EEE Requires Urgent Action, Experts Say

Janis C. Kelly

November 25, 2019

"This year's EEEV [eastern equine encephalitis virus] outbreaks a harbinger of a new era of arboviral emergences," experts warn in an article published online November 21 in the New England Journal of Medicine.

Anthony S. Fauci, MD, director, National Institute of Allergy and Infectious Diseases (NIAID), and colleagues agree with other experts about the need for a coordinated "national defense strategy for arboviruses and other vectorborne diseases."

Fauci has some experience in this type of effort. He was one of the principal architects of the President's Emergency Plan for AIDS Relief, launched in 2003 and credited with saving millions of lives throughout the developing world.

"Sadly, the United States' ability to control arboviral diseases is little better in 2019 than it was more than a century ago, when William Crawford Gorgas eliminated A aegypti from Havana and the Panama Canal Zone," the authors write.

EEEV Widespread, Hard to Diagnose

EEEV is one of the deadliest arthropod-borne virus (arbovirus) diseases transmitted by mosquitoes. In the 2019 US outbreak, mortality was nearly 50% among symptomatic patients.

"EEEV would be impossible to eradicate in our environment. It occasionally spills over into humans, leading to the kind of cases we have seen this year, but our challenge is that there is no rapid point-of-care diagnosis that can distinguish EEE from many of the other 13,000 infectious diseases. The early symptoms (fever, malaise, headache, muscle aches, nausea, vomiting) look pretty much like flu," lead author David M. Morens, MD, told Medscape Medical News. Morens is senior advisor to the director of the NIAID.

EEEV lurks in reservoirs of arthropods and in vertebrate hosts. The virus spreads from Culiseta melanura mosquitoes to tree-perching birds such as American robins in forested wetlands. It then spills over to infect dead-end hosts such as humans, equids (horses, donkeys), deer, swine, pheasants, and other poultry via "bridging vectors" of other mosquito types that feed on both birds and mammals.

In humans, EEEV passes from infected mosquito saliva into perivascular dermal tissue, where it infects Langerhans and dendritic cells, which then migrate to lymphoid tissue. The virus replicates there and produces systemic viremic seeding.

Fast Progression to Neurologic Damage

After about a week, the patient might present with flulike symptoms, but viral isolation, polymerase chain reaction analysis of blood and spinal fluid, and EEEV-specific IgM test results are usually negative. Within 5 days after symptom onset, the patient develops neurologic signs "indistinguishable from those associated with enteroviral meningoencephalitis, which is also prevalent in late summer," the authors write.

Early diagnosis is complicated by the fact that EEEV can be found only in the nervous system, not in the blood, in the first days after infection. "We can't take samples out of the brain looking for virus on the off chance that the patient who looks like flu might have EEE," Morens said.

By the time definitive serologic diagnosis is possible (within 1 week after infection) neurologic damage (typically involving the basal ganglia and thalami) has already occurred and can be seen on brainstem imaging, he explained. "The patient is already damaged, and even if we had a way to treat, it is too late."

The authors note that although 96% of those infected with EEEV remain asymptomatic, one third of those who develop symptoms die, and the rest of those who become symptomatic suffer permanent neurologic damage. This is often severe enough that patients require custodial care for the rest of their lives.

"Given the seriousness of the disease, social support and counseling of the patient and family are critically important," the authors state.

Little Progress on EEEV Treatment

So far, antiviral drug screening has failed to identify a drug that is effective against EEEV. One reason is that the drug must cross the blood-brain barrier. The lack of an animal model also hampers EEE treatment research.

That leaves only supportive care, often in an intensive care unit with use of a ventilator. Patients are not infectious and do not need to be isolated.

What Can Be Done Now About EEE

Morens said that until the development of rapid point-of-care diagnosis and effective treatment, public health measures are key to managing the increase in EEEV infections. He added that these measures should include ongoing education and early-warning notification for clinicians, as well as vector control by state and local authorities.

"We know the general geographic range of EEEV, including hotspots in Massachusetts and Florida, and that should drive efforts to educate the public about mosquito avoidance. We also know that most EEEV infections in the US occur in the summer and fall, so professional societies might target their education to those periods and send out timely reminders," Morens said.

"However, it is important to note that public health in the US is grossly underfunded, meaning that we will need millions of additional dollars, most notably at the state and local levels, to adequately address the threats we face from arbovirus-borne diseases."

Clinicians who encounter possible cases of EEE should first report to their county and state health departments, who will then bring in the Centers for Disease Control and Prevention if needed.

Morens does not expect that an EEEV vaccine will become available anytime soon. He added, "Even if a vaccine were available, we would not know whom to vaccinate, apart from people working in laboratories with EEEV."

Sadly, the United States' ability to control arboviral diseases is little better in 2019 than it was more than a century ago, when William Crawford Gorgas eliminated A aegypti from Havana and the Panama Canal Zone, Dr David Morens and colleagues

National Defense Strategy for Arboviruses

The authors echo the calls of other experts for a "national defense strategy for arboviruses and vector-borne diseases." They suggest that such a strategy include expanded research into EEE and other vector-borne infections; development of EEE animal models; EEEV vaccine research; EEE treatment (both therapeutic and supportive); public health initiatives for monitoring vectors and preventing arbovirus infections; and development of clinical guidelines for diagnosing and treating EEE infection.

Despite the unknowns, enough information does exist to develop initial guidelines for clinicians treating suspected or confirmed cases of EEE infection, Morens noted. "Case studies, including brainstem neuroimaging, serology, and virology, are potentially publishable, and each would contribute to our cumulative understanding of these infections," he added.

"Currently, nobody is leading the team — not the World Health Organization, not the federal government, not any philanthropic organization. The world has only a small number of experts who have been studying these viruses. They have access to only tiny amounts of funding. That needs to change," Morens continued.

One of those experts is Scott C. Weaver, PhD, perhaps the foremost US authority on EEEV. He told Medscape Medical News that researchers trying to pin down changes in EEEV pathogenicity and transmissibility are largely unable to obtain viral isolates for study. This problem is driven by federal regulatory requirements regarding transport and study of any organism classified as a "select agent." Such requirements are "harming our ability to respond to arbovirus outbreaks," he explained.

The authors conclude, "Given the near certainty of future emergences, arboviruses constitute a real and present danger. Although EEE is not yet a disease of major national importance, this year's spike in cases exposed our inadequate preparation for emergent disease threats."

Morens commented that, in light of reports of laboratory workers becoming infected through workplace exposure to aerosolized EEEV, the potential use of EEEV as a bioweapon should also be considered.

The authors and Weaver have disclosed no relevant financial relationships. Morens' comments do not represent official NIAID policy.

N Engl J Med. Published online November 21, 2019. Full text

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