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Healio
Issue: May 2017
ByThomas M Yuill, PhD
ByDonald Kaye, MD, MACP
May 16, 2017
6 min read
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West Nile virus: The US epidemic

Issue: May 2017
ByThomas M Yuill, PhD
ByDonald Kaye, MD, MACP
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The sudden appearance of six cases of West Nile virus encephalitis in New York City in 1999 for the first time in the Americas took the biomedical community by surprise. What followed epidemiologically was even more shocking, and knowledge of the consequences of the infection are still evolving.

That year, there were 62 cases of severe disease reported, mainly central nervous system disease, with seven deaths (case-fatality rate, 11%). This was the tip of the iceberg, because until the development of serological tests, the much more common asymptomatic or mild forms of the infection could not be detected.

Thomas M. Yuill

Over the next 5 years, the epidemic of West Nile virus (WNV) infection spread north to Canada, south to Florida, Mexico and the Caribbean islands, and west to the Pacific coast. The number of cases detected in the U.S. was only 66 in 2001, but that number jumped to more than 4,000 in 2002. The peak year was in 2003, with almost 10,000 cases reported in the U.S. After that, the number of cases nationally stayed under 3,000 except in 2006 (n = 4,269), 2007 (n = 3,630) and 2012 (n = 5,674). The total number of cases reported over the 18 years of the epidemic is about 46,000. However, these numbers are very deceptive in that 21,405 (47%) of all cases reported over the years have been neuroinvasive. Simply stated, because less than 1% of cases progress to neuroinvasive disease (NID), there have been more than 2 million cases of WNV infection in the 18-year period. In a typical year, there are more than 1,000 cases of NID, which translates to more than 100,000 cases of WNV infection each year. A study of blood donors from 2010-2012 calculated a weighted ratio of NID cases to WNV infections in the general population of 1:141. The study concluded that in the 3-year period there were 555,037 cases of WNV infections. This 1:141 ratio would result in more than 3 million cases of WNV infection in the 18 years.

In recent years, the states with the highest numbers of reported cases of WNV infection have been California (especially Southern California) and Texas.

Donald Kaye

Horses are the most commonly affected domestic animals. Those that become ill usually have encephalitis, and 33% die. In 2003, there were more than 5,000 cases of WNV in horses reported. The yearly numbers rapidly decreased in subsequent years, with 377 in 2016. The decrease since 2003 is due to the availability of a commercial vaccine.

A variety of wild bird species are infected with WNV and are the most important hosts in nature for maintenance, amplification and spread of the virus geographically. Interestingly, early on it was speculated that the presence of antibodies to St. Louis encephalitis virus (SLEV), closely related to WNV, would provide enough antigenic cross-protection to prevent the establishment of WNV where SLEV was endemic. Obviously, that did not happen. Some wild mammals have been shown to be infected in nature as well. Tree squirrels (western and eastern grey squirrels and fox squirrels) can become infected and may develop neurological disease and viremias of sufficient magnitude and duration to provide infectious blood meals for vector mosquitoes.

WNV is an arbovirus of the Flavivirus group. In the U.S., more than 40 species of mosquitoes belonging to at least 10 genera have been found to be WNV positive. The most important species belong to the genus Culex. Some, like those in the C. pipiens complex, bite mainly birds; they are ornithophagic and transmit virus among susceptible birds. Others, like C. tarsalis in the Western U.S., may shift host preferences from avian to mammalian hosts late in the transmission season. Other mosquitoes bite humans (anthropophagic) and not birds. For humans to become infected, a bridge vector is needed — a mosquito that bites birds but will sometimes also bite humans. In the U.S., such species include hybrids of the bird-biter C. pipiens and a very closely related mosquito, C. molestus, that bites people. Other bridge vectors are C. restuans, C. salinarius and Aedes vexans. The actual mosquito vectors depend on their geographical distribution. Thus, unlike many other mosquito-borne diseases (such as dengue, chikungunya, Zika and yellow fever), human or other mammalian hosts are not required for transmission in the mosquito-human cycle.

Uncommon methods of transmission for WNV infection are transfusion, organ transplantation, maternal-fetal interaction and breast milk. Humans and many other animals are susceptible to the infection but serve as dead-end hosts as the level of viremia is low. In the U.S., the disease occurs mainly in humans and horses. In humans, the infection is either asymptomatic or very mild in at least 80% of cases. About 20% develop fever and other symptoms suggestive of a viral illness.

The most severe manifestation of WNV infection is NID, which has a mortality rate of about 10%. Neuroinvasive disease includes encephalitis, meningitis, meningoencephalitis, and a syndrome resembling poliomyelitis (acute flaccid paralysis). Severe disease is most frequent in men (60% of cases) and in people aged older than 50 years. More than 50% of patients who survive NID have long-term cognitive sequelae. Persistent neurological abnormalities have been found in patients with NID, with some reportedly developing new abnormalities between short-term follow-up (1-3 years) and long-term follow-up (8-11 years).

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In immunocompromised patients, there have been a few reports of persistent WNV in blood, spinal fluid and the brain. It has been demonstrated that WNV can persist in urine long after the acute infection. In one study, five of 25 patients who developed WNV encephalitis were found to have the virus in their urine as late as 6 years after recovery.

There is no treatment available for WNV infection other than supportive therapy.

Of concern is a study recently presented at the 2016 annual meeting of the American Society of Tropical Medicine and Hygiene that suggested that the effects of WNV infection may be long lasting. Investigators from Baylor College of Medicine studied more than 4,144 patients who had WNV infection in Texas between 2002 and 2012. The investigators reported that 286 of them died in the first 90 days after infection (presumably mainly due to the acute WNV infection). An additional 268 people died during the rest of the follow-up period. The patients with NID were more likely to die of renal disease or from an unrelated infectious disease compared with the general population. This effect was said to be most marked in patients aged younger than 60 years. They concluded that mortality is greatly increased in the first 6 years after infection compared with the general population.

If these observations are confirmed, they would be an additional strong motivational factor toward developing a human vaccine. There is a human vaccine in investigational trials funded by the NIH and developed by scientists at the Oregon National Primate Research Center at Oregon Health & Science University in Portland. A phase 1 clinical trial has been completed. To date, there is no information to suggest that any pharmaceutical company is interested in developing it into a commercially available product.

However, there are multiple effective vaccines available for horses.

  • For more information:
  • Donald Kaye, MD, MACP, is a professor of medicine at Drexel University College of Medicine, associate editor of the International Society of Infectious Diseases’ ProMED-mail, section editor of news for Clinical Infectious Diseases and an Infectious Disease News Editorial Board member.
  • Thomas M. Yuill, PhD, is a ProMED virus diseases moderator and professor emeritus, department of pathobiological sciences and department of forest and wildlife ecology, University of Wisconsin-Madison.

Disclosures: Kaye and Yuill report no relevant financial disclosures.

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