EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Rabies is usually transmitted to humans through bites of infected animals; however, it can rarely be transmitted through deceased donor organs or tissues when not suspected. Here, we report a case of rabies transmission in a child. The child was a 5-year-old girl who was admitted to the pediatric intensive care unit with encephalitis of unexplained cause 3.5 months after she received a kidney transplant from a deceased donor. The laboratory and imaging studies did not reveal any explanation for her rapidly declining clinical and neurologic condition, which ended with death 4 days after admission. Death of another recipient from the same donor led to an investigation that revealed rabies as the cause. Both corneas were explanted from other recipients to prevent further death. Polymerase chain reaction sequence analysis of the corneas was consistent with a rabies virus from the same donor’s state of residence. Rabies transmission, although rare, should be suspected when a donor comes from or has visited endemic countries. Donors with unclear causes of death should be rejected.

Key words : Deceased donor, Donor-derived infection, Encephalitis of unexplained cause

Rabies is a neurotropic virus with the highest mortality rate of known infectious diseases.¹ Human-to-human transmission of rabies is thought to be a rare event. However, because rabies is invariably fatal once symptoms occur, public health investigations of human rabies cases are necessary to prevent further cases of this high-consequence disease.² Most rabies infections are acquired from the bite of an infected animal; however, tissue and organ transplants from patients who died of undiagnosed rabies have resulted in death to recipients several weeks after transplant.³

This case report describes a 5-year-old girl who presented to the emergency department of Al Jahra Hospital in Kuwait with status epilepticus and respiratory failure for which she was immediately intubated and shifted to the pediatric intensive care unit. The child had received a kidney transplant 3.5 months previously at the Organ Transplant Center (OTC) in Kuwait from a deceased donor for end-stage kidney disease owing to a congenital dysplastic kidney disease.

The posttransplant period was uneventful, and the patient was started on triple immunosuppressive drugs comprising steroids, tacrolimus, and mycophenolate mofetil. Her recent clinical and laboratory investigations were satisfactory, including blood pressure and allograft renal functions. During the current admission, the patient was febrile, tachycardic, hypertensive (blood pressure of 150/120 mm Hg), and irritable while on mechanical ventilation. She gradually started to develop violent movements, uncontrolled excitement, lethargy, vomiting, loss of consciousness, and generalized seizures. Laboratory investigations revealed she was seronegative for Cytomegalovirus, Epstein-Barr virus (EBV), Human papilloma virus (HPV), hepatitis B, hepatitis C, and human immunodeficiency virus. Cytomegalovirus antigenemia in the blood by the DNA polymerase chain reaction (PCR) method was positive with a viral load of 9834 IU/mL; the blood EBV and HPV DNA PCR results were both negative; cerebral spinal fluid revealed 94 cells, and 99% of them were monocytes with normal protein and glucose concentrations. Cerebral spinal fluid virology for Cytomegalovirus, EBV, and HPV were negative. The graft function was normal, as well as the rest of her routine blood workup. Computed tomography brain and abdominal ultrasonographic scans were normal. The working diagnosis on admission was infective encephalitis in an immunocompromised patient. Thus, immunosuppressive drugs were withheld, and the OTC was informed about the case.

Death of a second kidney recipient 2 weeks earlier at the OTC without reaching a diagnosis led to suspicion of a donor-derived cause. The donor was an Indian man, residing in Kuwait, who developed brain death after admission 3 months earlier with respiratory failure followed by cardiac arrest. On contacting his father in India, it was revealed that he visited India several months earlier and was bitten by a dog. The liver and heart of the same donor had been transplanted in Saudi Arabia; the heart recipient died with no definite diagnosis, and the liver recipient was still in an intensive care unit.

At this point, transmission of rabies infection through organ donation was highly suspected. Serology of the girl was taken, but it failed to confirm rabies as the specific immunoglobulin M and immunoglobulin G tests were both negative. Treatment given to the patient consisted of mechanical ventilation support, anticonvulsants, antibacterial and antiviral agents, antihypertensive agents, and steroids. Vaccination and specific immunoglobulins against rabies were not given because the patient was already symptomatic. Four days after admission to the pediatric intensive care unit, the patient developed cardiac arrest that did not respond to full resuscitative measures, and the patient was declared dead.

The 2 cornea recipients were shown to be asymptomatic; however, both corneas were explanted to prevent further death, and all recommendations for potential postexposure prophylaxis (PEP) against rabies were started. Corneas were sent to a rabies laboratory of the Centers for Disease Control and Prevention (Atlanta, GA, USA), and rabies was confirmed as the sequence analysis of the nucleoprotein gene of rabies virus was consistent with a rabies virus variant found in dogs in the border region between Pakistan, India, and Bhutan.

As soon as this rabies case was identified, all persons who had contact with the patient were rapidly identified and assessed to provide appropriate recommendations for PEP and prevent the disease.^4,5 Specific immunoglobulin and vaccination protocols against rabies were started according to the recommendations of the preventive medicine department in the Ministry of Health in Kuwait.

Rabies infection should be considered in the differential diagnoses of unexplained rapid neurologic decline in transplant patients occurring several weeks to months after transplant, particularly in those who have received organs from deceased donors with uncertain causes of death.

Our patient had received a kidney transplant 15 weeks before onset of symptoms, which is perhaps an incubation period slightly longer than the 3 to 12 weeks previously reported for transplant-associated rabies infections.^3,4,6 However, longer incubation periods of over 1 year have also been reported.⁴

Donor-derived rabies was suspected only after symptoms developed in the present case but not when the recipient of the other kidney presented with almost similar conditions. That diagnosis had been complicated by the absence of detectable humoral immune response. However, negative serologic findings would suggest that rabies infection had been acquired from the donor of the transplanted kidney and that immunosuppression did not allow the development of the patient’s antibody response requiring a qualitative rabies PCR result to confirm the diagnostic hypothesis. Our present case prompted an investigation for the origin of the rabies in the donor, and further genetic sequence testing of the donor’s cornea identified a donor source.

Our patient did not receive any of the specific PEP agents because these have been reported to be ineffective after onset of symptoms.^1,4

This case report describes a donor-derived infection caused by an unidentified (at the time of procurement) donor infection with rabies. Therefore, it highlights the importance of proper assessment of deceased donors for the risk of transmittable diseases. This report should mandate consideration of what might be done to further reduce these events. Vora and colleagues⁷ suggested a number of enhancements to reduce risks, including implementation of a standardized approach for recognizing encephalitis among potential donors and, in cases that meet criteria for encephalitis, storing specimens for posttransplant testing. Specific informed consent from potential organ recipients is advocated for donors who meet criteria for encephalitis, and a uniform donor questionnaire to better screen for rabies exposure is also suggested.

To be effective, these general recommendations need to be translated into policy, but what would that policy look like and would it actually enhance patient safety? Improvements in the donor questionnaire specifying potential rabies exposures might be helpful. In the current case, no questions regarding exposure to rabies were asked before donation. Had this information been obtained before organ transplant, infection with rabies virus may have been considered and the organs not offered for donation.

Reducing the risk of donor-derived infection requires understanding the current system of screening potential donors,⁸ which includes the organ procurement organization managing the process to obtain a medical and social history from individuals familiar with the donor. Information that might reasonably be expected to affect potential recipients (eg, a history of recent bite of an animal that might not be detected on routine serologic donor screening tests) must be communicated to transplant programs.⁹ Limitations include the availability of friends and family and their familiarity with the donor’s exposures and behaviors.⁸ Reducing the risk implies also being able to develop new screening tests without loss of donors due to false positive results, improving communication between donor and recipient centers, and considering any early posttransplant disease as potentially donor derived to prevent morbidity or mortality in other recipients.

It is worth mentioning here that, under the current system of the organ procurement in the United States established by the Organ Procurement and Transplantation Network, episodes of unexpected donor-derived infection are rare. From 2008 to 2011, 113 622 patients received solid-organ transplants from 57 488 donors. Donor-derived disease (infection and malignancy) developed in 139 recipients (0.1%), resulting in 29 deaths (0.03%).¹⁰ A relevant comparison to make is that, during the same period, 26 852 people died waiting for an organ transplant.¹¹

To the best of our knowledge, this is the first published case report of a child who died several months after kidney transplant from a deceased donor who died of undiagnosed rabies.

The most notable aspect of this report surrounds the implications for improving the current system of screening potential donors and the overall safety of solid-organ transplant to reduce the risk of donor-derived infection. Although rare, clinicians should consider rabies in cases of encephalitis of unexplained causes in kidney transplant recipients, particularly from deceased donors.

Volume: 15 Issue: 3 June 2017

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