Heads-Up on Keystone Virus Disease

ONE OF THE most recent disease discoveries, Keystone virus, was identified in wildlife in 1964, but the first human case wasn’t confirmed until the summer of 2018, when scientists identified it as the cause of a Florida teenager’s 2016 illness.¹ Still, because it is such a recently discovered disease, physicians, researchers and public health agencies do not yet know the full extent of the risks Keystone virus poses, including the normal progression of an infection, all possible vectors or the answers to a host of other questions.

With the first case now identified in humans, one question is: How many others have been infected? Researchers suspect the number is probably fairly large in the Florida area, where the virus has been found in the local mosquito population and wildlife for decades.¹ And, an official with the Florida Department of Health told USA Today there was a reported case of a young child diagnosed with Keystone virus infection in 1964 near Sarasota, although no further details were provided to the newspaper.²

However, the fact that it is not really known how many human infections have occurred at least suggests the risks of Keystone probably aren’t severe at this point. Otherwise, more cases would have been diagnosed and reported.

What Is Keystone Virus?

The Keystone virus belongs to a family of about a dozen or so arboviruses known as the California serogroup (CSG), one of 18 serogroups belonging to the genus Orthobunyavirus in the Peribunyaviridae family. Other members of this group include the California encephalitis virus, the La Crosse virus, the snowshoe hare virus and the Jamestown Canyon virus. All are transmitted by mosquito, and most can infect other mammals such as white-tailed deer and raccoons. The Keystone virus seems to be carried by several species of mosquito, including Aedes atlanticus and Aedes infirmatus, among others.²

Many of the viruses in this serogroup are associated with encephalitis in both animals and humans. But, the Florida teenager diagnosed with Keystone virus did not develop any symptoms of encephalitis, and instead exhibited only a rash and fever.³

In studies looking at other CSG viruses with known human infections, researchers have determined that due to generally mild symptoms, human infection rates are almost certainly underreported. However, in rare cases of CSG infection, the disease can progress to encephalitis or meningoencephalitis. One case in particular led to permanent brain damage (postencephalitic dementia) in a 73-year-old New Brunswick man who had to be relocated to an assisted living facility.⁴ It is believed he was infected with Jamestown Canyon or snowshoe hare virus.

In the typical life cycle of a CSG virus, it is transmitted by a vector (mosquito or tick) to a warm-blooded host, where new viruses are replicated. When an uninfected vector feeds on the now-infected host, the virus enters the mosquito or tick, and the cycle repeats. However, in some cases, the mammal or bird is infected by the virus, but the virus is unable to replicate itself in its environment. In this case, the host can still become ill, but it will not pass on the virus. This is known as a “dead-end host.”

The 2016 Florida patient is unlikely the first to contract an infection from Keystone virus since earlier studies have shown up to one-fifth of people in the Tampa area had Keystone antibodies in their system. 5 However, researchers point out that this was the first case of a person becoming ill with noticeable symptoms directly attributed to Keystone virus. And, because the boy’s symptoms were fairly mild and similar to those of other viruses, it is likely prior Keystone infections were simply undiagnosed or attributed to influenza or other common viruses.⁶

Transmission of Keystone Virus

Keystone disease is caused when the Keystone virus is introduced into the body — almost assuredly via a mosquito bite. Studies to date have indicated the Keystone virus, which was first described in samples taken from Keystone, Fla., near Tampa 54 years ago, is largely confined to the Gulf Coast of the United States, but can extend from Texas to Maryland.⁷

Symptoms and Progression of Keystone Virus Infection

With only a single diagnosed case so far, it’s far too early to speak of general symptoms or disease progression of Keystone virus infection. However, the diagnosed boy was brought by his family to urgent care during the Zika virus outbreak of 2016 after he developed a fever and rash. His symptoms did not worsen, and he never developed encephalitis, which is known to occur with some other California serogroup infections.¹

Looking again at other CSG infections in humans, thesymptoms and progression are roughly the same as with other viruses: low-grade fever and possible rash. In rare cases, as noted above, CSG infections have progressed to encephalitis. With other CSG infections, symptoms typically manifest in three to 15 days after infection, and the illness will usually run its course in approximately one week. Researchers believe most CSG infections are asymptomatic, and patients never even know they had the virus.

However, until more cases are diagnosed and studied, it will not be known with any specificity what the “normal” progression of Keystone virus disease is. Researchers are making only educated guesses based on the one diagnosed patient and their knowledge of how Keystone virus’ closest relatives have affected humans.

Diagnosis of Keystone Virus

Currently, there is no common test to diagnose Keystone virus infection. It took 18 months of intense laboratory work to diagnose the only confirmed case.⁸ If a patient has an undiagnosed viral infection and has spent time in the Southeastern United States, a possible Keystone diagnosis could be made through a process of elimination. If symptoms worsen, particularly if encephalitis develops, and no other cause can be determined, a physician may consider contacting researchers at the University of Florida for additional follow-up.

Treatment of Keystone Virus

There are no antiviral drugs that target Keystone virus. Treatment is palliative, which is the same for other viral infections. In mild cases, the patient will be advised to drink plenty of fluids and rest. Over-the-counter anti-inflammatory drugs such as aspirin, acetaminophen and ibuprofen can help reduce fever.

In the rare case that encephalitis develops, that condition would become the immediate focus of treatment. The Centers for Disease Control and Prevention’s (CDC) guidelines for the closely related La Crosse virus disease (LACV) emphasizes the need for immediate hospitalization and supportive care. Encephalitis caused by LACV can result in seizures, but CDC notes that nearly all patients who contract LACV-caused encephalitis recover completely, with no recurring or ongoing symptoms.⁹

Prevention of Keystone Virus

Keystone virus infection is prevented in the same manner as other diseases spread by mosquito such as malaria or Zika: Cover as much of the body as possible with light-colored clothing, including full-length sleeves and pants; sleep under mosquito netting; keep doors and windows closed (or use screens); and use insect repellents containing DEET, IR3535 or icaridin (all of which are safe for use by pregnant women).¹⁰ Keystone can also be prevented by draining standing water around one’s home after a rain, including empty flower pots, wading pools and other containers where mosquitoes can breed. Public health agencies should work with local authorities on vector control: draining nonprotected bodies of water (including abandoned or unused swimming pools), spraying for mosquito larvae and restoring habitat for birds, fish and other animals that prey on mosquitoes.

Ongoing Research

Most research into Keystone virus is currently in the very basic stage. Questions being investigated include: How common is it in humans? What is its range? What threat, if any, does it pose to both public health and individual patients? Until these fundamental questions are answered, further questions into a cure, improved treatment options or even a vaccine are unlikely to gain funding or much in the way of interest from the larger research community.

In several interviews, the authors of the University of Florida study who diagnosed the teenage boy with Keystone virus infection indicated they are continuing to study the virus, and are trying to answer the basic questions posed above.

But, as of early October, the National Institutes of Health’s ClinicalTrials.gov portal listed no studies into Keystone virus or any of the other California serogroup viruses discussed. There are, however, some 330 studies listed investigating arbovirus infections, including some looking at new methods of mosquito control and eradication that hold promise for preventing Keystone virus as well.

Looking Ahead

This is truly a “breaking story” in medical research right now. Since Keystone virus has been identified for more than a half-century and there is only a single confirmed human case, the current threat to public health seems low. However, physicians who practice in the Gulf Coast region should be vigilant and consider looking at Keystone virus as a possible cause of otherwise unexplained, undiagnosed infections — particularly with patients likely to have been exposed to mosquito bites. More evidence about how common Keystone virus is, its geographic range and the typical course of infection should become more established in the years to come.