Arboviruses

Dx
Background
Lab Tests

Diagnosis

Indications for Testing

Patient with meningitis/encephalitis presenting during mosquito season

Laboratory Testing

Initial testing
- CBC with differential – lacks sensitivity/specificity but may aid in ruling out bacterial etiology
- Cerebrospinal fluid (CSF)
  - Cell count
  - Gram stain with culture
  - Culture – limited use because of low sensitivity
  - CNS disease – consider ordering multiple panel tests on CSF and serum to rule out other viral illnesses (eg, varicella-zoster virus [VZV], herpes simplex virus [HSV])
  - Protein
  - Glucose
  - Cellular profiles
    - WNV
      - Lymphocytic pleocytosis <1,000 cells/mm³
      - Neutrophils may predominate in early infections
      - Protein – moderately increased
      - Glucose – normal
    - St. Louis encephalitis
      - Lymphocytic pleocytosis <200 cells/mm³
      - Protein – >200 mg/dL in majority
      - Glucose – normal
    - Bunyavirus
      - Lymphocytic pleocytosis <200 cells/mm³
      - Protein – mildly increased
    - Togavirus
      - Lymphocytic pleocytosis 1,200-2,000 cells/mm³
      - Protein – elevated
      - May have increased CSF opening pressure
Serum or CSF antibody testing
- Majority of cases are diagnosed by serology
- Best evidence for infection is a significant change (fourfold increase) in titer on two appropriately timed specimens done at the same laboratory
  - Appropriate timing – acute and convalescent samples ≥2 weeks apart
  - IgG usually negative in first 2 weeks of infection
  - Positive IgG without increase in convalescent sample and/or with negative IgM may indicate past exposure

Imaging Studies

MRI more sensitive than CT
- MRI may be normal
- Findings vary but include increased T2 signal in basal ganglia, thalamus, and brainstem
- If patient has focal neurologic signs and symptoms, MRI or CT should be performed prior to lumbar tap

Other Tests

EEG – if patient has seizures or is comatose
- May show diffuse slow waves, focal sharp waves, seizures
- No specific findings for viral encephalitis

Differential Diagnosis

Infectious
- Viral
  - HSV
  - VZV
  - Enterovirus
  - Rubeola
  - Rabies
  - Dengue fever
  - Colorado tick fever
- Bacterial
- Parasitic
- Meningitis
- Brain abscess
Tumor
- Metastatic disease
- Brain tumor
Vasculitis
- Systemic lupus erythematosus
- Behçet disease
Demyelinating disease
- JC virus
- Paraneoplastic syndrome

Clinical Background

Arthropod-borne viruses are transmitted to humans by arthropod bites and cause a spectrum of disease, from a mild viral syndrome to encephalitis.

Epidemiology

Prevalence
- >300 cases reported annually in U.S.
- Seasonal – April to October
Age – young children and elderly more likely to have severe disease
Transmission – mosquito bite

Organisms

More than 500 species of arbovirus
RNA viruses of importance in the U.S. include the following
- Bunyavirus – California encephalitis (CE) serogroup
  - La Crosse virus
    - Primarily in upper Mississippi River valley
  - Jamestown Canyon virus
    - Upper midwestern states and New York
  - Snowshoe hare virus
    - Southern Canada
  - Mosquito species
    - Aedes triseriatus
- Flavivirus
  - St. Louis encephalitis
    - Present in nearly all of the U.S.
    - Mosquito species
      - Culex pipiens and C. quinquefasciatus
        Gulf Coast; Ohio and Mississippi River valleys
      - C. nigripalpus
        Florida
      - C. tarsalis
        Western states
  - Japanese encephalitis (JE) virus
    - Leading cause of viral encephalitis in Asia
    - Rare in U.S.
    - Mosquito-borne Culex tritaeniorhynchus group
  - West Nile virus encephalitis (WNV)
    - Endemic in U.S.
    - Mosquito species
      - C. tarsalis
    - Refer to Dengue fever virus for more information
- Togaviruses
  - Eastern equine encephalitis (EEE)
    - Present in the eastern half of the U.S.
    - Mosquito species
      - Aedes vexans, Coquillettidia perturbans, Ochlerotatus sollicitans and canadensis
  - Western equine encephalitis (WEE)
    - Present in western and midwestern U.S.
    - Mosquito species
      - C. tarsalis

Risk Factors

Older age
Outdoor activity during peak mosquito activity (morning and evening)

Clinical Presentation

Commonly asymptomatic
Nonspecific flu-like symptoms/illness
- Fever
- Headache
- Myalgias
- Nausea, anorexia
- Cough
- Sore throat
Acute encephalitis (neuro-invasive disease)
- Lasts a few days to months with slow and sometimes incomplete recovery
- EEE has more abrupt onset and shorter, more severe course than arbovirus encephalitides
- Presentation begins as nonspecific illness but progresses to any of the following
  - Cognitive dysfunction
  - Memory impairment
  - Muscle weakness
  - Paralysis
  - Seizures
  - Coma
WNV
- Acute flaccid paralysis can occur
  - Causes poliomyelitis-like syndrome with involvement of anterior horn cells in spinal cord
  - Meningo encephalitis occasionally complicates disease
  - Mortality – 5-20% in affected patients
    - Up to 70% in affected patients >75 years

Treatment

Supportive care
Recovery may be prolonged

Indications for Laboratory Testing

Tests generally appear in the order most useful for common clinical situations
Click on number for test-specific information in the ARUP Laboratory Test Directory

Test Name and Number	Recommended Use	Limitations	Follow Up
CBC with Platelet Count and Automated Differential 0040003 Method: Automated Cell Count/Differential	Initial evaluation of white blood cell count and differential in infectious diseases	Findings not specific for arbovirus infections
Cell Count, CSF 0095018 Method: Cell Count/Differential	Evaluation of white blood cell count and differential in suspected infectious meningitis/encephalitis	Findings not specific for arbovirus infections
Protein, Total, CSF 0020514 Method: Reflectance Spectrophotometry	Evaluation of protein level in suspected infectious meningitis/encephalitis	Findings not specific for arbovirus infections
Cerebrospinal Fluid (CSF) Culture and Gram Stain 0060106 Method: Stain/Culture/Identification	Identify agent of presumed meningitis
Glucose, CSF 0020515 Method: Enzymatic	Help differentiate viral from bacterial source
Meningoencephalitis Panel, Serum with Reflex to HSV Type 1 and Type 2 Glycoprotein G-Specific Ab, IgG 2001764 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Chemiluminescent Immunoassay	Evaluate patients presenting with possible meningitis/encephalitis Panel includes CE, EEE, St. Louis encephalitis, WEE, WNV, measles, mumps, VZV, HSV types 1 and 2, and lymphocytic choriomeningitis (LCM) antibodies	May be cross-reactive positivity in tests for related viruses (eg, flaviviruses)
Meningoencephalitis Panel, CSF with Reflex to HSV Type 1 and Type 2 Glycoprotein G-Specific Ab, IgG 2001765 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Chemiluminescent Immunoassay	Evaluate patients presenting with possible meningitis/encephalitis Panel includes CE, EEE, St. Louis encephalitis, WEE, WNV, measles, mumps, VZV, HSV types 1 and 2, and LCM antibodies	May be cross-reactive positivity in tests for related viruses (eg, flaviviruses)
Arbovirus Antibodies, IgG and IgM, Serum 2001594 Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Enzyme-Linked Immunosorbent Assay	Panel includes St. Louis encephalitis, WNV, EEE, and WEE antibodies	May be cross-reactive positivity in tests for related viruses (eg, flaviviruses)
Arbovirus Antibodies, IgG and IgM, CSF 2001597 Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Enzyme-Linked Immunosorbent Assay	Panel includes St. Louis encephalitis, WNV, EEE, and WEE antibodies	May be cross-reactive positivity in tests for related viruses (eg, flaviviruses)
West Nile Virus Antibodies, IgG and IgM by ELISA, Serum 0050226 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay	Detect WNV-specific IgG and IgM, with a clinical suspicion of WNV	Because other members of the Flaviviridae family (St. Louis encephalitis virus or Dengue fever virus) show extensive cross-reactivity with WNV, serologic testing specific for these species should also be performed Results must be correlated with clinical history and other data	Repeat in 10-14 days if results equivocal
West Nile Virus RNA by RT-PCR 0050229 Method: Qualitative Reverse Transcription Polymerase Chain Reaction	Confirm positive antibodies test or clarify equivocal serologic test results
Japanese Encephalitis Virus Antibodies, IgG and IgM by ELISA 2005689 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay	Detection of antibodies indicates current or past infection		Repeat testing in 10-14 days if results are equivocal

Additional Tests Available

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Arbovirus Antibodies, IgM, Serum 2001592 Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Arbovirus Antibodies, IgG, Serum 2001593 Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Arbovirus Antibodies, IgM, CSF 2001595 Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Arbovirus Antibodies, IgG, CSF 2001596 Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Enzyme-Linked Immunosorbent Assay
California Encephalitis Antibody, IgM by IFA, Serum 0098731 Method: Semi-Quantitative Indirect Fluorescent Antibody
California Encephalitis Antibody, IgG by IFA, Serum 0050508 Method: Semi-Quantitative Indirect Fluorescent Antibody
California Encephalitis Antibody, IgM by IFA, CSF 0098898 Method: Semi-Quantitative Indirect Fluorescent Antibody
California Encephalitis Antibody, IgG by IFA, CSF 0098893 Method: Semi-Quantitative Indirect Fluorescent Antibody
Eastern Equine Encephalitis Antibody, IgM by IFA, Serum 0098733 Method: Semi-Quantitative Indirect Fluorescent Antibody
Eastern Equine Encephalitis Antibody, IgG by IFA, Serum 0050509 Method: Semi-Quantitative Indirect Fluorescent Antibody
Eastern Equine Encephalitis Antibody, IgM by IFA, CSF 0098729 Method: Semi-Quantitative Indirect Fluorescent Antibody
Eastern Equine Encephalitis Antibody, IgG by IFA, CSF 0098896 Method: Semi-Quantitative Indirect Fluorescent Antibody
Japanese Encephalitis Virus Antibody, IgG by ELISA 2005687 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Japanese Encephalitis Virus Antibody, IgM by ELISA 2005685 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay
St. Louis Encephalitis Antibody, IgG by IFA, CSF 0098895 Method: Semi-Quantitative Indirect Fluorescent Antibody
St. Louis Encephalitis Antibody, IgG by IFA, Serum 0050507 Method: Semi-Quantitative Indirect Fluorescent Antibody
West Nile Virus Antibody, IgM by ELISA, Serum 0050236 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay
West Nile Virus Antibody, IgG by ELISA, Serum 0050234 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay
West Nile Virus Antibodies, IgG and IgM by ELISA, CSF 0050228 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay
West Nile Virus Antibody, IgG by ELISA, CSF 0050238 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay
West Nile Virus Antibody, IgM by ELISA, CSF 0050239 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Western Equine Encephalitis Antibody, IgM by IFA, Serum 0098734 Method: Semi-Quantitative Indirect Fluorescent Antibody
Western Equine Encephalitis, Antibody, IgM by IFA, CSF 0098730 Method: Semi-Quantitative Indirect Fluorescent Antibody
Western Equine Encephalitis Antibody, IgG by IFA, CSF 0098897 Method: Semi-Quantitative Indirect Fluorescent Antibody
Western Equine Encephalitis Antibody, IgG by IFA, Serum 0050514 Method: Semi-Quantitative Indirect Fluorescent Antibody