College of American Pathologists
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Transplantation nightmare: Four deaths, one culprit, countless questions

September 2004
Lauren Phillips

The transplants went well: On May 4, 2004, three patients at Baylor University Medical Center in Dallas received what they hoped would be life-saving organs—a liver and two kidneys—from a single 20-year-old Arkansas donor who had died of a subarachnoid hemorrhage. The next day, a fourth patient received a liver transplant from a different donor, along with a segment of iliac artery from the Arkansas donor, which had been harvested and stored for future use. Within six weeks, all four recipients would be dead of rabies, the first confirmed cases of rabies transmission through solid organ transplantation.

On June 8, the day after the first death, Elizabeth C. Burton, MD, Baylor’s director of autopsy pathology, was looking for an answer to what caused the death of the man before her, who had returned to the hospital with tremors, lethargy, and anorexia 24 days after receiving a liver transplant.

Neural imaging performed in the two weeks between his readmission and death had raised concerns about encephalitis and meningitis, so Dr. Burton took a small section of the brain and drew cerebrospinal fluid and had the lab perform viral, fungal, mycobacterial, and bacterial cultures. "But it all came back negative," she says. "We weren’t able to rule out anything." Although serology testing while the man was hospitalized was negative for West Nile virus, Dr. Burton hadn’t ruled that out either.

It would be almost a month before nonspecific cerebral edema was replaced as a final diagnosis not with West Nile or any of the other emerging diseases that are top of mind today, but with rabies—"one of the oldest infectious diseases that we know about and one about which we still have things to learn.

"People say, ’Ah, tremors, lethargy, rapid neurologic deterioration—these are classic symptoms of rabies.’ But they’re not because there’s a huge differential that the clinicians have to look at," Dr. Burton says. Rabies, which had killed five people in the United States in the previous two years, was at the bottom of the list.

The mystery only deepened, the morning after that first autopsy, when Dr. Burton learned there were two other patients in the hospital who had received transplants from the same donor, both with similar CNS-related symptoms, and the second patient had just died. "At that point, I had alarms going off. I immediately thought there’s something infectious and it’s probably common to all three of these patients," she says.

She called a local neuropathologist, whom she enlisted as a consultant, and then a pathologist at the Centers for Disease Control and Prevention. The CDC quickly assembled a team—pathologists, virologists, epidemiologists—to look into the cases. By the time the second patient’s autopsy was begun, communication had been established among the CDC, Baylor’s head of transplantation, the attending physician on two of the cases, and the Texas Department of Health. "What happened here in terms of communication and teamwork—probably within five hours or so—is just phenomenal," Dr. Burton says.

She handled the second autopsy differently. "We actually took out spinal cord, which is not something you usually do." They also froze slices of fresh brain tissue and separately placed smaller portions of the brain in formalin fixative so that they could look at slides sooner.

She and her CDC colleagues decided her next move should be to ask the clinical pathologist to hold all of the fluids drawn while the transplant patients were alive (they’re generally retained for about seven days) in case further tests were needed. And, to help the third patient, who was still alive, she arranged for the clinical pathologist to send some of his fluids to a CDC laboratory in Colorado where serology and cultures would be done.

While Dr. Burton was away for the weekend, a case came in for autopsy of a liver transplant recipient who had died from an "encephalitis-type picture," Dr. Burton says. Since no one knew that the liver transplant had included a vessel from the Arkansas donor, no one connected it with the other three transplant cases under investigation. "It got handled pretty much routinely," Dr. Burton says. "Except that my fantastic autopsy assistant, who is really on the ball and knew that West Nile was suspected in this case, said, ’You know, Dr. Burton would probably freeze a little bit of that brain tissue.’" Which they did. At the time, however, little further thought was given to this case.

Not long after, the pieces of the brain from the second patient were sufficiently fixed to be examined microscopically. "What we saw," Dr. Burton says, "was an encephalitis with a lot of ischemic injury. This knocks out the neurons, which makes it really hard to see Negri bodies." It is also hard to see what you aren’t looking for, she says ruefully.

"So we were basically working as fast as we could, before and after the third patient died, looking at neurotropic viruses, discussing the cases daily, and sending the CDC an unbelievable number of specimens, over 100 specimens—wet tissue, frozen tissue, all kinds of fluids. And all the testing is coming up negative.

"At one point, I suggested to the CDC pathologist that we do electron microscopy on the brain tissue and have someone who is good at looking at virus structures look at it, because they may be able to look at the morphology of the virus by EM, and that would give us a clue as to where to focus our testing again."

And then the turning point: Suckling mice that had been inoculated at the CDC with brain tissue from one of the kidney recipients developed symptoms and died. Electron microscopy was done, and there it was—rabies—in the brains of the mice.

"Now that we had something definite to look for," Dr. Burton says, "we were able to confirm the diagnosis in all three of the patients with multiple types of testing," including direct fluorescent antibody and immunohistochemical stains specific for rabies. "I’ve gone back and studied these cases and you can see the Negri bodies in some of the neurons on the hematoxylin-and-eosin-stained sections. They were there all along. We just hadn’t been looking for them."

The final piece of the puzzle fell into place when the CDC confirmed the presence of rabies antibodies in the organ donor’s serum, which had been frozen as a matter of routine, and the Arkansas Department of Health determined he had been bitten by a bat. "So whether his subarachnoid hemorrhage was the result of the rabies we don’t know for sure," Dr. Burton says. CDC experts, though they admit they’re uncertain, think it’s unlikely.

One week later she would see those Negri bodies again. While reviewing all pending autopsy cases in which patients had died within the same period as the three known rabies victims, Dr. Burton came upon the suspected West Nile case that had been autopsied in her absence. After getting together with the pathologist who did that autopsy and reviewing the CNS slides, she says, "I saw inclusions that I thought were very suggestive of Negri bodies."

Having no idea that this fourth patient had a connection to the Arkansas organ donor, Dr. Burton was worried about a possible nosocomial infection. "I went down to the lab and pulled some CSF from when the patient was still alive, and I had some frozen tissue and blood and other fluids." She worked with the CDC staff to have the specimens flown to the CDC in Atlanta that same day, where rabies experts worked into the night. "It was after midnight when they called me back to say it was rabies in this case, too."

As they became aware of this fourth case, the CDC assembled an on-site team to help determine the mode of transmission and to help with the ongoing risk assessment of those who might have been exposed to one of the four recipients or to the donor, who had variously been at home or in hospitals in Texas, Arkansas, Oklahoma, and Alabama before they died. (The donor’s lungs had been transplanted into a patient in an Alabama hospital, who died of intraoperative complications.) With hospitals and health departments in four states on board, as well as the organ procurement organizations, Dr. Burton says, "it just snowballed." Later that day, surgeons reviewed the hospital record for the case and realized that they had, in fact, used a segment of iliac artery from the same Arkansas donor whose organs were transplanted into the first three patients.

In light of the unusually large amount of antigen found in one of the transplanted kidneys, suggesting that these immunosuppressed patients might have taken on an unusually large viral load, the CDC added bile, urine, and other fluids to the risk-assessment criteria, which are normally limited to exposure to saliva. "They’re just being more cautious with this because we haven’t unraveled everything," Dr. Burton explains.

By July 9, postexposure prophylaxis had been initiated in about 174 people, or 19 percent of the nearly 1,000 people who had been assessed.

For the larger transplant community important questions remain, among them the mechanism of transmission. How did the virus get from the solid organs of the donor to the central nervous system of the recipients?

At this point, no one can say for sure. Arjun Srinivasan, MD, a medical epidemiologist in the CDC’s Division of Healthcare Quality Promotion, was a member of the team that worked on the cases. It’s possible, he says, "that the virus is present in the transplanted organs, and perhaps gets taken up by the surrounding neurons in the recipients, which may be especially likely given that surrounding neurons may suffer minor damage during the transplantation procedure."

In the case of the fourth patient, who received the iliac artery segment, Gregory J. Davis, MD, professor in the Department of Pathology and Laboratory Medicine at the University of Kentucky College of Medicine and associate chief medical examiner of the Commonwealth of Kentucky, speculates that rabies was transmitted via the nerves that travel along the blood vessel.

The team at the CDC is continuing to study the specimens from all four cases.

Meanwhile, transplant professionals are beginning to address some of the other issues the events at Baylor raised. With all four recipients transplanted at the same hospital, it was possible for physicians to make the critical connections sooner. "If all four of those organs had gone to four different hospitals," Dr. Burton says, "it would have been much more difficult to tie all this together." Of course, the connection to the fourth victim, the person who received only a vessel and not an organ from the Arkansas donor, was not made until the last moment.

This underscores the need for a system, equivalent to the one that tracks organs, to track vessels such as that iliac artery that are set aside for future use, Dr. Burton says. Dr. Davis, vice chair of the CAP’s Forensic Pathology Committee, agrees: "Tracking where human tissue comes from makes perfect sense to me because that is the only way you’re going to be able to do an epidemiologic study of this nature."

More compel ling but more problematic is the issue of autopsy for organ donors. Says Dr. Burton, "This case is a prime example of how important autopsies are, what their value is in public health, in quality of care, and in process improvements." That the Arkansas donor wasn’t autopsied tells her that Baylor’s policy of requiring or at least encouraging autopsies of organ donors is a good one. "We do it as a matter of routine here," she says of patients who die within her institution, citing an arrangement whereby her autopsy service performs donor autopsies at the request of the Southwest Transplant Alliance.

Many members of the CAP Autopsy Committee are of the opinion that organ donors should be autopsied routinely. "That would be the ideal situation," says committee chair Kim Collins, MD, of the Department of Forensic and Autopsy Pathology, Medical University of South Carolina, Charleston. "In a perfect world, it would be so advantageous to autopsy all of the donors."

Says Dr. Davis, "I think the routine autopsy of individuals who are deceased and who become organ donors should be standard across the nation." Instead, every jurisdiction in the U.S. is different. "In some places there may be a pro forma autopsy done in all cases where a person is an organ or tissue donor, but in other states, even other counties within a single state, that might not be the case," Dr. Davis says. The National Association of Medical Examiners, the American Academy of Forensic Sciences, and the CAP are working to standardize the heterogeneous laws, he adds, though some heterogeneity will be inevitable because different areas of the country have different levels of resources.

Also standing in the way of uniform laws are the lack of reimbursement for the autopsy, younger physicians’ lack of familiarity with the procedure, and clinicians’ misconception that high-technology testing leaves nothing to be discovered through autopsy. In reality, says Dr. Davis, 25 to 40 percent of autopsies show diagnostic discrepancies. "That’s why we do them in the first place."

In the case of this Arkansas organ donor, it is unlikely that autopsy would have picked up the rabies infection, says the CDC’s Dr. Srinivasan, since subarachnoid hemorrhage has never been reported in autopsies or on brain imaging of patients with rabies.

However, he adds, "We can see that it was the autopsies of the recipients that led to the diagnosis in this case. So there is a suggestion there that autopsies of organ donors may have a role in improving overall organ safety."

The Organ Procurement and Transplantation Network and the United Network for Organ Sharing have issued a statement that, in light of the recent events at Baylor University Medical Center, "transplant professionals will revisit existing screening procedures to identify any means of further reducing the risk of disease transmission." Dr. Srinivasan hopes that such a review will not focus exclusively on rabies. "I think the more important question is, Are there ways to improve the overall detection of potential infectious diseases?"

This could include adding more pointed questions about exposure to bats to donor-screening protocols, something that might have prevented the deaths of the four transplant recipients at Baylor. It could include moves toward fostering greater communication between organ procurement organizations and those who implant the organs, something the physicians interviewed for this story believe is critical. It should not, they say, include adding rabies to the list of diseases for which donors are routinely tested. "We can’t test for everything," Dr. Burton says. "It’s not logical or cost-effective."

Troubling issues, no easy answers. And nothing routine. "It’s amazing to me," Dr. Burton says, "that you take one of the oldest infectious diseases we know about and we put it in this whole different setting and it becomes so complex. But it’s still there, and we’re learning more about rabies."

Lauren Phillips is a writer in Bellingham, Wash.