West Nile Virus

US Pharm. 2023;48(8):38-42.

ABSTRACT: West Nile virus (WNV) remains a worldwide emerging disease in the infectious disease realm and has been for several decades. Despite this, options for management of this disease include only supportive and preventive care. With an understanding of the impact of WNV, its etiology, risk factors for acquiring the disease, risk factors for severe disease, in addition to knowing the current standard of care and preventive care, the importance of recognizing WNV and the need for new strategies for management and prevention can be realized.

West Nile virus (WNV) is part of the Flaviviridae family, specifically the Flavivirus genus.^1-3 It is a small, single-stranded RNA virus that consists of structural proteins containing a capsid, premembrane, envelope, and seven nonstructural proteins that encode a polyprotein ultimately used to create mature virions.^2,3 The structural proteins house and form viral particles, aid in binding cellular proteins and entry of the virus, and create the nucleocapsid region, while the nonstructural proteins play roles in the replication of the viral RNA, protein translation, virion assembly and maturation, and regulation of host immune responses.⁴ The virions use the host secretory pathway to travel to the cytoplasm, where they mature and are released by exocytosis.² WNV has a high replication and mutation rate, allowing for adaptation to selective pressures.³

WNV is the most significant cause of viral encephalitis worldwide and is the reason for the most common mosquito-borne infection in humans in the United States.³ WNV was first found in northwest Uganda in 1937.^1,5-7 It was not until the 1950s that it was recognized as a public-health threat due to epidemics of fever and encephalitis that it caused in the Middle East.⁷ By the mid-1990s, frequent outbreaks in humans were seen in the Mediterranean basin, Romania, and the Volga delta in southern Russia. It was previously prevalent throughout Africa, parts of Europe, the Middle East, West Asia, and Australia, and it has now spread to the Americas from Canada to Venezuela.⁶

The first human case of WNV in the U.S. occurred in New York City in 1999, resulting in a large outbreak in the U.S. for several years.^1,5,7 WNV can be found in all 48 contiguous states and two-thirds of counties in the U.S., with the highest incidence in the West Central and Mountain regions, especially the Great Plains.⁷ Now, there are annual human cases of WNV infection. Most cases are reported from July through September, with the majority occurring from mid-July through the end of August. The occurrences are challenging to predict due to WNV’s sporadic nature and geographical focal pattern. Currently, there are more than 55,000 reported cases in humans, with 27,000 of those manifesting as neuroinvasive disease and 2,600 deaths between 1999 and 2021.⁸

Between 1999 and 2012, the economic burden of WNV is estimated to be approximately $780 million in direct healthcare costs and indirect costs.¹ The individual cost burden for those who develop encephalitis can range from $4,000 to $325,000 but can be even higher in cases of acute flaccid paralysis. Those with West Nile fever can incur costs ranging from $500 to $24,000. These costs are even higher when nonmedical costs are considered. With severe cases, about 10% will result in death.⁹ Approximately 40% of those who develop West Nile neuroinvasive disease do not return to their baseline health.¹⁰

Transmission

WNV maintains its life cycle through transmission between birds and mosquitoes.^1,6,11 Although many different mosquitoes can transmit WNV, the Culex genus is the most common mosquito vector. Mammals, including humans and horses, can be infected but exhibit only low levels of viremia that cannot maintain the virus life cycle. Birds, on the other hand, can serve as a reservoir and amplifying host of WNV.⁶ Outbreaks seem to occur around major migratory bird routes. The American robin is the most common host for the transmission of WNV in the U.S.⁴

Mosquitoes acquire the virus through a blood meal of an infected bird, and the virus then spreads to the midgut epithelial cells and travels to the salivary glands of the mosquito. Once a mosquito feeds, it inoculates the skin of the host. WNV replicates in a variety of cells including neutrophils, macrophages, and keratinocytes. Once the virus is spread, it undergoes an amplification phase that involves visceral-organ dissemination and subsequently possibly the neuroinvasive phase, which involves the central nervous system (CNS).² WNV could also spread through blood transfusions, organ transplantation, or breastfeeding.^4,7 Percutaneous and aerosol infections in laboratory workers have also been reported.⁷

Cases of WNV have only continued to increase. Factors contributing to its epidemic and pandemic emergence and reemergence are likely due to expanding flaviviruses and their vectors, such as feeding patterns of mosquitoes, climate change, urbanization, population growth, and international travel.^1,3-5,12 These factors increase the risk of unintentional transportation of infected vectors and vector adaptation to new habitats or environments. For example, precipitation can play an important role in the distribution of bodies of water that allow for mosquitoes and birds to come into contact.^12,13

WNV and Culex mosquitoes are found in temperate climates or areas with irrigation.¹² The changes in the seasons allow for mosquitoes to feed primarily on birds in the spring and then switch hosts later in the summer or fall. Chances of transmission are increased when birds, mosquitoes, and humans reside in the same area around sources of water. Temperature can also affect when mosquitoes emerge during the springtime, when they mature into adults, how well they reproduce, how well they transmit the virus, and how long they live. Drastic temperatures can limit the life cycle of mosquitoes by altering human outdoor activity and the migratory patterns, breeding patterns, and geographical distribution of birds. Considering these contributing factors could help predict and prevent WNV and help scientists understand the pattern of distribution and outbreaks of the disease.

Signs and Symptoms

Approximately 80% of those infected with WNV are asymptomatic, increasing the risks for underdiagnosing and for transmission.^1,3,10,11,13 Those who develop symptoms have an incubation period of 2 to 14 days, but that can last up to 21 days in immunocompromised hosts.^1,2 Approximately 20% of those infected will develop a fever and experience headache, tiredness, body aches, nausea, vomiting, diarrhea, and possibly a skin rash and swollen lymph nodes.¹¹ Less than 1% develop neuroinvasive disease and present with headache, high fever, neck stiffness, stupor, disorientation, coma, tremors, convulsions, muscle weakness, or paralysis.^3,4 Meningoencephalitis occurs more often in male, elderly, and immunocompromised patients and those with cardiovascular or chronic diseases. Meningoencephalitis is associated with high morbidity and mortality.^4,8

Long-term complications from neuroinvasive disease include weakness, fatigue, and cognitive dysfunction in addition to memory loss, depression, and difficulty concentrating.^5,14 These complications can take a year to resolve, although it has been suggested that those with comorbid conditions can take even longer to recover.¹⁴ Myocarditis, pancreatitis, and fulminant hepatitis can occur as extraneurologic manifestations.²

It is suggested that hypertension, cerebrovascular disease, chronic renal disease, alcohol abuse, and diabetes are potential risk factors for severe WNV infections.⁷ One study revealed that there may be certain comorbidities and signs or symptoms that could suggest survival in those with WNV.¹⁴ It found that those who succumbed to the disease presented with fever. Of note, altered mental status that manifested as either confusion or delirium was more likely in those who died (55.67%) compared with those who survived (39.77%). Patients who succumbed and died also experienced weight loss, anorexia, or kidney and urinary complications approximately three times more than those who survived. In contrast, those who survived tended to experience headache, walking and balance issues, and rash more often than those who did not. With regard to other medical conditions, patients more often succumbed to WNV infections if they had cancer, transplantation, or transfusions. Surprisingly, no difference was found between those who survived and those who died in patients with diabetes, cardiovascular comorbidities, other infections, autoimmune disorders, preexisting neurologic conditions, and smoking.

The most commonly used diagnostic tool for WNV is the detection of immunoglobulin M (IgM) antibodies to the virus in the serum or cerebrospinal fluid (CSF) with the use of an enzyme-linked immunosorbent assay (MAC-ELISA).^10,13 A confirmation using a plaque-reduction neutralization test (PRNT) is recommended due to the cross reactivity with other flaviviruses. The presence of IgM antibodies in the CSF is sufficient to make a diagnosis since immunoglobulin is a large molecule and cannot cross the blood-brain barrier. There are a couple of drawbacks, as testing can be time-consuming, especially since conducting confirmatory tests and testing for IgM antibodies can take 3 to 8 days after symptom onset to appear, opening the window for possible false-negative results.¹⁰ Tests for IgM also unfortunately lack sensitivity (54% for ELISA and 45% for immunofluorescence assay), so false-positive results may occur due to infections from or vaccinations against other flaviviruses. WNV is also detected in high concentrations in the urine for up to several weeks after infection, and IgM antibodies can be detected up to 8 years after infection in approximately 20% of those affected.^3,10 Tests for WNV RNA could be used, but detection can be difficult due to short durations of viremia and persistence of noninfectious RNA.² Additionally, the sensitivity of the test for WNV RNA in the urine was only 58.3% compared with that of whole blood, which was 86.8%.¹⁰

Treatment

To this date, there are no unique therapies to treat WNV infections. No specific drug target for WNV has been identified.¹⁵ The process is challenging since the virus uses host cell mechanisms to replicate. The primary treatment for WNV remains supportive care.^4,11,13,15 Pain medication is often used to manage headaches. Rehydration or antiemetics may be needed due to nausea and vomiting.^11,15 Antimicrobials for secondary infections may be necessary.¹⁵ Intensive care may be needed in cases involving seizures, increased intracranial pressure, and respiratory failure. Clearance of the virus can take a few weeks, but it can take 6 to 8 weeks before improvement in neurologic impairment can be seen; little progress is seen after 12 weeks.^4,15

There are a few therapies that have been suggested for treating WNV infections, including interferon alpha 2b (INF α2b), ribavirin, and IV immunoglobulin (IVIG).¹⁵ The challenge for treatment is that the period of viremia is so short that it is usually cleared by the time of presentation. Therefore, treatment modalities would have to decrease intracellular viral load or prevent the spread to the CNS while also reducing the inflammatory response.¹¹ INF α2b has demonstrated in vitro activity against WNV before cell entry and infected cells.¹⁵ It inhibits viral polypeptides involved in the replication process. Case reports seem to suggest that the best outcome results from early administration of INF α2b. Unfortunately, the use of INF α2b did not produce favorable outcomes during a couple of outbreaks in Israel and the U.S. in the 2000s, so the effectiveness in vivo is still in question. Ribavirin has also demonstrated in vitro activity against RNA and DNA viruses by decreasing replication. However, similar to INF α2b, despite a few case reports suggesting efficacy with ribavirin therapy, patients who were receiving ribavirin and INF α2b treatment for hepatitis C still developed WNV infections. IVIG works by interfering with antigen presentation and produces an anti-inflammatory effect by binding to the Fc portion of immunoglobulin. It seems to yield promising results at a dosage of 0.4 grams/kilogram per day for 5 days. Other therapies such as corticosteroids have been suggested but did not produce any beneficial results when they were studied.

Prevention

There are currently neither specific therapies to treat WNV nor human vaccines, which makes prevention the key to managing WNV.¹⁶ Relying on human case reports or human case surveillance alone results in lag time since symptom onset can take several weeks or longer to manifest and outbreaks can occur quickly.⁷ Prevention should be carried out through public education, reducing vector exposure, community-based mosquito-control programs, and attempting to reduce mosquito bites.^1,6-8,11 These measures could include educating the public to wear long sleeves and pants, avoiding outdoor activities during prime mosquito-activity times, and using insect repellent. The most effective insect repellents to use on the skin include diethyltoluamide (DEET), picaridin (KBR 3023), IR3535, para-menthane-diol (PMD), 2-undecanone, or oil of lemon eucalyptus.^7,11,13 The U.S. Environmental Protection Agency (EPA) has a list of EPA-registered insect repellents that are proven safe and effective. Longer protection comes from higher concentrations. Permethrin is also effective as an insecticide but should be used only on clothing or fabric and not on the skin.¹¹ Culex mosquitoes tend toward trees and vegetation and are nighttime biters.³ Awareness of their behaviors and educating the public on those behaviors can minimize exposure to mosquito bites.^1,4 Other measures include the ridding of mosquito breeding grounds, using chemicals to kill adult mosquitoes or larvae, and public education on how to eliminate sources of standing water.

The CDC also developed a surveillance tool called ArboNET to monitor for avian mortality and vector surveillance to detect avian mortality before detecting positive mosquitoes or human cases.^7,10 The goal would be to identify disease burden, identify impending outbreaks, and trace information to allow for timely responses, including seasonal, geographic, and demographic patterns in human outcomes.⁷ Vector surveillance would be a crucial part to predicting outbreaks. This includes larval surveillance, which would involve sampling a wide range of aquatic habitats to find sources for vectors and evaluating larval-control measures. Adult mosquito surveillance would involve regular sampling at fixed sites in habitats where the mosquitoes are likely to be. Determining disease presentation and outcome is prudent to identify patterns of disease, those who are at risk for severe disease, and modes of human transmission. When human cases are identified, it is important to interview the patients and obtain their demographic information, clinical presentation, date of onset of illness or blood donation, whether hospitalization was required, travel history in the 4 weeks leading to symptom onset, organ transplantation history or blood donation history in the 4 weeks leading to symptom onset, pregnancy status if applicable, and breastfeeding if applicable. If blood or tissue donation occurred within 4 weeks prior to symptom onset, it is crucial that this be reported so that the infected products can be quarantined and potential infected individuals be identified.

Multiple attempts at WNV vaccines have been made. However, due to the unpredictability of WNV, the difficulty of assessing efficacy and safety in clinical trials, potential cost concerns, and uncertainty if vaccinated individuals can be distinguished from infected persons have hindered its development progress.^8,17,18 The duration of immunity is also unclear. Another concern includes antibody-dependent enhancement wherein the binding of antibodies does not neutralize the virus and leads to increased uptake of the virus into the host instead. Vaccines for birds have been considered, but the challenge to implementing a vaccination protocol involves feasibility in vaccinating wild species of target host birds.¹⁷ Ideally, vaccines would be available at the ready for when outbreaks do occur not only to limit the spread of WNV infections but also to evaluate the safety and efficacy, duration of immunity, and extent of protection of that vaccine.

Future Directions

Continued public-health surveillance and education are of utmost importance. Involving the media in communicating vector control and surveillance, specifically sharing the mosquito adulticide used and schedule for adulticide, may allow the community to better understand the benefits and risks associated with the program. Education to providers and infection control are essential to increase reporting of identified WNV cases.⁷ Blood donation centers should also have established protocols and guidelines for reporting blood donors found to have WNV. Education to the public should include reporting dead birds and mosquito problems. Additionally, clear, concise, targeted messages toward high-risk populations, including people with extensive outdoor exposure, homeless individuals, those living in residencies without window screens, and the elderly, could be utilized to ensure appropriate communication and prevention. Examples include involving local spokespersons, placing messages strategically to increase viewing by targeted populations, reaching out to social service groups, creating donation drives for insect repellents, or initiating community service projects to install window screens for those with financial or physical barriers.

Measures for vector control continue to be of interest. It has been suggested that widespread application of organophosphate or synthetic pyrethroid insecticides can be used.² Another direction includes completing genome sequencing of WNV during different times and in different places to generate a dataset to better understand which strains are causing outbreaks, where the transmission networks are, if there is any connection between those outbreaks, and if there are any potential patterns of outbreaks.¹⁹ Uncovering those connections could help not only in controlling vectors and forecasting outbreaks but also in decreasing the reintroduction of WNV and the transmission of the virus beyond one season. Unfortunately, these tasks could be potentially a huge and costly undertaking requiring large-scale collaborations.

Vaccines can also play a part in prevention of WNV, although the measurement for effectiveness of the vaccine is not currently defined and the standard for measuring immunogenicity is inconsistent across studies.²⁰ Several areas of interest for vaccine development include vaccination against the vector and host. One suggested target is vaccination against the proteins in mosquito saliva.² There have also been considerations for vaccines for birds, but the feasibility is called into question due to potential limited access, namely wild species and administration strategies. However, it could be a future path for domestic populations and wild species housed in wildlife centers, rehabilitation, or recreational facilities.¹⁷ It is proposed that the most ideal vaccine designed for humans would be one that generates a strong, long-lasting protective immune response without the need for multiple booster doses.²⁰

Conclusion

Despite the fact that several decades have passed since the introduction of WNV to the U.S., there are no specific therapies for treating WNV disease or vaccinations to prevent it. Surveillance efforts of vectors and hosts continue to be the mainstay of management in hopes of preventing outbreaks from occurring. Improvement in the protection of the community and education on its part in vector control and personal protection are crucial to minimizing WNV infections while vaccine development is still under investigation. Large-scale collaborative efforts and community involvement can also improve education and methods of prevention.

REFERENCES

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