ICU Management & Practice, ICU Volume 12 - Issue 4 - Winter 2012/2013
The increasing spread of West Nile virus (WNV)
infection is worrying and requires that all intensivists be ready to recognise
and diagnose the disease. Most individuals infected with WNV are asymptomatic,
while one-fifth experience a flu-like illness and less than 1% develop neuroinvasive
disease.
Introduction
West Nile virus, the most widely distributed arbovirus, belongs to
the genus Flavivirus, within the family of Flaviviridae. WNV was
firstly isolated in the West Nile province of Uganda in 1937 from the blood of
a woman suffering a mild flu-like illness. The first cases of WNV in its
encephalitic form were reported in Algeria in 1994, and the first large
outbreak with a high number of neuroinvasive cases occurred in Bucharest,
Romania, in 1996. WNV was introduced to New York City in 1999, where it was
responsible for a huge epidemic (Hayes 2001). Within subsequent years, the WNV
appeared ubiquitous in most states east of the Rocky Mountains, as well as in
some Canadian provinces. The number of yearly reported cases in the US has
increased from 1,021 in 2010, and 712 in 2011 (with 57 and 43 deaths,
respectively) to 5,054 cases in 2012 by November 6, including 228 deaths. Of
these 5,054 cases, 2,559 (51%) were classified as neuroinvasive disease and
2,495 (49%) as non neuroinvasive disease (Centers for Disease Control and
Prevention, 2012).
The European Centre for Disease Prevention and Control monitored the
WNV fever situation during the transmission season (June to November), and
reported 130 probable and confirmed autochthonous cases in EU member states and
207 in neighbouring countries in 2011. As per figures on 8 November, 2012, 235
human cases of WNV fever have been reported in the EU and 587 cases in
neighbouring countries so far this year (European Centre for Disease Prevention
and Control, 2012). The spread of WNV has raised concerns regarding its
presence in the Old World and the risks for epidemics of the neuroinvasive disease
(Relter 2010). In light of this, all intensivists should know about WNV disease
and be ready to recognise and diagnose it in their patients.
Virus and Transmission
WNV is a small spherical RNA virus, translated into a polyprotein,
which is proteolytically processed to three structural
and seven non-structural proteins. The latter hamper the host antiviral
response, antagonising complement activation and inhibiting interferon-β
promoter activation. It has recently been
proposed that WNV can be grouped into seven lineages. Two major genetic
lineages of WNV have been well described: lineage one is widespread and
contains isolates from Europe, the USA, the Middle East, India, Africa and
Australia (Barzon et al. 2012). Lineage two contains isolates from Southern
Africa and Madagascar, and since 2004 from central and eastern Europe. In 2010
it caused outbreaks in Romania and Greece (De Filette et al. 2012).
Interestingly, high and low neuroinvasive phenotypes exist in both lineages,
but mutations responsible for increasing virulence in lineage two viruses have
been described.
WNV
lives in mosquitoes of genus Culex, which are considered the predominant
vectors. Mosquitoes become infected with WNV after biting birds with highlevel
viremia, and may transmit it when taking a blood meal from a host. Indeed,
birds can also be infected via the oral route and by consumption of dead or
dying infected birds. In birds, the incubation period is 10 to 14 days; the
infection is associated with high mortality in Northern America but not in
Europe (Relter, 2010). Humans and horses are "dead-end" hosts because
the viremia is insufficient to infect a feeding naive mosquito. However,
transmission in humans has been reported after blood transfusion, organ transplantation,
or from a mother to her newborn via the intrauterine route or by breast milk
(De Filette et al. 2012).
There is indirect evidence that WNV is transported to European
temperate areas by migratory birds during spring migration. In addition, the
transport technologies and increasing global trade of the last decades may have
allowed infected mosquitoes to be transported by shipping, aeroplanes, and
people travelling. Accordingly, at the county scale in eastern and western
North America, human WNV incidences have increased with urbanisation and
agriculture, respectively (Kilpatrick 2011).
Following inoculation from the bite of an infected mosquito, WNV
replicates in the keratinocytes and then disseminates to the local lymph nodes
causing a viremia. The WNV may pass into the central nervous system without
disrupting the blood–brain barrier (BBB) (Rossi et al. 2010), but perivascular
inflammation of lymphocytes and macrophages with glial cell upregulation has
been found (Turtle et al. 2012).
Clinical Characteristics
Most of the individuals infected with WNV are asymptomatic.
Approximately 20% of infected individuals develop an acute febrile flu-like
illness after an incubation period of two to 14 days, with fever, malaise,
myalgia, fatigue, skin rash, lymphadenopathy, vomiting and diarrhoea (Kramer et
al. 2007; Rossi et al. 2010). Only approximately one in 150 infected
individuals (Tyler 2010) and 5% of
patients with symptomatic WNV infection (Rossi et al. 2010) develop neuroinvasive
disease. The major categories of neuroinvasive disease include meningitis,
encephalitis, and acute flaccid paralysis, with frequent overlap between these
syndromes. Patients who develop encephalitis are typically older than those
with meningitis or acute flaccid paralysis, and have a worse prognosis (Kramer
et al. 2007). Additional risk factors for development of encephalitis include
immunosuppression, hypertension, diabetes mellitus, and liver disease (Tyler 2010).
WNV meningitis is clinically similar to other forms of “aseptic”
meningitis and is characterised by fever, headache, stiff neck, and
photophobia. Cranial nerve palsies, particularly of the facial nerve, occur in
about 20% of cases. The cerebrospinal fluid (CSF) shows a pleocytosis with a
mean of about 200 cells/mm3, an elevated protein level, and a normal glucose
level. Almost half the patients have an initial polymorphonuclear pleocytosis rather
than the lymphocytic pleocytosis generally characteristic of viral meningitis
(Tyler 2010).
Patients with encephalitis have clinical or laboratory evidence of
brain parenchymal involvement. Signs may include fever, headache, altered
consciousness, disorientation, focal neurologic signs, dysarthria, seizures, tremor,
ataxia, parkinsonism, and weakness. When present, magnetic resonance imaging
(MRI) abnormalities typically consist of areas of increased signal on T2 and
fluid attenuated inversion recovery sequences that occur in the thalamus, basal
ganglia, and upper brainstem (Tyler 2010, Kramer et al. 2007).
Acute
asymmetric flaccid paralysis is a poliomyelitis-like illness that occurs in 5%
to 10% of patients with neuroinvasive disease. More than half the affected
patients have associated encephalitis with concomitant findings of
parkinsonism, myoclonus, or tremor. Approximately 90% have associated fever and
headache. The flaccid paralysis is due to a selective lesion of spinal anterior
horns by WNV. There is minimal or no sensory disturbance, and cranial nerves
are usually normal, but bowel and bladder functions are disturbed in some patients.
Most patients have substantial muscle ache in the lower back. Deep tendon
reflex can be diminished in severely paralysed limbs, and muscular atrophy
develops in the late phase of the illness (Kramer et al. 2007).
MRI scans may be normal or show focal abnormal signal intensity within the anterior horns of the spinal cord (Kramer et al. 2007). Electromyography and nerve conduction velocity studies show reduced or absent compound muscle action potentials with relatively preserved sensory neural action potentials. Electromyography abnormalities due to evidence of denervation develop after several weeks (Tyler 2010).
Diagnosis
CSF examination should be performed in order to differentiate WNV
infection from stroke, meningitis-encephalitis due to bacteria or other
viruses, myopathy, and Guillain-Barre syndrome (Rossi et al. 2010).
Nevertheless, the diagnosis of WNV disease is based on specific serologic
testing, so IgM and IgG ELISA should be used for testing serum and CSF. IgM
serum antibodies develop within eight days and are still present at three
months post-infection in almost all patients (De Filette et al. 2012; Kramer et
al. 2007). The long persistence of WNV IgM after onset of infection could
confound interpretation of serology results in patients subsequently presenting
with clinical syndromes that resemble WNV infection (Diamond, 2009). Specimens
submitted for arboviral serology should also be tested against other
arboviruses that are known to be active or present in the given area. Detection
of CSF WNV IgM antibodies is diagnostic of neuroinvasive WNV disease, as the
presence of large size IgM molecules, which cross the BBB poorly, in CSF is
generally indicative of intrathecal synthesis. However, WNV isolation attempts should be performed in CSF or postmortem brain
tissue. Confirmation of virus isolate identity can be accomplished by indirect
immunofluorescence assay using virus-specific monoclonal antibodies, nucleic
acid detection, or virus neutralisation. Real timepolymerase chain reaction
(RT-PCR) after amplification of the genetic material requires specialised
equipment, and may not detect new emerging mutated WNV strains (Tyler 2010; De
Filette et al. 2012).
Treatment and Prognosis
There is no specific treatment for WNV infection. The supportive care required by patients with neuroinvasive disease includes respiratory support, nutrition, analgesia and sedation, and prevention of secondary infections (Capuzzo et al, 2011). In fact, nearly half of the patients may have respiratory impairment requiring intubation or tracheostomy (Kramer et al. 2007). A mortality rate of approximately 12 to 15% for WNV encephalitis has been reported in the US (O'Leary et al. 2004; Sejvar 2007). Long-term complications like fatigue and weakness are common. Movement disorders, cognitive complaints and functional disability may occur after WNV neuroinvasive disease, and WNV paralysis in particular may result in limb weakness and ongoing morbidity (Sejvar 2007). Most adult patients admitted to a rehabilitation facility with WNV have required follow-up physical therapy after discharge from rehabilitation (Hoffman et al. 2012).
Conclusions
Intensivists should be aware of the possible risks for epidemics of the WNV neuroinvasive disease. The following factors are associated with the neuroinvasive WNV infection and may strike a chord, prompting physicians to consider WNV:
i) Seasonality, which varies according to bird migration in different geographic regions, and in temperate areas in late summer;
ii) Common flu-like symptoms before neurological impairment; and
iii)Presence of comorbidities, which are possibly responsible for immune system impairment, such as through the ensuing use of steroids.