History and exam

Key diagnostic factors

common

presence of risk factors

Key risk factors include working/living/travelling in wooded wetlands or swamps in endemic areas, and exposure to mosquitoes.

fever (≥37.5°C)

Reported as a presenting symptom in around 83% to 100% of patients with EEEV infection.[2][36]

Usually acute in onset.

Typically resolves in 1 to 2 weeks in the absence of neurological symptoms.

headache

Reported as a presenting symptom in around 64% to 75% of patients with EEEV infection.[2][36]

Usually acute in onset and often intense/severe, particularly if there is neurological/central nervous system (CNS) involvement.

Typically resolves in 1 to 2 weeks in the absence of neurological symptoms.

seizures

Reported on initial presentation in around 25% to 71% of patients with EEEV infection.[2][36]

A sign for neurological/CNS involvement.

Seizures are most frequently generalised in nature and less commonly partial complex.[36]

Neurological/CNS involvement is most commonly seen in those aged over 50 years or under 15 years. However, neurological involvement due to Madariaga virus (MADV) infection is more prevalent in children.[16]

Other diagnostic factors

common

nausea/vomiting

Reported as a presenting symptom in around 61% to 64% of patients with EEEV infection.[2][36]

myalgias/arthralgias

Reported as a presenting symptom in around 29% to 36% of patients with EEEV infection.[2][36]

neck stiffness (nuchal rigidity)

Reported on initial presentation in around 36% to 64% of patients with EEEV infection.[2][36]

A sign for neurological/CNS involvement.

Neurological/CNS involvement is most commonly seen in patients aged over 50 years or under 15 years. However, neurological involvement due to Madariaga virus (MADV) infection is more prevalent in children.[16]

focal weakness (decreased motor function)

Reported on initial presentation in around 3% to 23% of patients with EEEV infection.[2][36]

A sign for neurological/CNS involvement.

Neurological/CNS involvement is most commonly seen in patients aged over 50 years or under 15 years. However, neurological involvement due to Madariaga virus (MADV) infection is more prevalent in children.[16]

photophobia

Reported as a presenting symptom in around 3% to 29% of patients with EEEV infection.[2][36]

A sign for neurological/CNS involvement.

Neurological/CNS involvement is most commonly seen in patients aged over 50 years or under 15 years. However, neurological involvement due to Madariaga virus (MADV) infection is more prevalent in children.[16]

abdominal pain

Reported as a presenting symptom in around 7% to 22% of patients with EEEV infection.[2][36]

altered mental status

Confusion is reported in around 44% of patients with EEEV infection.[36]

A sign for neurological/CNS involvement.

Neurological/CNS involvement is most commonly seen in patients aged over 50 years or under 15 years. However, neurological involvement due to Madariaga virus (MADV) infection is more prevalent in children.[16]

uncommon

cranial nerve palsy

Reported on initial presentation in around 7% to 8% of patients with EEEV infection.[2][36]

A sign for neurological/CNS involvement.

Neurological/CNS involvement is most commonly seen in patients aged over 50 years or under 15 years. However, neurological involvement due to Madariaga virus (MADV) infection is more prevalent in children.[16]

tremors

A sign for neurological/CNS involvement.

Neurological/CNS involvement is most commonly seen in patients aged over 50 years or under 15 years. However, neurological involvement due to Madariaga virus (MADV) infection is more prevalent in children.[16]

drowsiness

A sign for neurological/CNS involvement.

Neurological/CNS involvement is most commonly seen in patients aged over 50 years or under 15 years. However, neurological involvement due to Madariaga virus (MADV) infection is more prevalent in children.[16]

meningismus

A sign for neurological/CNS involvement.

Neurological/CNS involvement is most commonly seen in patients aged over 50 years or under 15 years. However, neurological involvement due to Madariaga virus (MADV) infection is more prevalent in children.[16]

diarrhoea

Reported in up to 8% of patients with EEEV infection.[2][36]

Often accompanied by nausea, vomiting, and abdominal pain.

cerebral oedema

A sign for neurological/CNS involvement.

Neurological/CNS involvement is most commonly seen in patients aged over 50 years or under 15 years. However, neurological involvement due to Madariaga virus (MADV) infection is more prevalent in children.[16]

intracranial hypertension

A sign for neurological/CNS involvement.

Neurological/CNS involvement is most commonly seen in patients aged over 50 years or under 15 years. However, neurological involvement due to Madariaga virus (MADV) infection is more prevalent in children.[16]

aseptic meningitis

A sign for neurological/CNS involvement.

Neurological/CNS involvement is most commonly seen in patients aged over 50 years or under 15 years. However, neurological involvement due to Madariaga virus (MADV) infection is more prevalent in children.[16]

haemophagocytic lymphohistiocytosis

Reported in an infant with acute EEEV infection.[4] The infant had neurological injury and died.

A sign for neurological/CNS involvement.

Neurological/CNS involvement is most commonly seen in patients aged over 50 years or under 15 years. However, neurological involvement due to Madariaga virus (MADV) infection is more prevalent in children.[16]

hemiparesis

A sign for neurological/CNS involvement.

Neurological/CNS involvement is most commonly seen in patients aged over 50 years or under 15 years. However, neurological involvement due to Madariaga virus (MADV) infection is more prevalent in children.[16]

Risk factors

strong

travel/residence in endemic areas

Endemic areas include swamp/wetlands along the east coast of North America or rural/tropical areas of Central and South America.

Case reports have identified exposure to swamp and wetlands along the eastern seaboard of North America as a possible risk factor for EEEV infection.[28] This is in keeping with the known habitat of North American EEEV mosquito vectors, Culiseta melanura and Coquillettidia perturbans.[29]

EEEV has also been found in South America where it has caused human disease in eastern Panama and other Latin American countries, albeit very rarely. South American EEEV (now known as the Madariaga virus [MADV]) has a different genetic lineage to North American EEEV. It is also less virulent than North American EEEV and associated with significantly less mortality.

No epidemiological studies have been conducted to determine the risk factors for EEEV disease.

working in endemic areas

Endemic areas include swamp/wetlands along the east coast of North America or rural/tropical areas of Central and South America.

Spending long periods working outdoors in endemic areas increases the likelihood of being bitten by mosquito, which increases the risk of EEEV infection.[15]

In a serosurvey conducted in Panama, cattle ranching for >20 hours/week was found to be associated with seropositivity for Madariaga virus (MADV) infection (odds ratio [OR] 2.4 [95% CI 1.0 to 5.6]).[17]

In the same serosurvey conducted in Panama, farming was also found to be associated with seropositivity for MADV infection (OR 3.1 [95% CI 1.3 to 7.4]).[17]

No epidemiological studies have been conducted to determine the risk factors for EEEV disease.

outdoor recreational activities in endemic areas

Endemic areas include swamp/wetlands along the east coast of North America or rural/tropical areas of Central and South America.

Spending long periods doing outdoor recreational activities in endemic areas increases the likelihood of being bitten by mosquito, which increases the risk of EEEV infection.[15]

In a serosurvey conducted in Panama, fishing >10 hours/week was found to be associated with seropositivity for Madariaga virus (MADV) infection.[17]

No epidemiological studies have been conducted to determine the risk factors for EEEV disease.

seasonal factors favouring breeding of mosquitoes

Most cases of EEEV infection occur from late spring through to early autumn, but very rarely cases have been reported in winter in subtropical endemic areas (e.g., the Gulf coast of the US).[15]

age <15 years or >50 years

Neurological/central nervous system involvement (e.g., encephalitis) and severe disease is most commonly seen in those aged under 15 years or over 50 years. However, neurological involvement due to Madariaga virus (MADV) infection is more prevalent in children.[16]

occupational exposure (laboratory)

Animal studies have demonstrated that aerosol transmission of EEEV, in addition to subcutaneous injection, is possible.[30][31]

Handling high virus concentrations, mouth pipetting, and engaging in activities that generate aerosols (e.g. tissue homogenisation, centrifugation) are risk factors for occupational infection in the laboratory setting.

weak

bioterrorism

EEEV is considered a potential bioterrorism weapon as it can be produced in large amounts in aerosolised form.

In the US, EEEV (and other alphaviruses) is classified as a Category B agent by the Centers for Disease Control and Prevention (CDC), which is the second highest threat category.

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