A complex array of factors contributed to the death of the first human recipient of a genetically modified pig heart, but the surgeon-scientists behind the historic procedure say the lack of evidence for organ rejection raises hopes for the future of xenotransplantation.
Performed on January 7 at the University of Maryland School of Medicine (UMSOM), the surgery was the only available treatment option for 57-year-old David Bennett, who did not qualify for a traditional heart transplant and was in end-stage heart failure. The surgery was considered an early success because the patient lived for two months with a strong functioning heart showing no obvious signs of rejection, according to a new paper published recently in the New England Journal of Medicine.
Within days of the transplant, Mr. Bennett was weaned from extracorporeal membrane oxygenation (ECMO) and he went on to participate in active rehabilitation for nearly two months.
“We were incredibly encouraged by his progress. His heart was strong, almost too strong for his frail body, but he had a strong will to live,” says study co-leader Bartley Griffith, MD, Professor of Surgery and The Thomas E. and Alice Marie Hales Distinguished Professor in Transplantation at UMSOM.
The transplanted pig heart functioned well for several weeks and displayed none of the typical signs of rejection by the patient’s body, even when it was carefully examined during an autopsy, according to the analysis in the paper.
“We are very encouraged by this finding, and it suggests that the genetically-modified pig heart and the experimental drug we used to prevent rejection worked effectively in tandem to demonstrate that xenotransplants can potentially save future lives,” says study co-leader Muhammad M. Mohiuddin, MD, Professor of Surgery and Scientific/Program Director of the Cardiac Xenotransplantation Program at UMSOM.
The study found that several factors may have ultimately contributed to Bennett’s death, including the use of intravenous immunoglobulin, IVIG, a drug that was given to the patient twice during the second month after the transplant to help prevent rejection and infection. The drug contains antibodies against pig cells that may have interacted with the pig heart, causing a reaction that damaged the heart muscle. The heart was also found to contain evidence of DNA from a latent pig virus called porcine cytomegalovirus (pCMV) through highly sensitive testing that was first detected several weeks after the surgery and was later confirmed during autopsy of the organ.
The ongoing investigations have yet to find evidence that the virus caused an infection in the patient or infected any tissues or organs beyond the heart. Whether the latent virus caused damage to the transplanted heart, contributing to the heart failure, remains under investigation. “We consider this to be an important learning experience,” Mohiuddin adds. “Knowing what we know now, we will alter some of our practices and techniques in the future.”
About 110,000 Americans are currently waiting for an organ transplant, and more than 6,000 patients die each year before getting one, according to the federal government’s organdonor.gov. Xenotransplantation potentially could save thousands of lives, but it does carry a unique set of risks, including the possibility of triggering a dangerous immune response that can cause the body to reject the organ.
“Our findings on autopsy did not show evidence of rejection,” said Dr. Griffith, who is also the Clinical Director of the Cardiac Xenotransplantation Program at UMSOM. “Instead, we saw a thickening and later stiffening of the heart muscle leading to diastolic heart failure, which means the heart muscle was not able to relax and fill the heart with blood as it is supposed to.”
Before the surgery, infection control measures were carefully followed to help safeguard against known pig pathogens. The donor pig was raised in a facility using methods designed to prevent pCMV and other potential pathogens from infecting donor animals. The healthy donor pig used for the xenotransplant was screened for pathogens multiple times. It was tested just before shipment to Maryland, and just before the transplant a few days later, protocols that were accepted by the FDA.
“As a prerequisite of FDA emergency authorization, we put together a hospital infection prevention plan to safeguard against the transmission of any known or unknown porcine pathogens to hospital staff and other patients,” said study co-author Kapil Saharia, MD, MPH, Assistant Professor of Medicine at the Institute of Human Virology at UMSOM. The plan included special isolation procedures, use of personal protective equipment, special handling of patient samples, and sequestration of medical instruments and equipment used for invasive procedures. “These practices remained in place for physicians and hospital staff while Mr. Bennett was treated at the University of Maryland Medical Center,” said Dr. Saharia, who is also Chief of Solid Organ Transplant Infectious Diseases Service at UMMC.
As plans move forward for future clinical trials, more sophisticated testing techniques are being developed and validated to ensure that this virus or any other does not go undetected.