A leading cause of chronic liver disease in the U.S., transmission of HCV to transplant patients poses a small but real threat to recipients. Although transplant centers follow strict serum screening requirements, transmission of HCV via organ donation can spread the disease to several patients. In fact, an HCV antibody-negative donor may be HCV RNA-positive and pass the disease on to the transplant recipient. But the donor’s status would not be known unless nucleic acid testing, in addition to standard anti-HCV screening, was performed prior to the transplant procedure. However, costs associated with making this testing routine can be prohibitive to many hospitals and transplant centers. This issue of Strategies takes a closer look at one case of HCV transmission through transplantation that may suggest a need for FDA-mandated nucleic acid screening.
A recent study in the Annals of Internal Medicine (2005; 143(9):648-654) described an unusual case of an anti-HCV-negative organ and tissue donor who was the source of HCV infection in multiple transplant recipients. The donor—a man in his 40s with no signs of liver disease—died of an intracranial hemorrhage in October 2000. His pre-mortem serum had tested anti-HCV-negative with a second-generation enzyme immunoassay. Over the course of the next two years, forty people received transplants from this donor, eight of whom later developed HCV infection with viral isolates related to those of the donor.
Barna D. Tugwell, MD, of the Division of General Medicine at the Queen Elizabeth II Health Sciences Centre (Halifax, Nova Scotia) and lead author of the study, said that the donor was properly screened and his risk factors evaluated to the best of the organ procurement agency’s ability. Still, the HCV infection was missed because the donor was probably in the 8- to 10-week “window period” of infection before the development of detectable anti-HCV. “The blood screening was done appropriately, but it simply did not pick up the infection,” Tugwell said. “Performing an HCV RNA test may have prevented transmission, but nucleic acid testing is not currently required by the FDA.”
Making a Case for “Stat” Nucleic Acid Testing
Tugwell points out that HCV nucleic acid testing in post-mortem serum is not standard procedure for organ and tissue donors, as the FDA only recently approved a nucleic acid test for use in such specimens. But the donor could have been tested for HCV RNA after brain death. “After brain death, the organs were being sustained in preparation for donation, so theoretically an RNA test could have been done during that time,” Tugwell said. “But because the test is not required and it takes one to two days to complete, it was probably impractical when they were trying to recover and transplant the organs within a limited window of opportunity.”
Three of the eight individuals infected in this case were organ recipients, and given the time constraints for organ transplantation, Tugwell says that those infections were probably not preventable. But she believes that the five people who acquired HCV through tissue transplantation—performed many months later—might have had their infections prevented had nucleic acid testing been performed.
D. Robert Dufour, MD, Chief of Pathology at the Veteran’s Administration Medical Center in Washington, DC, says that while the absence of a “stat” RNA test presents a major barrier to routine testing, improved speed in nucleic acid testing is theoretically possible and new instrumentation may be on the horizon to speed the process. He cautions, however, that cost and complexity will likely make stat testing difficult in most settings.
“While new automated methods for measuring HCV RNA will probably become available in the next few years, the cost may be prohibitive to most hospitals, even to transplant centers,” Dufour said. “The new instrumentation is likely to be used only by facilities that do a large volume of testing, such as blood centers.” He explained that most nucleic acid testing methods involve a number of cycles, so that even state of the art tests—like a real-time polymerase chain reaction (PCR)—are lengthy processes which require a lot of “hands-on” work before being placed on an instrument. At least for the foreseeable future, then, stat nucleic acid testing may not be a practical alternative to current methods.
A Rare Occurrence
According to a 2004 study in the New England Journal of Medicine (2004; 351:751-759), the probability of undetected viremia with HCV in antibody-negative tissue donors is 1 in 42,000, although the actual rate of transmission remains unknown since most tissues undergo processing—such as irradiation—to reduce the risk of infection. That study demonstrated that the probability of viremia with HCV would be reduced to 1 in 421,000 donors if nucleic acid testing were performed on individual donors. The cost of eliminating one HCV-infected donor would be $2.3 million, a price tag that Dufour says compares favorably to the cost of performing nucleic acid testing in blood donors in order to prevent HCV infection. Although the FDA does not require nucleic acid testing for HCV in organ donors as they do for blood donors, Dufour suggests that the regulatory requirements are likely to change in the coming years. Organ procurement organizations are also studying the role of HCV nucleic acid testing in donors, although they are very concerned that the speed of the recovery process not be sacrificed. Paul Morrissey, MD, past chairman of the Organ Procurement Organization (OPO) committee of the United Network for Organ Sharing (UNOS), says that while there are obvious advantages to requiring nucleic acid testing in all organ donors, there are many practical hurdles to overcome.
“Only a small number of transplant centers currently perform nucleic acid testing and most of those do not do it around the clock,” he said. “In some cases you might have to fly the organs halfway across the country in the middle of the night to a center that can test them, and then wait for results before you can place all the organs in different recipients. It becomes quite cumbersome.” Morrissey confirms, however, that the subject has been of increasing interest to UNOS, and the organization would like to get OPOs throughout the country organized in support of broader access to nucleic acid testing and the development of a stat nucleic acid test. In support of that goal, he encourages laboratorians who have experience with nucleic acid testing or an interest in HCV to contact UNOS with recommendations about how to best implement nucleic acid testing in transplant centers.
Interested laboratorians should contact Hilary Kleine of UNOS at email@example.com.
Richard Pizzi is the Editor of Clinical Laboratory News. He can be reached by email.