Treatment and prevention of West Nile virus infection

INTRODUCTION — West Nile (WN) virus, a member of the Japanese encephalitis virus antigenic complex, can lead to a wide range of clinical symptoms from asymptomatic disease to severe meningitis and encephalitis.

Management and prevention of WN virus are discussed below. The clinical manifestations and epidemiology of the infection are discussed elsewhere. (See "Epidemiology and pathogenesis of West Nile virus infection" and "Clinical manifestations and diagnosis of West Nile virus infection".)

TREATMENT — Supportive care remains the mainstay of treatment for WN virus infection. (See 'Supportive care' below.)

The potential use of several different therapeutic agents has also been described [1-11]. However, there are no data to support the routine use of any agents, and uncontrolled studies or case reports suggesting treatment efficacy should be cautiously interpreted, since the clinical course and outcomes with WN virus neuroinvasive disease are highly variable [1,2]. (See 'Agents with potential benefit' below and 'Agents without benefit' below.)

Supportive care — Treatment of WN virus infection is primarily supportive.

Supportive therapy may include pain control for headaches; if nausea and vomiting are present, antiemetic therapy and rehydration may be beneficial. (See "Characteristics of antiemetic drugs".)

Patients with encephalitis should be monitored for signs and symptoms of elevated intracranial pressure and seizures. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'Clinical manifestations'.)

In some patients, particularly those with poliomyelitis-like symptoms, airway protection and ventilatory support may be needed. (See "The decision to intubate".)

Agents with potential benefit — In patients with WN fever, there is no clear role for treatments other than supportive care. (See 'Supportive care' above.)

There are certain agents that may be of potential benefit for treatment of patients with WN virus neuroinvasive disease; however, data are conflicting, and the risks and benefits of using one of these agents must be determined on a case-by-case basis. These agents include:

●Corticosteroids – The rationale for corticosteroid therapy in the setting of WN virus is to inhibit proinflammatory mediators that may contribute to the pathogenesis of WN virus in the central nervous system. Several individual case reports have described clinical improvement after administration of high-dose corticosteroids for a variety of neurological complications of WN virus infection (eg, acute flaccid paralysis, opsoclonus myoclonus ataxia) [12-15]. However, in a nonrandomized series of patients with neuroinvasive disease, no difference was noted in the duration of hospitalization for the 18 patients treated with prednisone or other steroids compared with untreated patients [16].

●Intravenous immunoglobulin – There is a theoretical benefit of administering intravenous immunoglobulin (IVIG) in patients with WN virus neuroinvasive disease who have humoral deficiencies. In the United States and Europe, high titer neutralizing antibodies have been demonstrated in plasma as a consequence of recurring WN virus outbreaks [9,17], and animal studies suggested there may be a potential role for the use of IVIG for the prevention and treatment of WN virus infection [9,10,18].

However, IVIG has been administered to immunocompromised patients with varied outcomes [11,19-21]. In, a randomized, placebo-controlled safety trial in 62 patients with neuroinvasive disease (the majority who were immunocompetent) failed to find benefit of a high-titered IVIG derived from Israeli donors, although this trial was designed to determine safety and not efficacy [11].

Limited data have also suggested a potential benefit of interferon alfa therapy, but interferon should not be used for treatment of WN virus infection given the toxicity associated with interferon and the limited data supporting its use. Alfa interferon was found to be effective against WN virus in in vitro and in animal models [3-5]. In addition, rapid neurologic improvement was demonstrated in two patients with serologically confirmed WN virus infection who presented with deteriorating mental status and progression to coma and were treated with standard interferon alfa-2b within 72 hours of presentation [6]. However, it remains unclear if the change in clinical status in these patients was due to interferon or to spontaneous improvement, which has been documented in untreated WN virus infection [1]. In addition, another report described two patients who developed WN fever after mosquito exposure while receiving interferon alfa-2b and ribavirin for hepatitis C infection [7].

Agents without benefit — There does not appear to be a role for treatment of WN virus disease with the following agents given lack of efficacy:

●Ribavirin – The antiviral agent ribavirin has demonstrated in vitro activity against WN virus, but therapeutic efficacy has not been demonstrated. Ribavirin increased mortality in Syrian golden hamsters when administered two days after inoculation [3]. In addition, during an outbreak in Israel, ribavirin appeared to be ineffective and possibly detrimental when it was used in an uncontrolled, nonblinded fashion in some patients with WN virus neuroinvasive disease [8].

●Acyclovir – There does not appear to be a role for acyclovir in the treatment of WN virus infection based upon data from retrospective case series [16,22]. In one report that included 49 patients treated with acyclovir, the duration of hospitalization did not differ compared with untreated patients [16]. In another series of 165 patients with neuroinvasive disease, 94 patients were treated with acyclovir for a median of eight days, and there was no clinical benefit compared with untreated patients [22].

PROGNOSIS — Serious adverse outcomes from WN virus infection are limited to the patients who develop neuroinvasive disease [23]. Older age is the most important predictor of risk [23-25]. Increased severity of neuroinvasive disease may also be seen in immunocompromised patients, such as solid organ transplant recipients [26,27].

In a review of 6744 patients with neuroinvasive disease in the United States from 2009 to 2018, the case fatality rate was 2 percent in patients with meningitis, 14 percent in patients with encephalitis, and 13 percent in those with acute flaccid paralysis [28]. The median age of patients with encephalitis was higher than that in patients with acute flaccid paralysis or meningitis (66, 60, and 52 years, respectively). Mortality was associated with advanced age (2 percent among patients <50 years comparted to 21 percent of those aged >70 years). A multinational study indicated that age and the presence of coma were independent predictors of fatal outcome [22].

Conflicting data have been published on the long-term prognosis of patients with neuroinvasive WN virus infection [1,29,30]:

●One study evaluated self-perceived health outcomes among 40 New York City residents who developed meningitis or encephalitis during the 1999 WN virus epidemic and survived [29]. At 12 months, only 37 percent achieved a full recovery, which was most likely to occur in patients less than 65 years of age. Long-term neurologic sequelae included muscle weakness, loss of concentration, confusion, and light-headedness.

●Another retrospective study evaluated 49 patients with laboratory-confirmed WN virus infection approximately one year after clinical presentation, including 38 patients who did not have neuroinvasive disease [31]. The most frequent somatic complaints (present in at least one-third of patients) were fatigue, memory problems, extremity symptoms (weakness, numbness or tingling, pain or myalgia), word-finding difficulty, and headaches. Standardized testing revealed moderate to severe depression in 24 percent. Physical examination documented tremor in six patients. Neuropsychological tests of motor function indicated that 69 percent of patients scored >2 standard deviations below the norm.

●In a longitudinal cohort study of 156 persons with WN virus infection (41 percent of whom had neuroinvasive disease), physical and cognitive function returned to normal in approximately one year [32]. The estimated times until 95 percent recovery of physical function was restored were significantly different in participants with neuroinvasive disease than in those without (175 days versus 121 days, respectively); however, time to recovery of mental function was similar between both patient groups. Lack of comorbid illness at baseline was associated with a faster rate of overall recovery.

●A longitudinal cohort study followed 103 persons with WN virus infection (62 percent had neuroinvasive disease) for up to eight years [33]. Many patients still reported symptoms one and eight years after infection (60 and 40 percent, respectively), possibly related to WN disease. Such symptoms included fatigue, weakness, and depression. Older patients and those with neuroinvasive disease were more likely to report continued symptoms.

●Health related quality of life was measured in 154 patients with WN virus infection who were followed for up to three years [34]. At baseline, quality of life scores (measured using the Medical Outcomes Survey Short Form 36) were much lower for those with neuroinvasive disease compared to those without neuroinvasive disease. This gap nearly closed after six months; however, after three years scores remained lower than population norms in both groups.

The long-term functional outcome of patients with WN virus poliomyelitis is variable. Most patients have incomplete recovery of limb strength resulting in profound residual deficits [1,26,35-37]. At one year follow-up, 18 of 27 patients with WN virus poliomyelitis had strength improvement, with improvement greatest during the first four months [37]. Quadriplegia and respiratory failure are associated with high morbidity and mortality, and recovery is slow and typically incomplete [37,38]. A smaller study has suggested that estimation of surviving motor unit numbers by motor unit number estimation (MUNE) may predict functional outcome [39].

PREVENTION — Prevention of infection includes personal protection measures, mosquito control programs, and blood donor screening. Surveillance programs that can detect an increase in arboviral activity are important so that prevention efforts (eg, personal protection, mosquito control) can be implemented and/or enhanced [40].

Personal protection measures — Personal protection measures to avoid mosquito exposure are a mainstay of prevention [41]. A variety of insect repellants are available. (See "Prevention of arthropod and insect bites: Repellents and other measures".)

Mosquito control — It is important to drain standing water where mosquitoes are likely to breed. In a case control study examining risk factors, only spending increased amounts of time outdoors and the presence of flooded basements correlated with infection [42].

Organized community mosquito control programs that employ integrated pest management techniques can also reduce the risk of WN virus infection [43]. Elimination of mosquito breeding sites and application of larvicides reduce the production of adult mosquitoes. When human or mosquito surveillance indicates heightened human infection risk, measures to reduce adult mosquitoes are undertaken, usually by truck-mounted or aerial insecticide spraying. These measures may considerably reduce subsequent human infection WN virus risk [44-46] with negligible pesticide exposure [47,48] and associated insecticide-related illness [49,50].

Blood donor screening programs — Blood donor screening for WN virus has greatly reduced, but not eliminated, the risk of transfusion transmission [51]. WN virus infection should be considered in recent transfusion recipients with unexplained, compatible illness. (See "Blood donor screening: Laboratory testing", section on 'West Nile virus'.)

Vaccine development — There has been great interest in a WN virus vaccine; however, there are no human vaccines for prevention of WN virus.

Four equine WN virus vaccines are licensed in the United States [52]:

●Three inactivated virus vaccines.

●A recombinant canarypox virus vaccine expressing the prM/E proteins of a 1999 WN virus isolate.

Two other vaccines have been marketed but are no longer available. One was a plasmid DNA vaccine encoding for prM/E proteins. The other was a live, attenuated recombinant vaccine constructed from an infectious clone of yellow fever 17D virus, in which two genes have been replaced by two similar genes of WN virus. This vaccine was recalled because of adverse events.

There are some encouraging preliminary data regarding potential candidate vaccines for humans:

●Four human candidate vaccines have undergone phase I clinical trials. These include a vaccine that utilized plasmid DNA expressing West Nile virus prM/E genes [53,54]; a recombinant E protein vaccine [55]; a chimeric live, attenuated vaccine that combined the West Nile virus prM/E with the DENV-4 nonstructural genes incorporating a 30-nucleotide deletion in the 3′UTR [56,57]; and a hydrogen peroxide-inactivated vaccine [58]. The first three of these vaccines produced seroconversion rates >95 percent and good neutralizing antibody titers while the hydrogen peroxide-inactivated vaccine only achieved a seroconversion rate of 31 percent. All these vaccines were well tolerated.

A formalin-inactivated vaccine underwent phase I/II trials simultaneously [59]. Limited data are available describing this trial and the vaccine's immunogenicity.

●In a phase II study, 45 healthy adults were inoculated with ChimeriVax-WN02, a live, attenuated recombinant yellow fever 17D virus-based vaccine [60]. All subjects developed neutralizing antibodies after a single injection, and the vaccine was well tolerated. The vast majority of subjects also developed specific CD4+ proliferative and CD8+ cytotoxic T-cell responses to WN virus antigens. A larger phase II trial subsequently found this chimeric vaccine safe and immunogenic in adults, including individuals who were >65 years of age [61,62].

SPECIAL CONSIDERATIONS DURING PREGNANCY — A causal relationship between WN virus and fetal abnormalities has not been proven. (See "Clinical manifestations and diagnosis of West Nile virus infection".)

The Centers for Disease Control and Prevention (CDC) has made the following recommendations for prevention of WN virus and for management of women who are infected during pregnancy [63,64]:

●Pregnant women should take precautions to protect themselves from bites from potentially infected mosquitoes (eg, avoid being outdoors at dawn and dusk, wear protective clothing, use insect repellants containing DEET). (See "Insect and other arthropod bites".)

●Pregnant women with meningitis, encephalitis, acute flaccid paralysis, or unexplained fever in an area of ongoing WN virus transmission should have serum tested for antibody to WN virus. If laboratory tests indicate recent infection with WN virus, the infection should be reported to the local or state health department, and the woman should be followed to determine the outcome of her pregnancy. (See "Clinical manifestations and diagnosis of West Nile virus infection", section on 'Diagnosis'.)

●If WN virus infection is diagnosed in pregnancy, care is supportive. An ultrasound examination of the fetus to screen for abnormalities should be considered no sooner than two to four weeks after onset of symptoms.

Amniotic fluid, chorionic villi, or fetal serum can be tested for evidence of WN virus infection. However, the sensitivity, specificity, and predictive value of these tests to evaluate fetal WN virus infection are not known, and the clinical consequences of fetal infection have not been determined. In cases of spontaneous or induced abortion, testing of all products of conception for evidence of WN virus infection is advised to document the effects of WN virus infection on pregnancy outcome.

●Screening asymptomatic women for WN virus infection is not recommended because there is no treatment and the consequences of infection during pregnancy have not been well-defined.

●Clinical evaluation is recommended for infants born to mothers known or suspected to have WN virus infection during pregnancy (table 1). Further evaluation should be considered if any clinical abnormality is identified or if laboratory testing indicates that an infant might have congenital WN virus infection (table 2).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Infectious encephalitis".)

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 5^th to 6^th 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 10^th to 12^th 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 AND RECOMMENDATIONS

●Treatment – The treatment of West Nile (WN) virus infection is primarily supportive. The use of several different therapeutic agents has been described, but there is insufficient evidence for routine use. (See 'Treatment' above.)

●Prognosis – Serious adverse outcomes from WN virus infection are limited to patients who develop neuroinvasive disease. Older age is the most important predictor of risk, although increased severity of neuroinvasive disease may also be seen in immunocompromised patients. (See 'Prognosis' above.)

●Prevention – Personal protection measures include the use of mosquito repellents; general programs to protect public health include mosquito control programs and blood donor screening. A human vaccine is not yet available. (See 'Prevention' above.)

●Considerations during pregnancy – Although a causal relationship between WN virus and fetal abnormalities has not been proven, pregnant women should take precautions to protect themselves from bites from potentially infected mosquitoes (eg, avoid being outdoors at dawn and dusk, wear protective clothing, use insect repellants containing DEET). If WN virus infection is diagnosed in pregnancy, care is supportive. (See 'Special considerations during pregnancy' above.)