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Recovery of a Patient from Clinical Rabies — California, 2011

Recovery of a Patient from Clinical Rabies — California, 2011

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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.


Reported by
Jean Wiedeman, MD, PhD, Jennifer Plant, MD, Univ of California-Davis Medical Center; Carol Glaser, MD, DVM, Sharon Messenger, PhD, Debra Wadford, PhD, Heather Sheriff, Curtis Fritz, DVM, PhD, California Dept of Public Health. Ann Lindsay, MD, Mary McKenzie, Christina Hammond, MPH, MSN, Eric Gordon, County of Humboldt Public Health Br; Charles E. Rupprecht, VMD, PhD, Div of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases; Brett W. Petersen, MD, EIS officer, CDC. Corresponding contributor: Brett W. Petersen, bpetersen@cdc.gov, 404-639-5464.


Editorial Note
Rabies is a neurotropic viral illness, most commonly transmitted to humans from the bite of an infected animal. Although rabies is preventable with PEP, no proven cure exists after the onset of symptoms (1). Even with advanced supportive care, the case-fatality rate approaches 100% (2). Consequently, management approaches generally focus on palliation (1,3). However, in 2004, an adolescent female treated with a novel protocol became the first person to survive documented clinical rabies without previous vaccination (4). In 2009, another unvaccinated adolescent female with a history of bat exposure, symptoms of encephalitis, and positive rabies virus serology recovered from a presumed abortive rabies infection after receiving only basic supportive care (5). The patient described in this report is the third unvaccinated person to recover from clinical rabies in the United States.

Antemortem diagnosis of human rabies should include laboratory testing of serum, saliva, CSF, and a nuchal skin biopsy to optimize diagnostic yield because any one test can be variably positive. Detection of viral antigen by direct fluorescent antibody testing, isolation of rabies virus from saliva or central nervous system tissue, identification of rabies virus–specific antibody in CSF, identification of rabies virus–specific antibody in the serum of an unvaccinated person, or detection of viral RNA in saliva, other fluids, or tissue are strong indicators of acute infection. Any one of these findings in a clinically compatible case fulfills the case definition for human rabies established by the Council of State and Territorial Epidemiologists (6). Viral isolation, detection of viral antigens, identification of viral nucleic acid, and detection of rabies virus neutralizing antibodies are not specifically required for diagnosis and are not consistently found in all human rabies cases (2). Neither infectious virus, viral antigens, nor viral nucleic acid have been detected from any of the reported U.S. survivors of clinical rabies. Experimental studies of abortive rabies in mice have identified, in rare cases, mice that survived infection but did not develop neutralizing antibodies to rabies virus (7).

The diagnosis of rabies in this case was based on identification of rabies virus–specific antibodies in serum and CSF in the setting of a compatible clinical syndrome, high-risk animal contact, and absence of a likely alternative diagnosis. The significant pharyngeal dysfunction leading to intubation in this case was especially suggestive of rabies. This degree of dysphagia rarely is observed in other causes of encephalitis, and it influenced the decision to test for rabies. The diagnosis of rabies was made 3 days after hospital admission. This relatively early diagnosis likely minimized the number of health-care workers and others who had unprotected contact with the patient during the time in which she could potentially shed virus. Early diagnosis also might have affected the clinical outcome by focusing treatment at an early stage. Clinicians caring for patients with acute progressive encephalitis should consider rabies in the differential diagnosis and coordinate with health departments for laboratory diagnostic testing when indicated. Once a diagnosis of rabies has been established, clinical management should focus primarily on comfort care and adequate sedation of the patient (1,3). Experimental treatment might be considered after detailed discussions and informed consent by the patient, family, or legal representatives, particularly if the patient is young, healthy, and at an early stage of clinical disease (1).

The only reported suspicious animal contact that the patient experienced was with unvaccinated cats at her school. Although rabies was not identified in any cats from the school, the most recent rabid cat in California was reported in 2008 from the same California county in which the patient lived. A total of 303 rabid cats were reported in the United States in 2010, and two cases of human rabies have been attributed to cats since 1960 (8–10). All domestic cats, dogs, and ferrets should be vaccinated against rabies. Public education should emphasize avoidance of all wild and potentially unvaccinated animals and the importance of seeking medical evaluation for exposures to suspect rabid animals.

Acknowledgments
Staff members of the Humboldt County Dept of Health and Human Svcs; Edward Powers, DVM, and other staff members of the California Dept of Public Health. Rodney Willoughby, MD, Medical College of Wisconsin. Jesse Blanton, MPH, Richard Franka, DVM, PhD, Ivan Kuzmin, MD, PhD, Felix Jackson, MS, Michael Niezgoda, MS, Lillian Orciari, MS, Sergio Recuenco, MD, DrPH, Andres Velasco-Villa, PhD, Pamela Yager, Div of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, CDC.

References
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February 3, 2012 / 61(04);61-65