Misdiagnosis Tied to Death From Rabies Infection

Janis C. Kelly

January 15, 2019

Rabies still poses a deadly, albeit rare, threat in the United States, a recent case report detailing a May 2017 fatal exposure shows. The patient was the ninth death from rabies in the United States since 2008 due to travel abroad.

The latest case highlights the importance of prompt diagnosis and the limits of post-exposure prophylaxis (PEP), researchers from the Virginia Department of Health and the Centers for Disease Control and Prevention (CDC) write in the January 4 issue of Morbidity and Mortality Weekly Report.

The patient, a 65-year-old woman, initially presented for medical care due to pain and paresthesia in her right arm after returning from a yoga tour in India and was diagnosed with carpal tunnel syndrome. The fact that she had been bitten by a puppy 6 weeks earlier while in India was not initially known to healthcare providers, and the possibility of rabies was not initially considered.

Lead author Julia Murphy, DVM, state public health veterinarian at the Virginia Department of Health, told Medscape Medical News that rabies should be considered in differential diagnosis of patients with signs or symptoms of encephalitis or myelitis, including autonomic instability, dysphagia, hydrophobia, paresis, and paresthesia, particularly if a nonspecific prodrome preceded the onset of these signs by 3 to 4 days.

"Progressive worsening of neurologic signs is characteristic of rabies and should be considered as a positive indicator for rabies. Patient history is important to identify a possible exposure to rabies and other encephalitides; however, rabies should never be ruled out based solely on the absence of definite exposure history," Murphy said.

Although the canine rabies virus variant was eradicated in the United States in 2004 due to stringent requirements for vaccination of domestic animals, it remains endemic in 122 other countries and kills over 59,000 persons per year worldwide. Of the 23 cases of human rabies diagnosed in the US since 2008, seven were contracted from dog bites sustained in other countries. India "has the world’s largest incidence of dog-mediated human rabies deaths," according to the authors.

In the current case, the patient had washed the bite with water but did not seek medical attention for it either in India or after returning to the United States. She presented at an urgent care medical facility 6 weeks later for pain and paresthesia in her right arm, was diagnosed with carpal tunnel syndrome, and was prescribed hydrocodone and an NSAID. The following day she was evaluated at a hospital for shortness of breath, anxiety, insomnia, and difficulty swallowing water. Diagnostic tests were unremarkable, and she was given 0.75 mg of lorazepam for a presumed panic attack and discharged. In her car in the parking lot she experienced claustrophobia and shortness of breath, returned to the hospital emergency department and was given an additional 0.25 mg lorazepam and again discharged.

The following day she was transported from home by ambulance to the emergency department of a second hospital with chest discomfort, shortness of breath, progressive paresthesia, and increased anxiety. She was agitated, tachycardic, and intermittently tachypneic, and showed dysmetria (a rare type of ataxia) on neurologic exam. By evening she was agitated, combative, and was gasping for air when attempting to drink water. During this period hospital staff had been following standard infection prevention precautions.

At that point hospital staff questioned her family about animal exposure and learned about the dog bite. By the next morning the patient required endotracheal intubation and mechanical ventilation, and EEG showed severe encephalopathy. She was sedated with ketamine and midazolam, and the Virginia Department of Health was notified of possible rabies. (The authors explain that PEP was not indicated because it is ineffective after onset of rabies symptoms.)

Rabies was confirmed by real-time RT-PCR detection of virus RNA in saliva and skin biopsy specimens, as well as by direct fluorescent antibody demonstration of rabies virus antigen in the skin biopsy. Sequencing identified a canine rabies virus variant associated with dogs in India.

Ten days after the initial symptom onset, the experimental Milwaukee protocol for persons with rabies was implemented along with favipiravir, but 2 days later the patient developed "profuse oral secretions." Further aggressive treatment, including interferon beta, was ineffective, and at 19 days after initial symptom onset the family decided to withdraw advanced medical support, and the patient died. Rabies virus was isolated from her brain tissue after death.

Public Health Investigation

The late recognition of this rabies case in a patient who had been treated at 2 hospitals and lived in a communal household necessitated a public health investigation. Investigators identified 240 healthcare providers potentially at risk, of whom 72 had been exposed to potentially infectious materials and for whom PEP was recommended. PEP was administered to 64 providers at a cost of $235,000.

Because the patient was assumed to have had communicable rabies 2 weeks before symptom onset, 13 other residents of the commune where she lived were examined, and 4 were advised to initiate PEP. These included three who had direct contact with the patient's saliva and one who had been bitten by the patient. "The circumstances of this bite were related to the patient’s clinical condition," Murphy said. "It was reported that, as the patient's symptoms worsened and she experienced altered mental status, she bit one of the residents of the commune where she was living." 

Pretravel Prevention and Early PEP

Murphy said that this case highlights the importance of counseling those traveling or working in rabies-endemic countries about steps to take before possible rabies exposure, as well as after. As part of pretravel planning, international travelers should be encouraged to incorporate discussions about risk of rabies exposure and how to handle an exposure should it arise. 

"A traveler may also want to consider pre-exposure rabies vaccinations if a prolonged stay is planned or travel will be in remote areas where medical care might be difficult to obtain," Murphy said.

The authors recommend pretravel rabies vaccination for those involved in activities such as camping, hiking, biking, adventure travel, or caving — activities that put them at risk for animal bites — as well as for those undertaking extended visits, such as the yoga tour.

The rabies vaccine is highly effective when given prior to symptom onset, but survival is rare once the patient begins to exhibit signs of rabies. "To date, fewer than 10 documented cases of human survival from clinical rabies have been reported, and only two did not have a history of pre- or post-exposure prophylaxis," Murphy said.

"Once a patient presents with symptoms of rabies, it is almost always too late to save that person’s life, so providing patients with the right tools and information to prevent this disease is paramount. Anyone who has been bitten by an animal should immediately wash the wound thoroughly with soap and water and seek medical care as soon as possible. Patients assessed as exposed to rabies are encouraged to initiate the post-exposure vaccine series promptly." 

Depending on the animal involved and the animal rabies epidemiology of the country, PEP would include the rabies vaccine and rabies immune globulin (RIG).

"If [a] vaccine is available locally," Murphy said, "it should be initiated regardless of the availability of RIG in that country. If [a] vaccine is not available, travelers may need to be medically evacuated (either to the United States or to a nearby location where vaccine is available)." She said that travelers who receive post-exposure rabies vaccinations outside of the United States may need additional treatment upon returning to the US and should consult with their healthcare provider and/or state or local health departments for additional advice.

Healthcare providers who suspect that a patient might have been exposed to rabies should report those concerns to public health officials. "Local and state health officials, working in collaboration with the CDC, can offer guidance, clinical consultation and diagnostic support," Murphy continued. "Clinicians who are unsure about reporting procedures in their jurisdictions are encouraged to contact their local health departments. Another great resource for zoonotic disease consultation is a state health department's State Public Health Veterinarian." 

The National Association of State Public Health Veterinarians provides a directory of designated and acting state public health veterinarians.

More information for human healthcare providers about the clinical aspects of human rabies infections can be found on the CDC's "Information for Doctors" webpage.  

More information for international travelers about rabies considerations can be found on the CDC’s rabies webpage.

The authors have disclosed no relevant financial relationships.

MMWR. Published online January 4, 2019. Full text

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