Fatal rabies in a child

Key points

• Rabies is a neurotropic infection that is rare in Canada and almost always fatal once symptoms develop.

• Rabies postexposure prophylaxis is highly effective in preventing infection in exposed humans if administered promptly and before onset of rabies symptoms.

• Any direct human contact with a bat is an indication for rabies postexposure prophylaxis and should be discussed with the regional public health authority.

• No established efficacious therapies are available for treatment of rabies once symptom onset has occurred.

An immunocompetent 11-year-old boy presented with odynophagia and emesis to an urban hospital emergency department in Ontario, Canada. Seven days before presentation, he had developed progressive right-sided facial paresthesia and numbness, followed by anorexia and right-sided facial swelling. Four days after symptom onset, he had been prescribed oral valacyclovir (1 g, 3 times daily) at a local urgent care clinic for presumed Bell palsy secondary to herpes simplex virus; however, he was unable to tolerate this because of odynophagia. He had no history of allergies, sick contacts, tick bites, or recent travel outside the country.

In the emergency department, the patient appeared systemically well, and his vital signs were normal, apart from tachycardia of 134 beats/min. Physical examination revealed mild sensory deficits in the right trigeminal nerve distribution and mucosal ulcers in the upper and lower gingiva. The rest of the neurologic and oropharyngeal examinations were normal, with no apparent facial swelling noted. His serum electrolytes, glucose, and creatinine levels were normal, as was his complete blood count, except for an increased leukocyte count (18.1 [reference 4.5 to 13.5] × 10⁹/L).

The patient’s family reported that, during a visit to a cottage in northern Ontario 19 days before symptom onset, the boy had been awoken by a bat on his nose and mouth. He had swatted the bat off his face; his father had caught the bat in a cooking pot and released it outside. The child had no visible lesions on his face, and his parents did not consider that the bat had behaved erratically. Therefore, they did not seek medical assessment.

Because of the history of bat exposure, the emergency physician notified the local public health authority for consideration of rabies postexposure prophylaxis (PEP) the next day. The patient was discharged home with a presumed diagnosis of herpes gingivostomatitis.

The next morning, the patient again presented to the emergency department with new right-sided facial weakness, decreased sensation, and slurred speech. He was afebrile and hemodynamically stable with the exception of tachycardia of 139 beats/min. He was admitted to hospital with a working diagnosis of severe herpes gingivostomatitis with Bell palsy and managed with intravenous acyclovir (290 mg every 8 h) and oral prednisone (50 mg daily). While awaiting admission, he developed fever (39.1°C), dysphagia, confusion, and visual hallucinations. Computed tomography (CT) of his head was normal. By evening, his condition had rapidly worsened, with onset of multiple cranial nerve deficits (including bulbar palsy) and hypersalivation. He was intubated for airway protection and admitted to the pediatric intensive care unit (PICU); urgent consultation with the infectious diseases service was sought.

When we saw the patient in the PICU, we strongly suspected rabies, given the bat exposure and typical neurologic features. We also considered other more common infectious encephalitis pathogens such as herpes simplex virus, enterovirus, and West Nile virus, as well as noninfectious causes such as acute disseminated encephalomyelitis, autoimmune encephalitis, and neuromyelitis optica spectrum disorder. In addition to a general infectious workup, which did not yield an alternate diagnosis, we sent serum, cerebrospinal fluid (CSF), saliva, and nuchal skin biopsy samples for rabies-specific testing. Results from his CSF testing showed a lymphocytic pleocytosis (leukocytes 272 [reference 0 to 5] × 10⁶/L, 88% lymphocytes, elevated protein (1.22 [reference < 0.45] g/L), and normal glucose (3.5 [reference 2.7 to 4.4] mmol/L). Magnetic resonance imaging (MRI) of his brain showed hyperintense lesions in the brainstem, with prominence in the medulla oblongata, left caudate nucleus, cerebral grey matter (with confluence in the right posterior temporal and occipital lobes), and cervical spinal cord. These findings were nonspecific but compatible with rabies.

We prescribed intravenous ceftriaxone (2 g every 12 h), vancomycin (850 mg every 6 h), and acyclovir (580 mg or 10mg/kg every 8 h) until salivary polymerase chain reaction (PCR) confirmed the diagnosis of rabies on day 4 of admission. Subsequent testing by the Canadian Food Inspection Agency identified a bat rabies virus variant. We considered use of intraventricular rabies immune globulin (RIG), but given its invasive nature and lack of established efficacy, the patient’s family chose not to go ahead with this treatment, a decision that was supported by the health care team. We also considered an adeno-associated virus gene therapy expressing an antibody, but this was not pursued because of limited availability of the gene therapy, lack of proven efficacy, and the patient’s rapid neurologic decline.

The patient’s hospital course was complicated by autonomic dysfunction, ventilator-associated pneumonia, and progressive neurologic decline. By day 5 of admission, his brainstem reflexes were absent. Life-sustaining therapies were withdrawn on day 17 of admission, and he died peacefully with his family at his bedside.

Discussion

Human rabies is caused by rabies virus, a neurotropic RNA virus in the genus Lyssavirus and family Rhabdoviridae, transmitted through inoculation of virus-laden saliva into tissue — typically via bites, scratches, or mucosal exposure. It causes viral encephalitis that is almost always fatal but can be prevented effectively with PEP. Human rabies is exceedingly rare in Canada, with only 28 cases reported since 1924.¹ This patient’s was the first case of locally acquired rabies reported in Ontario since 1967.

In North America, bats, skunks, raccoons, and foxes are the primary animal reservoirs, with bat exposures accounting for most human cases.² Bats pose a particular risk because bites or scratches may be small and are easily overlooked, and patients may not recollect or recognize a bat exposure.

Rabies has a fatality rate of almost 100%, although 34 survivors have been documented,² with most experiencing severe neurologic sequelae. The key to preventing the onset of infection is prompt PEP after exposure, which is nearly always effective. A systematic review found only 122 cases of rabies in people treated with PEP between 1980 and 2022, despite an estimated 29 million PEP recipients annually over the same period; many cases were associated with delays in seeking care, deviations from appropriate care practices, errors in the administration of RIG, and immunosuppression.³ Early recognition of exposure and timely PEP remain the only effective means of rabies prevention.

In Canada, PEP should be initiated in consultation with local public health authorities, who can help guide risk assessment, management decisions, and procurement. Although some health care facilities stock rabies vaccine and RIG, availability and access pathways vary by jurisdiction, and coordination commonly occurs through provincial or territorial public health programs, with administration in emergency departments or by other designated health care providers. Postexposure prophylaxis regimens for immunocompetent patients are provided in Table 1. Adverse effects associated with PEP are generally mild and include reactions at injection sites and transient systemic symptoms. Anaphylaxis has rarely been reported; very rare neurologic events such as Guillain–Barré syndrome have been described, without an established causal association with modern rabies vaccines.⁴

Table 1:

Postexposure prophylaxis for rabies in immunocompetent patients⁴

Postexposure prophylaxis	Patients unimmunized against rabies virus	Patients previously immunized* against rabies virus
Wound management	Immediately clean the wound to its full depth by flushing it with soap and water for approximately 15 min. Avoid suturing the wound.	Immediately clean the wound to its full depth by flushing it with soap and water for approximately 15 min. Avoid suturing the wound.
Human RIG	Administer 20 IU/kg of human RIG immediately (day 0). Inject as much of the dose as possible into and around the wound tissue, with any remainder given intramuscularly at a site distant to vaccine administration. Do not mix in the same syringe as the vaccine.	Not required
Rabies vaccine†	Administer 1 dose (1.0 mL) of vaccine immediately (day 0), intramuscularly at a site distant to human RIG administration, followed by 3 subsequent doses on days 3, 7, and 14. Do not mix in the same syringe as the human RIG.	Administer 1 dose (1.0 mL) of vaccine† intramuscularly immediately (day 0), followed by 1 subsequent dose on day 3.

Note: HDCV = human diploid cell vaccine, PCECV = purified chick embryo cell culture vaccine, RIG = rabies immune globulin.

^*People are considered previously immunized against rabies if they have documentation of a complete course of pre-exposure or postexposure prophylaxis with HDCV or PCECV, or have documentation of complete immunization with other types of rabies vaccine with demonstration of acceptable concentration of neutralizing rabies antibody in serum after completion of the series.

^†Rabies vaccines in Canada include HDCV or PCECV.

Any direct human contact with a bat, even in the absence of a visible bite or scratch, is an indication for PEP and should be discussed with public health authorities.⁴ In the circumstance that the bat is available for rabies testing, and results can be obtained within 48 hours, PEP could be held pending the results. In the common circumstance that a bat is found in the bedroom of a sleeping person with no recognized physical contact, this is not considered an indication for PEP. The patient we described reported a bat resting on his face, which is an indication for PEP; however, medical attention was not sought because no obvious bite was noted. This highlights an important gap in public awareness. Although rabid bats may show unusual behaviour — such as appearing during the daytime, resting on the ground or someone’s face, having difficulty flying, or being easily approached — the absence of these behaviours does not exclude rabies.

After replicating at the inoculation site, the rabies virus travels via retrograde axonal transport along peripheral nerves to the central nervous system. Early symptoms are often nonspecific — fever, malaise, fatigue — followed by pain and paresthesias at the site of viral entry due to infection in sensory ganglia. These are followed by symptoms and signs of infection in the spinal cord and brain, depending on the site of entry. Our patient’s symptomatology reflected the facial site of exposure, with progression from trigeminal and facial nerve involvement to bulbar dysfunction and encephalopathy. The oral mucosal ulcers noted on initial examination, which are not typical of rabies, were likely owing to trauma secondary to loss of sensation.

In patients in whom symptomatic rabies is suspected, multiple specimens should be collected and sent to the Canadian Food Inspection Agency (for viral detection) or the National Microbiology Laboratory (for antibody assays) (Table 2).⁵ The most sensitive tests are reverse transcription PCR of saliva and nuchal skin biopsy. Rabies virus–specific antibodies in serum or CSF samples support the diagnosis but are commonly absent in the first 2 weeks after infection and may still be absent later. Computed tomography of the brain is typically normal. Magnetic resonance imaging may also be normal or show hyperintense lesions in various regions of the brain, most commonly the brainstem, spinal cord, and basal ganglia, as in this patient. Testing of CSF commonly reveals lymphocytic pleocytosis, elevated protein levels, and normal glucose levels. Importantly, negative results from laboratory tests do not exclude infection, emphasizing the need for clinical judgment and repeat testing when suspicion remains high.

Table 2:

Antemortem diagnostic laboratory testing for rabies in Canada⁵

Test characteristic	Specimen
	Saliva	Skin biopsy	Cerebrospinal fluid	Cerebrospinal fluid	Serum
Detected element*	Virus	Virus	Virus (low-sensitivity specimen)	Antibody	Antibody
Collection†	Multiple 2–3-mL specimens taken 12–24 h apart	Specimen of at least 5 mm in diameter, taken from nape of neck; transport in moistened gauze prevent drying out	1 mL	2 mL	2 mL
Sample storage temperature	−20°C or lower	4°C or −20°C	−20°C or lower	4°C or −20°C	4°C or −20°C
Laboratory technique	Real-time RT-PCR	Fluorescent antibody technique or real-time RT-PCR	Real-time RT-PCR	Rabies antibody neutralization technique	Rabies antibody neutralization technique

Note: RT-PCR = reverse transcription polymerase chain reaction

^*Specimens for virus detection should be sent to the rabies unit of the Canadian Food Inspection Agency. Specimens for antibody detection should be sent to the rabies unit of the National Microbiology Laboratory.

^†In sterile container, tube, or vial.

Once neurologic symptoms develop, rabies is almost always fatal. Management is supportive, focusing on airway protection, ventilation, and control of autonomic instability. Death typically occurs within 7 to 14 days of symptom onset, although supportive critical care may delay the timing of death. Despite decades of research, no proven effective therapy exists after symptom onset. The Milwaukee protocol, which involves induced coma and N-methyl-D-aspartate receptor antagonism, gained attention following its use in a single survivor in 2004,⁶ but it has since failed to demonstrate efficacy.^2,7,8 It is now recommended that the Milwaukee protocol not be used.^8,9 Recent reports of rabies survivors, particularly in India, likely reflect advances in modern supportive critical care and an increased number of attempts at aggressive care in patients with rabies.^2,8 In this patient, we considered both intraventricular RIG administered via an Ommaya reservoir (requiring surgical implantation) and an adeno-associated virus gene therapy expressing an antibody,¹⁰ but did not pursue either of them because of limited availability of the gene therapy, lack of proven efficacy, the patient’s neurologic decline, and the values and preferences of the family.

This case illustrates several critical points about rabies. Rabies is almost always fatal, with no established efficacious therapies, making prevention crucial. Rabies PEP is highly effective if administered promptly, in consultation with public health authorities, after any direct human contact with a bat, even in the absence of visible lesions. Bats may or may not show classic signs of rabies; hence, any direct human contact with bat is considered high risk. Clinicians should ask patients with progressive neurologic symptoms compatible with rabies about exposure to potentially rabid animals.

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