U.S. Rabies Update: Survival from Rabies, and Death in a Haitian Woman

Abstract and Commentary

By Michele Barry, MD FACP and Brian G. Blackburn, MD

Dr. Barry is the Senior Associate Dean for Global Health at Stanford University School of Medicine and Dr. Blackburn is a Clinical Assistant Professor in the Division of Infectious Diseases and Geographic Medicine at Stanford University School of Medicine.

Drs. Barry and Blackburn report no financial relationships to this field of study.

Synopsis: An 8-year-old girl from rural California who had been scratched by unvaccinated cats developed flaccid paralysis and rabies encephalitis. She was treated with a therapeutic coma protocol and survived after a 52-day hospitalization. This is the second report of recovery from rabies after induction of therapeutic coma and the third report of recovery from clinical rabies in an unvaccinated host. A 73-year-old woman who acquired rabies from a dog bite in Haiti died despite intensive supportive care without therapeutic coma induction. Since 1994, nearly all dog-associated rabies cases in the U.S. have been imported, and this was the third case of rabies imported from Haiti since that time.

Sources:

  1. CDC. Recovery of a Patient from Clinical Rabies – California 2011 MMWR 2012;61:61-65
  2. CDC. Imported Human Rabies – New Jersey 2011 MMWR2012 60;1734-1736

In May 2011, an 8-year-old girl developed sore throat, vomiting, and swallowing difficulties. During two emergency room visits with diffuse abdominal pain, she was given intravenous fluids and diagnosed with a viral illness. During a third emergency room visit for abdominal pain, weakness and sore throat, she was confused and choked while trying to drink radiographic contrast medium for a CT scan. She developed respiratory distress, was intubated and admitted to a pediatric intensive-care unit. She had bilateral lower extremity weakness, and a CSF analysis revealed 6 WBCs, protein 62 mg/dL and normal glucose concentration. Over the next few days she developed ascending flaccid paralysis, fever and decreased consciousness. MRI scanning revealed abnormalities in the periventricular white matter, cortical and subcortical regions. Electromyography revealed a severe demyelinating motor polyneuropathy.

IgG and IgM rabies virus specific antibodies were detected in both her serum and CSF by indirect fluorescent antibody (IFA) testing. With a presumptive diagnosis of rabies, the patient was sedated with ketamine and midazolam, then given amantadine, nimodipine, fludrocortisone, and hypertonic saline. To avoid blunting of an immune response, neither rabies immunoglobulin nor rabies vaccine were administered. Her course was complicated by severe autonomic instability, supraventricular tachycardia and significant hypertension. She was successfully extubated 15 days after hospitalization and discharged 37 days later with a residual foot drop that ultimately resolved. She has no lasting cognitive impairment.

The girl resided in rural Humboldt County, CA and had not traveled internationally in the six months prior to illness onset. She had never been vaccinated against rabies. Although her family owned pigs, birds, dogs, and a horse, the most likely source of rabies in this case was felt to have been scratches by two different unvaccinated, free-roaming cats at her school 9 weeks and 4 weeks prior to her illness. Although only two cases of human rabies in the U.S. have been attributed to cats since 1960, the most recent rabid cat in California was reported from the same county as the patient's residence, in 2008.

In July 2011, a 73 year-old Haitian woman was admitted to a New Jersey hospital with right shoulder pain, chest pain, headaches and hypertension. When given oral pain medication she developed difficulty swallowing and refused further testing. She then visited two other emergency departments with shortness of breath, ataxia and hallucinations. A blood chemistry panel and head CT were normal, but when she developed incoherence, fever and upper extremity tremors, she was transferred to an ICU where a presumptive diagnosis of encephalitis was made. MRI scanning revealed only chronic periventricular white matter changes; EEG showed subclinical seizures, and CSF revealed 7 lymphocytes/microliter. Rabies virus antigens were detected in a nuchal skin biopsy by direct fluorescent antibody testing, and rabies virus RNA was detected in the biopsy and saliva by PCR testing. Sequencing revealed a rabies virus associated with a Haitian canine variant. She was declared brain dead two weeks after admission and she expired despite supportive care in an intensive care unit. The patient had visited Haiti three months prior to her hospitalization, where she was bitten by a dog that she had adopted. A week before hospitalization, she had complained of right arm numbness and headaches.

Commentary

Rabies is a neurotropic viral illness that is characterized by severe encephalopathy and generalized paresis. Although preventable by post-exposure prophylaxis, no proven therapy exists after the onset of clinical symptoms. Post-exposure prophylaxis for unvaccinated patients consists of wound washing, passive immunization with rabies immune globulin and a series of 4 doses of rabies vaccine for immunocompetent hosts1,2 Survival has rarely been reported after onset of symptoms and death usually occurs within seven to fourteen days, as described in the imported case from Haiti.2

The young girl from California is the third unvaccinated person reported to have survived clinically apparent rabies in the United States. In two of these three cases, including the present case, coma induction by what is sometimes referred to as the "Milwaukee protocol" may have been life-saving.3 Of note, both patients were young and healthy, and presented at an early stage of the disease. A third case of presumptive abortive human rabies that never required intensive care has been described in an adolescent girl from Texas with a history of encephalitis and positive serology after a history of bat exposure.4 This case was extremely unusual, as case-fatality after onset of symptoms is essentially 100%, and it was suspected that abortive rabies may have occurred because of an exuberant host immune response.

The only suspicious animal contact for the 8 year old girl from California was with free-roaming cats at her school. Inspection of her home found no evidence of bats. The number of rabies cases among domestic animals has declined markedly in the United States, but varies regionally. Rabid cats represent the majority (62%) of reported rabid domestic animals presumably due to fewer cat vaccination laws and free-roaming of cats.5 In 2010, 303 cats were reported rabid in the US compared with 69 dogs. However, only two cases of human rabies have been attributed to cats since 1960.5 Risk between cats and dogs varies regionally and on the Texas-Mexico border dogs represent a greater risk. Most of the 303 rabid cats were reported from states where raccoon rabies is enzootic.5

For travelers, dogs remain the greatest risk for acquisition of rabies.1 The history of the 73 year-old woman who had traveled to Haiti, had been bitten by a dog two months prior, and had not sought medical attention is typical for rabies. Since 2000, eight human rabies cases associated with dog bite exposures have been reported in the United States, all acquired abroad. In the developing world, dogs represent a major source of rabies, in contrast to the U.S. where the major reservoir is wild animals, and where 96% of all domestically acquired human rabies infections have been associated with bat rabies virus variants. This is the third U.S. case of rabies related to dog exposure imported from Haiti in recent years.

Rabies is frequently not considered early in the clinical course of affected patients, but clinicians caring for patients with acute progressive encephalitis should always consider rabies in the differential diagnosis. Although there is no standard treatment for rabies once symptoms begin, early diagnosis may allow consideration of experimental interventions in appropriate patients and can also limit secondary exposures, thus minimizing the need for post-exposure prophylaxis [PEP]. The incubation period can vary depending on bite site but is usually 1-3 months.1 Ante-mortem diagnoses should include laboratory testing of serum, saliva, CSF and a nuchal skin biopsy to optimize yield as these tests have variable sensitivity. Interestingly, neither infectious virus, viral antigens nor rabies viral nucleic acid have been detected in any of the three surviving cases, raising the question of patient survival due to robust immune responses during intensive care support. For this reason, immunization with vaccine and human rabies immune globulin [HRIG] is not recommended once rabies encephalitis has been diagnosed in order to prevent blunting of the immune response.

A major clue to rabies in all of these cases was dysphagia and difficulty swallowing. This significant degree of dysphagia rarely is seen with encephalitis due to other causes. CDC recommends that all domestic cats, dogs and ferrets be vaccinated against rabies. Travelers to countries endemic for rabies should consider pre-exposure rabies vaccination, especially if immediate access to appropriate medical or biologics such as HRIG is limited or whenever the potential of exposure to rabies is high.1 Even if an animal exposure does occur, rabies is preventable if post-exposure prophylaxis is administered soon after exposure. In countries where canine rabies is endemic, all dog bites should be managed as a rabies exposure unless the dog's disease-free status can be confirmed.

References

  1. Rupprecht CE, et al. In: Brunette GW, ed. CDC Health Information for International Travel: The Yellow Book 2012. New York: Oxford University Press, 2012:272-278.
  2. Rupprecht CE, et al. Use of a reduced (4-dose) vaccine schedule for post exposure prophylaxis to prevent human rabies: recommendations of the Advisory Committee on Immunization Practices. MWWR 2010:59(RR-2)1-9.
  3. Willoughby, et al. Survival after Treatment of Rabies with Induction of Coma. NEJM 2005;352:2508-14.
  4. CDC. Presumptive Abortive Human Rabies- Texas 2009. MMWR 2010; 59:185-90.
  5. Blanton JD, et al. Rabies Surveillance in the United States during 2010. J Am Vet Med Assoc 2011;239:773-83.