WEST NILE VIRUS

'West Nile virus' (WNV) is a virus of the family ''Flaviviridae''; part of the Japanese encephalitis (JE) antigenic complex of viruses, it is found in both tropical and temperate regions. It mainly infects birds, but is known to infect humans, horses, dogs, cats, bats, chipmunks, skunks, squirrels, and domestic rabbits. The main route of human infection is through the bite of an infected mosquito.
Image reconstructions and cryoelectron microscopy reveal a 45-50 nm virion covered with a relatively smooth protein surface. This structure is similar to the dengue fever virus; both belong to the genus flavivirus within the family ''Flaviviridae''. WNV is a positive-sense, single strand of RNA, it is between 11,000 and 12,000 nucleotides long which encode seven non-structural proteins and three structural proteins. The RNA strand is held within a nucleocapsid formed from 12 kDa protein blocks; the capsid is contained within a host-derived membrane altered by two viral glycoproteins.

Contents

Symptoms

Transmission and susceptibility

History

Overwintering mechanism

Geographic distribution

Recent outbreaks

Surveillance methods

Control

Treatment research

Sources

External links

Symptoms

WNV has three different effects on humans. The first is an asymptomatic infection; the second is a mild febrile syndrome termed West Nile Fever;^[1] the third is a neuroinvasive disease termed West Nile meningitis or encephalitis.^[2] In infected individuals the ratio between the three states is roughly 110:30:1.^[3]
The second, febrile stage has an incubation period of 3-8 days followed by fever, headache, chills, diaphoresis, weakness, lymphadenopathy, and drowsiness. Occasionally there is a short-lived truncal rash and some patients experience gastrointestinal symptoms including nausea, vomiting, loss of appetite, or diarrhea. All symptoms are resolved within 7-10 days, although fatigue can last for some weeks and lymphadenopathy can take up to two months to resolve.
The more dangerous encephalitis is characterized by similar early symptoms but also a decreased level of consciousness, sometimes approaching near-coma. Deep tendon reflexes are hyperactive at first, later diminished. There are also extrapyramidal disorders. Recovery is marked by a long convalescence with fatigue.
More recent outbreaks have resulted in a deeper study of the disease and other, rarer, outcomes have been identified.The spinal cord may be infected, marked by anterior myelitis with or without encephalitis.^[4] WNV-associated Guillain-Barré syndrome has been identified^[5] and other rare effects include multifocal chorioretinitis (which has 100% specificity for identifying WNV infection in patients with possible WNV encephalitis)^[6] hepatitis, myocarditis, nephritis, pancreatitis, and splenomegaly.^[7][8][9]

Transmission and susceptibility

The virus is transmitted through mosquito vectors, which bite and infect birds. The birds are amplifying hosts, developing sufficient viral levels to transmit the infection to other biting mosquitoes which go on to infect other birds (in the Western hemisphere the American robin and the American crow are the most common carriers) and also humans. The infected mosquito species vary according to geographical area; in the US ''Culex pipiens'' (Eastern US), ''Culex tarsalis'' (Midwest and West), and ''Culex quinquefasciatus'' (Southeast) are the main sources.^[10]
In mammals the virus does not multiply as readily, and it is believed that mosquitoes biting infected mammals do not further transmit the virus,^[11] making mammals so-called dead-end infections.
A 2004 paper in ''Science'' found that ''Culex pipiens'' mosquitoes existed in two populations in Europe, one which bites birds and one which bites humans. In North America 40% of ''Culex pipiens'' were found to be hybrids of the two types which bite both birds and humans, providing a vector for West Nile virus. This is thought to provide an explanation of why the West Nile disease has spread more quickly in North America than Europe.
It was initially believed that direct human-to-human transmission was only caused by occupational exposure,^[12] or conjunctival exposure to infected blood.^[13] The US outbreak revealed novel transmission methods, through blood transfusion,^[14] organ transplant,^[15] intrauterine exposure,^[16] and breast feeding.^[17] Since 2003 blood banks in the US routinely screen for the virus amongst their donors.^[18] As a precautionary measure, the UK's National Blood Service runs a test for this disease in donors who donate within 28 days of a visit to the United States or Canada.
The more severe outcomes of WNV infection are clearly associated with advancing age^[19] and a patient history of organ transplantation.^[20] A genetic factor also appears to increase susceptibility to West Nile disease. A mutation of the gene CCR5 gives some protection against HIV but leads to more serious complications of WNV infection. Carriers of two mutated copies of CCR5 made up 4 to 4.5% of a sample of West Nile disease sufferers while the incidence of the gene in the general population is only 1%.^[21][22]
There is no vaccine for humans. A vaccine for horses based on killed viruses exists; some zoos have given this vaccine to their birds, although its effectiveness there is unknown. Dogs and cats show few if any signs of infection. There have been no cases of direct canine-human or feline-human transmission, but these common pets may incubate the virus and pass it along through mosquitoes.[1]
For humans to escape infection the avoidance of mosquitos is key^[23] - remaining indoors at dawn and dusk, wearing light-colored clothing which protects arms and legs as well as trunk, using insect repellents on both skin and clothing (such as DEET, picaradin, or oil of lemon eucalyptus for skin and permethrin for clothes).^[24] Treatment is purely supportive: analgesia for the pain of neurologic diseases; rehydration for nausea, vomiting, or diarrhea; encephalitis may also require airway protection and seizure management.
On August 19, 2006, the LA Times reported that the expected incidence rate of West Nile was dropping as the local population becomes exposed to the virus. ''"In countries like Egypt and Uganda, where West Nile was first detected, people became fully immune to the virus by the time they reached adulthood, federal health officials said."'' [2] However days later the CDC said that West Nile cases could reach a 3-year high because hot temperatures had allowed a larger brood of mosquitoes. [3] Reported cases in the U.S. in 2005 exceeded those in 2004 and cases in 2006 exceeded 2005s totals.

History

Studies of phylogenetic lineages have determined that WNV emerged as a distinct virus around 1000 years ago.^[25] This initial virus developed into two distinct lineages, Lineage 1 and its multiple profiles is the source of the epidemic transmission in Africa and throughout the world, while Lineage 2 remains as an Africa zoonose.
WNV was first isolated from a feverish adult woman in the West Nile District of Uganda in 1937 during research on yellow fever. A series of serosurveys in 1939 in central Africa found anti-WNV positive results ranging from 1.4% (Congo) to 46.4% (White Nile region, Sudan). It was subsequently identified in Egypt (1942) and India (1953), a 1950 serosurvey in Egypt found 90% of those over 40 years in age had WNV antibodies. The ecology was characterized in 1953 with studies in Egypt^[26] and Israel.^[27] The virus became recognized as a cause of severe human meningoencephalitis in elderly patients during an outbreak in Israel in 1957. The disease was first noted in horses in Egypt and France in the early 1960s and found to be widespread in southern Europe, southwest Asia and Australia.
The first appearance of West Nile virus in the Western hemisphere was in 1999 with encephalitis reported in humans and horses, and the subsequent spread in the United States may be an important milestone in the evolving history of this virus. The American outbreak began in the New York City area, including New Jersey and Connecticut, and the virus is believed to have entered in an infected bird or mosquito, although there is no clear evidence.^[28] The US virus was very closely related to a lineage 1 strain found in Israel in 1998. Since the first North American cases in 1999, the virus has been reported throughout the United States, Canada, Mexico, the Caribbean and Central America. There have been human cases and horse cases, and many birds are infected. Both the US and Israeli strains are marked by high mortality rates in infected avian populations, the presence of dead birds - especially corvidae - can be an early indicator of the arrival of the virus.
A very high level of media coverage through 2001/2002 raised public awareness of West Nile virus. This disproportionate coverage was most likely the result of successive appearances of the virus in new areas.
Environmentalists have condemned attempts to control the transmitting mosquitoes by spraying pesticide, saying that the detrimental health effects of spraying outweigh the relatively few lives which may be saved, and that there are more environmentally friendly ways of controlling mosquitoes. They also question the effectiveness of insecticide spraying, as they believe mosquitoes that are resting or flying above the level of spraying will not be killed; the most common vector in the northeastern U.S., ''Culex pipiens'', is a canopy feeder.

Overwintering mechanism

Vertical transmission of West Nile Virus from female ''Culex pipiens'' mosquitoes to their progeny has been demonstrated in the laboratory. It has been suggested that vertically infected ''Culex'' could survive the winter to initiate a WNV amplification cycle the following spring. ''Culex'' mosquitoes spend the winter hibernating in protected structures such as root cellars, bank barns, caves, abandoned tunnels and other subterranean locations. The first overwintering adult mosquitoes to test positive for WNV were collected in New York, 2000. Since then positive samples have been identified in New Jersey, 2003 and in Pennsylvania, 2003, 2004 and 2005.^[29]

Geographic distribution

West Nile virus has been described in Africa, Europe, the Middle East, west and central Asia, Oceania (subtype Kunjin), and most recently, North America.
Recent outbreaks of West Nile virus encephalitis in humans have occurred in Algeria (1994), Romania (1996 to 1997), the Czech Republic (1997), Congo (1998), Russia (1999), the United States (1999 to 2003), Canada (1999–2003), and Israel (2000).
Epizootics of disease in horses occurred in Morocco (1996), Italy (1998), the United States (1999 to 2001), and France (2000). In 2003, West Nile virus spread among horses in Mexico.

In the US in 2002, West Nile virus was documented in animals in 44 states and the District of Columbia with Illinois, Louisiana, Michigan, and Ohio reporting the most deaths. By 2003, 45 states and D.C. had reported human cases.

Recent outbreaks

'United States': From 1999 through 2001, the CDC confirmed 149 cases of human West Nile virus infection, including 18 deaths. In 2002, a total of 4,156 cases were reported, including 284 fatalities. 13 cases in 2002 were contracted through blood transfusion. The cost of West Nile-related health care in 2002 was estimated at $200 million. The first human West Nile disease in 2003 occurred in June and one West Nile-infected blood transfusion was also identified that month. In the 2003 outbreak, 9,862 cases and 264 deaths were reported by the CDC. At least 30% of those cases were considered severe involving meningitis or encephalitis. In 2004, there were only 2,539 reported cases and 100 deaths. In 2005, there was a slight increase in the number of cases, with 3,000 cases and 119 deaths reported. 2006 saw another increase, with 4,261 cases and 174 deaths.

See also Progress of the West Nile virus in the United States
'Canada': One human death occurred in 1999. In 2002, ten human deaths out of 416 confirmed and probable cases were reported by Canadian health officials. In 2003, 14 deaths and 1,494 confirmed and probable cases were reported. Cases were reported in 2003 in Nova Scotia, Quebec, Ontario, Manitoba, Saskatchewan, Alberta, British Columbia, and the Yukon. In 2004, only 26 cases were reported and two deaths; however, 2005 saw 239 cases and 12 deaths. By October 28, 2006, 127 cases and no deaths had been reported. One case was asymptomatic and only discovered through a blood donation. Currently in 2007, 58 Manitobans have confirmed cases of West Nile and and one person has died.^[30] 17 people have either tested positive or are suspected of having the virus in Saskatchewan, and only one person has tested positive in Alberta.^[31]
Saskatchewan has reported 826 cases of West Nile plus three deaths.^[32]
'Israel': In 2000, the CDC found that there were 417 confirmed cases with 326 hospitalizations. 33 of these people died. The main clinical presentations were encephalitis (57.9%), febrile disease (24.4%), and meningitis (15.9%).^[33]
'Romania': In 1996-1997 about 500 cases occurred in Romania with a fatality rate of nearly 10%.

Surveillance methods

West Nile virus can be sampled from the environment by the pooling of trapped mosquitoes, testing avian blood samples drawn from wild birds and sentinel chickens, as well as testing brains of dead birds found by various animal control agencies and the public. Testing of the mosquito samples requires the use of RT-PCR to directly amplify and show the presence of virus in the submitted samples. When using the blood sera of wild bird and sentinel chickens, samples must be tested for the presence of West Nile virus antibodies by use of immunohistochemistry (IHC)^[34] or Enzyme-Linked Immunosorbent Assay (ELISA).^[35]
Dead birds, after necropsy, have their various tissues tested for virus by either RT-PCR or immunohistochemistry, where virus shows up as brown stained tissue because of a substrate-enzyme reaction.

Control

West Nile control is achieved through mosquito control, by elimination of mosquito breeding sites, larviciding active breeding areas and encouraging personal use of mosquito repellents. The public is also encouraged to spend less time outdoors, wear long covering clothing, apply bug repellant that contains DEET and ensure that mosquitoes cannot enter buildings.

Treatment research

Morpholino antisense oligos conjugated to cell penetrating peptides have been shown to partially protect mice from WNV disease.^[36] There have also been attempts to treat infections using ribavirin, intravenous immunoglobulin, or alpha interferon.^[37] GenoMed, a US biotech company, has found that blocking angiotensin II can treat the "cytokine storm" of West Nile virus encephalitis as well as other viruses.^[38]

Sources

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2. Smithburn K C, Jacobs H R. "Neutralization-tests against neurotropic viruses with sera collected in central Africa." ''Journal of Immunology'' 1942; 44: 923.
3. Tsai T F, Popovici F, Cernescu C, Campbell G L, Nedelcu N I. "West Nile encephalitis epidemic in south eastern Romania." ''Lancet'' 1998; 352: 767-771
4. Sejvar J J, Haddad M B, Tierney B C, Campbell G L, Marfin A A, VanGerpen J A, Fleischauer A, Leis A A, Stokic D S, Petersen L R. "Neurologic manifestations and outcome of West Nile virus infection." ''JAMA'' 2003; 290: 511-515.
5. Ahmed S, Libman R, Wesson K, Ahmed F, Einberg K. "Guillain-Barre syndrome: an unusual presentation of West Nile virus infection." ''Neurology'' 2000; 55: 144-146.
6. Abroug F, Ouanes-Besbes L, Letaief M, Ben Romdhane F, Khairallah M, Triki H, Bouzouiaia N. "A cluster study of predictors of severe West Nile virus infection." ''Mayo Clinic Proceedings'' 2006; 81: 12-16.
7. Perelman A, Stern J. "Acute pancreatitis in West Nile Fever." ''American Journal of Tropical Medicine and Hygiene'' 1974; 23: 1150-1152.
8. Omalu B I, Shakir A A, Wang G, Lipkin W I, Wiley C A. "Fatal fulminant pan-meningo-polioencephalitis due to West Nile virus." ''Brain Pathology'' 2003; 13: 465-472
9. Mathiot C C, Georges A J, Deubel V. "Comparative analysis of West Nile virus strains isolated from human and animal hosts using monoclonal antibodies and cDNA restriction digest profiles." ''Res Virol'' 1990; 141: 533-543.
10. Hayes E B, Komar N, Nasci R S, Montgomery S P, Oleary D R, Campbell G L. "Epidemiology and transmission dynamics of West Nile virus disease." ''Emerging Infectious Diseases Journal'' 2005a; 11: 1167-1173
11. Taylor R M, Hurlbut H S, Dressler H R, Spangler E W, Thrasher D. "Isolation of West Nile virus from ''Culex'' mosquitoes." ''Journal of the Egyptian Medical Association'' 1953; 36: 199-208
12. CDC. "Laboratory-acquired West Nile virus infections - United States,2002." ''MMWR'' 2002c; 51: 1133-1135.
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14. CDC. "Investigation of blood transfusion recipients with West Nile virus infections." ''MMWR'' 2002b; 51: 823.
15. CDC. "West Nile virus infection in organ donor and transplant recipients - Georgia and Florida, 2002." ''MMWR'' 2002e; 51: 790.
16. CDC. "Intrauterine West Nile virus infection - New York, 2002." ''MMWR'' 2002a; 51: 1135-1136.
17. CDC. "Possible West Nile virus transmission to an infant through breast-feeding - Michigan, 2002." ''MMWR'' 2002d; 51: 877-878.
18. CDC. "Detection of West Nile virus in blood donations - United States, 2003." ''MMWR'' 2003; 52: 769-772
19. Panthier R, Hannoun C, Beytout D, Mouchet J. "Epidemiology of West Nile virus. Study of center in Camargue." ''Annales de l'Institut Pasteur'' (Paris) 1968; 115: 435-445.
20. Kumar D, Drebot M A, Wong S J, Lim G, Artsob H, Buck P, Humar A. "A seroprevalence study of West Nile virus infection in solid organ transplant recipients." ''American Journal of Transplantation'' 2004; 4: 1883-1888.
21. Chemokine receptor CCR5 promotes leukocyte trafficking to the brain and survival in West Nile virus infection, , WG, Glass, Journal of Experimental Medicine, 2005
22. CCR5 deficiency increases risk of symptomatic West Nile virus infection, , WG, Glass, Journal of Experimental Medicine, 2006
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30. http://www.gov.mb.ca/health/wnv/index.html
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35. Immunodominant epitopes on the NS1 protein of MVE and KUN viruses serve as targets for a blocking ELISA to detect virus-specific antibodies in sentinel animal serum, , RA, Hall, Journal of Virological Methods, 1995
36. In vitro resistance selection and in vivo efficacy of morpholino oligomers against West Nile virus, , Tia S, Deas, Antimicrob Agents Chemother, 2007
37. Hayes E B, Sejvar J J, Zaki S R, Lanciotti R S, Bode A V, Campbell G L. "Virology, pathology, and clinical manifestations of West Nile virus disease." ''Emerging Infectious Diseases Journal'' 2005b; 11: 1174-1179.
38. Moskowitz DW, Johnson FE. The central role of angiotensin I-converting enzyme in vertebrate pathophysiology. Curr Top Med Chem. 2004;4(13):1433-54. PMID: 15379656.

External links

★ U.S. Centers for Disease Control and Prevention (CDC) pages

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★ West Nile virus topic page

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★ World map of West Nile and related viruses

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★ 2003 case count

★ U.S. National Institute for Occupational Safety and Health (NIOSH) pages

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★ Recommendations for Protecting Outdoor Workers from West Nile Virus Exposure

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★ Recommendations for Protecting Laboratory, Field, and Clinical Workers from West Nile Virus Exposure

★ Vaccine Research Center (VRC) - Information concerning WNV vaccine research studies

★ US map of West Nile virus

★ Canadian Case Surveillance

★ L. Peterson, M. Marphin. "West Nile virus: A Primer for the Clinician", ''Annals of Internal Medicine,'' Vol. 137 No. 3, August 2002.

★ D. J. White, D. L. Morse (eds.). "West Nile virus: Detection, Surveillance, and Control", ''Annals of the New York Academy of Sciences'', Vol. 951, 2001.

★ ''Nature'' news article on West Nile paralysis

★ CBC News Coverage of West Nile in Canada

★ West Nile Fever in Europe

★ Encephalitis Global, Inc.

★ Harvard University fact sheet on West Nile Virus

★ West Nile Cases Drop as Immunities Emerge, Experts Say

★ Nash D, Mostashari FM, Fine A, et al. N Engl J Med. 2001 Jun 14;344(24):1807-14 The outbreak of West Nile virus infection in the New York City Area in 1999