalovirus.
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