Transmission of rabies virus from an organ donor to four transplant recipients

Authors


Abstract

Background

In 2004, four recipients of kidneys, a liver, and an arterial segment from a common organ donor died of encephalitis of an unknown cause.

Methods

We reviewed the medical records of the organ donor and the recipients. Blood, cerebrospinal fluid, and tissues from the recipients were tested with a variety of assays and pathological stains for numerous causes of encephalitis. Samples from the recipients were also inoculated into mice.

Results

The organ donor had been healthy before having a subarachnoid hemorrhage that led to his death. Encephalitis developed in all four recipients within 30 days after transplantation and was accompanied by rapid neurologic deterioration characterized by agitated delirium, seizures, respiratory failure, and coma. They died an average of 13 days after the onset of neurologic symptoms. Mice inoculated with samples from the affected patients became ill seven to eight days later, and electron microscopy of central nervous system (CNS) tissue demonstrated rhabdovirus particles. Rabies-specific immunohistochemical and direct fluorescence antibody staining demonstrated rabies virus in multiple tissues from all recipients. Cytoplasmic inclusions consistent with Negri bodies were seen in CNS tissue from all recipients. Antibodies against rabies virus were present in three of the four recipients and the donor. The donor had told others of being bitten by a bat.

Conclusions

This report documenting the transmission of rabies virus from an organ donor to multiple recipients underscores the challenges of preventing and detecting transmission of unusual pathogens through transplantation. (Liver Transpl 2005;11:1295–1297.)

Srinivasan A, Burton EC, Kuehnert MJ, Rupprecht C, Sutker WL, Ksiazek TG, et al. Transmission of rabies virus from an organ donor to four transplant recipients. N Engl J Med 2005; 352: 1103-1111.

Comments

Srinivasan et al. reported on transmission of rabies from a common donor whose liver and 2 kidneys were transplanted to 3 recipients. A fourth recipient who received the donor's iliac artery segment for a liver transplant vascular graft procedure also acquired infection.1 (In addition, a fifth patient received lungs harvested from the same donor, but he died of intraoperative complications.)

All 4 transplant recipients developed altered mental status (confusion, agitation, tremors, and delirium) 20 to 30 days after transplantation. Mechanical ventilator support was required soon thereafter, and the patients died an average of 13 days (range, 7-23 days) after neurologic symptoms appeared.

The organ donor, a 20-year-old man, had been seen at hospital emergency departments with complaints of nausea, vomiting, abdominal pain, and difficulty swallowing, rapidly progressing to include confusion and agitation and truncal ballistic movements.1, 2 Soon after hospital admission, he developed tachycardia and hypertension. A small subarachnoid hemorrhage was demonstrated by brain computed tomography, and toxicologic evaluation revealed the presence of cocaine and marijuana. Seizures, coma, and hyperpyrexia followed. A repeat computed tomography study demonstrated a large subarachnoid hemorrhage and brain herniation. He was declared brain dead 92 hours after hospital admission. It was only upon postmortem investigation that the patient's friends mentioned that he had previously reported being bitten by a bat.

Detailed postmortem laboratory studies revealed that the donor's serum contained rabies immunoglobulin G and immunoglobulin M antibody and that rabies virus was present in recipients' brain and spinal cord tissue. Sequencing data indicated that rabies virus isolates in all recipients were identical3 and antigenic typing demonstrated a bat-variant associated strain of rabies virus.

Although rabies virus has been transmitted by corneal transplants,4 this is the first report of transmission by solid organ or vascular tissue transplantation. Very recently, similar transmission of rabies to at least 3 recipients has been reported in Germany.5

Rabies Virus

Rabies virus, a rhabdovirus (derived from the Latin rabere, to rave) in the genus Lyssavirus, is a bullet-shaped, single negatively stranded RNA virus. Six other members of the Lyssavirus genus are recognized but rarely cause human disease.

In most cases, rabies virus in an infected animal's saliva is introduced into a wound at the time of a bite, or more infrequently by salivary contamination of an open wound or abrasion. The virus spreads centripetally from nerve endings in muscle or skin to the central nervous system; after intraneuronal replication it then disseminates centrifugally to other organs. Rarely, infection may be acquired by inhalation of airborne virus-laden particles, for example in cave explorers or after accidental laboratory exposure.

The incubation period of rabies is from 1 to 3 months, but it may be as long as several years, depending on inoculum size and wound location and severity. Approximately 80% of infected individuals develop the furious or encephalitic form of disease; in the remainder a paralytic or dumb form occurs, mimicking Guillain-Barré syndrome. Death typically follows within 2 weeks. Survival following rabies infection has been reported in only 6 human cases.6

Epidemiology and Ecology of Rabies

In the United States, human infection is rare. Only 55 cases have occurred in the last 25 years.2 The disease is endemic throughout Africa, Asia, Latin America, and the Indian subcontinent.

Although human rabies infection is not prevalent in the United States, animal infection is still a concern. In recent years, a dramatic decrease in rabies among domestic animals has been offset by an increase in wildlife disease. Among over 7,000 cases in animals in 2003, infection was present in wild animals in the vast majority (raccoons, 36.7%; skunks, 29.4%; bats, 16.9%; foxes, 6.4%); dogs, cats, and other domestic or farm animals constituted only 8.6% of known cases.7

The high prevalence of animal rabies in Mexico is of particular concern because of the large numbers of individuals migrating between that country and the United States. Transplant surgeons who make decisions about the suitability of potential donors should therefore obtain a detailed travel history and inquire about possible animal exposure (see “Implications for Organ Transplantation”).

Particularly sobering is the fact that in the United States, no definite animal exposure could be identified as a source of many human cases. Among 32 cases in the United States from 1980 to 1996, 25 (78%) could not be traced to a specific animal exposure. Molecular studies, however, found that insectivorous bats were the probable source in many of these cases, suggesting that many bat exposures are unrecognized.8 In the same report, it was noted that the diagnosis of rabies was often not considered prior to death, as was the case in the 4 patients described by Srinivasan et al.2

Unresolved Questions in Rabies Transmission

Our understanding of the pathogenesis of rabies infection focuses on intraneuronal spread of virus, but clearly the virus enters animal saliva to transmit infection in the nature. The transplant-associated cases raise the question of where in the transplanted organs the virus was sequestered. The possibility of blood transmission, perhaps through circulating or intravascular macrophages, must be considered.

Laboratory experiments in mice demonstrated that the virus is able to replicate in macrophages and possibly can remain latent.9 This may explain cases of rabies that occur many years after an animal exposure.10 Moreover, strains unique to specific animals may possess unique tissue or cell tropism. Morimoto and colleagues found that 2 different strains of the virus, the coyote street rabies virus and the silver-haired bat variant rabies virus, showed similar tropism when injected into mouse brain, but when injected intramuscularly or intranasally, the bat strain was less neuroinvasive.11 The bat strain had an affinity for fibroblasts and epithelial cells, permitting it to replicate locally in the skin and then to penetrate nerves.11

Implications for Organ Transplantation

Since the initial description of rabies transmission by corneal transplantation in 1979, 7 additional cases have been reported from other countries.4 The corneal donor in the U.S. case died of flaccid paralysis of unclear etiology, and rabies developed in the corneal transplant recipient 4.5 weeks later.12

Unsuspected rabies was also present in the donor reported by Srinivasan et al.1, 2 The donor sought medical attention several times before being admitted to the hospital, and even then rabies was not suspected because of misleading details in the patient's history and in-patient evaluation. Toxicology studies indicated presence of cocaine and marijuana, and brain computed tomographies demonstrated an expanding subarachnoid hemorrhage.

In the cases reported from Germany, the donor had spent time in India and showed no signs of rabies infection.5

Although these cases illustrate the potential for transmission of infectious agents by organ transplantation, Burton et al. have noted that even if the number of human cases in the United States increased 100-fold, the risk of rabies transmission by organ transplantation would be less than 1 in 1012.2

Should organ transplantation from a rabies-infected donor occur, prompt preventive treatment with rabies vaccine and rabies immune globulin is indicated. Recipients of transplanted organs and any healthcare workers exposed to saliva or other potentially virus-laden secretions or tissue should receive prophylaxis in accord with current guidelines.4 In fact, in the current report, postexposure prophylaxis was given to 174 individuals who were assessed and had a contact with the organ recipients and the donor.13 Once symptoms of infection occur, there is no known effective treatment. A recent report of a survivor of rabies infection received ketamine, midazolam, ribavirin, and amantadine along with induced coma, but such treatment must be considered experimental at this time.6

The small likelihood of transmission should not detract from the fact that rabies is almost universally fatal. Can careful donor screening measures prevent transplant-associated rabies in the future? So far as we are aware, there are no formal recommendations to screen all donors for the presence of rabies antibody. Canadian procedures call for screening for human immunodeficiency virus, hepatitis B, human T-lymphotropic virus, Epstein-Barr virus, cytomegalovirus, and syphilis.14 A compulsory questionnaire asks whether the donor has sustained a previous bat bite. In the United States, United Network for Organ Sharing guidelines leave donor acceptance criteria to the discretion of individual organ procurement organizations.15 At the very least, in view of these recent cases of rabies transmission, transplant physicians should evaluate potential donors' travel histories and include questions concerning animal (and particularly bat) exposures as part of the screening procedure. Potential donors with unexplained mental or neurologic symptoms should be evaluated carefully for the possibility of central nervous system infection.

Ancillary