7/23/13
by Nancy Walsh
Staff Writer, MedPage Today

A third instance of rabies transmission following organ transplantation has occurred, with a patient dying 18 months after receiving a kidney from a deceased donor who was not known to be infected with the rabies virus, researchers reported.

The extended incubation period was an unusual clinical feature because in the two previous episodes of transmission, all unvaccinated recipients developed symptoms within 6 weeks and died, according to Matthew Kuehnert, MD, of the CDC in Atlanta, and colleagues.

Also distinctive was the fact that three other individuals who received organs from the same donor remained asymptomatic and only developed rabies antibodies after post-exposure prophylaxis, the investigators wrote in the July 24/31 Journal of the American Medical Association.

Those previous cases had suggested “a high infectivity rate and an incubation period of approximately 6 weeks in unvaccinated immunosuppressed recipients of solid organs from donors with rabies,” according to the investigators.

However, in the present case, that pattern wasn’t followed. The organ donor was an apparently healthy male who had returned from a fishing trip and developed symptoms of nausea, vomiting, and paresthesias, and then seizures, altered mental status, dysphagia for liquids, and hemodynamic instability.

The presumed diagnosis at the time of death was ciguatera — a marine toxin found in certain reef fish — poisoning.

Family members reported no known exposure to rabies, and examination of the cerebrospinal fluid found no evidence of infectious disease.

Subsequent investigations determined that ciguatera poisoning was “extremely unlikely,” because of the water temperature, and the final diagnosis was severe gastroenteritis.

The recipient initially was diagnosed with sciatica when seen for hip pain radiating to the leg, but was subsequently hospitalized with symptoms including fever, diaphoresis, and abdominal pain in the region of the transplanted kidney.

Encephalopathy followed, along with hemodynamic instability, and death occurred 3 weeks after admission.

Serologic tests conducted shortly before he died found IgG and IgM antibodies to rabies virus as well as neutralizing antibodies to the virus in serum.

His family members indicated that he had no exposures to infected animals, so local authorities and the CDC conducted an investigation of the kidney transplant as a possible source of the infection.

It turned out that the donor had a history of exposure to wildlife, including trapping raccoons in North Carolina, and had been bitten twice by the animals, which were not available for rabies testing.

Only one previous case of rabies contracted from a raccoon bite has been reported, but they are the most commonly infected animal in the U.S.

Testing of retained serum and central nervous system (CNS) samples from the donor revealed encephalitis, necrosis of neurons, and intracytoplasmic inclusions in the cortex suggestive of rabies, along with viral antigens and RNA.

Gene sequencing of tissues from both donor and recipient revealed a 99.9% match of the N gene, and phylogenetic analysis traced the source as a single county in North Carolina, “confirming organ transplantation as the route of transmission,” the researchers reported.

None of the three asymptomatic patients developed rabies, which has raised questions “about mechanisms of rabies virus spread within a host, the cells and tissues in which the virus resides during lengthy incubation periods, and how the virus evades the immune system,” the investigators noted.

They suggested that contributing factors could include different immunosuppressive regimens in those patients following their transplants, the type of organ, and quantity of virus present, although the precise reasons remain uncertain.

“This transmission event provides an opportunity for enhancing rabies awareness and recognition and highlights the need for a modified approach to organ donor screening and recipient monitoring for infectious encephalitis,” they observed.

They called for a “standardized approach” to identify cases of infectious encephalitis among donors and for the establishment of a case definition with specific clinical criteria that could be used for screening.

“Concerted efforts to improve screening of donors with suspected encephalitis, to carefully consider risks and benefits of transplanting organs from these donors, and to better monitor transplant recipients for rapid recognition of infection may improve patient management and prevent further transmission,” Kuehnert and colleagues concluded.

In an accompanying editorial, Daniel Kaul, MD, of the University of Michigan in Ann Arbor agreed that improvements are needed in identifying donors with infections of the CNS.

However, he pointed out that there are obstacles to this, including the possibility of confounding causes of death such as head injury in some cases that obscured the presence of infection.

Kaul stated that wider educational efforts need to include all clinicians involved in the care of donors, including infectious disease, neurology, and critical care specialists.

“Although the risk of donor-derived disease is inherent in the process of organ transplantation and cannot be eliminated, raising awareness of the risk of using donors with undiagnosed CNS infection is the best way to reduce the occurrence of transmissions,” he observed.

And it’s also important to remember that far more people have died while awaiting a transplant than from transplant-related infections or malignancy, he noted.

“The number of people who died waiting for a transplant over the past 7 years is in the tens of thousands, and this type of case is extremely rare. You have to get the balance right,” Kaul said toMedPage Today.

• Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner