Raccoon rabies virus variant transmission through solid organ transplantation

Abstract

Importance: The rabies virus causes a fatal encephalitis and can be transmitted through tissue or organ transplantation. In February 2013, a kidney recipient with no reported exposures to potentially rabid animals died from rabies 18 months after transplantation.

Objectives: To investigate whether organ transplantation was the source of rabies virus exposure in the kidney recipient, and to evaluate for and prevent rabies in other transplant recipients from the same donor.

Design: Organ donor and all transplant recipient medical records were reviewed. Laboratory tests to detect rabies virus-specific binding antibodies, rabies virus neutralizing antibodies, and rabies virus antigens were conducted on available specimens, including serum, cerebrospinal fluid, and tissues from the donor and the recipients. Viral ribonucleic acid was extracted from tissues and amplified for nucleoprotein gene sequencing for phylogenetic comparisons.

Main outcomes and measures: Determination of whether the donor died from undiagnosed rabies and whether other organ recipients developed rabies.

Results: In retrospect, the donor's clinical presentation (which began with vomiting and upper extremity paresthesias and progressed to fever, seizures, dysphagia, autonomic dysfunction, and brain death) was consistent with rabies. Rabies virus antigen was detected in archived autopsy brain tissue collected from the donor. The rabies viruses infecting the donor and the deceased kidney recipient were consistent with the raccoon rabies virus variant and were more than 99.9% identical across the entire N gene (1349/1350 nucleotides), thus confirming organ transplantation as the route of transmission. The 3 other organ recipients remained asymptomatic, with rabies virus neutralizing antibodies detected in their serum after completion of postexposure prophylaxis (range, 0.3-40.8 IU/mL).

Conclusions and relevance: Unlike the 2 previous clusters of rabies virus transmission through solid organ transplantation, there was a long incubation period in the recipient who developed rabies, and survival of 3 other recipients without pretransplant rabies vaccination. Rabies should be considered in patients with acute progressive encephalitis of unexplained etiology, especially for potential organ donors. A standard evaluation of potential donors who meet screening criteria for infectious encephalitis should be considered, and risks and benefits for recipients of organs from these donors should be evaluated.

Figure 1.

Clinical Course of the Transplant Recipients Who Received Solid Organs From a Donor With Rabies RVNAs indicates rabies virus neutralizing antibodies.

Figure 2.

Histopathologic Features of Rabies Encephalitis in the Deceased Kidney Recipient and Organ Donor A, Midbrain of the deceased kidney recipient showing diffuse microgliosis and mixed inflammatory cell infiltrates (hematoxylin-eosin, original magnification ×50). B, Intracytoplasmic inclusion typical of rabies in a neuron in the hippocampus of the deceased kidney recipient (hematoxylin-eosin, original magnification ×158). C, Rabies virus–infected neurons in the midbrain of the deceased kidney recipient (immunohistochemical [IHC] staining; immunoalkaline phosphatase stain, naphthol-fast red substrate [chromogen] with hematoxylin counterstain, original magnification ×100). D, Encephalitis in the donor characterized by perivascular lymphocytic cuffing, microglial proliferation, and neuronal necrosis (hematoxylin-eosin, original magnification ×50). E, Intracytoplasmic inclusions typical of rabies in cerebral neurons of the donor (hematoxylin-eosin, original magnification ×100). F, Widespread IHC staining of rabies virus antigen in cerebral neurons of the donor (immunoalkaline phosphatase stain, naphthol-fast red substrate [chromogen] with hematoxylin counterstain, original magnification ×100).

Figure 3.

Phylogenetic Reconstruction of the Rabies Viruses Infecting the Deceased Kidney Recipient and Donor The N gene sequences of the rabies viruses infecting the deceased kidney recipient and donor are shown in relation to N gene sequences of common rabies virus variants circulating in the United States. The phylogenetic reconstruction was generated with the neighbor-joining method under the maximum composite likelihood model to estimate nucleotide substitutions. The bootstrap method with 1000 iterations was used to assess the confidence of the branching pattern (numbers at the nodes). Branches are color coded according to reservoir host, with triangles representing collapsed branches with a common origin. The Duvenhage virus was used as an outgroup to better visualize the evolutionary relationships among rabies virus clades. Independent geographic foci associated with the raccoon rabies virus variant circulating in the eastern United States, in black, are shown along with the corresponding state (2-letter abbreviations). Enclosed in the rectangle on the left is a magnified projection showing the topology of the collapsed North Carolina cluster, which includes sequences obtained from various rabid animals, the deceased kidney recipient, and the donor.