Eye on ID

Triple E: A severe zoonotic disease

Thomas Yuill 
Thomas M. Yuill
Donald Kaye 
Donald Kaye

Eastern equine encephalitis, or EEE, is a serious disease of horses and, rarely, humans. However, there was an unusual and dramatic increase in human cases in the United States in 2019. Historically, the CDC reported 72 neuroinvasive cases in the U.S. from 2009 to 2018. During those 10 years, there was an average of seven cases of neuroinvasive disease each year, with a low of three in 2009 and a high of 15 in 2012. Most cases were reported from Florida, Massachusetts, Michigan, New York and North Carolina. In 2019, the human case number was five times higher than the average, with eight states involved (see Table). Some of the affected localities even cancelled outdoor activities to reduce the risk for becoming infected. It is unclear why the increase occurred and if it will continue in future years.

The number of equine cases also was relatively high in 2019 (also shown in the Table). There were more cases reported in 2019 than in the previous 5 years. Cases in horses usually occur before those in humans — a clear warning to human health providers that the virus is being actively transmitted in that locality.

The virus

Eastern equine encephalitis virus (EEEV) is an RNA virus and a member of the genus Alphavirus, part of the family Togaviridae. EEEV is closely related to western equine encephalitis virus and Venezuelan equine encephalitis virus. There are four groups, or lineages, of EEEV. Group I, which is responsible for most human disease, is endemic in North America and the Caribbean. Groups IIA, IIB and III are found mainly in Latin America and primarily cause disease in horses and only rarely cause human disease.

EEE Table

Epidemiology

In the U.S., EEEV is actively transmitted in freshwater hardwood swamps in the Atlantic and Gulf Coast states and in the Great Lakes region. The virus circulates between birds and Culiseta melanura or Culiseta morsitans mosquitoes, in which EEEV replicates to high titers and permits efficient transmission. Because these mosquitoes are mainly passerine bird feeders and rarely feed on humans, other species of mosquitoes generally provide a bridge between the swamp ecosystems and humans and equine animals. These bridge species include Aedes vexans, Coquillettidia perturbans, Ochlerotatus canadensis and Ochlerotatus sollicitans, which occasionally feed on viremic birds and then, after several days when the virus replicates and reaches salivary glands, go on to feed on nearby people and horses, transmitting the virus to them. However, a recent study in Massachusetts indicated that C. melanura occasionally does feed on mammals and could provide a bridge for infection of humans, horses and other animals. That study isolated EEEV in high titers from Aedes cinereus mosquitoes in Connecticut and concluded that this species may serve as a bridge vector there as well. The peak incidence for EEE is in August and September.

EEE is a severe disease in horses. Up to 90% of equine animals infected with EEEV die, usually within 3 to 7 days after onset of illness. Many other mammals that can occasionally get this disease include cattle, alpacas, swine, llamas, dogs, cats, deer and goats.

Horses and humans are dead-end hosts for the EEEV because the concentration of virus in the blood is generally too low to infect biting mosquitoes.

The question remains open as to why there were so many EEE cases last year. The factors that affect EEE outbreaks are complex and interacting. EEEV transmission requires ample populations of vector mosquitoes combined with susceptible host birds. Rainfall can create mosquito breeding sites. High temperatures can accelerate the rate at which mosquito larvae grow and increase the speed at which the virus can replicate in the mosquito. Temperature and humidity can affect the longevity of individual mosquitoes and, hence, the days that they are available to transmit the virus.

Clinical disease

Only about 4% to 5% of human EEEV infections result in encephalitis. Individuals aged younger than 15 years or older than 50 years are at greatest risk for experiencing neurologic disease. After an incubation period of 4 to 10 days following the bite of an EEEV-infected mosquito, there may be an abrupt onset of chills and fever, arthralgia, myalgia and a general feeling of malaise that can last 1 to 2 weeks. The great majority of infections then subside. In more severe cases, fever may continue with headache, irritability, restlessness, drowsiness, anorexia, vomiting, diarrhea, cyanosis, seizures, cranial nerve palsies and coma. Death may occur in about 40% of these encephalitis cases. Mild to severe neurological sequelae are common among survivors, with death occurring within a few years among the more severely affected patients.

Diagnosis

Presumptive diagnosis of EEE disease can be made on clinical grounds, especially when there have been cases recently in the region or if the patient can provide a reliable travel history placing them in an area where other cases have occurred recently. Examination of cerebrospinal fluid (CSF) usually reveals a predominance of neutrophils, especially early in the course of the disease. The protein is elevated, and the glucose is normal. CT scans and MRIs of the brain are abnormal, as are electroencephalograms. Confirmation of an EEE diagnosis requires laboratory support. Serum or CSF can be tested to detect virus-specific immunoglobulin M or neutralizing antibodies. Serologic testing can be done using IgM-capture enzyme-linked immunosorbent assay (ELISA), microsphere-based immunoassay or IgG ELISA. Tissues from autopsy can be tested by PCR for viral RNA, by histochemistry or by virus isolation. Results may not be available for 4 to 14 days, depending on the tests used and the workload in the laboratory where the samples are processed. Relatively few laboratories can carry out these tests. The CDC is the reference laboratory for EEE. Test results confirming an EEE diagnosis must be sent promptly to the state health department.

Treatment and prevention

Treatment for EEE is supportive because there is no specific recommended therapy available. There have been a limited number of case reports suggesting that IV immunoglobulin may have a positive effect on the clinical course.

Although there is an inactivated vaccine available for horses, no vaccine is commercially available for humans.

Local governments can initiate mosquito control measures, which may involve eliminating breeding sites, treating them with insecticides to kill larvae and pupae or spraying to kill adults. Efforts should also be made to eliminate standing water in areas around houses.

Because there is no vaccine or preventive drug available for human use, the best, and really only, preventive measure available for individuals is to avoid mosquito bites, specifically: covering bare areas of skin with long sleeves and long pants, use of mosquito repellents such as DEET and use of permethrin-treated clothing, The CDC provides detailed information on repellant use and other measures to avoid mosquito bites and how to reduce mosquito breeding sites.

Summary and conclusions

EEE is a bad disease. Although there is no treatment available, preventive measures can be taken.

There may not be as many EEE cases in 2020 as there were in 2019, but it is certain the virus will not disappear from its endemic areas in the Eastern and Midwestern U.S. The public must remain aware that the risk for EEEV infection is not zero, and people should take appropriate preventive measures to “fight the bite” by protecting themselves and their family members and by vaccinating their horses.

Disclosures: Kaye and Yuill report no relevant financial disclosures.

Thomas Yuill 
Thomas M. Yuill
Donald Kaye 
Donald Kaye

Eastern equine encephalitis, or EEE, is a serious disease of horses and, rarely, humans. However, there was an unusual and dramatic increase in human cases in the United States in 2019. Historically, the CDC reported 72 neuroinvasive cases in the U.S. from 2009 to 2018. During those 10 years, there was an average of seven cases of neuroinvasive disease each year, with a low of three in 2009 and a high of 15 in 2012. Most cases were reported from Florida, Massachusetts, Michigan, New York and North Carolina. In 2019, the human case number was five times higher than the average, with eight states involved (see Table). Some of the affected localities even cancelled outdoor activities to reduce the risk for becoming infected. It is unclear why the increase occurred and if it will continue in future years.

The number of equine cases also was relatively high in 2019 (also shown in the Table). There were more cases reported in 2019 than in the previous 5 years. Cases in horses usually occur before those in humans — a clear warning to human health providers that the virus is being actively transmitted in that locality.

The virus

Eastern equine encephalitis virus (EEEV) is an RNA virus and a member of the genus Alphavirus, part of the family Togaviridae. EEEV is closely related to western equine encephalitis virus and Venezuelan equine encephalitis virus. There are four groups, or lineages, of EEEV. Group I, which is responsible for most human disease, is endemic in North America and the Caribbean. Groups IIA, IIB and III are found mainly in Latin America and primarily cause disease in horses and only rarely cause human disease.

EEE Table

Epidemiology

In the U.S., EEEV is actively transmitted in freshwater hardwood swamps in the Atlantic and Gulf Coast states and in the Great Lakes region. The virus circulates between birds and Culiseta melanura or Culiseta morsitans mosquitoes, in which EEEV replicates to high titers and permits efficient transmission. Because these mosquitoes are mainly passerine bird feeders and rarely feed on humans, other species of mosquitoes generally provide a bridge between the swamp ecosystems and humans and equine animals. These bridge species include Aedes vexans, Coquillettidia perturbans, Ochlerotatus canadensis and Ochlerotatus sollicitans, which occasionally feed on viremic birds and then, after several days when the virus replicates and reaches salivary glands, go on to feed on nearby people and horses, transmitting the virus to them. However, a recent study in Massachusetts indicated that C. melanura occasionally does feed on mammals and could provide a bridge for infection of humans, horses and other animals. That study isolated EEEV in high titers from Aedes cinereus mosquitoes in Connecticut and concluded that this species may serve as a bridge vector there as well. The peak incidence for EEE is in August and September.

EEE is a severe disease in horses. Up to 90% of equine animals infected with EEEV die, usually within 3 to 7 days after onset of illness. Many other mammals that can occasionally get this disease include cattle, alpacas, swine, llamas, dogs, cats, deer and goats.

Horses and humans are dead-end hosts for the EEEV because the concentration of virus in the blood is generally too low to infect biting mosquitoes.

The question remains open as to why there were so many EEE cases last year. The factors that affect EEE outbreaks are complex and interacting. EEEV transmission requires ample populations of vector mosquitoes combined with susceptible host birds. Rainfall can create mosquito breeding sites. High temperatures can accelerate the rate at which mosquito larvae grow and increase the speed at which the virus can replicate in the mosquito. Temperature and humidity can affect the longevity of individual mosquitoes and, hence, the days that they are available to transmit the virus.

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Clinical disease

Only about 4% to 5% of human EEEV infections result in encephalitis. Individuals aged younger than 15 years or older than 50 years are at greatest risk for experiencing neurologic disease. After an incubation period of 4 to 10 days following the bite of an EEEV-infected mosquito, there may be an abrupt onset of chills and fever, arthralgia, myalgia and a general feeling of malaise that can last 1 to 2 weeks. The great majority of infections then subside. In more severe cases, fever may continue with headache, irritability, restlessness, drowsiness, anorexia, vomiting, diarrhea, cyanosis, seizures, cranial nerve palsies and coma. Death may occur in about 40% of these encephalitis cases. Mild to severe neurological sequelae are common among survivors, with death occurring within a few years among the more severely affected patients.

Diagnosis

Presumptive diagnosis of EEE disease can be made on clinical grounds, especially when there have been cases recently in the region or if the patient can provide a reliable travel history placing them in an area where other cases have occurred recently. Examination of cerebrospinal fluid (CSF) usually reveals a predominance of neutrophils, especially early in the course of the disease. The protein is elevated, and the glucose is normal. CT scans and MRIs of the brain are abnormal, as are electroencephalograms. Confirmation of an EEE diagnosis requires laboratory support. Serum or CSF can be tested to detect virus-specific immunoglobulin M or neutralizing antibodies. Serologic testing can be done using IgM-capture enzyme-linked immunosorbent assay (ELISA), microsphere-based immunoassay or IgG ELISA. Tissues from autopsy can be tested by PCR for viral RNA, by histochemistry or by virus isolation. Results may not be available for 4 to 14 days, depending on the tests used and the workload in the laboratory where the samples are processed. Relatively few laboratories can carry out these tests. The CDC is the reference laboratory for EEE. Test results confirming an EEE diagnosis must be sent promptly to the state health department.

Treatment and prevention

Treatment for EEE is supportive because there is no specific recommended therapy available. There have been a limited number of case reports suggesting that IV immunoglobulin may have a positive effect on the clinical course.

Although there is an inactivated vaccine available for horses, no vaccine is commercially available for humans.

PAGE BREAK

Local governments can initiate mosquito control measures, which may involve eliminating breeding sites, treating them with insecticides to kill larvae and pupae or spraying to kill adults. Efforts should also be made to eliminate standing water in areas around houses.

Because there is no vaccine or preventive drug available for human use, the best, and really only, preventive measure available for individuals is to avoid mosquito bites, specifically: covering bare areas of skin with long sleeves and long pants, use of mosquito repellents such as DEET and use of permethrin-treated clothing, The CDC provides detailed information on repellant use and other measures to avoid mosquito bites and how to reduce mosquito breeding sites.

Summary and conclusions

EEE is a bad disease. Although there is no treatment available, preventive measures can be taken.

There may not be as many EEE cases in 2020 as there were in 2019, but it is certain the virus will not disappear from its endemic areas in the Eastern and Midwestern U.S. The public must remain aware that the risk for EEEV infection is not zero, and people should take appropriate preventive measures to “fight the bite” by protecting themselves and their family members and by vaccinating their horses.

Disclosures: Kaye and Yuill report no relevant financial disclosures.

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