Although rare, rabies remains a cause for concern

  • Infectious Disease News, May 2014

In the United States, cases of human rabies are rare. In 2012, only one case was reported to the CDC.

In this century, the number of human deaths caused by rabies in the United States has drastically declined, from more than 100 cases per year to an average of just two or three cases a year, according to the CDC. This decline is due to vaccination programs that have virtually eliminated domestic dogs as reservoirs of the disease and the availability of rabies vaccine and rabies immunoglobulin for humans.

Rabies is a disease that has always been considered fatal once symptoms set and has the potential to infect anyone. In the United States, the concern lies mostly with bat bites, which are sometimes so quick and almost painless, people do not realize they happen. In different regions of the United States, certain terrestrial animals also pose a risk, primarily skunks, raccoons and foxes.

 

Charles Rupprecht, VMD, MS, PhD, Ross University School of Veterinary Medicine, said only a few mammals serve as reservoirs of rabies, but any mammal can serve as a vector of the disease if they are infected.

Reprinted with permission from Ross University School of Veterinary Medicine 

“There has been an expansion of skunk rabies in Colorado, but on the East Coast, raccoon rabies is the major concern,” Jesse Blanton, MPH, an epidemiologist in the CDC’s poxvirus and rabies branch, told Infectious Disease News. “But on top of that, there are 12 to 15 variants of bat rabies, which is a concern for everyone, everywhere in the United States."

Human rabies is rare in the United States, but it is still concerning, as bats, raccoons, skunks, foxes and coyotes, as well as other potential vectors, are found coast to coast. Infectious Disease News spoke with several experts from different fields to learn why rabies is a concern, how to proceed with potential cases of rabies and prevention measures.

Reservoirs of rabies

Rabies is a Lyssavirus that can infect any mammal and has adapted to the mammalian central nervous system. All mammals are believed to be susceptible to the disease, but only certain mammalian species serve as reservoirs, including raccoons, skunks, foxes, coyotes and mongooses.

In the United States, canine rabies has been eliminated. In the rest of the world, however, dogs remain the primary source for rabies: 90% of the global burden of rabies in humans is due to dogs. Canine rabies is endemic in parts of Asia, Africa and Latin America.

“Of all the animals that serve as reservoirs, it’s the human-animal bond between people and dogs that likely explains why they are the mammalian species most responsible for human infection,” Charles Rupprecht, VMD, MS, PhD, professor of epidemiology and public health at Ross University School of Veterinary Medicine, St. Kitts, West Indies, told Infectious Disease News. “In areas where canine rabies is endemic, socioeconomic and other factors have prevented the routine delivery of vaccination to individual animals.”

In 2012, there were 6,162 rabid animals and one human rabies case reported to the CDC from 49 states and Puerto Rico, a 2.1% increase from 2011. Among the reported rabid animals, most were raccoons (31.7%), bats (27.3%) and skunks (25%).

Although only a handful of mammals serve as reservoirs of rabies, any mammal can serve as a vector of the disease if they are infected, Rupprecht said. Human-to-human transmission may also occur, most often via tissue and solid organ transplantation. In 2013, there was one reported rabies case in a man who had recently received a kidney transplant. The deceased donor was believed to have died of severe acute gastroenteritis. Upon testing banked samples of the patient, a rabies diagnosis was confirmed.

“There were many confounding factors that led to why rabies wasn’t recognized in this patient,” Blanton said. “First and foremost is the fact that rabies is a rare disease in the United States, and it’s not the go-to diagnosis.”

The problem with bats

Although most animal bites reported to authorities are primarily from wild animals other than bats, bats still are responsible for the vast majority of human rabies in the United States.

“There are other common animals that might be transmitting the virus that humans are in contact with more often,” M. Douglas Baker, MD, director of pediatric emergency medicine at Johns Hopkins Children’s Center, told Infectious Disease News. “But because we tend to those injuries quickly, the risk of contracting rabies is lower because we give rabies immunoglobulin and other prophylactic care. The trouble with bat exposure is that you can have a bat bite and not even know it. Bat teeth are tiny, and the bites that they inflict are such small caliber that the site of injury can close quickly and be clinically unapparent.”

Most people are less understanding of bats, compared with other wild animals, because they are small-bodied and the bites do not usually pose an immediate need for medical attention, Rupprecht said. Bat bites are often smaller than a pinprick, but even a small pinprick can cause the virus particles to be inoculated.

In addition to the small bite, bats are a risk anywhere, not just in rural areas where there are dense populations of terrestrial rabies reservoirs.

“Bats are opportunistic and they exploit human dwellings, even in urban areas,” Rupprecht said. “Any bite, by any bat, anywhere, carries the same relative risk of rabies acquisition as a lone raccoon bite.”

Most patients who die of rabies die of no known exposure, according to Rodney Willoughby, MD, a pediatric infectious disease specialist at Children’s Hospital of Wisconsin and professor at the Medical College of Wisconsin. Willoughby said 80% to 90% of the people who die of rabies in this country acquired it from a bat.

“If you’re unable to report contact with a bat because you’re too young, or intoxicated or asleep, then you are exposed to rabies and statistically, it’s 100% fatal,” Willoughby told Infectious Disease News. “You have to prevent it upfront. The disease has been vaccine-preventable since the late 1800s, and I find it appalling that we still have human rabies.”

Immediate action needed

The amount of time it takes for a person or animal to develop rabies after exposure to the virus depends on a variety of factors, including the dose of the virus, the route of entry, the severity of the exposure, the virus type and the particular host, Rupprecht said.

As far as dose of the virus, the more virus that enters the body, the shorter the incubation period. In addition, most exposures by bite will result in a shorter incubation period as opposed to a mucosal exposure. Multiple bites close to the face and head may cause a shorter incubation period than one bite to the leg. Some variants are more virulent than others, causing shorter incubation periods, and lastly, the infected person’s own immune system may have an effect.

According to Blanton, the typical human incubation time for rabies is approximately 60 days. However, there have been cases of rabies with an incubation time as little as 7 days and the longest incubation period documented is in excess of 8 years. In the 2013 case of rabies transmission by organ transplantation, the incubation period of the organ donor was 18 months.

Regardless of the incubation period, it is important for people who are potentially exposed to rabies to receive treatment for their wound as quickly as possible, to prevent the virus from moving to the central nervous system.

“The longer you go without treatment, the higher your odds are of developing the disease because the virus has a longer time to access the central nervous system,” Rupprecht said. “Even though it may take long for symptoms to develop, there is a narrow window to intervene.”

M. Douglas Baker

M. Douglas Baker

This applies to every bite, by any animal in any location. There is no difference from animals in urban, suburban and rural animals.

“Unfortunately, with regard to rabies, you’re guilty until proven innocent,” Baker said. “If you’re bitten by an animal that you can’t guarantee doesn’t have rabies, then you are considered exposed and need to receive prophylaxis. This includes domestic cats and dogs that have opportunities for outdoor exposures to wild animals.”

Postexposure prophylaxis involves administration of rabies immunoglobulin to a patient at the site of the wound after proper washing and then four doses of the rabies vaccine given for 14 days.

Travel and pre-exposure prophylaxis

Because some bites, particularly those from bats, often go unnoticed, postexposure prophylaxis is not always possible. In addition, some countries do not have access to the rabies immune globulin and/or rabies vaccines that are given for postexposure prophylaxis.

Of the two to three human rabies cases that occur each year in the United States, usually at least one is acquired while traveling internationally in rabies-endemic areas, Blanton said. Rabies vaccine is an option for travelers to these areas.

According to Stephen Gluckman, MD, professor of medicine at the Hospital of the University of Pennsylvania and medical director of Penn Global Medicine, the average traveler should have some level of concern, but most travelers do not need rabies vaccination before travel.

It is a judgment call, he said, that depends on the length of the trip, the nature of the trip and how simple it will be to obtain the vaccine and immunoglobulin if they have been exposed to the virus.

“I see several hundred people a year for travel advice, and I give the rabies vaccine about five times per year,” Gluckman told Infectious Disease News. “If it were less expensive, that threshold might change. A course of rabies vaccine costs about $1,500, and it’s never covered by insurance when given pre-exposure.”

As far as giving the vaccine universally as part of the childhood vaccine regimen, in the United States this would not be feasible because canine rabies is no longer a threat due to the 50-state requirement that dogs be vaccinated against rabies, Willoughby said.

Rodney Willoughby

Rodney Willoughby

With only two to three people per year being diagnosed with rabies in the United States, it would not be cost-effective to immunize 4 million children a year to prevent these cases, he said.

“It makes sense in places where there is much less money being spent to prevent rabies in animals,” Willoughby said. “The problem is that this is a disease of dogs and livestock, which is part of agriculture. Agriculture agencies don’t want to spend money on preventing human diseases, and the human agencies don’t want to spend money on something that can be prevented by addressing issues with dogs and livestock.”

Willoughby said several studies have suggested that it makes sense to immunize children against rabies where it is endemic, and it is also being pursued as a routine travel vaccination for some countries.

Recognition and treatment

Because rabies is so rare, very few physicians have actually seen a case and may not recognize the disease. Willoughby said there are a few symptoms that can be considered diagnostic for rabies. The first is that it causes a lot of pain and itching on the limb that was bitten. A second is myoclonic jerks involving the bitten limb.

One of the hallmarks of rabies is strange and unusual behavior, which is due to cerebral dysfunction. This could mean anxiety and confusion, agitation, insomnia, hallucinations and dysphagia or hydrophobia.

“Rabies tends to wax and wane,” Willoughby said. “You can be highly abnormal, but then be normal minutes later. Very few other infections do that. These are helpful diagnostic clues.”

But once the symptoms set in, survival is rare. However, if the patient receives aggressive supportive treatment within the first 5 days of hospitalization, the patient may have a chance at survival. Willoughby said prophylactic use of mineralocorticoids to prevent the salt wasting that occurs around day 5 of hospitalization can prevent many problems. The mineralocorticoids also help treat the cerebral artery spasms that happen around day 6 to 8.

Map of terrestrial rabies reservoirs in the United States during 2010. Raccoon rabies virus variant is present in the eastern United States, Skunk rabies in the Central United States and California, Fox rabies in Texas, Arizona, and Alaska, and Mongoose rabies in Puerto Rico.

Map of terrestrial rabies reservoirs in the United States during 2010. Raccoon rabies virus variant is present in the eastern United States, Skunk rabies in the Central United States and California, Fox rabies in Texas, Arizona, and Alaska, and Mongoose rabies in Puerto Rico.

Source: CDC

In addition, Willoughby said, any rabies treatment requires heavy patient sedation to prevent fatal heart arrhythmias.

“Essentially, when a patient develops rabies, the brain actually kills the patient,” Willoughby said. “When patients die of rabies, there is nothing pathologically wrong with the brain, suggesting that it’s more of a physiological or behavioral death rather than something caused by viral destruction of the brain. This is the basis of our protocols for treating rabies.”

Unconventional treatment

In 2004, a girl diagnosed with rabies managed to survive the infection and has remained alive with very few complications. The treatment she received became known as the Milwaukee protocol. It was improvised at the last minute by Willoughby and colleagues on the assumption that rabies is recoverable with intensive care.

“The hypothesis is that if you can maintain the patient alive, the immune response would clear the rabies virus,” Willoughby said. “We offered deep sedation to prevent the brain from killing the patient and allowing the immune response to arrive. If it arrives soon enough and vigorously enough, the patient can survive and have very good function.”

Willoughby said it is controversial, but as a result of the protocol, six additional people have survived rabies. It has also allowed the disease to be studied more because the patients are surviving long enough to be studied better.

“Rabies is hard to study in humans because human cases are so rare and nobody has spent time looking at animal models of rabies treatment,” he said. “There are a fair number of animals that survive rabies as part of vaccine studies, but nobody looks at what happens to the recovering animal and they are euthanized. We are throwing the baby out with the bathwater.”

There appears to be a variety of biochemical disorders in rabies and very little anatomic damage, leading Willoughby and others to consider rabies a metabolic disorder because the infection causes metabolic derangements. The same may apply to other infections as well, Willoughby said.

“That’s a seismic shift in terms of how you look at infections,” he said. “It’s not a new idea, but it gets rediscovered occasionally. If you support and correct those metabolic arrangements, then patients do much better and can survive. This breathes new life into infectious diseases because there are things you can do using the whole of medicine that may improve the outcomes of these patients. — by Emily Shafer

For more information:

CDC. Rabies in the U.S. Available at: www.cdc.gov/rabies/location/usa/index.html. Accessed April 28, 2014.
Dyer J. J Am Vet Med Assoc. 2013;243:805-815.

Disclosure: Baker, Blanton, Gluckman, Rupprecht and Willoughby report no financial disclosures.