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original article
Transmission of Rabies Virus from an Organ
Donor to Four Transplant Recipients
Arjun Srinivasan, M.D., Elizabeth C. Burton, M.D., Matthew J. Kuehnert, M.D.,
Charles Rupprecht, V.M.D., Ph.D., William L. Sutker, M.D.,
Thomas G. Ksiazek, D.V.M., Ph.D., Christopher D. Paddock, M.D.,
Jeannette Guarner, M.D., Wun-Ju Shieh, M.D., Ph.D., Cynthia Goldsmith, M.S.,
Cathleen A. Hanlon, V.M.D., Ph.D., James Zoretic, M.D., Bernard Fischbach, M.D.,
Michael Niezgoda, M.S., Waleed H. El-Feky, M.D., Lillian Orciari, M.S.,
Edmund Q. Sanchez, M.D., Anna Likos, M.D., M.P.H., Goran B. Klintmalm, M.D.,
Denise Cardo, M.D., James LeDuc, Ph.D., Mary E. Chamberland, M.D., M.P.H.,
Daniel B. Jernigan, M.D., M.P.H., and Sherif R. Zaki, M.D., Ph.D.,
for the Rabies in Transplant Recipients Investigation Team*
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.
From the Divisions of Healthcare Quality
Promotion (A.S., D.C., D.B.J.) and Viral and
Rickettsial Diseases (M.J.K., C.R., T.G.K.,
C.D.P., J.G., W.-J.S., C.G., C.A.H., M.N., L.O.,
J.L., M.E.C., S.R.Z.), National Center for Infectious Diseases, and the Epidemic Intelligence Service Branch, Division of Applied
Public Health Training, Epidemiology Program Office (A.L.), Centers for Disease Control and Prevention, Atlanta; Baylor University Medical Center, Dallas (E.C.B., W.L.S.,
B.F., W.H.E., E.Q.S., G.B.K.); and the Texas
Department of State Health Services, Austin (J.Z.).
* Members of the Rabies in Transplant Recipients Investigation Team are listed in
the Appendix.
N Engl J Med 2005;352:1103-11.
Copyright © 2005 Massachusetts Medical Society.
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.
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1103
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r
abies is an acute encephalitis
caused by viruses in the genus Lyssavirus, family Rhabdoviridae, that is nearly
uniformly fatal in unvaccinated hosts. Although the
virus is present in animal reservoirs, infection in humans is rare in the United States, with only two cases reported in 20031,2 and no more than six cases
reported in any year in the past decade.3 The primary
mode of transmission is through the bite of an infected animal, most commonly a bat in the United
States.4 Although transmission of rabies virus from
corneal transplants has previously been described,5
to our knowledge, no cases ascribed to organ or vascular-tissue transplants have been reported.
In May 2004, physicians at a hospital in Texas
diagnosed encephalitis in three recipients of a liver and two kidneys from a common organ donor. It
was later discovered that encephalitis also developed in a fourth patient, who had received a vascular graft from the same donor during liver transplantation. All four patients became progressively
obtunded, lapsed into coma, and died within 50 days
after transplantation. The initial diagnostic evaluation revealed no cause of the encephalitis, and assistance was sought from the Centers for Disease
Control and Prevention (CDC) and the Texas Department of State Health Services. We report the results
of this investigation.
case reports
transplant recipients
In May 2004, encephalitis was diagnosed in three
recipients of a liver and two kidneys (Patients 2, 3,
and 4 in Fig. 1) from a common organ donor. In all
three patients, signs and symptoms of altered mental status and progressively worsening encephalitis developed within 30 days after transplantation.
Major clinical events and immunosuppressive medications are summarized in Figure 1. All patients
had rapid neurologic deterioration characterized by
agitated delirium and seizures. Respiratory failure requiring intubation developed within 48 hours
after the onset of neurologic symptoms. Examination of cerebrospinal fluid from the three patients
showed pleocytosis, with an average of 18 cells
per cubic millimeter (range, 7 to 35), and elevated
protein levels (mean, 135 mg per deciliter; range,
17 to 331). Neurologic imaging in the week after
the onset of symptoms showed no evidence of an
acute cerebral process. Magnetic resonance imaging (MRI) performed later in the course of illness
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demonstrated diffuse signal abnormalities, most
often in the temporal lobes, basal ganglia, brain
stem, and hippocampi on T2-weighted and fluidattenuated inversion recovery images (Fig. 2). There
was minimal enhancement after the administration of gadolinium. The patients died an average of
13 days after the onset of neurologic symptoms
(range, 7 to 23).
organ donor
Four days before death, the organ donor was seen
twice at an emergency department for nausea, vomiting, and difficulty swallowing. He was subsequently admitted to another hospital with altered mental
status requiring intubation. Physical examination
revealed a temperature of 38.1°C (100.5°F) and fluctuating blood pressures, including systolic measurements of more than 200 mm Hg. On admission, a
urine toxicology screen was positive for cocaine and
marijuana, and computed tomography of the brain
demonstrated a subarachnoid hemorrhage. The
hemorrhage progressed, and the neurologic symptoms, including seizures and coma, worsened. The
patient was declared brain-dead within four days
after presentation. Donor-eligibility screening and
testing performed by an organ-procurement organization, including a review of premortem blood,
urine, and sputum bacterial cultures, did not detect any signs or symptoms of infection precluding
solid-organ donation. The patient’s kidneys, lungs,
and liver were removed for transplantation; in addition, iliac arteries were harvested for potential
use in vascular reconstruction during the liver transplantation. In part because of the positive toxicology result, nonorgan tissues (e.g., tendons) were not
removed. During contact investigations conducted after the rabies diagnoses were made, friends of
the donor indicated he had reported being bitten
by a bat.
methods
clinical and epidemiologic review
Medical records of the donor and infected transplant recipients were reviewed to characterize clinical courses and diagnostic evaluations. After the
laboratory diagnosis of rabies infection in the three
organ recipients, case finding was performed to
search for other possible cases. Hospital autopsy
records on patients with encephalitis were reviewed
for pathological findings consistent with the presence of rabies. Also, charts of patients who had been
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rabies transmission from an organ donor to four recipients
Hospitalization
Agitation,
seizures,
fever,
sepsis
Hemodynamic
instability
Delirium
Home
Organ or Tissue Transplanted
Sepsis
Patient 1
Iliac Artery
X
Incision and
Tacrolimus,
drainage
mycophenolate
of septic
mofetil,
abdominal
prednisolone
abscess
Ventilation Death
Hepatic-artery
revision
Fever
Diffuse tremors,
sleepiness
Death
Liver
X
Tacrolimus,
Death mycophenolate
mofetil,
prednisolone
X
Ventilation
Agitation,
seizures
Donor
Mild Abdominal
rejection flank pain
Patient 3
Fever
Death
Kidney
X
Appendectomy Ventilation,
hemodynamic
instability
Cyclosporine,
sirolimus,
prednisone
Confusion, Fever
Hemodynamic
agitation,
instability
myoclonus
Patient 4
Kidney
X
19
ne
ne
Ju
16
Ju
13
ne
Ju
10
ne
Ju
ne
Ju
Ju
ne
4
1
ne
ne
Ju
29
Ju
26
ay
ay
M
23
M
M
ay
20
17
ay
M
ay
M
ay
14
11
7
Transplant
nephrectomy,
immunosuppression
stopped
Ventilation
M
8
ay
ay
M
5
M
2
ay
M
M
ay
ril
29
Tacrolimus,
mycophenolate
mofetil,
prednisone
Ap
Death
22
Patient 2
Hemodynamic
instability
Figure 1. The Clinical Course of Four Recipients of Rabies-Infected Tissue or Organs.
matoxylin and eosin and various immunohistochemical stains according to a method described
previously.6 For immunohistochemical assays,
3-µm tissue sections were deparaffinized, rehydrated, and digested in proteinase K. Tissue sections
were incubated for 60 minutes at room temperature
with a hyperimmune rabbit antiserum or mouse
laboratory methods
ascitic fluid with reactivity to rabies virus. After
Formalin-fixed, paraffin-embedded tissue speci- sequential application of the appropriate biotinymens, obtained at autopsy, were stained with he- lated linked antibody, avidin–alkaline phosphatase
on the same floor as a patient with rabies and who
had also had a lumbar puncture or neurology consultation for altered mental status were examined
for documented clinical findings consistent with
the presence of rabies. Procedures for organ recovery and handling were also reviewed.
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fluorescence antibody assay according to a previously described method.9 Immunohistochemical
studies were performed as described above, and formalin-fixed tissues were embedded for examination by electron microscopy.
results
review of transplantation records
Figure 2. Axial Fluid-Attenuated Inversion Recovery MRI
Scan Showing Profound Signal Abnormalities within the
Bilateral Frontal and Temporal Lobes, Hippocampi, Basal
Ganglia, and Medulla in Patient 2.
complex, and naphthol fast-red substrate, sections
were counterstained in Meyer’s hematoxylin and
mounted with the use of aqueous mounting medium. Serologic analyses, detection of viral antigen in tissue by means of fluorescence microscopy, and identification of rabies virus variants were
performed as described previously.7,8 Controls included serum specimens from noninfected animals,
tissues from humans with nonrabies encephalitides, and rabies-infected human tissues. Immunohistochemical assays for various other viral, rickettsial, and protozoan agents of encephalitis were also
performed on tissues from recipients.
Vero E6 cells were inoculated with CSF and 10
percent tissue suspensions from three of the four
rabies-infected recipients (Patients 2, 3, and 4).
Suckling mice were inoculated intracranially and
intraperitoneally with cerebrospinal fluid and 10
percent clarified homogenates of brain tissue, spinal cord, and kidney suspensions. Tissue cultures
and suckling mice were observed daily for cytopathic effects and signs of illness, respectively. Tissues obtained from suckling mice that developed
neurologic signs or died were fixed in 10 percent
neutral buffered formalin or 2.5 percent buffered
gluteraldehyde or were frozen for further evaluation. At 14 days, the Vero E6 cells were suspended
in saline, fixed on glass slides, and tested for the
presence of rabies virus antigen by means of a direct
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All organs obtained from the donor were transplanted; the lung recipient died of intraoperative
complications. Iliac arteries from the donor were
not used during the liver transplantation in Patient
2 and were placed in a sterile container and stored
for potential use in subsequent transplantation procedures. One day after the organs were transplanted, the iliac-artery segment was retrieved and used
to construct a vascular graft for another liver-transplant procedure (in Patient 1).
rabies case finding
In addition to the three initial cases noted by physicians, autopsy review identified a fourth patient
(Patient 1 in Fig. 1) in whom progressive, fatal encephalitis had developed after liver transplantation.
This patient had received the vascular segment from
the rabies-infected donor. A review of the medical
records of patients who had been on the same floor
as a patient with rabies and who had had a lumbar
puncture or neurology consultation for altered mental status revealed no further cases of encephalitis
consistent with the presence of rabies.
pathological findings
Histopathological evaluation of tissues from all
four rabies-infected transplant recipients demonstrated diffuse, predominantly lymphohistiocytic,
infiltrates and microglial nodules involving the cerebrum, brain stem, cerebellum, and spinal cord.
Cytoplasmic inclusions consistent with Negri bodies were identified throughout the central nervous
system (CNS), particularly in the Purkinje cells of
the cerebellum and in neurons of the frontal cortex,
thalamus, hippocampus, midbrain, and pons (Fig.
3A). Lymphohistiocytic infiltrates involving the peripheral nerves, heart, and kidneys were also noted
in some patients. Electron microscopy of the midbrain of Patient 4 demonstrated abundant rhabdovirus particles (Fig. 3B). Intracytoplasmic rabies virus
antigens were detected on immunohistochemical staining in neurons from multiple areas of the
CNS (Fig. 3C); in peripheral nerves of the trans-
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rabies transmission from an organ donor to four recipients
planted kidneys, liver, and arterial graft (Fig. 4); and
in renal tubular epithelium, smooth muscle, histiocytes, and vascular endothelium. No tissues were
positive for enteroviruses, human herpesviruses 1
and 2, West Nile and other flaviviruses, eastern
equine encephalomyelitis virus, lymphocytic choriomeningitis virus, Cache Valley virus, henipaviruses, measles virus, spotted fever and typhus group
rickettsiae, Toxoplasma gondii, or Trypanosoma cruzi
on immunohistochemical analysis. Direct fluorescence antibody staining also demonstrated rabies
virus antigens in CNS tissues from all recipients.
A
C
serologic analyses and viral
identification
Antibodies (IgM and IgG) reactive to rabies virus
were present in the donor’s serum at the time of
death. Antibodies were also present in three of the
four recipients in samples obtained on postoperative days 35 and 36; both IgM and IgG antibodies
were present in one kidney recipient (Patient 3) and
the recipient of the donor’s liver (Patient 2), whereas only IgG antibodies were present in the patient
who received the arterial segment (Patient 1). Antigenic typing revealed a previously characterized rabies virus variant associated with bats.
B
cell culture and mouse inoculations
All suckling mice had neurologic abnormalities or
had died seven to eight days after inoculation. Thinsection electron microscopy of CNS tissue demonstrated rhabdovirus particles, and IHC testing detected rabies virus antigens in mouse CNS tissues.
Cultures of Vero E6 cells inoculated with brain, spinal cord, and kidney from a kidney recipient demonstrated rabies virus antigen on staining with DFA.
discussion
This report describes the transmission of rabies virus through the transplantation of solid organs and
vascular material. Four patients who received transplants — three organs and one vascular segment
— from a donor with unrecognized rabies infection
subsequently died of rabies. The transmission of
rabies from corneal transplants has been described
previously.5
Rabies is seldom included in the differential diagnosis of encephalitis in the absence of a documented exposure or suggestive history.8,10 The
symptoms in the cases reported here, including
fever, changes in mental status, and autonomic
n engl j med 352;11
Figure 3. Histopathological Findings in Patient 4.
Panel A shows multiple intracytoplasmic viral inclusions (Negri bodies, arrows)
in neurons in the CNS of Patient 4, who received a kidney from the rabiesinfected donor. In Panel B, an electron micrograph shows typical inclusions
in the midbrain. Virions are sectioned longitudinally (arrowhead) and transversely (arrows). The virions averaged 65 nm in diameter. Panel C shows immunohistochemical staining (red) of rabies virus antigens in the CNS.
instability, were, in retrospect, consistent with a diagnosis of rabies. However, the diagnosis was complicated by the absence of a history of exposure at
presentation and by the number of other potential
causes of illness in these immunosuppressed patients. A history of a bat bite in the donor was discovered during contact interviews only after rabies
had been diagnosed, and the investigation initiated. The diagnosis in the donor was further complicated by the presence of a subarachnoid hemor-
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A
B
C
D
of
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Figure 4. Immunohistochemical Staining (Red) of Rabies Virus Antigens in Peripheral Nerves of the Liver (Panels A and B),
Kidney (Panel C), and Arterial-Graft Transplants (Panel D).
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rabies transmission from an organ donor to four recipients
rhage in the setting of hypertension and a positive
toxicology screen for cocaine. It is not known whether rabies infection was the cause of the subarachnoid hemorrhage, since this finding has not been
noted in previous reports.11-13
Signs of rabies developed in all four transplant
recipients within 30 days after infection. According to previous reports, symptoms developed within 30 days after an animal bite in only 25 percent of
patients.10 It is unknown whether the shorter incubation period in these patients was due to the immunosuppression, the route of transmission, or
both. The effect of immunosuppression on rabies
infection is currently not well understood. In reports
of rabies transmission from corneal transplants in
patients who were not immunosuppressed and did
not receive postexposure prophylaxis, symptoms
developed an average of 26 days after transplantation,14-17 suggesting that implantation of material
from infected donors may lead to a shorter incubation period. Three of our patients presented with
commonly described symptoms of tremors and
changes in mental status, whereas the fourth presented with abdominal and flank pain, which may
have been neuropathic, and changes in mental status occurred about 48 hours later. The rapidly progressive encephalitis, with death occurring an average of 13 days after the onset of symptoms, is
consistent with the course in other reports.4
There is only one reported case of recovery from
clinical rabies by a patient who had not received preexposure or postexposure prophylaxis against rabies.18 However, administration of postexposure
prophylaxis with rabies immune globulin and vaccine is highly effective in preventing infection after exposure. In a previous report, administration
of postexposure prophylaxis probably prevented
infection in a patient who had received a cornea
from a donor with rabies.19
This report and another, describing the transmission of West Nile virus through solid-organ transplantation,20 underscore the potential for transmission of unexpected infectious diseases through
organ transplantation. Recognition and prevention of transplant-transmitted infections may be
improved in various ways, including enhanced donor screening and testing, the development of
standardized procedures related to storage and use
of donor vascular segments, as well as methods to
track their use or nonuse, and enhanced means of
detection and diagnosis of illnesses in recipients.
To minimize the risk of transmitting infections
n engl j med 352;11
during organ transplantation, the Organ Procurement and Transplantation Network (OPTN) has
established standards that require organ-procurement organizations to assess the risks of infectious
diseases through screening questions and blood
testing for selected bloodborne viral pathogens
and syphilis.21 Questions about potential exposure
to rabies are generally not included, and laboratory
testing for rabies infection is not performed. Organs can be procured from donors who are febrile,
provided that the medical director of the organ-procurement organization and the transplantation physicians agree that the cause of the fever does not
pose an unacceptable risk to the recipient. Given
the growing importance of emerging and reemerging infectious diseases, the ability of general improvements in the donor-screening process, rather than disease-specific measures, to increase organ
safety should be evaluated. A proposed revision
of OPTN policies would expand the list of potentially transmittable diseases and conditions that
clinicians should consider in determining a donor’s
eligibility.22 The revision emphasizes that when any
of these conditions is known or suspected in a donor, this information should be conveyed immediately to the organ-procurement organization as
well as to all transplantation centers that received
organs from the donor.
The successful use of donor arterial conduits
has been reported in liver transplantation23-26 and
in the management of vascular complications in
recipients of both hepatic transplants27,28 and renal
transplants.29 As with organs, these vessel segments
have the potential to transmit infection. A careful
accounting of and an ability to track donated material, such as vessel conduits, are essential in efforts
to link unexplained illnesses or deaths to a common
organ donor and will increase the probability of
quickly identifying all recipients who may be at risk
from donor infections. Proposed revisions of the
policies of both OPTN22 and the Joint Commission
on Accreditation of Healthcare Organizations30
may help address the storage of vessel conduits and
documentation of their use or nonuse.
Our investigation underscores the challenge in
detecting and diagnosing infections that occur in
recipients of organs or tissues from a common donor. The potential for disease transmission from
a donor as a cause of illness or death may not be
considered in the evaluation of an individual recipient. In this investigation, and in the previous report of the transmission of West Nile virus through
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transplantation, the ability to connect illnesses to
a common organ donor was facilitated by the fact
that multiple recipients were hospitalized at the
same facility. Improved national detection of unexpected or serious outcomes among transplant
recipients may facilitate the discovery of transplant-related transmission of emerging and unusual pathogens by allowing connections to common
donors to be made. The ability to make retrospective diagnoses of infections in organ donors when
unexplained deaths or illnesses occur in recipients is
hampered by the limited availability of donor samples, particularly tissue; currently, only serum samples from organ donors are retained for any length
of time. Investigations into possible transplantation-associated infections would be facilitated by
the availability of selected, archived tissue samples
from the donor and by autopsy reports and materials. An improved diagnostic ability may have important implications for other patients who received
material from the donors and for contacts of the
patients and donors.
As organ and tissue transplantation becomes
of
medicine
more common, the potential risks of disease transmission may increase. Cases of transplantationassociated infections provide important opportunities to review practices in an attempt to enhance
the safety of transplantation without affecting the
organ supply. The Department of Health and Human Services, including the CDC, is working with
other partners in the organ- and tissue-transplantation community to review donor-screening practices, the use of retained vascular segments, and surveillance of recipients for illness. Clinicians who
care for organ-transplant recipients should continue to be aware of the potential for disease transmission through transplantation and the challenges
in recognizing atypical presentations of infections
in this immunosuppressed population. Clinicians
should report unexpected outcomes or unexplained
illnesses in transplant recipients to their local organand tissue-procurement organization.
We are indebted to the state health departments in Oklahoma and
Alabama, to the Southwest Transplant Alliance, and to the staff of
the Baylor University Medical Center for their assistance with this
investigation.
appendix
The other members of the Rabies in Transplant Recipients Investigation Team are as follows: J.A. Comer, J. Dillaha, B. Flow, D. Johnson,
J. McQuiston, M. J. Opatowsky, N. Pascoe, D. Perrotta, P. Rollin, D. Swerdlow, B. Tierney, J. D. Walker, F. Wilson, and P. Yager.
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