The cause of death of the world's first swine heart transplant patient was announced, or it may be related to infection with the porcine virus

On Jan. 7, Metz reported on a sensational and groundbreaking procedure— scientists and clinicians at the University of Maryland School of Medicine successfully transplanted a pig's heart into an adult patient with end-stage heart disease.

This is the first time in the history of world medicine that a pig heart has been successfully transplanted into the human body, and it is a milestone in the field of heart xenotransplantation. (For more information, see: World First!) The United States successfully transplanted "pig hearts" to living people, why did xenotransplantation choose pigs? ）

Unfortunately, on March 9, local time, the University of Maryland Medical Center released an obituary on its official website, announcing that David Bennett, the first patient to undergo pig heart transplant surgery, died 2 months after the operation.

Surviving for 2 months is not a long time alone, but it is undoubtedly a "medical miracle" for a patient with advanced heart disease who once relied on the in vitro life support system (ECMO) to maintain his life!

The obituary mentions that Bennett's condition began to deteriorate a few days ago. In a situation where he was clearly unable to recover, he eventually received palliative care. His son said he was very grateful to the hospital for providing his father with the last chance to survive and was honored to participate in this experimental treatment.

Image source: medicalxpress

However, in statements at the time, doctors did not give a clear cause of death for the patient.

In April, Bennett's then-attending physician, Dr. Bartley Griffith, revealed at the American Transplant Society's webinar that they had detected POBCD DNA in patients' hearts. On May 4, the MIT Technology Review also mentioned that the viral infection could most likely lead to a sudden exacerbation of Bennett's condition and even death.

Bugs not taken into account

Xenotransplantation refers to the fact that organ transplantation occurs between different species. However, due to the different species, xenotransplantation can easily trigger a strong immune response, triggering the rejection of the organ, resulting in the death of the transplant recipient. At the same time, pig organs often carry a variety of viruses, and direct transplantation is obviously not feasible.

With these factors in mind, these organ donor pigs had undergone 10 specific genetic modifications before birth, including knocking out 3 genes that "may cause immune rejection," inserting 6 human genes that "prevent blood from clotting in the heart," and knocking out 1 "overgrowth" gene. Not only does it reduce the immune response that the organs can produce, but it also does not carry any pathogens.

So the detection of porcine CMV in Bennett's heart is a very surprising thing. For now, Revivicol, a biotech company that designs and raises these genetically compiled pigs, has yet to publicly respond.

图源:MIT Technology Review

In fact, porcine CYTOME infection is an infectious disease between pigs, mainly invading the respiratory system of pigs, causing symptoms such as pneumonia and runny nose. There is currently no definitive indication of a transmission to humans.

Jay Fishman, a transplant infection specialist at Massachusetts General Hospital, also believes that the virus detected in Bennett's heart cannot infect human cells, and even if it spreads further, it will not pose a risk to humans.

Joachim Denner, from the Institute of Virology at the Free University of Berlin, however, disagrees. The fact that porcine cmUV does not infect healthy people does not mean that the virus does not damage organs and further trigger adverse reactions in patients.

Two years ago, Denner's team transplanted pig hearts into baboons. Experiments at the time showed that in the presence of viruses in donor pigs, the pigs transplanted to baboons could detect extremely high-capacity viruses in their hearts, and the baboons' life spanned only a few weeks. But in the absence of any infection, pig hearts transplanted into baboons can survive for more than half a year.

So, Denner argues, the same thing happens to people. Viral DNA was detected in Bennett's heart, possibly because pigs themselves carry porcine CMV, but were not detected.

"It's a latent virus that's hard to detect. If the U.S. team uses better detection methods, the virus could be detected and cleared. Unfortunately, the donor pigs were infected and the virus was transmitted through transplants. “

On April 20, Dr. Griffith said at a webinar of the American Transplant Society that the detection of swine virus in Bennett's heart was not a bad thing for xenotransplantation. If death is due to swine cytomegalovirus, it means that xenotransplantations that do not carry the virus can survive longer, and this infection can be prevented.

The true cause of death remains to be explored

Denner said Bennett's death could not be entirely blamed on the virus. "Don't forget that this patient is very sick. Maybe the virus played a role, but not the only reason. ”

Understanding the true cause of Bennett's death is of great implication for the development of xenotransplantation in the future. Without POV, could patients live longer? Is the virus infection the trigger, or is it the direct cause of death? At present, Dr. Griffith cannot give an accurate answer, and everything is still inconclusive.

Image source: medicalxpress

First of all, the transplanted pig heart did not fail due to immune rejection, and on the 34th day after the transplant, the heart was still beating strongly. This shows that scientists have passed the "first hurdle".

Next, dr. Griffith's team faced a "second hurdle" of using state-of-the-art blood tests to grasp the health of the pig's heart. This time, however, they had a minor oversight.

According to Dr. Griffith, on the 20th day after surgery, they detected very low levels of porcine CYTOV in the blood of patients, but at the time it was considered a detection error. Meanwhile, a special blood test takes about 10 days, during which time the virus has multiplied rapidly in Bennett's heart, triggering a "cytokine explosion."

Griffith recalled afterwards that Bennett did show signs of infection on the 43rd day after surgery, including difficulty breathing, loss of concentration, and reluctance to speak.

The "third hurdle" that doctors face follows, how to control the patient's immune system while fighting the infection?

Prior to this, porcine CMV infection had never been treated in humans. In the end, they decided to inject Bennett with a drug called cidofovir, which was originally intended to treat CYTOV infections in AIDS patients. Taking into account the patient's fragile immune system, the doctor also gave him an intravenous immunoglobulin.

Within 24 hours, Bennett's condition improved. However, a week later, the patient's condition deteriorated again and his heart began to fail. Bennett didn't survive two months, but the exploration was worth it.

Source: Xinhua News Agency

After reviewing the entire course of the disease, attending physician Dr. Griffith said, "I suspect that during an outbreak of inflammation, the patient develops a leak of capillaries, causing the heart to edema, which in turn transforms into fibrous tissue, ultimately causing severe and irreversible diastolic heart failure." ”

Fishman of Massachusetts General Hospital also believes that from the Bennett cases he has heard, the syndrome does look like it was caused by a virus.

Nevertheless, it is still too early to determine the cause of Bennett's death, and researchers are still doing further combing and exploring. In addition, the team of doctors is concerned that they have injected human antibodies into patients twice, which may be a wrong move. Those blood products contain antibodies that produce immune rejection in pigs, which can damage organs.

Although Bennett died, from his surgery, scientists were able to explore more information related to xenotransplantation, benefiting future patients, alleviating organ shortages, and saving more lives. As Bennett's son puts it, "Hopefully this story will be the beginning, not the end, of hope."

Bibliography:

https://www.technologyreview.com/2022/05/04/1051725/xenotransplant-patient-died-received-heart-infected-with-pig-virus/

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