West Nile  fever

West Nile virus is a mosquito-borne flavivirus that is maintained in an enzootic cycle between mosquitoes and birds. Humans and horses are incidental dead-end hosts. Most human infections are asymptomatic and the majority of clinical cases of WN infections are mild and present with flu-like symptoms, including fever, headache and body aches. In more severe cases, most often observed among elderly, there may be signs of encephalitis, meningo-encephalitis or meningitis.  In Europe, West Nile virus outbreaks are erratic and spatially and temporally limited phenomena, occurring quite unpredictably, even if all conditions appear to be present in a definite place. The disease is under surveillance at EU level. There is no specific treatment for West Nile virus infection and a vaccine is not available. The best way to prevent West Nile virus infection is to avoid mosquito bites.

The pathogen

Clinical features and sequelae

• Most human infections are asymptomatic. In 1999 a survey found that only 20% of WN seropositive individuals in New York reported symptoms consistent with WN fever; approximately half had visited a physician at the time of illness.
• Most clinical cases of WN infections are mild and present with flu-like symptoms, including fever, headache and body aches. Weakness, malaise, anorexia, lymphadenopathy, nausea and vomiting may also be seen. An erythematous maculo-papular or morbilliform skin rash occasionally develops on the neck, trunk, arms or legs. Most uncomplicated infections resolve in 3–6 days.
• In more severe cases, there may be signs of encephalitis, meningo-encephalitis or meningitis. The symptoms may include high fever, headache, neck stiffness, stupor, disorientation, tremors, convulsions, severe muscle weakness, flaccid paralysis and coma. Ataxia, cranial nerve abnormalities, myelitis, eye pain, polyradiculitis and seizures have also been seen. In some outbreaks, myocarditis, pancreatitis, and fulminant hepatitis occur. An estimated 1 out of 140 to 320 infections results in meningitis or encephalitis.
• The case fatality rate in patients with neuro-invasive illness ranges from 4% to 14%; it can reach 15–29% in patients over 70 years old. There is evidence that concurrent disease such as diabetes or immuno-suppression increases the risk of death. Seriously ill patients may suffer substantial long-term morbidity after recovery; fatigue, memory loss, difficulty walking, muscle weakness and depression have been reported.

Transmission

• The incubation period is 3–14 days. The viremia in humans is low and of short duration. Humans do not participate in the chain of transmission and are considered dead-end hosts.
• Modes of transmission:
  • WN virus is maintained in an enzootic cycle between Culicidae mosquitoes and birds. Environmental conditions may favour high viral amplification with significant numbers of bridge-vector mosquitoes (i.e. mosquitoes that feed on both birds and mammals) becoming infected, which then can spread the virus to humans, horses and other incidental hosts.
  • Culex mosquitoes appear to be the most important maintenance vectors for WN virus, but mosquito species from other genera are also susceptible to infection. In Asia and Russia, ticks have been found infected, but their role in transmission is uncertain.
  • The risk of local transmission of WN virus depends on the simultaneous presence of the virus, competent amplifying hosts and mosquito vectors, and susceptible human hosts. There is ample evidence that WN virus is transported by migratory birds. Virus transmission by blood transfusions or organ transplants has been documented.
  • Rare cases of zoonotic transmission have been described during horse or bird autopsy.
• Unusual transmission that has happened in the past:
  • Direct transmission between animals has not been seen in experimentally infected chicken or turkeys, but has been documented in geese, crows and raptors. Infected humans and horses do not seem to spread the virus to other mammals. Transmission between mosquitoes by co-feeding has also been experimentally demonstrated. Person-to-person transmission has not been reported.
• Transmission from mother to child. 
  • Intrauterine infection seems a very rare event

Diagnostics

• The diagnosis of WN infection relies on the detection of specific IgM antibodies which are present in cerebrospinal fluid and serum specimens from patients with clinical symptoms. The test should always include other closely related flaviviruses for comparison.
• Confirmation of the diagnosis needs to be done by neutralisation assays.
• Viral direct detection by RT-PCR can be performed on blood or CSF and on cerebral biopsies from deceased patients. The viremia is very short and limited to the early phase of the disease.

Case management and treatment

• There is no specific treatment for WN virus infection. In more severe cases, people usually need to be hospitalised for supportive treatment including intravenous fluids, help with breathing and nursing care.

Epidemiology

• The West Nile virus most likely emerged in Africa and is now distributed worldwide: outbreaks may occur in humans, birds, and horses in the Americas, Africa, Europe, Russia, Middle East Asia and Australia. In Europe, WN virus outbreaks are erratic and spatially and temporally limited phenomena, occurring quite unpredictably, even if all conditions appear to be present in a definite place.
• West Nile transmission in known to be present in Europe since a long time: in the 1960s the virus emerged in southern France in the Camargue. Yet, the first large outbreak in humans was reported from Bucharest, Romania in 1996-1997.  Since then, infection in humans and/or horses have been reported from the Czech Republic (1997), France (2000, 2003, 2004, 2006), Italy (1998, 2008, 2009), Hungary (2000-2009), Romania (1997-2001, 2003-2009), Spain (2004) and Portugal (2004). In 2010, the ecological parameters in Central European and Mediterranean countries were favourable for the transmission of WNV to humans. A human outbreak was reported from the Central Macedonia Region in northern Greece and human cases were reported from Romania, Hungary, Italy and Spain in August-September 2010. At the same time a large outbreak in humans was reported from Volgograd in Russia, as well as cases in Turkey and infections were also confirmed in donkeys in Bulgaria and horses in Portugal and Morocco. [link to WN 2010 map]
• West Nile virus is a notifiable disease in the EU.
• The EU case definition (Commission decision of 28 April 2008 amending Decision  2002/253/EC laying down case definitions for reporting communicable diseases to the Community network under Decision No 2119/98/EC of the European Parliament and of the Council):
  • Clinical criteria: any person with fever OR at least one of the following two:
    •  Encephalitis
    •  Meningitis
  • Laboratory criteria
        Laboratory test for case confirmation. At least one of the following four:
    • Isolation of WNV from blood or CSF
    • Detection of WNV nucleic acid in blood or CSF
    • WNV specific antibody response (IgM) in CSF
    • WNV IgM high titre AND detection of WNV IgG, AND confirmation by neutralisation

       Laboratory test for a probable case

• WNV specific antibody response in serum

       Laboratory results need to be interpreted according to flavivirus vaccination status

• Epidemiological criteria At least one of the following two epidemiological links:
  • Animal to human transmission (residing, having visited or having been exposed to mosquito bites in an area where WNV is endemic in horses or birds)
  • Human to human transmission (vertical transmission, blood transfusion, transplants)
• Case classification
  • Possible case: NA
  • Probable case: Any person meeting the clinical criteria AND with at least one of the following two:
    • an epidemiological link
    • a laboratory test for a probable case
  • Confirmed case: Any person meeting the laboratory criteria for case confirmation

Public health control measures

• Blood donation restrictions and/or nucleic acid testing have to be considered in areas where WN virus is circulating. In the EU, there are specific regulations regarding blood safety with a 28-day deferral after leaving an area with ongoing transmission of WNV to humans (Directive 2004/33/EC of 22 March 2004).
• It is important to reduce the number of mosquito breeding sites in outdoor areas by draining sources of standing water and removing rubbish and discarded items that could collect water.
• Measures aiming to control adult mosquito vectors can be applied in an outbreak situation but its impact is not well known.
• Human vaccines are not available but some candidate vaccines are under development.

Personal protection and prevention

• All age groups can be infected but advanced age and certain health conditions are risk factors for severe disease outcomes (see clinical features and sequelae).
• The best way to prevent WN infection is to avoid mosquito bites. Many mosquitoes are most active at dusk and dawn. People can use insect repellents when they are outdoors and wear long sleeves and trousers at these times, or consider staying indoors during these hours. In areas with high mosquito populations, good screens on windows and doors can keep mosquitoes out.

Advice to travellers

• As no specific treatment or vaccine is available, the best way to prevent WN infection is to avoid mosquito bites.

References

1. Commission Directive 2004/33/EC of 22 March 2004.
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9. Schuffenecker I, Peyrefitte C, El Harrak M, Murri S, Leblond A, Zeller H. Re-emergence of West Nile virus (WNV) in Morocco in 2003: evidence for genetic stability of the WNV strains involved in equine outreaks in the Western Mediterranean basin. Emerg Infect Dis 2004;11:306–309.
10. Sejvar J, Bode A, Marfin A, Campbell G, Ewing D, Mazowiecki M et al. West Nile virus-associated flaccid paralysis. Emerg Infect Dis 2005;11:1021–1027.
11. Zeller HG, Schuffenecker I. West Nile virus: an overview of its spread in Europe and the Mediterranean basin in contrast to its spread in the Americas. Eur J Clin Microbiol Infect Dis 2004;23(3):147–56.