Version May 2024
INTRODUCTION — West Nile (WN) virus, a member of the Japanese encephalitis virus antigenic complex, was first isolated in a blood sample in a patient from the West Nile province of Uganda in 1937 [1]. This RNA virus was initially considered of minor public health importance [2]. It emerged from obscurity in 1999 when the first incursion of the virus into North America caused 62 cases of encephalitis and seven deaths in New York [3]. WN virus activity has now been detected in all 48 continental states and the District of Columbia [4]. WN virus causes both sporadic infection and outbreaks that may be associated with severe neurologic disease.
The epidemiology and pathogenesis of West Nile virus will be addressed here. The clinical manifestations, diagnosis, and treatment of infection are discussed elsewhere. (See "Clinical manifestations and diagnosis of West Nile virus infection" and "Treatment and prevention of West Nile virus infection".)
EPIDEMIOLOGY — WN virus is one of the most widely distributed of all arboviruses with an extensive distribution in the Old World, throughout Africa, the Middle East, parts of Europe and the former Soviet Union, South Asia, and Australia [5]. The virus had not been detected in the Americas before the 1999 New York City outbreak. It is unknown how WN virus got to the United States. While initial phylogenetic studies suggested a Middle Eastern origin for the North American WN virus [6,7], subsequent analysis indicated that WN strains now circulating in Europe and Israel originated from the same independent location, probably North Africa [8]. WN virus is now considered endemic in North America [4].
Patterns of illness — Since the first discovery of WN virus, infrequent human outbreaks were mostly reported in groups of soldiers, children, and healthy adults in Israel and Africa [9-12]. These outbreaks were associated with only minor illness in the majority of patients; some case fatalities were associated with increasing age. In one of the largest outbreaks reported, thousands of self-limited and relatively mild clinical cases, consisting of fever, rash, and polyarthralgias occurred in South Africa, resulting in an epidemic attack rate of 55 percent [13].
However, since the mid-1990s, outbreaks of WN virus infection associated with severe neurologic disease began to occur in North Africa (Algeria [1994, 1997], Tunisia [1997], Sudan [2002]); Europe (Romania [1996]); Russia (1999); Israel (2000); North America (United States [1999], Canada [2002]); and India (2011) [4,14-19]. In each of these outbreaks, the mortality among patients with meningitis and encephalitis was approximately 10 percent, and occurred more often in older patients. Since 2002, outbreaks have also occurred in multiple southern European countries, with annual epidemic cycles in some countries related to the spread of WN virus lineage 2 strains [20-23].
Incidence in the United States — Since 2000, the ArboNET national surveillance system has tracked WN virus in the United States, and WN virus is the leading cause of domestically acquired arboviral disease [4,24]. Most studies indicate that increased WN virus incidence is related to above-average temperatures, with variable impact of precipitation [25,26].
Only about 1 to 2 percent of West Nile fever cases are reported [24] since most infected persons are asymptomatic, do not seek medical care for mild symptoms, or are not tested for WN virus. Thus, the most accurate trend data derive from monitoring cases of invasive neurologic disease [27]. The incidence of neuroinvasive disease varies considerably across the United States (figure 1). Updated reports are available on the United States Centers for Disease Control and Prevention (CDC) website.
From 1999 to 2019, a total of 51,801 confirmed and probable cases of WN virus disease, including 25,290 cases of neuroinvasive disease, were reported to the CDC from 48 states, the District of Columbia, and Puerto Rico [28]. Only 19 human cases of WN neuroinvasive disease were reported in the United States in 2000 and 64 in 2001. However, from 2002 to 2018, the number of reported neuroinvasive disease cases ranged from 386 to 2946; the three largest outbreaks occurred in 2002 (2946 cases), 2003 (2866 cases), and 2012 (2873 cases).
The large multistate outbreak in 2012 was widespread, with 43 states reporting a higher incidence of neuroinvasive disease in 2012 compared with the median for 2004 to 2011; more than half of these cases were reported from four states and 29 percent were reported from Texas alone [29]. The incidence rate of WN neuroinvasive disease in Dallas county was 7.30 per 100,000 residents in 2012, which was significantly higher than the largest previous Dallas County outbreak of 2.91 per 100,000 in 2006 [30]. The largest focal outbreak to date occurred in Maricopa County (Phoenix) in 2021, with more than 800 neuroinvasive disease cases reported as of November 2021 [31].
However, serologic surveys and extrapolations from blood donor screening data indicate that neuroinvasive disease following infection is infrequent, with estimates ranging from 1 in 140 to 1 in 256 infections resulting in meningitis or encephalitis [14,32-35]. By extrapolation, the 24,657 cases of invasive neurologic disease reported in the United States through 2018 would imply that from 3.4 to 6.3 million persons have been infected. Serological surveys indicate that even in areas experiencing outbreaks, less than 10 percent of the population is infected with WN virus [14,32,35,36].
Human illnesses usually peak in late summer or early fall (figure 2) [4]. As an example, cases peaked in late August during the 2012 outbreak in Dallas county, with 92 percent having illness onset during July through September [30]. The seasonal variation is because mosquitoes emerge in the spring in temperate climates, which begins viral amplification in the bird-mosquito-bird cycle. Viral amplification peaks in early fall; the risk of infection then decreases in humans when female mosquitoes begin diapause and infrequently bite. However, sporadic cases can occur throughout the year in southern states.
Incidence in Canada — The epidemiology and ecology of WN virus in Canada reflect that of the northern United States. The virus is now endemic in all Canadian provinces. Through 2019, a total of 6423 patients with WN virus disease have been reported in Canada, ranging from 5 to 2401 annually [37]. The first human cases were reported in 2002, with 414 illnesses reported from Quebec and Ontario. The largest outbreaks occurred in 2003 (1488 cases) and 2007 (2401 cases).
Incidence in Latin America and the Caribbean — WN virus was first detected south of the United States border in 2001, when a resident of the Cayman Islands developed WN virus encephalitis [38]. By 2003, the virus was detected in El Salvador, Guatemala, and Belize [39]; by 2004 in Colombia and Venezuela [40]; and by 2005 in Argentina [41].
However, isolation of virus has been infrequent and documented avian, equine, and human morbidity are scant [42,43]. Documented human infections have been limited to a few patients in the Cayman Islands [38], Cuba [44], Haiti [45], Puerto Rico [46], northern Mexico [47], and Brazil [48].
The reasons for the discrepancy between the serologic evidence indicating widespread WN virus circulation in the Caribbean, Central and South America, and Mexico and the lack of substantial avian, equine, or human morbidity remain a mystery.
Incidence in other countries — From the 1960s through the 1980s, WN virus was isolated infrequently from mosquitoes, birds, horses, and humans in southern Europe. The first large human outbreak in Europe occurred in Romania in 1996 [14]. Since that time, outbreaks and sporadic human cases have occurred in an expanding area roughly extending from Spain, Italy, Greece, through the Balkans, Ukraine, and the Russian Federation (Volgograd, Astrakchan, and Rostov) [49]. From 2010 to 2018, 110 to 991 neuroinvasive disease cases were reported in European Union countries [50]. The largest outbreak occurred in 2018 with 991 human cases, a total exceeding the previous seven years combined. Among European Union countries, Greece, Italy, and Romania have reported the most cases. Cases and outbreaks also frequently occur in Israel.
Transmission — Nearly all human infections with WN virus are due to mosquito bites. Birds are the primary amplifying hosts, and the virus is maintained in a bird-mosquito-bird cycle. Humans, horses, and many other vertebrates serve as incidental hosts and are not felt to be important for transmission since viremia is both short-lived and low-grade [51,52].
Rarely, transmission can also occur from mother to child in utero, or from an infected donor to a blood or organ transplant recipient. Transmission has also been documented via breast milk [53], occupational percutaneous exposure [54], conjunctival exposure [55], and by unidentified means in a dialysis center [56].
Mosquitoes — Mosquitos that transmit WN virus are usually of the Culex species, which vary by geographic area. The major mosquito vectors in Africa and the Middle East are Culex univittatus and Culex pipiens molestus, and in Asia, Culex tritaeniorhynchus. WN virus has been recovered from ticks in Russia, but it is not clear what role they play in maintaining or disseminating the virus.
Surveillance has identified 66 mosquito species infected with the WN virus in North America. WN and the St. Louis encephalitis viruses appear to share the same maintenance vectors (see "St. Louis encephalitis"). Culex pipiens (northern house mosquito) is an important maintenance vector in the northern United States and Canada, Culex pipiens quinquefasciatus (southern house mosquito) is important in the southern United States, and Culex tarsalis is important in the western United States and Canada [57].
Birds as amplifying hosts — Numerous passerine birds develop prolonged high levels of viremia and serve as amplifying hosts. In many countries, the birds remain asymptomatic [58,59]. As an example, avian WN virus mortality in Europe is uncommon, presumably due to long standing coevolution of viruses and hosts following introduction by virus-infected migratory birds from Africa.
By contrast, significant avian mortality has been noted in Israel, the United States, and Canada, where similar strains of the virus have circulated [9,60]. High mortality has been noted among American crows and other North American corvids (ravens, jays, and other crows) [61]. Decreases in populations of American crows have been sustained, and impacts on other species mostly have recovered to previous abundances [62]. Single nucleotide changes in the NS1-2B and NS3 genes appear responsible for the increased mortality in American crows [58,63,64].
In the early years following the spread of WN in the United States, a higher incidence of WN infection was noted to occur in residents who live in high crow-mortality areas compared with those who reside outside of these areas [65]. However, decreasing susceptible bird populations and waning interest in avian mortality surveillance have decreased the value of dead crow sightings as an indicator of virus activity.
Donated blood — Transmission has been described via transfused blood, red blood cells, platelets, and fresh frozen plasma [66]. However, universal screening of the United States and Canadian blood supplies has nearly eliminated the risk of transfusion-transmitted WN virus infection [52,67,68]. Nevertheless, a small residual risk remains from donations with low viremia not detected by nucleic acid testing (NAT) in the minipool or individual donation format used by blood centers [69-71]. (See "Blood donor screening: Laboratory testing", section on 'West Nile virus'.)
Organ transplant — In 2002, transmission via donated organs was first documented when four recipients of organs from a common donor developed WN virus infection [72]. Serum from the day of organ harvest was positive for WN virus by NAT and culture. A second transmission occurred in 2005 in which three of four organ recipients developed WN virus infection [73]. Since then, additional transmission clusters have been published in the United States [74-76] and one in Italy, all from deceased donors [77]. Serum from the donors in several clusters were negative for WN virus RNA, suggesting that transmission can occur from virus sequestered in organs in the absence of detectable viremia in serum.
Transplacental — Transplacental transmission of WN virus can occur [78,79]. In 2002, for example, a case of congenital infection following second trimester infection in the mother was reported [79]. In addition, the CDC registry tracked pregnancies from 2003 to 2004 and identified 77 women infected with WN virus in 16 states [78]. Of the 72 infants followed, three infants (4 percent) had symptomatic WN virus disease at or shortly after birth. These infants were born to women who had developed symptomatic WN virus infection within three weeks of delivery. Although cord blood or infant serum at the time of delivery were not available, intrauterine infection or infection at the time of delivery was possible.
However, transmission appears to be rare. A retrospective study among 549 infants born after a community-wide epidemic of WN virus examined the relationship between birth outcomes and possible exposure to WN virus during pregnancy [80]. Cord blood samples looking for immunoglobulin M (IgM) antibodies to WN virus provided no evidence of congenital WN virus infections, and there were no significant clinical differences between infants of exposed and unexposed mothers.
PATHOGENESIS — The pathogenesis of severe infection with WN virus is not well understood.
Dissemination — During feeding, the mosquito injects virus-laden saliva into the host. Dissemination of WN virus following subcutaneous inoculation can be described in three phases: early phase (replication in keratinocytes and skin-resident dendritic cells, including dermal dendritic cells and Langerhans cells), visceral-organ dissemination phase (viral replication in the draining lymph nodes, and viremia and spread to visceral organs, including the spleen) and central nervous system (CNS) phase (invasion of the CNS) [81].
In mouse models, the primary viremia is cleared in approximately one week, at which time virus levels in the CNS increase and neurological manifestations appear [82]. The mechanisms by which WN virus enters the CNS are not precisely known, but likely include [83-86]:
●Direct viral crossing of the blood-brain barrier due to cytokine-mediated increased vascular permeability
●Infection or passive transport through endothelium or choroid plexus epithelial cells
●Trafficking of infected tissue macrophages across the blood-brain barrier
●Infection of olfactory neurons
●Direct axonal retrograde transport from infected olfactory or peripheral neurons
Humoral immunity — As with other flaviviruses, humoral immunity is critical for protection from WN virus. As an example, mice genetically deficient in B cells had increased WN viral loads in the CNS, and the infection was lethal at lower doses of virus compared with controls [87]. In addition, the presence of neutralizing antibody correlates with protection from flaviviruses, and passive transfer of IgG antibody can protect against WN challenge [88]. (See "Treatment and prevention of West Nile virus infection", section on 'Treatment'.)
Cell intrinsic innate immunity — Innate antiviral defenses are also critical for control of WN virus, as demonstrated in mouse models and evidenced by extreme susceptibility to infection in persons with certain immunocompromising conditions. These innate defenses include the production of type I interferons and proinflammatory cytokines, the expression of antiviral genes, and the subsequent activation of the adaptive immune response [81,83,89-93]. WN virus infection is sensed by pattern-recognition receptors, including retinoic acid-inducible gene 1 protein (RIG-1)-like receptors and Toll-like receptors, which recognize distinct viral signatures known as pathogen-associated molecular patterns. These receptors subsequently trigger downstream signaling pathways that activate the innate immune defenses, including the production of interferons-alpha/beta. Interferons-alpha/beta subsequently stimulate genes that inhibit viral replication, modulate the adaptive immune response, and possibly tighten the blood-brain barrier to limit neuroinvasion [90].
Complement — The complement system is a large family of proteins that recognize pathogen-associated molecular patterns, altered cell surface ligands, and immune complexes. Complement suppresses WN viral infection by inducing several antiviral effector functions of the immune response [81], and has been demonstrated to prevent lethal WN infection in mice [83].
However, WN virus may evade complement-mediated control via its nonstructural protein (NS)-1. NS-1 binds and recruits the complement regulatory protein factor H, which may lower the ability of the immune system to target WN virus by decreasing complement-mediated recognition of infected cells [94].
PATHOLOGY — Histological findings in WN neuroinvasive disease include microglial nodules with variable loss of neurons, perivascular cuffing by mononuclear cells, and neuronophagia [95]. The most impacted areas of the central nervous system (CNS) include the medulla, pons, thalamus, and substantia nigra of the basal ganglia. In the spinal cord, involvement of the anterior horns and anterior spinal nerve roots lead to lower motor neuron loss [75,95].
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: West Nile virus infection (Beyond the Basics)")
SUMMARY
●Epidemiology – West Nile (WN) virus is one of the most widely distributed of all arboviruses with an extensive distribution in the Old World, throughout Africa, the Middle East, parts of Europe and the former Soviet Union, South Asia, and Australia. The virus had not been detected in North America before the 1999 New York City outbreak. (See 'Epidemiology' above.)
●Transmission – Nearly all human infections with WN virus are due to mosquito bites. Birds are the primary amplifying hosts, and the virus is maintained in a bird-mosquito-bird cycle. Mosquitoes that transmit WN virus are usually of the Culex species, which vary by geographic area. Other less common routes include transfused blood and transplanted organs. (See 'Transmission' above.)
●Pathogenesis – Humoral immunity, cell intrinsic innate immunity, and the complement system all contribute to the host’s ability to prevent severe WN virus infection. (See 'Pathogenesis' above.)
●Pathology – Histological findings in WN neuroinvasive disease include microglial nodules with variable loss of neurons, perivascular cuffing by mononuclear cells, and neuronophagia. (See 'Pathology' above.)
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