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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. The genetic material of WNV is a positive-sense, single strand of RNA, which is between 11,000 and 12,000 nucleotides long; these genes 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.

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; the third is a neuroinvasive disease termed West Nile meningitis or encephalitis. In many infected individuals the ratio between the three states is roughly 110:30:1.

The second, febrile stage has an incubation period of 2 to 8 days followed by fever, headache, chills, diaphoresis (excessive sweating), weakness, lymphadenopathy (swollen lymph nodes), drowsiness, pain in the joints and symptoms like those of influenza or the flu. 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 to 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. WNV-associated Guillain-Barré syndrome has been identified and other rare effects include multifocal chorioretinitis (which has 100% specificity for identifying WNV infection in patients with possible WNV encephalitis), hepatitis, myocarditis, nephritis, pancreatitis, and splenomegaly.

Mortality rate

In the United Statesmarker in 2007, "A total of 3,630 cases of WNV neuroinvasive disease (WNND) and 124 deaths were reported." This means that of extremely serious infections of WNV, 3.4% were fatal and the general total mortality rate was likely much less than 4% as most cases are not severe.

Transmission and susceptibility

Transmission

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 hemispheremarker 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.

In mammals the virus does not multiply as readily (i.e. does not develop high viremia during infection), and it is believed that mosquitoes biting infected mammals do not ingest sufficient virus to become infected, 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 WNV. This is argued to provide an explanation of why the West Nile disease has spread more quickly in North America than Europe. However, these conclusions have been disputed.

Susceptibility

It was initially believed that direct human-to-human transmission was only caused by occupational exposure, or conjunctival exposure to infected blood. The US outbreak revealed novel transmission methods, through blood transfusion, organ transplant, intrauterine exposure, and breast feeding. Since 2003, blood banks in the US routinely screen for the virus amongst their donors. 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 Canadamarker.

The more severe outcomes of WNV infection are clearly associated with advancing age and a patient history of organ transplantation and diabetes. 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%.

Recently, the potential for mosquito saliva to impact the course of WNV disease was demonstrated. Mosquitoes inoculate their saliva into the skin while obtaining blood. Mosquito saliva is a pharmacologic cocktail of secreted molecules, principally proteins, that can affect vascular constriction, blood coagulation, platelet aggregation, inflammation, and immunity. It has become clear that mosquito saliva alters the immune response in a manner that may be advantageous to a virus. Studies have shown that it can specifically modulate the immune response during early virus infection, and mosquito feeding can exacerbate WNV infection leading to higher viremia and more severe forms of disease. It is unknown what benefit, if any, the mosquito receives by assisting the virus in this manner, so it is likely that the virus is simply exploiting the preexisting qualities of mosquito saliva developed for other purposes.

There is no vaccine for humans. A vaccine for horses (ATCvet code: ) 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 known cases of direct canine-human or feline-human transmission; although these pets can become infected, it is unlikely that they are in turn capable of infecting native mosquitoes and thus continuing the disease cycle.

Avoiding mosquito bites is the most straightforward means to avoid infection—remaining indoors (while preventing mosquitoes from entering) at dawn and dusk, wear light-colored clothing that covers arms and legs as well as trunk, use insect repellents on both skin and clothing (such as DEET, picaradin, or oil of lemon eucalyptus for skin and permethrin for clothes). If one becomes infected, generally, 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.

Reported cases in the U.S. in 2005 exceeded those in 2004, and cases in 2006 exceeded 2005's totals. On August 19, 2006, the LA Times reported that the expected incidence rate of WNV 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. However, just days later, the CDC said that WNV cases could reach a three-year high because hot temperatures had allowed a larger brood of mosquitoes.

History

Studies of phylogenetic lineages have determined that WNV emerged as a distinct virus around 1000 years ago. 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 has been posited as one of the possible causes of Alexander the Great's early death based on reports of avian deaths before his illness period.

WNV was first isolated from a feverish 37 year old woman at Omogo in the West Nile District of Uganda in 1937 during research on yellow fever virus. 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 Egyptmarker (1942) and Indiamarker (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 Egyptmarker and Israelmarker. 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 Francemarker in the early 1960s and found to be widespread in southern Europe, southwest Asia and Australia.

The first appearance of WNV in the Western hemisphere was in 1999 with encephalitis reported in humans, dogs, cats, and horses, and the subsequent spread in the United Statesmarker may be an important milestone in the evolving history of this virus. The American outbreak began in the New York Citymarker area (specifically, College Point, Queensmarker) and was later seen in New Jerseymarker and Connecticutmarker; the virus is believed to have entered in an infected bird or mosquito, although there is no clear evidence. 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. The Barbary Macaque, Macaca sylvanus was the first non-human primate to contract WNV. 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 high level of media coverage through 2001/2002 raised public awareness of WNV. This coverage was most likely the result of successive appearances of the virus in new areas, and had the unintended effect of increasing funding for research on this virus and related arthropod-borne viruses. Such research has expanded our understanding of viruses transmitted by mosquitoes.

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.

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 Algeriamarker (1994), Romaniamarker (1996 to 1997), the Czech Republicmarker (1997), Congomarker (1998), Russiamarker (1999), the United States (1999 to 2009), Canada (1999–2003), and Israelmarker (2000).

Epizootics of disease in horses occurred in Moroccomarker (1996), Italymarker (1998), the United States (1999 to 2001), and Francemarker (2000). In 2003, West Nile virus was found in horses in Mexico.



In the US in 2008, West Nile virus was reported in animals in 47 states, D.C. and Puerto Rico. 45 states and D.C. reported human cases in 2008 with only Maine, Alaska and Hawaii having never had a human case. (Maine has had occasional animal cases.)

Recent outbreaks

United States: From 1999 through 2001, the CDC confirmed 149 West Nile virus infections, 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 WNV-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 4,269 cases and 177 deaths. In 2007, the number of cases reported decreased to 3,623 and the number of deaths dropped to 124. In 2007, 1,227 cases of wnv neuroinvasion disease and 117 deaths occurred. In 2008, West Nile surveillance data reported to CDC, a total of 28 states have reported 236 cases of human WNV illness. A total of 137 cases for which such data were available occurred in males, median age patients was 48 years. Dates of illness onset ranged from Jan. 17 to Aug. 14: Two cases were fatal.

West Nile Virus Cases in the United States


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 Scotiamarker, Quebecmarker, Ontariomarker, Manitobamarker, Saskatchewanmarker, Albertamarker, British Columbiamarker, and the Yukonmarker. 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. In 2007, 445 Manitobans had confirmed cases of WNV and two people died with a third unconfirmed but suspected. 17 people have either tested positive or are suspected of having the virus in Saskatchewan, and only one person has tested positive in Alberta.Saskatchewanmarker has reported 826 cases of WNV plus three deaths.. The spread of West Nile Virus infected mosquitoes to British Columbia for the first time was reported in 2009

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%).

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 dogs and sentinel monkeys, 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 WNV antibodies by use of immunohistochemistry (IHC) or Enzyme-Linked Immunosorbent Assay (ELISA).

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 virus warning sign in Southern California.
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.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.

An effective horse vaccine was introduced by Fort Dodge Animal Health (Wyeth).

Treatment research

AMD3100, which had been proposed as an antiretroviral drug for HIV, has shown promise against West Nile encephalitis. Morpholino antisense oligos conjugated to cell penetrating peptides have been shown to partially protect mice from WNV disease. There have also been attempts to treat infections using ribavirin, intravenous immunoglobulin, or alpha interferon. GenoMed, a U.S. biotech company, has found that blocking angiotensin II can treat the "cytokine storm" of West Nile virus encephalitis as well as other viruses.

In 2007 the World Community Grid launched the Discovering Dengue Drugs – Together project. This uses a distributed network of volunteers' computers via the Berkeley Open Infrastructure for Network Computing (BOINC) to perform computer simulations of interacting molecules. Thousands of small molecules are screened for potential anti-viral properties with respect to West Nile and related viruses.

See also



Notes

External links




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