Rabies case studies

Case 1
The case involves an 8 year old girl who survived clinical rabies.

Overview
In May 2011, a girl aged 8 years from a rural county in California was brought to a local emergency department (ED) with a 1-week history of progressive sore throat, difficulty swallowing, and weakness. After she developed flaccid paralysis and encephalitis, rabies was diagnosed based on 1) detection of rabies virus–specific antibodies in serum and cerebrospinal fluid (CSF), 2) a compatible clinical syndrome in the patient, and 3) absence of a likely alternative diagnosis. The patient received advanced supportive care, including treatment with therapeutic coma. She was successfully extubated after 15 days and discharged from the hospital 37 days later to continue rehabilitation therapy as an outpatient. The public health investigation identified contact with free-roaming, unvaccinated cats at the patient's school as a possible source of infection. Several of these cats were collected from the school and remained healthy while under observation, but at least one was lost to follow-up. A total of 27 persons received rabies postexposure prophylaxis (PEP) for potential exposures to the patient's saliva. No further cases of rabies associated with this case have been identified. Rabies prevention efforts should highlight the importance of domestic animal vaccination, avoidance of wildlife and unvaccinated animals, and prompt PEP after an exposure.

Case Report
On April 25, 2011, a girl aged 8 years visited her pediatrician with a complaint of a sore throat and vomiting when taking sotalol, a medication previously prescribed for her supraventricular tachycardia. Over the next few days, she developed swallowing difficulties and could drink only small amounts of liquids, but was able to carry on with daily activities. Three days after her initial visit, she was seen in a local ED for poor oral intake and was given intravenous fluids to treat dehydration. Two days later, she complained of abdominal pain without localization and neck and back pain, and was brought back to the ED, where she was evaluated and discharged home with a presumed viral illness. The next day, May 1, she returned for a third time to the ED with complaints of sore throat, generalized weakness, and abdominal pain suggestive of appendicitis. On physical examination, she was confused with a pulse of 108 beats per minute, blood pressure of 112/87 mmHg, and temperature of 96.7°F (35.9°C). Head and abdominal computed tomography (CT) were unremarkable. Chest CT was only remarkable for left lower lobe atelectasis. She choked while trying to drink oral radiographic contrast medium. Because of respiratory distress and acidosis shown by arterial blood gas analysis, she was intubated and placed on a ventilator. She was given intravenous fluids, ceftriaxone, and azithromycin and was transferred to a tertiary-care facility.

On admission to the pediatric intensive-care unit, neurologic examination revealed bilateral lower extremity weakness. Laboratory testing of peripheral blood drawn on May 1 showed 19,200 white blood cells/µL (normal range: 3,700–9,400 cells/µL). Infectious disease testing was negative at this time with the exception of a positive rhinovirus detected by polymerase chain reaction (PCR) on a respiratory specimen. Electrolytes and renal function were normal. Analysis of the CSF revealed six white blood cells/µL (normal range: zero to five cells/µL), protein of 62 mg/dL (normal range: 10–45 mg/dL), and glucose of 67 mg/dL (normal range: 45–75 mg/dL). Toxicology screen was negative. Over the next few days, the patient developed ascending flaccid paralysis, decreased level of consciousness, and fever. Magnetic resonance imaging of the brain revealed multiple T2 and flair signal abnormalities in the cortical and subcortical regions as well as in the periventricular white matter, with areas of restriction diffusion. Electromyography was consistent with a severe, primarily demyelinating, predominantly motor polyneuropathy with absence of electrical signals in the distal limb muscles in response to stimulation of the respective motor nerves. The patient was given a short course of ceftriaxone, levofloxacin, and azithromycin to treat possible bacterial pneumonia and Mycoplasma pneumoniae encephalitis and was started on levetiracetam for seizure prophylaxis.

On May 4, 2011, the California Encephalitis Project at the California Department of Public Health Viral and Rickettsial Disease Laboratory (VRDL) was asked to urgently test for enterovirus (EV) and West Nile virus (WNV). Enterovirus testing was requested because of the well-described cross-reactivity of EV and rhinovirus in molecular testing. PCR assays for EV and rhinovirus performed on respiratory samples showed no RNA for EV, but rhinovirus was detected. Serologic testing for WNV was negative. VRDL suggested testing for rabies, given the compatible clinical syndrome, and subsequently detected immunoglobulin G (IgG) and immunoglobulin M (IgM) rabies virus–specific antibodies in serum by indirect fluorescent antibody (IFA) testing.

With a presumptive diagnosis of rabies, the patient was sedated with ketamine and midazolam and started on amantadine and nimodipine to prevent cerebral artery vasospasm, and fludrocortisone and hypertonic saline to maintain her sodium at a level >140 mmol/L. Neither human rabies immunoglobulin nor rabies vaccine was administered.

During the first week of hospitalization, the patient developed autonomic instability manifested as significant hypertension. She required esmolol and nicardipine infusions as well as intermittent hydralazine and scheduled amlodipine. She also had frequent episodes of supraventricular tachycardia requiring adenosine. These resolved with repositioning of her central venous catheter. Cerebral artery spasm was not demonstrated by repeated transcranial Doppler ultrasound examinations and CT angiography of the head.

On May 8, the patient moved her head spontaneously. Over the next few days, she moved her head more, then began moving her arms and then her legs. With progressive improvement in her strength, she tolerated extubation on May 16 and was transferred to the pediatric wards 1 week later. On May 31, she was transferred to the rehabilitation service with residual left foot drop. At discharge on June 22, she showed no signs of cognitive impairment and was able to walk and perform activities of daily living.

Laboratory diagnostic testing
Serologic tests of CSF and serum for anti–rabies virus antibody, PCR tests of saliva and a nuchal biopsy for the presence of rabies RNA, and direct fluorescent antibody tests of the nuchal biopsy for rabies virus were performed. Rabies virus–specific antibodies in multiple serum samples collected May 3 through June 9 were detected by IFA at VRDL and CDC. Serum IFA titers peaked on May 11 at 1:64 for IgG and 1:160 for IgM (VRDL results). Rabies virus–specific antibodies also were detected in three separate CSF samples by IFA testing performed at CDC, with peak titers of 1:4 for IgG and 1:8 for IgM on May 8. Rabies virus neutralizing antibody titers were not detected in serum or CSF. Similarly, neither rabies virus antigens nor RNA were detected in any sample.

Extensive testing for other infectious and noninfectious etiologies was performed. The only positive results were M. pneumoniae IgM detected by a commercial laboratory. No IgG M. pneumoniae seroconversion was documented 4 months after illness onset, but the patient remained IgM-positive. Further testing did detect M. pneumoniae nucleic acid by PCR in a respiratory swab but not in CSF. The positive M. pneumoniae results were thought to be less significant than the rabies virus diagnostic results because the detection of nucleic acid from a respiratory specimen does not distinguish between infection and colonization and no evidence of M. pneumoniae within the central nervous system could be detected. Furthermore, detection of IgM in the absence of IgG seroconversion suggested the possibility of a false positive.

Public health investigation
The patient resided in a rural community in Humboldt County, had never traveled outside of California, and had no travel outside the county within 6 months preceding illness onset. She had no history of having received rabies vaccine. The patient confirmed having contact with free-roaming, unvaccinated cats at her school on several occasions. She was scratched by two different cats approximately 9 weeks and 4 weeks before illness onset but reported no bites. Local public health officials implemented a program to collect and identify cats at the school. The first cat was observed to be healthy, but a reliable description of the second cat was not available. All other cats collected at the school remained healthy under observation.

The family owned pot-bellied pigs, pet birds, dogs, and horses. The dogs and birds were reportedly healthy, but one of the horses had died from a presumed colonic torsion in November 2010. Although the patient reportedly had little to no contact with the horse, the horse was exhumed during May 2011 for rabies diagnostic testing. Brain tissue was not ideal for testing, and results were inconclusive. Inspection of the patient's residence by county environmental health staff found no evidence of bat infestation or structural defects that would permit entrance of bats.

Risk assessments performed on 208 classmates and other potential contacts at the patient's school identified two persons with possible exposures to the patient's saliva during April 17–27. Both had contact with the patient during wrestling practice and completed PEP because exposure of mucous membranes or open wounds to the patient's saliva could not be ruled out. Additionally, PEP was administered to eight family members for possible exposure of mucous membranes or open wounds to the patient's saliva. Three pediatric intensive-care unit nurses at the referral hospital and 14 health-care workers at the local ED initiated PEP, although three from the local ED did not complete the series after investigation determined that they did not meet criteria for exposure requiring PEP.

Case 2
A more well known case occurred in Fond du Lac County, Wisconsin in 2004. The patients name is Jeanna Giese and she has made it her mission to raise awareness of rabies. This case represents the sixth known occurrence of human recovery after rabies infection; however, the case is unique because the patient received no rabies prophylaxis either before or after illness onset.

Overview
Rabies is a viral infection of the central nervous system, usually contracted from the bite of an infected animal, and is nearly always fatal without proper postexposure prophylaxis (PEP). In October 2004, a previously healthy female aged 15 years in Fond du Lac County, Wisconsin, received a diagnosis of rabies after being bitten by a bat approximately 1 month before symptom onset. This report summarizes the investigation conducted by the Wisconsin Division of Public Health (WDPH), the public health response in Fond du Lac County, and the patient's clinical course through December 17. This is the first documented recovery from clinical rabies by a patient who had not received either pre or postexposure prophylaxis for rabies.

While attending a church service in September, the girl picked up a bat after she saw it fall to the floor. She released the bat outside the building; it was not captured for rabies testing, and no one else touched the bat. While handling the bat, she was bitten on her left index finger. The wound was approximately 5 mm in length with some blood present at the margins; it was cleaned with hydrogen peroxide. Medical attention was not sought, and rabies PEP was not administered.

Case Report
Approximately 1 month after the bat bite, the girl complained of fatigue and tingling and numbness of the left hand. These symptoms persisted, and 2 days later she felt unsteady and developed diplopia (i.e., double vision). On the third day of illness, with continued diplopia and onset of nausea and vomiting, she was examined by her pediatrician and referred to a neurologist. At that time, the patient continued to have blurred vision and also had partial bilateral sixth-nerve palsy. Magnetic resonance imaging (MRI) with and without contrast and magnetic resonance angiography (MRA) studies of her brain were normal, and the patient was sent home.

On the fourth day of illness, the patient's symptoms continued, and she was admitted to a local hospital for lumbar puncture and supportive care. On admission, she was afebrile, alert, and able to follow commands. She had partial sixth-nerve palsy, blurred vision, and unsteady gait. Standard precautions for infection control were observed. Lumbar puncture revealed a white blood cell count of 23 cells/µL (normal: 0 cells/µL) with 93% lymphocytes, a red blood cell count of 3 cells/µL (normal: 0 cells/µL), a protein concentration of 50 mg/dL (normal: 15--45 mg/dL), and a glucose concentration of 58 mg/dL (normal: 40--70 mg/dL). During the next 36 hours, she had slurred speech, nystagmus, tremors of the left arm, increased lethargy, and a temperature of 102oF (38.9oC).

On the sixth day of illness, the bat-bite history was reported, and rabies was considered in the differential diagnosis. The patient was transferred to a tertiary care hospital. Because rabies was recognized as a possibility, expanded infection-control measures, including droplet precautions and one-to-one nursing, were instituted at time of transport. On arrival, the patient had a temperature of 100.9oF (38.3oC), impaired muscular coordination, difficulty speaking, double vision, muscular twitching, and tremors in the left arm. She was somewhat obtunded but answered questions appropriately and complied with commands.

Blood serum, cerebrospinal fluid (CSF), nuchal skin samples, and saliva were submitted to CDC for rabies testing. MRI with and without contrast and angiogram/venogram sequences were normal. She had hypersalivation and was intubated. Rabies-virus--specific antibodies were detected in the patient's serum and CSF. Direct fluorescent antibody staining of nuchal skin biopsies was negative for viral antigen, and rabies virus was not isolated from saliva by cell culture. Rabies-virus RNA was not detectable by reverse transcriptase polymerase chain reaction assay of either sample. Therefore, identification of the virus variant responsible for this infection was not possible.

Clinical management of the patient consisted of supportive care and neuroprotective measures, including a drug-induced coma and ventilator support. Intravenous ribavirin was used under an investigational protocol. The patient was kept comatose for 7 days; during that period, results from lumbar puncture indicated an increase in antirabies IgG by immunofluorescent assay from 1:32 to 1:2,048. Her coma medications were tapered, and the patient became increasingly alert. On the 33rd day of illness, she was extubated; 3 days later she was transferred to a rehabilitation unit. At the time of transfer, she was unable to speak after prolonged intubation. As of December 17, the patient remained hospitalized with steady improvement. She was able to walk with assistance, ride a stationary cycle for 8 minutes, and feed herself a soft, solid diet. She solved math puzzles, used sign language, and was regaining the ability to speak. The prognosis for her full recovery is unknown.

To provide community members accurate information about rabies and its transmission, local and state health officials held a press conference on October 21. Public health officials and community pediatricians visited the patient's school to assess the need for rabies prophylaxis among students. WDPH distributed assessment tools to the local health department to screen health-care workers and community contacts of the patient for exposure to potentially infectious secretions. The patient's five family members, five of 35 health-care workers, and 27 of 55 community contacts received rabies PEP, either because of exposure to the patient's saliva during sharing of beverages or food items or after contact with vomitus. No health-care workers at the tertiary care hospital required PEP. Site inspection of the church revealed no ongoing risk for exposure to bats.