West Nile Virus

Introduction

West Nile virus (WNV) was first isolated in 1937 in the West Nile district of Uganda and was subsequently reported in other areas of Africa, the Middle East, Europe, South Asia, and Australia. For decades, infections with WNV were generally mild and infrequent. This changed in the 1990s as severe disease became increasingly common and widespread, due at least in part, to commerce and the dispersal of Culex pipiens mosquitoes, the introduction of WNV into house sparrows, and climate warming.

Bird and, later, human infections were first seen in the Western Hemisphere in the United States in 1999 and the virus began to overwinter in Culex mosquitoes in New York City in early 2000. WNV is now endemic throughout North, South, and Central America. Between 1999 and 2016, California, Colorado, and Texas reported greater than 5000 cases of WNV disease, with over 3000 cases of neuroinvasive disease in California and Texas alone. It should be noted that WNV had, essentially, not reached these Western states until 2002. In the United States in 2017, WNV infected people, birds, or mosquitoes in 47 states and the District of Columbia. Reported human disease incidence in that year was 2002. Of these, 1339 (67%) were neuroinvasive disease and 663 (33%) were nonneuroinvasive. These figures likely underestimate the true number of infections since most WNV infections in humans are asymptomatic.

In approximately 20% of those infected, a mild, self-limiting form of febrile illness ensues. A small number of those infected (less than 1%) develop the severe, potentially fatal neuroinvasive disease. Some survivors have long-term or permanent neurological damage. The recent rapid geographical spread of the virus and the increase in disease incidence and severity have brought WNV to the attention of both the healthcare community and the general public.

History

Infection with WNV typically resulted in occasional cases of mild, febrile illness from its discovery in 1937 until 1957, when an outbreak produced severe neurological symptoms in residents of Israeli nursing homes. This Israeli strain had a high mortality rate in geese. Such serious disease manifestations remained uncommon until the mid-1990s through the early 2000s. During that time period, large outbreaks of severe disease occurred in Algeria (1994), Romania (1996), Tunisia (1997), Russia (1999), the United States (1999–2005), Israel (2000), Sudan (2002), and Canada (2003–2004). Up to 60% of hospitalized patients developed the neuroinvasive disease, with a mortality rate of 4%–7%.

The Israeli strain of WNV is believed to have entered the United States during the late summer of 1999 from mosquitoes carried aboard cargo ships docking in New York Harbor or from infected exotic imported or migratory birds. Evidence suggests that the resulting outbreak in New York was amplified in house sparrows. A mutation in the WNV helicase gene led to high levels of viremia and mortality in American crows and a large number of crows were found dead in the affected region of New York. Several exotic zoo birds are also susceptible to severe infection. In the United States during that August, 62 cases of human West Nile disease, 59 of which were severe and resulted in hospitalization, and 7 deaths, occurred coincidentally with an epizootic outbreak in birds. The reported infections were all found in the vicinity of New York City, initially in a small area of the northern portion of the borough of Queens. Genetic sequencing suggests that the strain (NY99) originated in the Middle East, with close similarity to that circulating in Israel at the time. Both NY66 and the Israeli isolates are unusual in their ability to cause a high mortality rate in birds. Prior to this flavivirus outbreak, most cases of viral meningitis were caused by an enterovirus and primarily involved young children. Enteroviruses are transmitted by contact with contaminated fecal material. The people infected during the 1999 American outbreak did not know each other and had no common exposure history, but all spent time outdoors, particularly in the evenings. Serological testing of serum and cerebrospinal fluid (CSF) samples indicated that the causative agent was antigenically similar to Saint Louis encephalitis virus. WNV was later identified as the responsible virus for human disease.

In 2000, there were 21 reported cases in humans with 2 deaths, again occurring around New York City, particularly Staten Island. The epizootic in birds, however, had by this time spread to 12 states, ranging from Vermont to South Carolina, and the District of Columbia. That year also witnessed 63 cases of infection in horses from 7 states, with a 39% fatality rate. In 2001, 66 human cases and 9 deaths were reported. In 2002, the number of human cases increased to 4156 with 284 deaths, and in 2003, 9862 human cases with 264 deaths were reported in the United States. By this time, the disease had spread through much of the country. By 2004, West Nile disease had spread westward and was reported in almost all of the states in the continental United States as well as Canada. The state with the highest number of cases at that time was California. Significantly, the numbers of cases of human West Nile disease in the United States as a whole fell in 2004 and 2005 to less than 33% of the level found in 2003, perhaps due to the establishment of immunity in asymptomatic people. As WNV spread across the United States, it infected other highly competent avian hosts, including blue jays and American robins, which served as important amplification hosts. The original WNV NY99 strain was also replaced by the WN02 strain, which is transmitted more efficiently by the mosquito vectors, especially at high temperatures.

Over the last few years, West Nile disease incidence in the United States has fallen. From January 1 to December 16, 2008, the CDC was notified of 1370 cases of confirmed West Nile disease in the United States. Of these, 679 (49.6%) were West Nile fever, 640 (46.7%) were encephalitis or meningitis, 51 (3.7%) led to other/unspecified clinical manifestations, and 37 (2.7%) were fatal. The state with the highest number of cases (411 with 13 deaths) was California and accounted for 30% of the total number of cases in the country. Two other Western states, Arizona and Colorado, also had a high number of cases of West Nile disease (109 and 95, respectively), while nearby Utah, Nevada, and New Mexico had lower numbers (26, 16, and 9 cases, respectively). Mississippi, with a greatly different climate, reported 99 cases. The states with the highest incidence rates of human West Nile encephalitis/meningitis in 2008 were South Dakota, Kansas, and Nebraska. California, Arizona, and Nebraska also had the highest number of infected blood donors in 2008 (68, 26, and 13 positive donors, respectively). From 2009 to 2011, case numbers for the country as a whole were lower than those reported in 2008, but they resurged again in 2012. In that year, over 5500 WNV infections were reported, with the largest increase in Texas (1868 as opposed in 27 in 2011). The number of neuroinvasive disease cases also increased greatly, from 486 in 2011 and over 2800 in 2012. Fatal disease also increased in 2012, from 43 in 2011 to 286 in 2012. From 2013 to 2018, the total number of infections in the United States has remained steady, ranging from 2011 to 2700, and the number of deaths ranging from approximately 100 to 170.

A study of the influence of climate on human West Nile disease incidence in California, conducted on a monthly basis per county from 2006 to 2011, found only a weak correlation between human case numbers and temperatures (average, minimum, and maximum temperatures), while no such correlation existed between case numbers and either precipitation or drought (unpublished data). However, strong correlation coefficiencies (exceeding 0.8) were found between the reported numbers of infections in humans and birds and humans and mosquitoes on a per county basis by year in California from 2003 to 2014 in some, but not all counties (unreported data). Importantly, the reports of infection in both mosquitoes and birds preceded reported human cases by weeks. Monitoring numbers of infected mosquitoes may thus permit preventative measures to be implemented in only those counties where such strong correlations are found, while the public health funds could be put to other uses in counties with weak correlation or very low numbers of human cases over time. A low number of counties in several other states also have strong correlation coefficients between numbers of infected humans and mosquitoes, but this is not the case for most counties in most states (unpublished data).

West Nile disease appeared south of mainland United States in 2001, when a case of encephalitis was reported in the Cayman Islands. Surveillance of bird and horse blood found that antibodies to the virus were also present in Columbia, Cuba, the Dominican Republic, Jamaica, Guadeloupe, El Salvador, Mexico, and Puerto Rico, although disease incidence or death of animals or humans was rare. The lack of significant disease in these areas may indicate the presence of a less virulent viral strain or false-positive test results due to cross-reactivity with other flaviviruses.

West Nile disease among humans in Canada was first noted in 2002 as 426 people in Quebec and Ontario became ill and 20 died. As the number of cases in the United States peaked in 2003, 1494 cases with 10 deaths occurred in Canada. As in the United States, disease incidence in Canada fell in subsequent years. West Nile disease during 2008 was found in the southern portions of the Canadian provinces of Manitoba, Saskatchewan, and Ontario, while British Columbia and Alberta reported travel-related cases.

The Diseases

WNV disease is currently endemic in many areas of the world, including Africa, the Middle East, Southwestern Asia, Europe, and the Americas. In temperate regions (latitudes 23.5°–66.5°), the reported numbers of cases are most common during the late summer and fall, in accordance with the biting habits of its mosquito vectors. In warmer climates, such as the American South, the disease occurs year-round. See Davis et al. for an excellent review of WNV-induced disease.