The first clinical pig heart transplant: Was IVIg or pig cytomegalovirus detrimental to the outcome?

Abstract

The clinical course of the first patient to receive a gene-edited pig heart transplant was recently reported by the University of Maryland team. Although the pig heart functioned well for >40 days, serum anti-pig antibodies then increased, and the patient sadly died after 60 days. Because of his debilitated pre-transplant state, the patient never thrived despite excellent graft function for several weeks, and the cause of his demise continues to be uncertain. A few days before an increase in anti-pig antibodies was observed, the patient had received intravenous human immunoglobulin (IVIg), and whether this played a role in his cardiac deterioration has been discussed. Furthermore, mcfDNA testing indicated an increase in pig cytomegalovirus (CMV), and its possible role in the development of cardiac dysfunction has also been considered.On the basis of the limited data provided in the publication and on our previous investigations into whether IVIg contains anti-TKO pig antibodies and therefore might be deleterious to TKO pig organ xenografts, we suggest that the steady rise in anti-pig antibody titer was more consistent with the failure of the immunosuppressive regimen to prevent elicited anti-TKO pig antibody production, rather than from the passive transfusion of IVIg or the presence of pig CMV in the graft. Although the outcome of the Maryland experience was disappointing, valuable lessons were learned. Our attention was drawn to the potential risks of heart transplantation in a "deconditioned" patient, the administration of IVIg, the transmission of pig CMV, and of the difficulties in interpreting myocardial biopsy findings.

Porcine cytomegalovirus/porcine roseolovirus (PCMV/PRV): A threat for xenotransplantation?

“…Given the limited data so far, all discussion on the cause (or causes) remain speculative. [29][30][31] However, the clinical features described in the patient resemble the features observed in the baboons, which received a PCMV/PRV-positive heart. 22 This pioneering work, despite the outcome, did however yield some important insights for the management of PCMV/PRV.…”

“…It is important to note that the exact role of PCMV/PRV is unclear, and hopefully additional studies will shed some light on the specific contribution of PCMV/PRV to the course of the patient. Given the limited data so far, all discussion on the cause (or causes) remain speculative 29–31 . However, the clinical features described in the patient resemble the features observed in the baboons, which received a PCMV/PRV‐positive heart 22 .…”

Early testing of porcine organ xenotransplantation products in humans: Microbial safety as illustrated for porcine cytomegalovirus

“…Also, this event attracted worldwide attention 24 . The discussion is ongoing whether the dysfunction of the transplant was due to the reactivation of PCMV, 25 or due to injections with IVIg, because IVIg preparations can contain anti‐pig antibodies 26 …”

“…Evidently, the 2‐month survival of the heart transplant at UMD is a major step forward and is in line with data from nonclinical studies in nonhuman primates. It is logical to discuss the role of PCMV in limiting the survival, as well as the use of IVIg in treatment 26 . It is logical to ask the question of whether it was appropriate to use a donor with latent presence of PCMV: as stated above, the latency was not detected when the donor was selected.…”

“…24 The discussion is ongoing whether the dysfunction of the transplant was due to the reactivation of PCMV, 25 or due to injections with IVIg, because IVIg preparations can contain anti-pig antibodies. 26 The final study was at NYU Langone Transplant Institute in two brain-death individuals, conducted on June 16 and July 6, 2022. This study is thus far only documented in news media 27 and extensively on the website of the institution.…”