West Nile Virus

West Nile virus
Straight to the point of care
Last updated: Aug 10, 2023

Table of Contents
Overview 3
Summary 3
Definition 3
Theory 4
Epidemiology 4
Aetiology 4
Pathophysiology 5
Classification 5
Case history 5
Diagnosis 7
Approach 7
History and exam 9
Risk factors 12
Investigations 13
Differentials 15
Criteria 19
Management 21
Approach 21
Treatment algorithm overview 21
Treatment algorithm 23
Emerging 25
Primary prevention 25
Secondary prevention 25
Patient discussions 25
Follow up 26
Monitoring 26
Complications 27
Prognosis 28
Guidelines 29
Diagnostic guidelines 29
Treatment guidelines 29
Online resources 30
References 31
Disclaimer 40
West Nile virus Overview
Summary
West Nile virus is a notifiable condition. Standard precautions should be taken when handling blood, blood
products, or other body fluids that might be infected.
OVERVIEW
Most infections are asymptomatic; however, about 20% of people develop a self-limiting, influenza-like
illness. Of these patients, < 1% progress to neuroinvasive disease characterised by encephalitis, meningitis,
or flaccid paralysis syndrome (known as West Nile poliomyelitis).
Diagnosis is confirmed with serological testing in patients with suspected neuroinvasive disease. IgM can be
detected in most serum and cerebrospinal fluid (CSF) specimens at the time of clinical presentation.
Treatment is supportive. Patients with neuroinvasive disease require hospitalisation, respiratory support, and
intravenous fluids. No vaccine or specific antiviral treatment is available.
Definition
An infection caused by West Nile virus (WNV), a flavivirus of the family Flaviviridae, that is transmitted to
humans by mosquito bites or through contact with infected blood. The majority of cases are asymptomatic,
but infection can cause a self-limited influenza-like illness (West Nile fever or WNF) or, rarely, West Nile
neuroinvasive disease (WNND). Kunjin virus is a subtype of West Nile virus endemic to Oceania.
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West Nile virus Theory
Epidemiology
West Nile virus (WNV) has caused human infection in Africa, Europe, the Middle East, west and central Asia,
Oceania, and North America.[3] [4] It first appeared in the western hemisphere as an outbreak of encephalitis
THEORY
in New York City in 1999. Between 1999 and 2004, the disease spread across the US, into Canada, and to
the Caribbean islands and Latin America.[5] [6] Even in areas with abundant WNV-carrying mosquitoes, the
overall prevalence of infection has not exceeded 5%.[1]
In the US, 1126 human cases were reported in 2022, with 72.5% of cases classified as neuroinvasive
disease, and 89 deaths (an 8% case fatality rate). [CDC: West Nile virus data and maps] (https://
www.cdc.gov/westnile/statsmaps/data-and-maps.html) The incidence of neuroinvasive disease was nearly
25% higher in 2018 compared to the median incidence between 2008 and 2017, although in 2020, the
incidence of neuroinvasive disease incidence did drop by 59% compared to the median annual incidence
from 2010 through 2019.[7] West Nile virus is the most common cause of neuroinvasive arboviral disease in
the US, accounting for 92% of reported cases.[8] The largest outbreak in a US county occurred during May
to December 2021 in Maricopa county, Arizona (1487 cases and 101 deaths, a 6.8% case fatality rate). The
majority of cases occurred in older adults ≥60 years of age, and 64% of cases had neuroinvasive disease.[9]
[CDC: West Nile virus data and maps] (https://www.cdc.gov/westnile/statsmaps/data-and-maps.html)
A total of 1340 human cases were reported in the European Union and its neighbouring countries in 2022,
with 104 deaths (a 7.8% case fatality rate). This is the highest reported number of locally acquired cases
since the peak epidemic year in 2018.[10] The geographical range of human cases of WNV has also been
expanding to more northern and western parts of Europe, including detection of the virus in a bird and Culex
mosquitoes in the Netherlands in August and September 2020, and subsequently a human case in October
2020.[11]
Virus activity correlates with mosquito activity: in temperate regions, virus activity is highest from July to
October, and in warmer climates such as the southern US, virus activity is high year round. Age and immune
status do not seem to affect susceptibility to infection. However, older or immunocompromised individuals are
at higher risk of neuroinvasive disease.[12] There is no clear evidence of a predilection for either sex.
Aetiology
West Nile virus is an enveloped, spherical, single-stranded RNA arbovirus of the family Flaviviridae, which
belongs to the Japanese encephalitis complex. Other flaviviruses include yellow fever, dengue, Zika, and St.
Louis encephalitis viruses.[13] Kunjin virus is a sub-type of West Nile virus endemic to Oceania.
The virus primarily circulates between infected birds (>130 different species) and the insects that bite them,
usually female mosquitoes. The infected mosquitoes transmit the virus when they bite other animals (e.g.,
horses) or people.[12]
Rarely, the virus can be transmitted by transfusion of infected blood, transplantation of infected organs,
or transplacentally from mother to fetus. Other uncommon routes of transmission are needle-stick injuries
involving infected blood, exposure of the conjunctiva to infected blood, dialysis, or breast-feeding.[14] [15]
[16] [17] [18] [19]
4 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Aug 10, 2023.
Pathophysiology
The typical incubation period is between 2 and 6 days and may last up to 14 days.[20] The incubation period
can last even longer (up to 21 days) in immunocompromised patients.[16] After the mosquito injects virus-
THEORY
laden saliva into the patient, the virus probably replicates in dendritic cells at the bite site and then spreads to
lymph nodes and the bloodstream. Alternatively, the virus may enter the body through exposure to infected
blood or organ transplants. The pathogenesis of severe infection is not well understood. In neuroinvasive
disease, the virus crosses the blood-brain barrier into the central nervous system and directly infects
neurons, especially in the deep nuclei and grey matter of the brain, brain stem, and spinal cord, causing
neuronal inflammation, destruction, and death. The immune response to the virus may also contribute to
neuronal damage. Demyelination and gliosis may occur in prolonged disease.[21] [22] [23]
Classification
Clinical classification
West Nile virus infection is usually classified based on its presentation, although there is no formal
classification system.
• West Nile fever (WNF): occurs in approximately 20% of patients and is characterised by an influenza-
like illness that usually lasts 3 to 6 days but can persist for weeks or months.
• West Nile neuroinvasive disease (WNND): occurs in <1% of patients when the virus infects the central
nervous system.[1] Subtypes include:
• West Nile virus encephalitis

• West Nile virus meningitis
• West Nile virus poliomyelitis (or acute flaccid paralysis).
Case history
Case history #1
A 50-year-old man presents with a history of a sudden onset of fever, headache, fatigue, myalgia, and
generalised arthralgia. He has spent much of the summer months outdoors and recalls being bitten by
mosquitoes. On examination, the patient is pyrexial, has a maculopapular rash involving the trunk and
extremities, and has sub-mental lymphadenopathy.
Other presentations
Patients may also present with ocular symptoms (e.g., eye pain, visual disturbances, conjunctival
injection, multi-focal chorioretinal lesions, retinal haemorrhages), pharyngitis, generalised muscle
weakness, nausea/vomiting, splenomegaly, or signs and symptoms of complications including
pancreatitis (e.g., epigastric pain), myocarditis (e.g., dyspnoea, chest pain, palpitations), or hepatitis (e.g.,
right upper quadrant pain, jaundice).
5
Rarely, patients may develop neuroinvasive disease, which can present with signs and symptoms of
encephalitis (e.g., stupor, coma), meningitis (e.g., photophobia, stiff neck, Kernig's sign, Brudzinski's
sign), or West Nile poliomyelitis (i.e., a syndrome characterised by acute flaccid paralysis that resembles
poliomyelitis).
THEORY
Hepatitis, pancreatitis, and myocarditis are all rare complications.
Cases of congenital infection have been reported in pregnant women who are infected with West Nile
virus during pregnancy; however, the risk for adverse pregnancy and newborn outcomes appears to be
low.[2]
West Nile virus Diagnosis
Approach
Diagnosis is generally based on the history and physical examination; however, serological testing and
neuroimaging are recommended in patients with suspected neuroinvasive disease. West Nile virus infection
should be considered in any person with a febrile or acute neurological illness who has had recent mosquito
exposure, organ transplantation, or a blood transfusion.[20]
As the clinical features of infection are relatively non-specific, exposure history and public health information
regarding outbreaks aids interpretation of the clinical findings. Other causes of encephalitis and meningitis
should be considered in the differential diagnosis. West Nile virus encephalitis, meningitis, and poliomyelitis
are clinically indistinguishable from encephalitis, meningitis, and poliomyelitis due to other aetiologies.[20]
West Nile virus infection is a notifiable condition in some countries.
History
Ask the patient about a history of exposure to mosquitoes in areas of known West Nile virus (WNV)
transmission. Cases have been reported in Europe, the Middle East, Africa, parts of Asia including India,
North America, parts of Central America, and the Caribbean. Cases have also been reported in Australia;
however, infection is due to the Kunjin virus, a WNV sub-type. Rarely, there may be a history of blood
transfusion, needlestick injury, organ transplant, or illness in neonates whose mothers were infected with
WNV during pregnancy or while breastfeeding.[3] [4] [33]
Approximately 70% to 80% of people who are infected remain asymptomatic or subclinical.[20] Most
of the remaining patients develop an influenza-like illness that usually lasts 3 to 6 days, but can persist
for weeks or months (known as West Nile fever or WNF). Symptoms include headache, malaise, fever,
anorexia, abdominal pain, nausea, vomiting, generalised muscle weakness, myalgia and arthralgia, and
pharyngitis. The patient may also complain of visual disturbances, such as visual blurring, floaters, or eye
pain.[1]
West Nile neuroinvasive disease (WNND) occurs in <1% of patients with WNF, and can present with
DIAGNOSIS
signs and symptoms of encephalitis, meningitis, or poliomyelitis (acute flaccid paralysis).[20] Symptoms
include sudden onset of fever, severe headache, photophobia, seizures, mental status changes (e.g.,
depression, confusion, disorientation, memory loss), severe muscle weakness, or respiratory distress.[1]
Older or immunocompromised people are at higher risk of developing neuroinvasive disease.[12]
Hepatitis, pancreatitis, and myocarditis are all rare complications. Symptoms include right upper quadrant
abdominal pain (hepatitis), epigastric pain (pancreatitis), or chest pain, dyspnoea, and palpitations
(myocarditis).
Cases of congenital infection have been reported in pregnant women who are infected with West Nile
virus during pregnancy; however, the risk for adverse pregnancy and newborn outcomes appears to be
low.[2]
Physical examination
Patients with WNF may present with a morbilliform or maculopapular rash over the trunk and extremities.
Lymphadenopathy (typically submental) and splenomegaly may be present. Epigastric pain or tenderness
may indicate pancreatitis, while jaundice usually indicates hepatitis.
7
Perform an ophthalmoscopic examination in all suspected cases. This may reveal conjunctival injection,
retinal haemorrhages, multi-focal chorioretinal lesions (clustered in temporal and nasal regions of the
fundus periphery), chorioretinitis, and inflammatory vitritis.[34]
Movement disorders, including tremors, ataxia, myoclonus, and parkinsonism, are suggestive of
neuroinvasive disease. Neck stiffness and positive Kernig's and Brudzinski's signs indicate meningitis.
Confusion, which can progress to stupor or coma, indicates encephalitis. While generalised muscle
weakness occurs in patients with WNF, the paralysis in West Nile poliomyelitis is usually an asymmetric,
flaccid paralysis that affects the extremities and respiratory muscles. Cranial nerve palsies and bladder/
bowel dysfunction can occur in patients with poliomyelitis.[35]
Laboratory investigations
No investigations are required in patients with influenza-like symptoms (e.g., fever and headache) as the
diagnosis is clinical. If neuroinvasive disease is suspected, serological testing is required.
Test cerebrospinal fluid (CSF) for the presence of WNV-specific IgM antibodies using capture ELISA
(MAC-ELISA). The diagnosis is confirmed if the sample is positive. If the result is equivocal, or if there
is a history of exposure to other flaviviruses such as yellow fever virus, Japanese encephalitis virus, or
dengue virus (e.g., through infection or vaccination), confirm the diagnosis with CSF plaque reduction
neutralisation test (PRNT).[36]
If the diagnosis is in doubt, or if a CSF sample is not available, test paired serum samples. The first
sample should be taken during the acute phase of infection (initial presentation), with the second
sample taken during the convalescent phase (7 to 10 days later).[36] A 4-fold rise in titre between
the two samples confirms infection. If the result is equivocal, or if there is a history of exposure to
other flaviviruses, use PRNT to differentiate between WNV-specific antibodies and antibodies to other
flaviviruses. A positive result in a single serum sample indicates acute or previous infection, but does not
confirm infection as IgM antibodies can persist in serum for > 1 year. If no convalescent serum sample
is available, a positive result in a single serum sample (in addition to the presence of clinical signs and
symptoms) suggests probable WNV infection.[3] [21] [33] [37] [38] [39] [40]
DIAGNOSIS
Routine clinical laboratory investigations are generally non-specific.[20] Order liver function tests and
serum amylase/lipase in patients with suspected hepatitis or pancreatitis (i.e., patients with abdominal
pain or jaundice). Order a complete blood count in patients with symptoms of neuroinvasive disease. This
may show leukocytosis, anaemia, lymphopenia, or thrombocytopenia. Serum electrolytes may reveal
hyponatraemia. Perform a lumbar puncture in patients with suspected neuroinvasive disease.[38]
Viral cultures and tests to detect viral RNA (e.g., reverse transcriptase-polymerase chain reaction [RT-
PCR]) can be performed on blood, serum, CSF, or tissue samples; however, these tests are difficult
to perform, have low yield, and require laboratories with proper biosafety containment facilities, so are
generally not recommended. However, they can be used to confirm infection early in the course of illness
if necessary. One study found that RT-PCR can identify WNV RNA in 86% of whole-blood samples during
acute infection.[41] A negative result does not rule out infection.[3] [37] [42]
Imaging
Cranial imaging is necessary only to rule out other causes of neurological symptoms. Although MRI
is preferable, a CT scan is usually more readily available. Neuroimaging cannot confirm infection or
neuroinvasive disease, but it can help exclude other causes of meningitis, encephalitis, and flaccid
paralysis. CT scan of the head is usually normal. Brain MRI may be normal, even in severe encephalitis,
or demonstrate prominent signal abnormalities in the deep grey matter (posterior thalami and basal
ganglia) and/or cerebellum.[43]
History and exam

Key diagnostic factors
fever of sudden onset (common)
• Can occur in West Nile fever or neuroinvasive disease.
malaise (common)
• Can occur in West Nile fever.
myalgia (common)
arthralgia (common)
pharyngitis (common)
anorexia (common)
abdominal pain (common)

• Usually mild to moderate. Right upper quadrant pain suggests hepatitis, whereas epigastric pain
DIAGNOSIS
suggests that pancreatitis may be present.[44]
visual disturbances (common)

• Can occur in West Nile fever. Includes gradual visual blurring and loss, floaters and flashes, and eye
pain.[34]
headache (common)
• Mild to moderate headache occurs in West Nile fever. Severe headache raises suspicion of West Nile
meningitis or West Nile encephalitis.[43]
rash (common)
• Rash has been reported in 16% to 27% of patients with West Nile fever (WNF).[48] [49] More frequent
in WNF than in neuroinvasive disease. Transient (in some cases lasting <24 hours). Morbilliform,
maculopapular, non-blanching, and non-pruritic rash on the neck, torso, and extremities, sparing the
palms and soles. More frequent in younger than older patients.[50]
lymphadenopathy (common)
• Lymphadenopathy is often sub-mental.[44]
9
conjunctival injection (common)
• Seen in West Nile fever as well as neuroinvasive disease.
multi-focal chorioretinal lesions (common)

• Clustered in temporal and nasal regions of fundus periphery.[34]
chorioretinitis and inflammatory vitritis (common)

• Eye pain or redness, patient sees floating black spots/dots/streaks, light sensitivity, and excessive
tearing or blurred vision.
seizures (uncommon)
• Occur in West Nile encephalitis.[43]
respiratory distress (uncommon)

• May indicate West Nile poliomyelitis with respiratory muscle paralysis.[46] [47]
jaundice (uncommon)
• Raises suspicion of hepatitis or pancreatitis (which in some cases can cause jaundice).[51]
epigastric tenderness (uncommon)

• Raises suspicion of pancreatitis.[52]
mild confusion (uncommon)

• Raises suspicion of neuroinvasive disease.[53]
disorientation (uncommon)
stupor/coma (uncommon)
DIAGNOSIS
neck stiffness (uncommon)

• May indicate West Nile meningitis.[43]
Kernig's sign (uncommon)

• May indicate West Nile meningitis.[43] There is pain and resistance on attempting to extend the leg at
the knee with the thigh flexed at the hip.
Brudzinski's sign (uncommon)

• May indicate West Nile meningitis.[43] Neck flexion results in knee and hip flexion.
muscle paralysis (uncommon)

• Must distinguish between generalised muscle weakness associated with West Nile fever and flaccid
paralysis associated with West Nile poliomyelitis. The paralysis in West Nile poliomyelitis is usually
asymmetrical.
• Rarely, Guillain-Barre syndrome may develop.[54] [55] [56] Rhabdomyolysis and myositis have been
reported.[45]
parkinsonism (uncommon)
• May be seen in West Nile encephalitis or West Nile meningitis. May persist after infection has
resolved.[43]
ataxia (uncommon)
resolved.[43]
myoclonus (uncommon)
resolved.[43]
tremors (uncommon)
resolved.[43]
Other diagnostic factors

nausea/vomiting (common)
• Presence may suggest more severe disease.
generalised muscle weakness (common)

• Must distinguish between generalised muscle weakness associated with West Nile fever and flaccid
paralysis associated with West Nile poliomyelitis.
splenomegaly (common)
• More suggestive of West Nile fever than other viral infections, such as influenza or parainfluenza, that
are more common.
retinal haemorrhages (common)
DIAGNOSIS
• More suggestive of West Nile fever than other viral infections, such as influenza or parainfluenza, that
are more common.
chest pain, dyspnoea, palpitations (uncommon)

• Raises suspicion of myocarditis.[45]
photophobia (uncommon)
• May indicate West Nile meningitis.
depression (uncommon)
• Seen in neuroinvasive disease.[53]
loss of memory (uncommon)

• Seen in neuroinvasive disease. Word-finding difficulties may also occur and persist.[53]
bowel and bladder dysfunction (uncommon)

• Can occur in West Nile poliomyelitis.
11
cranial nerve palsies (uncommon)
• Can occur in West Nile poliomyelitis.
Risk factors
Strong
living in/visiting areas with high West Nile virus activity
• Cases have occurred in Europe, the Middle East, Africa, parts of Asia including India, Australia (due
to Kunjin virus, a sub-type of West Nile virus), North America, parts of Central America, and the
Caribbean.[3] [4]
mosquito bites
• Outdoor activities between dusk and dawn and having exposed skin while being outdoors increases
the risk of mosquito bites, especially in areas where there is significant vegetation or stagnant
water.[12]
• In temperate regions, mosquito activity and the risk of infection is greatest from the late spring to the
late summer/early autumn. In warmer climates, mosquito activity may be year-round.
blood transfusion
• Estimated risk of virus transmission ranged from 1.46 to 12.33 per 10,000 donations during the 2002
epidemic.[17]
organ transplant
• First documented case of virus transmission through organ transplantation was in 2002. Four cases
occurred in Toronto and 4 more in the south-eastern US in 2002.[16] [24] Three more cases were
reported in New York and Pennsylvania in 2005.[25] Other individual cases have been documented in
the US in 2013 and 2018.[8] [16]
DIAGNOSIS
needle-stick injuries
• Virus transmission has occurred through needle-stick injuries.[15]
Investigations
1st test to order
Test Result
serology positive result in CSF
sample or a 4-fold rise in
• Order when neuroinvasive disease is suspected. West Nile virus-
titre between two paired
specific IgM antibodies are identified using capture ELISA (MAC-
serum samples confirms
ELISA). Results are usually available in 24 to 48 hours.
• Cerebrospinal fluid (CSF) is the preferred sample. Paired serum neuroinvasive disease
samples are recommended only if a CSF sample is not available,
or the diagnosis is in doubt. One serum sample should be collected
during the initial presentation and another during the convalescent
phase (7 to 10 days later).[36] A positive IgM result in a single serum
sample indicates either acute or previous infection.
• Occasionally, IgM antibodies may persist in the CSF long after acute
infection. Serum IgM antibodies can persist for > 1 year. Sensitivity is
nearly 100% after the eighth day of illness.[3] [37][38][39] [40]
• Order a plaque reduction neutralisation test (PRNT) on CSF or
serum if the MAC-ELISA result is equivocal, or if the patient has
been exposed to other flaviviruses that can cause a false positive
result (e.g., yellow fever virus, Japanese encephalitis virus, dengue
virus).[3] [37][38][39] [40]
cerebrospinal fluid (CSF) analysis elevated protein;
elevated cell count;
• Order when neuroinvasive disease is suspected. Does not establish
polymorphonuclear
diagnosis, but suggests viral aetiology.[57] [58]
leukocytes or lymphocytic
predominance; decreased
glucose
full blood count may show leukocytosis,

anaemia, lymphopenia,
• Order when neuroinvasive disease is suspected.
thrombocytopenia
DIAGNOSIS
serum electrolytes may show hyponatraemia
• Order when neuroinvasive disease is suspected.
liver function tests elevated
• Order when moderate to severe abdominal pain (especially right
upper quadrant pain) or jaundice is present.[4] If elevated, this
suggests hepatitis, a rare complication.
serum amylase/lipase elevated
• Order when moderate to severe abdominal pain (especially
epigastric) or jaundice is present.[52] If elevated, this suggests
pancreatitis, a rare complication.
13
Other tests to consider
Test Result
MRI brain may be normal or may
show prominent signal
• Perform if suspicious of other causes of neurological symptoms.[43]
abnormalities in the
Not diagnostic, but can help to exclude other causes of meningitis,
deep grey mat ter and/or
encephalitis, and flaccid paralysis. Can also identify stroke, abscess,
cerebellum
or other mass.
• MRI is preferred over CT; however, CT is usually more readily
available.
CT head usually normal
• Perform if suspicious of other causes of neurological symptoms.[43]
Not diagnostic, but can help to exclude other causes of meningitis,
encephalitis, and flaccid paralysis. Can also identify stroke, abscess,
or other mass.
viral culture or reverse transcriptase-polymerase chain reaction virus isolation or viral
(RT-PCR) RNA detected
• Can be performed on blood, serum, CSF, or tissue samples;
however, these tests are difficult to perform, have low yield, and
require laboratories with proper biosafety containment facilities,
so are generally not recommended. However, they can be used to
confirm infection early in the course of illness if necessary. A negative
result does not rule out infection.[3] [37] [42]
DIAGNOSIS
Differentials
Condition Differentiating signs / Differentiating tests

symptoms
Herpes simplex • No differentiating signs and • Cerebrospinal fluid (CSF)
encephalitis symptoms. polymerase chain reaction
(PCR): positive for herpes
simplex virus RNA.
• MRI/CT head: shows focal
temporal lobe abnormalities.
• Electroencephalogram:
periodic lateralising
epileptiform discharges.[59]
[60]
St. Louis encephalitis • No differentiating signs and • Serology: 4-fold increase in

symptoms. virus antibody titre between
acute and convalescent
serum; detectable IgM
antibodies to virus in a single
serum or cerebrospinal
fluid (CSF) sample. Plaque
reduction neutralisation
test (PRNT) can delineate
West Nile virus from other
zoonoform viral infections.
• Virus isolation: virus can be
isolated from tissue, blood,
or CSF.[61] [62]
Eastern equine • No differentiating signs and • Serology: 4-fold increase in

encephalitis symptoms. virus antibody titre between
DIAGNOSIS
serum or CSF sample.
or CSF.[62]
Western equine • No differentiating signs and • Serology: 4-fold increase in

encephalitis symptoms. virus antibody titre between
serum or CSF sample.
or CSF.[62]
Viral meningitis (other • No differentiating signs and • CSF PCR or viral culture:
aetiology) symptoms. positive for the causative
virus and negative for
West Nile virus. However,
a negative PCR does not
15

symptoms
necessarily exclude viral
meningitis.
Bacterial meningitis • No differentiating signs and • CSF analysis: high protein,

symptoms. low glucose, CSF Gram
stain positive for specific
organisms.[63]
Cryptococcal meningitis • Always suspect in people • Cryptococcal polysaccharide

with a compromised antigen: positive in serum or
immune system (e.g., AIDS, CSF.
lymphoma). • Culture: positive for
Cryptococcus neoformans in
serum or CSF.
• CSF microscopy: India
ink stain detects the
organism.[64]
Tuberculous meningitis • No clear differentiating signs • CSF PCR: detection of acid-

and symptoms. fast bacilli.
• CT/MRI head: can show
cerebral tuberculomas or
basilar arachnoiditis.[65]
Guillain-Barre syndrome • Typically presents 1 to 8 • Diagnosis is usually

weeks following acute viral clinical.[66]
infection. • CSF analysis: shows
• There is no fever or elevated protein, no elevated
leukocytosis. cell count.
• Ascending symmetrical
weakness.
• No bowel or bladder
dysfunction.
• No concurrent
DIAGNOSIS
encephalopathy.
Poliovirus-associated • Residence or travel in • Virus culture (stool, CSF,

poliomyelitis endemic area. or pharynx): positive for
• Unimmunised status. poliovirus.
• Usually clinically and • Diagnosis is usually clinical.
pathologically identical to
West Nile poliomyelitis.
Zika virus infection • Residence in or travel to an • Reverse transcriptase PCR:

endemic region. positive for Zika virus RNA.
• Widespread maculopapular • Serology: positive for Zika
(sometimes morbilliform) virus antibodies.
rash is common; it is often
itchy.
• Non-purulent conjunctivitis or
conjunctival hyperaemia may
be present.
• Not associated with
neuroinvasive disease but
has been associated with

symptoms
Guillain-Barre syndrome
(GBS).
Dengue fever • Residence in or travel to an • Serology: positive for dengue

endemic region. virus antibodies.
• Biphasic fever and biphasic
rash (transient generalised
macular rash, followed
by a second morbilliform,
maculopapular rash).
• Bone pain.
Chikungunya virus • Residence in or travel to an • Reverse transcriptase PCR:

infection endemic region. positive for Chikungunya
• Prominent joint symptoms. virus RNA.
• Absence of signs of • Serology: positive for
neuroinvasive disease. Chikungunya virus
antibodies.
Leptospirosis • There is usually a history of • PCR: positive for Leptospira

exposure to contaminated RNA.
water or soil, or contact with • Serology (microscopic
infected animals or their agglutination test): positive
depositions. for Leptospira antibodies.
• Neurological involvement is • Blood or urine culture:
less common. positive for Leptospira .
• Biphasic presentation.
• Bilateral conjunctival
suffusion is pathognomonic.
• Muscle tenderness is
localised in calves.
• Pulmonary signs and
symptoms (e.g., cough,
dyspnoea).
DIAGNOSIS
• In severe cases, jaundice,
renal failure, and bleeding
can occur.
Malaria • Residence in or travel to an • Full blood count: may

endemic region. show anaemia and/or
• Inadequate or absent thrombocytopaenia.
malaria chemoprophylaxis. • Giemsa-stained thick and
• Neurological involvement is thin blood smears: detection
less common. of asexual or sexual forms
of the parasites inside
erythrocytes.
• Rapid diagnostic tests:
detection of parasite antigen
or enzymes.
Lyme disease • History of tick bite. • Positive serum antibody titre

• More chronic course and for Borrelia burgdorferi : total
gradual onset. Lyme titre or positive IgG
• Erythema chronicum and IgM.
migrans.
• Lyme arthritis.
17

symptoms
• Chronic radicular • Western blot (IgM/IgG): to
paraesthesias. confirm positive titres.[67]
[68]
Rock y Mountain spot ted • Characteristic rash appears • Serology: positive for
fever 2 to 6 days after fever onset. Rickettsia rickettsii .[70]
• Initially maculopapular
eruption that begins on
wrists and ankles and
spreads to trunk and
extremities, involving palms
and soles. Later becomes
petechial in appearance.[69]
Legionnaire's disease • Respiratory symptoms and • Serology: positive for

signs, such as cough, chest Legionella species.[71]
tightness, crackles, rhonchi, • Chest x-ray: shows
chest tightness.[71] pneumonia.[71]
Brain tumour • Neurological deficit usually • CT/MRI head: shows

focal. mass.[72]
• Symptom onset more
gradual.
Brain abscess • Neurological deficit usually • CT/MRI head: shows

focal. abscess.[73]
• Symptom onset more
gradual.
Stroke • Neurological deficit usually • CT/MRI head: shows

focal. infarction and/or
• Progression of signs/ haemorrhage.[74]
symptoms occurs over a few
hours, not days or weeks.
DIAGNOSIS
Sub-acute bacterial • Cardiac murmur and signs • Bacterial blood cultures:

endocarditis of congestive heart failure positive.
present. • Echocardiogram: shows
• Characteristic but less vegetations.
common features include
splinter haemorrhages,
Osler's nodes, Janeway
lesions, and Roth's spots.
Coronavirus disease 2019 • Residence in/travel to a • Real-time reverse

(COVID-19) country/area or territory transcription polymerase
with local transmission, chain reaction (RT-PCR):
or close contact with a positive for severe acute
confirmed or probable case respiratory syndrome
of COVID-19, in the 14 days coronavirus 2 (SARS-CoV-2)
prior to symptom onset. RNA.
Criteria
Centers for Disease Control and Prevention (CDC): arboviral
diseases, neuroinvasive and non-neuroinvasive - 2015 case
definition[75]
Clinical criteria
A clinically compatible case of arboviral disease is defined as follows.
• Neuroinvasive disease:
• Meningitis, encephalitis, acute flaccid paralysis, or other acute signs of central or peripheral
neurological dysfunction, and
• Absence of a more likely clinical explanation.
• Non-neuroinvasive disease:
• Fever as reported by the patient or a healthcare provider; and

• Absence of neuroinvasive disease; and
• Absence of a more likely clinical explanation.
Laboratory criteria for diagnosis:
• Isolation of virus from, or demonstration of specific viral antigen or nucleic acid in, tissue, blood,
cerebrospinal fluid (CSF), or other body fluid; or
• Four-fold or greater change in virus-specific quantitative antibody titers in paired sera; or
• Virus-specific IgM antibodies in serum with confirmatory virus-specific neutralising antibodies in the
same or a later specimen; or
• Virus-specific IgM antibodies in CSF or serum.
DIAGNOSIS
Case classified as probable when:
• Neuroinvasive disease meets the above clinical criteria for neuroinvasive disease, and meets the
laboratory criteria of virus-specific IgM antibodies in CSF or serum but with no other testing
• Non-neuroinvasive disease meets the above clinical criteria for non-neuroinvasive disease and the
laboratory criteria of virus-specific IgM antibodies in serum but with no other testing.
Case classified as confirmed when:
• Neuroinvasive disease meets the above clinical criteria for neuroinvasive disease and one or more of
the following laboratory criteria:
CSF, or other body fluid; or
• Virus-specific IgM antibodies in serum with confirmatory virus-specific neutralising antibodies in
the same or a later specimen; or
19
• Virus-specific IgM antibodies in CSF, with or without a reported pleocytosis, and a negative
result for other IgM antibodies in CSF for arboviruses endemic to the region where exposure
occurred.
• Non-neuroinvasive disease meets the above clinical criteria for non-neuroinvasive disease and one or
more of the following laboratory criteria:
or other body fluid, excluding CSF; or
• Virus-specific IgM antibodies in serum with confirmatory virus-specific neutralising antibodies in
the same or a later specimen.
DIAGNOSIS
West Nile virus Management
Approach
No specific antiviral treatment is available, and management is supportive. Patients with neuroinvasive
disease require immediate medical care with hospitalisation, respiratory support, and intravenous fluids.
West Nile fever

A large percentage of cases are mild and self-limited; therefore, treatment is similar to that for most
other influenza-like illnesses. Recommend rest, generous fluid intake, and treatment of symptoms
with non-prescription medications such as paracetamol. Advise the patient to seek medical attention
if the symptoms can no longer be adequately managed by non-prescription medications (e.g., severe
dehydration) or if they last more than 1 week. Advise the patient to seek immediate medical care if they
develop signs or symptoms of neuroinvasive disease (e.g., severe headache, photophobia, seizures, or
changes in mental state).[3] [37] [76]
West Nile neuroinvasive disease

Admit patient to hospital, start intensive supportive care immediately (e.g., intravenous fluids, respiratory
support, seizure management, infection management, prevention of venous thromboembolism), and
manage any other sequelae of meningitis, encephalitis, or paralysis.[3] [37] [76]
Patients with encephalitis require close monitoring for the development of seizures or elevated intracranial
pressure. Patients with encephalitis or poliomyelitis should have their airway monitored as acute
respiratory failure can develop rapidly. Ventilatory support for a prolonged period may be required.[26]
Rule out other treatable illnesses such as bacterial meningitis, herpes simplex encephalitis, or Guillain-
Barre syndrome. Herpes simplex infection has a definitive effective treatment but is often more difficult to
exclude than other treatable conditions such as bacterial meningitis. Therefore, if herpes simplex infection
cannot be excluded, and none of the other differentials can be confirmed, give intravenous aciclovir.[77]
There are no specific drug therapies for meningitis, encephalitis, and poliomyelitis caused by West Nile
virus, and there is no evidence that antivirals are effective.
Treatment algorithm overview

Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
Acute ( summary )
West Nile fever
1st supportive treatment

MANAGEMENT
if herpes simplex plus intravenous aciclovir

infection cannot be
excluded
21
MANAGEMENT West Nile virus Management
Treatment algorithm
Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
Acute
West Nile fever

Primary options
» paracetamol: 500-1000 mg orally every 4-6

hours when required, maximum 4000 mg/day
» Recommend rest, generous fluid intake, and

treatment of symptoms with non-prescription
medications such as paracetamol.
» Advise the patient to seek medical attention

if the symptoms can no longer be adequately
managed by non-prescription medications (e.g.,
severe dehydration) or if they last more than
1 week. Advise the patient to seek immediate
medical care if they develop signs or symptoms
of neuroinvasive disease (e.g., severe headache,
photophobia, seizures, or changes in mental
state).
» .[3] [37] [76]

West Nile neuroinvasive disease 1st supportive treatment
» Admit patient to hospital, start intensive

supportive care immediately (e.g., intravenous
fluids, respiratory support, seizure management,
infection management, prevention of venous
thromboembolism), and manage any other
sequelae of meningitis, encephalitis, or
paralysis.[3] [37] [76]
» Patients with encephalitis require close

monitoring for the development of seizures or
elevated intracranial pressure.[26]
» Patients with encephalitis or poliomyelitis

should have their airway monitored as
acute respiratory failure can develop rapidly.
Ventilatory support for a prolonged period may
be required.[26]
MANAGEMENT
» Rule out other treatable illnesses such as

bacterial meningitis, herpes simplex encephalitis,
or Guillain-Barre syndrome.
23
Acute
if herpes simplex plus intravenous aciclovir
infection cannot be
Treatment recommended for ALL patients in
excluded
selected patient group
Primary options
» aciclovir: 10 mg/kg intravenously every 8

hours for 10-21 days or until herpes simplex
infection is excluded
» Herpes simplex infection has a definitive

effective treatment but is often more difficult to
exclude than other treatable conditions such
as bacterial meningitis. Therefore, if herpes
simplex infection cannot be excluded, and none
of the other differentials can be confirmed, give
intravenous acyclovir.[77]
MANAGEMENT
Emerging
Experimental therapies
No therapies are recommended for the treatment of West Nile virus infection. However, there are numerous
case series and case reports regarding the use of various experimental treatments including immunoglobulin
(polyclonal or monoclonal), ribavirin, interferon, and corticosteroids. None of these therapies have shown
clear benefit; however, some physicians may use them in patients with neuroinvasive disease.[78]
Primary prevention
Community-level mosquito control programmes and personal protective measures are required for prevention
of West Nile virus infection.[26] Avoidance of mosquito bites is recommended, and strategies include staying
indoors between dusk and dawn, using insect repellent, wearing protective clothing such as long-sleeved
shirts and trousers, placing screens on windows, and removing standing water in which mosquitoes can
breed.[27]
Since 2003, all donated blood in the US has been screened for West Nile virus using nucleic acid
amplification tests.[28] [29] In other countries, such as the UK, a deferral policy has been adopted for blood
donors who have travelled.[30] Standard precautions should be taken when handling blood, blood products,
or other body fluids that might be infected with West Nile virus.
No vaccines are licensed for use in humans.[26] Vaccines are being studied in clinical trials, but are not
available as yet.[31] [32]
Secondary prevention
West Nile virus infection is a notifiable condition in some countries. Blood transfusions are currently screened
for West Nile virus in the US. Organ and tissue donors are not routinely screened in the US; however, some
collection agencies have incorporated screening of donors into their process.[33] People with confirmed
infection should not donate blood for 4 months after illness.[26]
Patient discussions
Patients who are discharged after being diagnosed with West Nile fever should be aware of symptoms of
neuroinvasive disease (e.g., any neurological change, mental status changes, limb weakness, paralysis,
or respiratory depression). They should also be aware of the rare manifestations of West Nile virus
infection such as significant abdominal tenderness and/or jaundice (indicating pancreatitis or hepatitis),
or chest pain, palpitations, and/or shortness of breath (indicating myocarditis). The patient should be
instructed to contact a healthcare provider as soon as possible if these symptoms develop.
Advice about preventing infection should be given to all patients. Mosquito bites should be avoided,
especially in areas and times of high West Nile virus activity. Avoidance strategies include staying indoors
from dusk to dawn, discarding stagnant water that may breed mosquitoes, and avoiding areas of heavy
vegetation that may harbour mosquitoes.[33] Insect repellent should be used, and clothes that cover the
whole body should be worn when outdoors.
[World Health Organization: West Nile virus] (http://www.who.int/mediacentre/factsheets/fs354/en)

MANAGEMENT
[Centers for Disease Control and Prevention: West Nile virus] (https://www.cdc.gov/westnile)
25
West Nile virus Follow up
Monitoring
Monitoring
FOLLOW UP
Patients with thromboembolic disease may require long-term anticoagulation with warfarin and monitoring
of the patient's International Normalised Ratio (INR). Patients with persistent neurological deficits may
require long-term cognitive follow-up.
Complications
Complications Timeframe Likelihood
FOLLOW UP
pneumonia short term low
Caused by hypoventilation due to respiratory muscle weakness and aspiration due to decreased level
of consciousness. Increased risk in immunocompromised people. Should be treated with appropriate
antibiotics.[49]
respiratory failure short term low
Occurs in neuroinvasive disease secondary to respiratory muscle weakness. Requires mechanical

ventilation and, if persistent, may require tracheostomy.[49] [55]
cerebral oedema short term low
Occurs in neuroinvasive disease. Treatment is usually supportive care, with respiratory support and
anticonvulsants if seizures develop. Safety and efficacy of intravenous corticosteroids has not been
established.[83] [84]
deep vein thrombosis short term low
Flaccid paralysis predisposes patients to deep vein thrombosis. Can be prevented or treated with
appropriate anticoagulation.[49]
bacterial superinfection short term low
Infection stresses the immune system and body, rendering the patient more susceptible to infections
from bacteria that are usually present (e.g., Staphylococcus , Streptococcus ) and may not cause an
active infection in a healthy individual. Therefore, the patient must be watched vigilantly for any signs of
a bacterial infection. For example, if a patient develops any respiratory symptoms, such as a cough, the
physician should have a lower threshold for ordering a chest x-ray to evaluate for pneumonia. Treat with
antibiotics specific to infection.
persistent fatigue variable high
Occurs in West Nile fever or neuroinvasive disease, and persists for months. More likely to persist in
neuroinvasive disease (especially West Nile encephalitis). Treatment is supportive.[82]
persistent headache variable high
Occurs in West Nile fever or neuroinvasive disease and persists for months. Can be treated with
analgesia.[82]
persistent cognitive changes variable medium
Can occur in patients with West Nile encephalitis, although one study found that cognitive deficits
can manifest regardless of infection severity.[87] Can be permanent and cognitive retraining may be
necessary.[43]
persistent limb weakness variable low
Occurs in West Nile poliomyelitis (WNP) following flaccid paralysis and may persist for months. Can be
treated with physiotherapy.[82] [85]
27
Complications Timeframe Likelihood

persistent movement disorders variable low
FOLLOW UP
Occurs in neuroinvasive disease and may persist for months. Can be treated with physiotherapy.[85] Rare
cases of opsoclonus myoclonus ataxia have been reported.[86]
hepatitis variable low
Hepatitis should be suspected if the patient has jaundice, right upper quadrant abdominal pain, and
tenderness. Frequently self-limiting, but could progress to fulminant hepatitis. This complication is very
rare, and treatment is supportive.
pancreatitis variable low
Typically presents with severe abdominal pain and elevated serum amylase/lipase. This complication is
very rare, and treatment is supportive.
myocarditis variable low
Suspected when cardiac echocardiogram or electrocardiography is abnormal, and cardiac enzymes

(troponin and creatine phosphokinase) are raised. Could result in life-threatening arrhythmias. This
complication is very rare, and treatment is supportive.
Prognosis
Most cases of West Nile fever resolve spontaneously and completely. However, fatigue, headache,
weakness, movement disorders, and concentration problems may persist for weeks or months.[20]
Severe neuroinvasive disease can result in death or permanent disability. Mortality usually results from
progressive neuronal dysfunction, cerebral oedema, and respiratory failure. West Nile meningitis tends to
be self-limiting with a good prognosis. In contrast, West Nile encephalitis and West Nile poliomyelitis carry a
much poorer prognosis as most people have long-lasting (>1 year) neurological problems.[43] Overall case
fatality rates for patients hospitalised for infection range from 4% to 18%.[5] [49][79]
A study of prospectively-acquired neurological outcomes data among 55 patients with neuroinvasive

disease in the US found that 93% of patients presented with significant neurological deficit on initial clinical
examination including weakness (49%), cognitive impairment (45%), tremor (35%), coma (25%), and
cranial neuropathy (16%). By the end of the 90-day follow-up, 33% of patients had returned to normal
neurological function. The mortality rate in this study was 13%, with 5 of the 7 patients who died presenting
with coma.[80]
In some patients, West Nile virus may persist in the kidneys after initial infection. It is currently unknown
whether this can cause kidney disease or hypertension. Further research is required.[81]
West Nile virus Guidelines
Diagnostic guidelines
United Kingdom
West Nile virus: epidemiology, diagnosis and prevention (ht tps://www.gov.uk/

guidance/west-nile-virus)
Published by: Public Health England Last published: 2018
North America
West Nile virus: information for healthcare providers (ht tps://www.cdc.gov/

westnile/healthcareproviders/index.html)
Published by: Centers for Disease Control and Prevention Last published: 2023
A guide to utilization of the microbiology laboratory for diagnosis of
GUIDELINES
infectious diseases (ht tps://www.idsociety.org/practice-guideline/practice-
guidelines)
Published by: Infectious Diseases Society of America and the American Last published: 2018
Society for Microbiology
West Nile virus surveillance and control guidelines (ht tp://www.cdc.gov/

westnile/resourcepages/pubs.html)
Treatment guidelines
United Kingdom
West Nile virus: epidemiology, diagnosis and prevention (ht tps://www.gov.uk/

guidance/west-nile-virus)
Published by: Public Health England Last published: 2018
North America
West Nile virus: information for healthcare providers (ht tps://www.cdc.gov/

westnile/healthcareproviders/index.html)
West Nile virus surveillance and control guidelines (ht tp://www.cdc.gov/

westnile/resourcepages/pubs.html)
29
West Nile virus Online resources
Online resources
1. CDC: West Nile virus data and maps (https://www.cdc.gov/westnile/statsmaps/data-and-maps.html)
(external link)
2. World Health Organization: West Nile virus (http://www.who.int/mediacentre/factsheets/fs354/en)

(external link)
3. Centers for Disease Control and Prevention: West Nile virus (https://www.cdc.gov/westnile) (external
link)
ONLINE RESOURCES
West Nile virus References
Key articles
• Hayes EB, Sejvar JJ, Zaki SR, et al. Virology, pathology, and clinical manifestations of West
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surveillance, prevention, and control. April 2022 [internet publication]. Full text (https://www.cdc.gov/
mosquitoes/guidelines/west-nile/introduction.html)
• Centers for Disease Control and Prevention. West Nile virus surveillance and control guidelines.
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westnile/resources/pdfs/WNV-therapeutics-summary-P.pdf)
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39
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Contributors:
// Authors:
Bruce Y. Lee, MD, MBA

Professor of Health Policy and Management
Executive Director, Center for Advanced Technology and Communication for Health (CATCH), Public Health
Informatics Computational and Operation Research (PHICOR), City University of New York (CUNY), New
York, NY
DISCLOSURES: BYL declares that he has no competing interests.
// Peer Reviewers:
Susan Stramer, PhD

Executive Scientific Officer
American Red Cross, Gaithersburg, MD
DISCLOSURES: SS declares that she has no competing interests.

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West Nile virus

Straight to the point of care

Last updated: Aug 10, 2023

[CDC: West Nile virus data and maps] (https://www.cdc.gov/westnile/statsmaps/data-and-maps.html)

• West Nile virus encephalitis

Hepatitis, pancreatitis, and myocarditis are all rare complications.

West Nile virus infection is a notifiable condition in some countries.

History and exam

abdominal pain (common)

visual disturbances (common)

multi-focal chorioretinal lesions (common)

chorioretinitis and inflammatory vitritis (common)

respiratory distress (uncommon)

epigastric tenderness (uncommon)

mild confusion (uncommon)

neck stiffness (uncommon)

Kernig's sign (uncommon)

Brudzinski's sign (uncommon)

muscle paralysis (uncommon)

Other diagnostic factors

generalised muscle weakness (common)

retinal haemorrhages (common)

chest pain, dyspnoea, palpitations (uncommon)

loss of memory (uncommon)

bowel and bladder dysfunction (uncommon)

full blood count may show leukocytosis,

Other tests to consider

Condition Differentiating signs / Differentiating tests

St. Louis encephalitis • No differentiating signs and • Serology: 4-fold increase in

Eastern equine • No differentiating signs and • Serology: 4-fold increase in

Western equine • No differentiating signs and • Serology: 4-fold increase in

Condition Differentiating signs / Differentiating tests

Bacterial meningitis • No differentiating signs and • CSF analysis: high protein,

Cryptococcal meningitis • Always suspect in people • Cryptococcal polysaccharide

Tuberculous meningitis • No clear differentiating signs • CSF PCR: detection of acid-

Guillain-Barre syndrome • Typically presents 1 to 8 • Diagnosis is usually

Poliovirus-associated • Residence or travel in • Virus culture (stool, CSF,

Zika virus infection • Residence in or travel to an • Reverse transcriptase PCR:

Condition Differentiating signs / Differentiating tests

Dengue fever • Residence in or travel to an • Serology: positive for dengue

Chikungunya virus • Residence in or travel to an • Reverse transcriptase PCR:

Leptospirosis • There is usually a history of • PCR: positive for Leptospira

Malaria • Residence in or travel to an • Full blood count: may

Lyme disease • History of tick bite. • Positive serum antibody titre

Condition Differentiating signs / Differentiating tests

Legionnaire's disease • Respiratory symptoms and • Serology: positive for

Brain tumour • Neurological deficit usually • CT/MRI head: shows

Brain abscess • Neurological deficit usually • CT/MRI head: shows

Stroke • Neurological deficit usually • CT/MRI head: shows

Sub-acute bacterial • Cardiac murmur and signs • Bacterial blood cultures:

Coronavirus disease 2019 • Residence in/travel to a • Real-time reverse

A clinically compatible case of arboviral disease is defined as follows.

• Fever as reported by the patient or a healthcare provider; and

Laboratory criteria for diagnosis:

West Nile fever

West Nile neuroinvasive disease

Treatment algorithm overview

1st supportive treatment

West Nile neuroinvasive disease

1st supportive treatment

if herpes simplex plus intravenous aciclovir

1st supportive treatment