Classification

General Characteristics and Epidemiology

Basic features of West Nile virus

• Taxonomy:
  • Flaviviridae family
  • Flavivirus genus
• RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure virus:
  • Single stranded
  • Positive sense
  • Linear
• Spherical
• Icosahedral symmetry
• Enveloped
• Size: approximately 50 nm

Associated disease

Two phylogenic lineages of West Nile virus cause the following diseases:

• West Nile fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
• Neuroinvasive disease:
  • Meningitis
  • Encephalitis
  • Acute flaccid paralysis

Epidemiology

• Number of cases in the United States 1999–2015:
  • 44,000 total
  • 20,000 with neuroinvasive disease
• Develop severe disease: < 1%
• Patient death rate if severe disease: 3%–15%
• One of the most widely distributed arbovirus diseases 
• Geographic distribution: 
  • Africa
  • Middle East
  • Europe
  • South Asia
  • Australia
  • North America
  • South America

Pathogenesis

Reservoir

• Primary host: birds
• Accidental hosts:
  • Horses 
  • Humans
  • Other mammals

Transmission

• Vector: Culex mosquitoes
• Blood transfusion
• Organ transplant
• Transplacental

Host risk factors

Higher risk for infection:

• Living in areas with high temperature and rainfall
• Living near stagnant water
• Living near immunologically naive, avian-host population

Higher risk for neuroinvasive disease:

• Age > 75 years old
• Immunosuppression:
  • Hematologic malignancy
  • Organ transplantation Organ Transplantation Transplantation is a procedure that involves the removal of an organ or living tissue and placing it into a different part of the body or into a different person. Organ transplantations have become the therapeutic option of choice for many individuals with end-stage organ failure. Organ Transplantation
  • Medications
  • Diabetes
• Other medical conditions:
  • Chronic renal disease
  • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension

Viral replication

• Virion interacts with cell surface receptors → endocytosis
• ↓ pH in the endosome → fusion of viral and endosomal membranes → uncoating of the virus
• Viral protein synthesis occurs in the rough endoplasmic reticulum (RER).
• Genomic replication occurs in invaginations of the RER → virions are repackaged and assembled
• Mature virions leave the cell.

Pathophysiology

• West Nile virus is injected into a host by a mosquito.
• Replication occurs in keratinocytes and dendritic cells.
• Spread through lymphatics → replication in lymph nodes
• Viremia occurs → spread to visceral organs → further replication
• Eventual spread to the CNS (mode of entry is unclear) → inflammatory response → neuron damage → neurologic manifestations

Clinical Presentation

The majority of patients are asymptomatic. Symptomatic disease can vary in severity and presentation.

West Nile fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever

Approximately 20% of infected patients will develop a mild, self-limited disease.

• Fever
• Headache
• Nausea and vomiting
• Anorexia
• Malaise
• Myalgia
• Eye pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
• Backache
• Rash:
  • Features:
    • Erythematous
    • Maculopapular
    • Morbilliform
    • May be pruritic
  • Distribution:
    • Chest
    • Back
    • Arms

Neuroinvasive disease

Approximately 1% of infected patients may experience:

• Meningitis:
  • Fever
  • Headache
  • Nuchal rigidity
  • Photophobia
• Encephalitis: 
  • Altered mental status
  • Severe muscle weakness
  • Parkinsonism:
    • Rigidity
    • Bradykinesia
    • Postural instability 
  • Tremor
  • Myoclonus
  • Seizures
• Acute flaccid paralysis:
  • Usually isolated, asymmetric limb paralysis
  • Respiratory paralysis may occur.
• Other manifestations:
  • Guillain-Barré syndrome Guillain-Barré syndrome Guillain-Barré syndrome (GBS), once thought to be a single disease process, is a family of immune-mediated polyneuropathies that occur after infections (e.g., with Campylobacter jejuni). Guillain-Barré Syndrome
  • Polyneuropathy Polyneuropathy Polyneuropathy is any disease process affecting the function of or causing damage to multiple nerves of the peripheral nervous system. There are numerous etiologies of polyneuropathy, most of which are systemic and the most common of which is diabetic neuropathy. Polyneuropathy
  • Cranial nerve palsy

Diagnosis

Definitive studies:

• Serology of serum or CSF
• PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR) to detect viral RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure
• Viral culture

Supporting evaluation:

• Blood testing:
  • Leukocytosis
  • Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia → SIADH SIADH Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of impaired water excretion due to the inability to suppress the secretion of antidiuretic hormone (ADH). SIADH is characterized by impaired water excretion leading to dilutional hyponatremia, which is mainly asymptomatic but may cause neurologic symptoms. S Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) due to encephalitis Encephalitis Encephalitis is inflammation of the brain parenchyma caused by an infection, usually viral. Encephalitis may present with mild symptoms such as headache, fever, fatigue, and muscle and joint pain or with severe symptoms such as seizures, altered consciousness, and paralysis. Encephalitis
• CSF examination:
  • Pleocytosis with lymphocyte predominance (neutrophil predominance early in the course)
  • Normal glucose levels
  • ↑ Protein
• MRI of the brain: enhancement in the leptomeninges, basal ganglia Basal Ganglia Basal ganglia are a group of subcortical nuclear agglomerations involved in movement, and are located deep to the cerebral hemispheres. Basal ganglia include the striatum (caudate nucleus and putamen), globus pallidus, substantia nigra, and subthalamic nucleus. Basal Ganglia, and thalami

Management

No antiviral therapy is currently available; management is supportive. In patients with neuroinvasive disease, the following may be needed:

• ICU care
• Intracranial pressure monitoring
• Seizure management
• Ventilator support for respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure or inability to protect the airway
• Occupational and physical therapy

Prevention

• Local mosquito control
• Insect repellent
• Protective clothing
• Blood and organ donor screening

Comparison of Similar Flavivirus Species

Differential Diagnosis

• Lyme disease Lyme disease Lyme disease is a tick-borne infection caused by the gram-negative spirochete Borrelia burgdorferi. Lyme disease is transmitted by the black-legged Ixodes tick (known as a deer tick), which is only found in specific geographic regions. Patient presentation can vary depending on the stage of the disease and may include a characteristic erythema migrans rash. Lyme Disease: a tick-borne infection caused by the gram-negative spirochete Spirochete Treponema is a gram-negative, microaerophilic spirochete. Owing to its very thin structure, it is not easily seen on Gram stain, but can be visualized using dark-field microscopy. This spirochete contains endoflagella, which allow for a characteristic corkscrew movement. Treponema Borrelia Borrelia Borrelia are gram-negative microaerophilic spirochetes. Owing to their small size, they are not easily seen on Gram stain but can be visualized using dark-field microscopy, Giemsa, or Wright stain. Spirochetes are motile and move in a characteristic spinning fashion due to axial filaments in the periplasmic space. Borrelia burgdorferi. The presentation can vary depending on the stage of the disease and may include the characteristic erythema migrans rash. Neurologic, cardiac, ocular, and joint manifestations are also common in later stages. The diagnosis relies on clinical findings and tick exposure, and is supported by serological testing. Antibiotics are used for treatment. 
• Ehrlichiosis Ehrlichiosis Ehrlichiosis is a tick-borne bacterial infection. The most common causative species include Ehrlichia chaffeensis, which infect and multiply within monocytes. The clinical presentation can vary widely, but often includes fever, malaise, headache, myalgia, and arthralgias. Ehrlichiosis and Anaplasmosis and anaplasmosis Anaplasmosis Anaplasmosis is a tick-borne bacterial infection. The most common causative species include Anaplasma phagocytophilum, which infect and multiply within granulocytes. The clinical presentation can vary widely, but often includes fever, malaise, headache, myalgia, and arthralgias. Ehrlichiosis and Anaplasmosis: tick-borne infections caused by Ehrlichia chaffeensis and Anaplasmosis phagocytophilum, respectively. Symptoms of ehrlichiosis and anaplasmosis Anaplasmosis Anaplasmosis is a tick-borne bacterial infection. The most common causative species include Anaplasma phagocytophilum, which infect and multiply within granulocytes. The clinical presentation can vary widely, but often includes fever, malaise, headache, myalgia, and arthralgias. Ehrlichiosis and Anaplasmosis include fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, headache, and malaise. Meningoencephalitis can also occur with severe disease. The diagnosis is made using PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR). Treatment of both diseases is with doxycycline.
• Rocky Mountain spotted fever Rocky Mountain Spotted Fever Rocky Mountain spotted fever (RMSF) is a bacterial infection caused by the obligate intracellular parasite Rickettsia rickettsii. Transmission occurs through an arthropod vector, most commonly the American dog tick (Dermacentor variabilis). Early signs and symptoms of RMSF are nonspecific and include a high fever, severe headache, and rash. Rocky Mountain Spotted Fever: a disease caused by Rickettsia Rickettsia Rickettsiae are a diverse collection of obligate intracellular, gram-negative bacteria that have a tropism for vascular endothelial cells. The vectors for transmission vary by species but include ticks, fleas, mites, and lice. Rickettsia rickettsii. Presentation includes fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, fatigue, headache, and rash following a tick bite. Diagnosis is made based on clinical features, rash biopsy, and serologic testing. Treatment involves antibiotics, including doxycycline.  
• Toxoplasmosis Toxoplasmosis Toxoplasmosis is an infectious disease caused by Toxoplasma gondii, an obligate intracellular protozoan parasite. Felines are the definitive host, but transmission to humans can occur through contact with cat feces or the consumption of contaminated foods. The clinical presentation and complications depend on the host's immune status. Toxoplasma/Toxoplasmosis: an infectious disease caused by Toxoplasma Toxoplasma Toxoplasmosis is an infectious disease caused by Toxoplasma gondii, an obligate intracellular protozoan parasite. Felines are the definitive host, but transmission to humans can occur through contact with cat feces or the consumption of contaminated foods. The clinical presentation and complications depend on the host's immune status. Toxoplasma/Toxoplasmosis gondii. Immunocompetent patients usually have no symptoms; immunocompromised patients may develop CNS toxoplasmosis or chorioretinitis Chorioretinitis Chorioretinitis is the inflammation of the posterior segment of the eye, including the choroid and the retina. The condition is usually caused by infections, the most common of which is toxoplasmosis. Some of these infections can affect the fetus in utero and present as congenital abnormalities. Chorioretinitis. The diagnosis is made with serology or PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR) testing. Immunocompetent patients may not need any treatment. The immunocompromised or patients with severe disease may require combination therapy with pyrimethamine, sulfadiazine, and leucovorin. 
• Herpes simplex encephalitis Encephalitis Encephalitis is inflammation of the brain parenchyma caused by an infection, usually viral. Encephalitis may present with mild symptoms such as headache, fever, fatigue, and muscle and joint pain or with severe symptoms such as seizures, altered consciousness, and paralysis. Encephalitis: a severe CNS infection caused by herpes simplex viruses. Patients develop rapid onset of fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, headache, an altered level of consciousness, focal neurologic deficits, and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures. The diagnosis is confirmed with PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR) testing of CSF. Hyperintense lesions in the temporal lobes may be seen on MRI. The treatment of choice is IV acyclovir.
• Poliomyelitis Poliomyelitis Poliomyelitis is an infectious disease caused by the poliovirus. Transmission occurs through the fecal-oral route and through respiratory aerosols. The majority of patients will be asymptomatic or have a mild, abortive presentation with flu-like symptoms. Those who develop nonparalytic poliomyelitis will develop signs and symptoms of aseptic meningitis. A very minor proportion of patients will progress to paralytic poliomyelitis. Poliovirus/Poliomyelitis: an infectious disease caused by the poliovirus Poliovirus Poliomyelitis is an infectious disease caused by the poliovirus. This virus is a member of the Picornaviridae family. It is a small, single-stranded, positive-sense RNA virus without a lipid envelope. Transmission occurs through the fecal-oral route and, occasionally, through respiratory aerosols. Poliovirus/Poliomyelitis. The majority of patients are asymptomatic or have mild, abortive presentation with flu-like symptoms. Nonparalytic poliomyelitis may present with aseptic meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis. A minor proportion of patients will progress to paralytic poliomyelitis with neurologic progression, including asymmetric flaccid paralysis. The diagnosis is determined by clinical presentation and supported by viral culture, PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR), and serology.  Management is supportive.
• Bacterial meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis: an acute infection of the meninges Meninges The brain and the spinal cord are enveloped by 3 overlapping layers of connective tissue called the meninges. The layers are, from the most external layer to the most internal layer, the dura mater, arachnoid mater, and pia mater. Between these layers are 3 potential spaces called the epidural, subdural, and subarachnoid spaces. Meninges. Patients present with headache, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, nuchal rigidity, and rapid clinical deterioration. A lumbar puncture is performed to make the diagnosis. Unlike viral meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis, CSF studies will show turbid fluid, hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia, and a high WBC count with neutrophil predominance. Gram stain and culture determine the causative bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview. Treatment includes antibiotics and corticosteroids. 
• Intracranial tumors: a benign or malignant growth of cells in the brain. Presentation includes headache, unexplained nausea or vomiting, blurred vision, and difficulty in speech or hearing. The diagnosis is made with a neurologic examination, imaging (MRI or CT), and sometimes biopsy. Management includes radiation, chemotherapy, and/or surgery.
• Brain abscess Brain abscess Brain abscess is a life-threatening condition that involves the collection of pus in the brain parenchyma caused by infection from bacteria, fungi, parasites, or protozoa. The most common presentation is headache, fever with chills, seizures, and neurological deficits. Brain Abscess: a collection of pus in the brain parenchyma due to infection. Presentation includes fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, headache, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, nausea, and vomiting. A definitive diagnosis from clinical presentation alone is difficult; therefore, the diagnosis is mainly based on imaging. Management includes antibiotic therapy and surgery to drain the abscess.