West Nile Virus

Overview

Practice Essentials The West Nile virus is one of the many members of the genus Flavivirus that are known to cause human disease. The life cycle of the West Nile virus involves the microbe's transmission from nonhuman animals to humans by way of Aedes, Culex, or Anopheles mosquitoes. The West Nile virus can infect horses, birds, dogs, and other mammals. [1, 2, 3] However, wild birds are apparently the optimal hosts for harboring and replicating the virus. Serologic testing to detect immunoglobulin M (IgM) antibodies is currently the best means [4] of diagnosing West Nile virus infection. The physical therapist can partially address the problems of increased muscle tone, weakness, decreased sensation, and poor endurance associated with the disease. The West Nile virus has been reported in Africa, Asia, Europe, the Middle East, and North America. In 1999, the first cases of West Nile virus disease were reported in New York City, with the infection subsequently spreading throughout the North American continent. [5] The West Nile virus causes serious manifestations in approximately 1% of persons who are infected, with increased morbidity and mortality in individuals older than 50 years. In hospitalized patients in New York City, neurologic sequelae of the West Nile virus included severe muscle weakness, with approximately 10% of patients developing a complete flaccid paralysis. [6, 7, 8] One in 150 West Nile virus infections results in encephalitis or meningitis, and the mortality rate for persons with severe illness is 3-15%. Individuals older than 75 years are at particular risk. [2] As the elderly population increases and the distribution of the West Nile virus spreads nationwide, a growing number of infected individuals may require comprehensive inpatient rehabilitation to overcome the virus's disabling effects. [9] A study by Hadler et al suggested that many US states may no longer have adequate surveillance systems for detecting and responding to outbreaks of West Nile virus. The investigators stated that although by 2004, with the aid of federal funding, well-developed West Nile virus surveillance systems existed in almost every state, by 2012, following a 61% decrease in federal funding, many health departments had reduced such surveillance and lacked a systematic, disease-based surveillance system for other arboviruses. [10] Signs and symptoms of West Nile virus Symptoms of mild infection may last 3-6 days and include fever in 20% of cases. Other symptoms include nausea, anorexia, malaise, myalgia, headache, backache, rash, eye pain, and vomiting. [2] Symptoms of more severe illness include severe muscle weakness, flaccid paralysis or increased muscle spasticity, photophobia, seizures, mental status changes, respiratory symptoms, and an erythematous, maculopapular, or morbilliform rash involving the neck, trunk, arms, or legs. [6, 11] Diagnosis and management of West Nile virus Serologic testing to detect immunoglobulin M (IgM) antibodies is currently the best means [4] of diagnosing West Nile virus infection. In an estimated one third of infected individuals, magnetic resonance imaging (MRI) scans show notable enhancement in the leptomeninges and periventricular areas. Brain injury from West Nile virus encephalitis or meningitis can result in cognitive, gross motor, and fine motor delays. Because infected patients have varying degrees of functional deficits, treatment programs must be individualized. Comprehensive rehabilitation using a team consisting of a physiatrist, nurse, physical therapist, occupational therapist, speech therapist, social worker/case manager, and neuropsychologist achieves best outcomes. Elderly patients who are severely deconditioned because of West Nile virus encephalitis may be predisposed to deep venous thrombosis (DVT). The inherent risk of having DVT is the development of a pulmonary embolus that can cause death. Prevention strategies include the use of thigh-high compression stockings, pneumatic compression devices, and subcutaneous, unfractionated or low–molecular weight heparins. Early mobilization and ambulation also may decrease the risk of DVT. Individuals with severe illness secondary to West Nile virus infection are at increased risk of pulmonary complications in the rehabilitation setting. Individuals with encephalitis may have a decreased level of consciousness, or they may suffer from dysphagia related to their neurologic injury, predisposing them to aspiration pneumonia. Swallow evaluation can be performed to identify the problem and to help in implementing the appropriate diet and feeding techniques to decrease the risk of aspiration. Phrenic nerve palsy has been described; this complication could lead to decreased expansion of the lungs, further increasing the risk of atelectasis and nosocomial pneumonia. Deep-breathing exercises, use of an inspiratory spirometer, and early mobilization and ambulation help to decrease the risk of these complications occurring.

Pathophysiology Examining the ways in which the West Nile virus may cross the blood-brain barrier to infect the nervous system, Verma et al infected primary human brain microvascular endothelial (HBMVE) cells with NY99, a neurovirulent strain of the virus. [12] The authors noted that the virus did not have a cytopathic effect on the HBMVE cells. Increased mRNA (messenger ribonucleic acid) and protein expression of the tight-junction protein claudin-1 and of 2 cell adhesion molecules (vascular cell adhesion molecule and E-selectin) were seen 2-3 days after cellular infection, the same time at which West Nile virus replication had peaked. The study provided evidence that infection of HBMVE cells by the West Nile virus enables the cell-free virus to enter the central nervous system without disturbing the barrier's integrity. In addition, the authors suggested that cell adhesion molecules may help to traffic West Nile virus – infected immune cells into the central nervous system.

Epidemiology Frequency United States The West Nile virus was introduced into the United States in 1999, in New York City. Since then, the disease has occurred with greater frequency in the Southern, Midwestern, and Western states. Symptoms of the infection first appear in the population in early June, with the peak incidence occurring in late August and tapering through early November. A large outbreak of West Nile virus infection in 2012 resulted in 5674 reported cases (51% of which were neuroinvasive), although the number of reported cases for 2013 dropped to 2469. In 2014, there were 2205 reported cases (61% of which were neuroinvasive), while in 2015, the number was 2175, with the incidence of neuroinvasive West Nile virus being 0.45 cases per 100,000 population nationally. [13, 14, 15, 16, 17, 18] In 2016, the number of US cases reported to the US Centers for Disease Control and Prevention (CDC) reached 2149, including 1309 neuroinvasive cases; the incidence of neuroinvasive disease was 0.41 per 100,000 population, comparable to the median incidence between 2002 and 2015. [19, 20] The infection data for 2018 was 2647 cases, including 1658 neuroinvasive disease cases. [21] In total, 50,830 cases of West Nile virus were reported to the Centers for Disease Control and Prevention (CDC) between 1999 and 2018, including 24,657 cases of neuroinvasive disease. [21] According to the CDC, in 2019 there were 1173 cases of domestic arbovirus disease reported for 47 states and the District of Columbia, with 971 of these (83%) being cases of West Nile virus. A classification of neuroinvasive disease was made for 633 (65%) of the West Nile virus cases, the incidence—0.19 cases per 100,000 population—being 53% below the median annual incidence for 2009-2018. [22] International The West Nile virus is most commonly identified in Asia, Africa, and the Middle East and is endemic in those parts of the world. [23] In the 1990s, outbreaks of West Nile virus encephalitis were reported in Algeria, the Czech Republic, France, Romania, Russia, and Israel. [2] In the Americas, since its introduction into the United States, in 1999, the West Nile virus has spread to Canada and into South America. [24] Mortality/Morbidity Reports indicate that less than 1% of persons who are infected with the West Nile virus develop severe illness; of individuals who have severe illness secondary to the infection, 3-15% die. Severe disease particularly affects the elderly. Advanced age is by far the greatest risk factor for neurologic disease, long-term morbidity, and death, especially in persons older than 75 years. In 2019, among US patients with West Nile virus neuroinvasive disease who died, the median age was 73 years. [14, 22] The total number of reported deaths from the West Nile virus in the United States between 1999 and 2016 was 2017 (4% of cases), including 1888 from neuroinvasive disease. [19] Race There is no known predisposition related to a particular ethnic group. Sex There is no known sex predilection. Men and women are affected equally. Age In the United States, the elderly are particularly disposed to illness from West Nile virus infection.

Clinical Presentation

History Mosquito bites may or may not be present in an infected person. A history of travel to or from an area that is known to harbor the virus is common. The incubation period for the West Nile virus is postulated to be approximately 5-15 days. Symptoms of mild infection may last 3-6 days and include fever in 20% of cases. Other symptoms include nausea, anorexia, malaise, myalgia, headache, backache, rash, eye pain, and vomiting. [2] Symptoms of more severe illness include severe muscle weakness, flaccid paralysis or increased muscle spasticity, photophobia, seizures, mental status changes, respiratory symptoms, and an erythematous, maculopapular, or morbilliform rash involving the neck, trunk, arms, or legs. [6, 11] The severity of the illness is related to the degree of central nervous system invasion by the virus.

Physical Signs of encephalitis and meningoencephalitis may be seen. These include mental status changes, such as confusion, stupor, or coma. Other findings include positive Brudzinski and Kernig signs, papilledema, cranial nerve involvement (eg, facial weakness, double vision, visual loss, decreased taste sensation), motor strength weakness, decreased sensation, hyperreflexia, and positive pathologic reflexes (eg, Babinski sign, Hoffman sign).

Causes The West Nile virus is transmitted to humans by the bite of an infected mosquito. Typically, warm climates and the summer months provide an ideal environment for mosquitoes to breed. [2, 25] Multiple mosquito bites and greater exposure to environments with a large mosquito population increase the risk of infection. However, some cases have been linked to organ transplantation, breastfeeding, and (possibly) blood transfusions. [26] A study by Paull et al indicated that drought is the main climate component that increases West Nile virus epidemics and that by the late 2040s, climate change–driven increases in drought severity could cause cases of the virus to triple in regions where human immunity to it is low. The investigators found some evidence that drought increases West Nile virus epidemics by altering the prevalence of mosquito infection, as opposed to increasing the number of mosquitoes. [27] Similarly, a study by Uelmen et al that looked at West Nile virus rates in Wisconsin indicated that environmental factors that favor West Nile virus transmission include increases in temperature and decreases in precipitation, as well as urbanization and human population growth, owing to their effect on mosquito biting rates. [28]

Differential Diagnoses

Diagnostic Considerations

These include the following:

• Bacterial meningitis

• Viral meningitis

• Ischemic stroke

• Hemorrhagic stroke

• Brain abscess

• Brain tumor

• Cat-scratch disease

• Herpes simplex

• Herpes simplex encephalitis

• Myasthenia gravis

• Hypoglycemia

• Leptospirosis

• Subarachnoid hemorrhage

• Tick-borne diseases, Lyme

• Tick-borne diseases, Rocky Mountain spotted fever

• Toxoplasmosis

• Tuberculosis

Differential Diagnoses

• Acute Poliomyelitis

• Guillain-Barre Syndrome

• Multiple Sclerosis

• Postpolio Syndrome

• Vertebrobasilar Stroke

• Zika Virus

Workup

Laboratory Studies See the list below:

• The complete blood count (CBC) may show elevated or normal leukocytes values.

• In cases of encephalitis, hyponatremia may be present. The complication of syndrome of inappropriate ADH (SIADH) secretion is a possibility.

• Cerebrospinal fluid (CSF) analysis may reveal elevated protein and increased leukocyte levels, with predominant lymphocytes. [29, 30] Glucose levels are usually normal rather than decreased.

• Serologic testing to detect immunoglobulin M (IgM) antibodies is currently the best means [4] of diagnosing West Nile virus infection.
  

  • IgM antibody-capture enzyme-linked immunosorbent assay (MAC-ELISA) has been used to detect IgM for the West Nile virus by using serum or CSF samples. [2, 31]

  • False-positive results may occur because of the close relationship of the West Nile virus to other flaviviruses.

  • In light of this limitation, the plaque reduction neutralization test (PRNT) may help to identify false-positive MAC-ELISA results caused by cross-reactions by other flaviviruses.

Imaging Studies See the list below:

• In acute disease, computed tomography (CT) scans do not show any evidence of abnormalities.

• In an estimated one third of infected individuals, magnetic resonance imaging (MRI) scans show notable enhancement in the leptomeninges and periventricular areas.

Histologic Findings Autopsy findings in some patients with West Nile virus infection reveal mononuclear inflammation that extensively involves the medulla, with some involvement of the cranial nerve roots. [32] However, these findings are not diagnostic for the infection.

Treatment & Management

Rehabilitation Program Physical Therapy Brain injury from West Nile virus encephalitis or meningitis can result in cognitive, gross motor, and fine motor delays. Because infected patients have varying degrees of functional deficits, treatment programs must be individualized. Comprehensive rehabilitation using a team consisting of a physiatrist, nurse, physical therapist, occupational therapist, speech therapist, social worker/case manager, and neuropsychologist achieves best outcomes. The physical therapist can partially address the problems of increased muscle tone, weakness, decreased sensation, and poor endurance. Mobility training, transfer training, and gait training are usually implemented, with range of motion and proper positioning attended to as well. Physical therapists are also important in providing exercises for muscle reeducation and for the improvement of strength, endurance, coordination, and balance, with the goal of returning the patient to independent function.

Occupational Therapy Occupational therapy focuses on the activities of daily living (ADLs), including bathing, dressing, feeding, and hygiene maintenance. Occupational therapists provide a program to maximize the use of the arms and hands with functional activities; they also address the cognitive issues that affect daily independent function. (See also Further Outpatient Care.) Speech Therapy Patients may develop dysarthria, dysphagia, or aphasia. A structured speech therapy program may improve their ability to swallow, help them recover speech and language function, and prevent complications, such as aspiration pneumonia. (See also Further Outpatient Care.)

Medical Issues/Complications Pressure ulcers The development and progression of a pressure ulcer can deeply affect the type, length, and cost of a patient's rehabilitation. Pressure ulcers are caused by prolonged pressure, shear forces, friction, and maceration. Means of preventing this complication include close monitoring of potential ulcer sites, frequent repositioning to reduce pressure on vulnerable areas, ensuring that adequate nutrition is provided, and cleaning and drying sites of perspiration, urine, or feces. Once a pressure ulcer develops and progresses, more severe complications (eg, wound infection, bacteremia, osteomyelitis) may enter the clinical picture. Deep venous thrombosis Elderly patients who are severely deconditioned because of West Nile virus encephalitis may be predisposed to deep venous thrombosis (DVT). The inherent risk of having DVT is the development of a pulmonary embolus that can cause death. Risk factors for DVT may include, among others, decreased mobilization, a history of smoking, and a history of premorbid medical conditions, such as coronary artery disease, diabetes mellitus, hypercoagulopathy, and peripheral vascular disease. Prevention strategies include the use of thigh-high compression stockings, pneumatic compression devices, and subcutaneous, unfractionated or low–molecular weight heparins. Early mobilization and ambulation also may decrease the risk of DVT. Doppler ultrasonography may be used to monitor for DVT, but its accuracy is limited, as has been shown in many studies. Pulmonary complications Individuals with severe illness secondary to West Nile virus infection are at increased risk of pulmonary complications in the rehabilitation setting. Individuals with encephalitis may have a decreased level of consciousness, or they may suffer from dysphagia related to their neurologic injury, predisposing them to aspiration pneumonia. Swallow evaluation can be performed to identify the problem and to help in implementing the appropriate diet and feeding techniques to decrease the risk of aspiration. Phrenic nerve palsy has been described. This complication could lead to decreased expansion of the lungs, further increasing the risk of atelectasis and nosocomial pneumonia. Deep-breathing exercises, use of an inspiratory spirometer, and early mobilization and ambulation help to decrease the risk of these complications occurring. Other A study by Greco et al suggested that West Nile virus infection could, in predisposed persons, contribute to the development of myasthenia gravis. In a study of 29 patients with myasthenia gravis, the investigators found that 17% of subjects demonstrated anti–West Nile virus immunoglobulin G (IgG), although none of the patients apparently had clinical signs or symptoms of the virus. [33]

Surgical Intervention No surgical indications are reported at this time.

Consultations See the list below:

• Physiatrist (physical medicine and rehabilitation specialist)

• Neurologist

• Infectious disease specialist

• Psychologist or neuropsychologist

Medication

Ongoing research is being pursued into the direct treatment of West Nile virus meningoencephalitis with interferon alpha and intravenous immunoglobulin G (Omr-IgG-am). Medications to manage West Nile virus–associated seizures, cognitive or behavioral issues, sleep problems, and muscle spasticity are often used.

Follow-up

Further Outpatient Care See the list below:

• Consultation with a psychologist or neuropsychologist may be helpful. [34]

• The neuropsychologist's role includes developing behavioral treatment plans, assessing the patient's cognitive and emotional function, and providing individual, group, and family therapy.

• The neuropsychologist also assesses the patient's attention, executive functions, personality, and memory, language, and visual-spatial abilities by using various specialized tests.

• Although the literature concerning the neuropsychologic assessment and cognitive rehabilitation of patients with encephalitis is limited, neurocognitive testing may be useful in identifying deficits, and neurocognitive therapy to treat those deficits plays a significant part in the rehabilitation process.

• The primary cognitive consequences of encephalitis involve attention, memory, information processing speed, and cognitive efficiency.

• As a part of a rehabilitation team, the neuropsychologist also collaborates with the speech therapist and occupational therapist to maximize the interplay between cognitive rehabilitation and function. [35]

Deterrence See the list below:

• The Centers for Disease Control and Prevention (CDC) offer the following 3 major suggestions to help prevent West Nile virus infection [36] :
  

  • Avoid mosquito bites.

  • Mosquito-proof the home.

  • Support community-based efforts in mosquito control and the prevention of West Nile virus infection. [37, 38]

• Avoiding mosquito bites
  

  • Individuals should apply insect repellent containing N,N -diethyl-meta-toluamide (DEET) to exposed skin whenever they go outdoors. In addition, using permethrin on clothing is very effective as an insecticide and as a repellent.

  • When possible, people should wear long sleeves, long pants, and socks when outdoors.

  • Mosquitoes can bite through thin clothing, so spraying clothes with repellent containing permethrin or DEET provides additional protection. However, repellents containing permethrin should not be applied directly to the skin, and repellent containing DEET should not be applied to skin under clothing.

  • The peak hours for mosquito bites are from dusk to dawn. Individuals are advised to use repellent and protective clothing in the evening and early morning or to consider avoiding outdoor activities during these times.

• Mosquito-proofing homes
  

  • Because mosquitoes lay their eggs in standing water, containers or bodies of standing water should be drained if possible.

  • People can help prevent mosquitoes from entering their homes by repairing or installing screens on their doors and windows.

• Supporting community-based efforts
  

  • Dead birds can indicate the presence of the West Nile virus in a community and should be reported to local health authorities.

  • Some communities have initiated mosquito-control programs. Local governments should have additional information about these programs.

  • Keeping the community clean by picking up garbage and draining standing water from vacant areas and parks can help to eliminate mosquito breeding grounds.

Prognosis The prognosis in West Nile virus is generally good. However, the elderly and persons with multiple medical complications have a poorer prognosis. A study by Yeung et al suggested that patients with acute West Nile virus score low with regard to health-related quality of life (HRQoL) but experience significant postacute improvement in HRQoL within 6 months. The investigators also reported that neuroinvasive disease, after adjusting for confounding, did not, either during up to 3-year follow-up or postacute infection, significantly predict HRQoL. The study did, however, find number of comorbidities and baseline utility scores to be predictors. [39]

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