Chapter 1
What Is West Nile Virus?

Viruses are submicroscopic organisms that can be seen only with an electron microscope. Their size is measured in nanometers; a nanometer is one billionth of a meter.

As small as they are, viruses are responsible for untold damage and suffering. They can infect many types of plants and animals, producing a wide range of illnesses and even death. They do this by entering a living cell and taking over the cell in order to replicate themselves. In fact, viruses cannot live on their own. They require a host animal or plant in which they can replicate so they can survive, and they must get inside a living cell to begin this process. "A virus relies entirely upon the host cell's ability to create the energy necessary to perform all of the manufacturing processes. Viruses do not come with batteries included,"³ point out scientists writing for the Virology Down Under website. Thus, the sole purpose of a virus is to enter living cells so it can make more viruses which can then get into more cells and reproduce.

The entrance of a virus into a cell is called a viral infection. It is this infection that can lead to disease. The host plant or animal's body then produces antibodies and other immune chemicals designed to kill the invading virus and rid the body of the infection. The antibodies also kill cells infected by the virus. Eventually either the body is free of the virus, which can no longer survive in the absence of infected cells, or else the virus overpowers the immune system and keeps replicating, leading to death in some instances.

Once a virus is inside a living cell, it uses the cell's machinery and chemicals to produce virus parts, which are assembled into new viruses that then leave the cell and go on to infect other cells. Viruses are made mostly of DNA (deoxyribonucleic acid) or RNA (ribonucleic acid), the fundamental genetic building blocks of living matter. The DNA or RNA is surrounded by an outer shell known as a capsid; this shell is made of protein. Some viruses also have another protein layer inside the capsid known as a core, and some have a fat and protein covering outside the capsid called an envelope. Viruses are classified according to size, shape, presence or absence of an envelope, type of genome (that is, whether the virus contains a single or double strand of DNA or RNA), and other factors.

West Nile Virus

The West Nile virus is classified as a flavivirus, or member of the family known as Flaviviridae. The Latin word flavus means "yellow"; the group of viruses is named after one of its best-known

First Isolation of West Nile Virus

In 1937, a group of doctors was studying yellow fever and related pathogens in the West Nile region of Uganda. They took a blood sample from a thirty-seven-year-old woman with a fever, and her blood contained a virus they had never seen before. They named the virus West Nile virus after the area where it was first discovered.

The researchers injected the infected woman's blood into the brains of laboratory mice, and all the mice died after becoming hyperactive, then weak, then falling into a coma. Some of the mice became paralyzed before dying. Subsequent experiments on rhesus monkeys showed the virus caused encephalitis followed by coma and death after it was injected into the brain. The researchers examined the deceased animals' brains and found the brains were swollen and contained lesions and extensive damage to nerve cells. The virus did not seem to affect organs other than the brain.

When the investigators tried giving the virus to rhesus monkeys intravenously rather then directly into the brain, the virus caused only fever and gave the monkeys immunity to its effects. Tests on other species of animals indicated that some became ill and died after being given the virus intravenously or directly into the brain, while others developed only fever and went on to produce antibodies that protected them from illness. Such research with the virus isolated from the Ugandan woman provided scientists important information about it and its effects on the nervous system of both humans and animals.

members, the virus that causes yellow fever. Flaviviruses have a single strand of RNA and an outer envelope, among other characteristics. They range in size from forty to sixty nanometers and can cause many types of ailments including fever, rash, and central nervous system illnesses.

Doctors first identified West Nile virus in the blood of a woman with a high fever in the West Nile province of Uganda, Africa, in 1937. It undoubtedly existed before this time, but no one had ever isolated the virus in a laboratory before this incident.

Soon after doctors identified the West Nile virus, other researchers showed that it was similar to other flaviviruses such as Saint Louis encephalitis virus, Japanese encephalitis virus, and Murray Valley encephalitis virus. All flaviviruses are spread to humans and other animals by mosquitoes or ticks. They are part of a group known as arboviruses, a term that is short for arthropod-borne viruses, because they are transmitted by blood-sucking arthropods.

Outbreaks Since the Virus Was Identified

Since West Nile virus was first identified, health experts have tracked many major outbreaks of disease related to this pathogen in areas where it is endemic (ever present), primarily in the Middle East and Africa. Even when no major outbreaks occur, though, the virus is still active in places like Israel, Egypt, and other Middle Eastern and African locales. Indeed, studies in the 1950s in Egypt found that about 60 percent of the people living along the Nile River had antibodies to West Nile virus in their blood, indicating that they had been infected with the virus at some point. The antibodies that the immune system manufactures to fight infections can remain in the body for long periods of time after the infection is gone, thereby giving the person immunity to the pathogen.

Doctors believe most Egyptians scrutinized in the 1950s studies were exposed to the virus in early childhood during the summer months, when mosquitoes are most active. Most did not develop serious disease and mainly experienced fever and minor aches and pains.

In recent years, notably in 1996 and 1999, experts in places such as Romania, Russia, and Israel have noticed that West Nile virus outbreaks have centered more in urban areas, where the disease was previously not prevalent. The virus has also resulted in large numbers of severe neurological (relating to the nervous system) problems and death when it strikes in places where it is usually uncommon.

Arboviruses

Arboviruses are found throughout the world. They are pathogens that can be spread by bloodsucking arthropods, including mosquitoes, ticks, fleas, lice, and sand flies. West Nile virus is an example of an arbovirus that is spread exclusively by mosquitoes. Most arboviruses are not contagious between humans—that is, they do not spread from one person to another except when directly inoculated into the blood.

More than eighty different arboviruses can cause human illnesses. They typically affect the central nervous system because these viruses have biochemical characteristics that attract them in particular to brain and nerve cells. They can also affect other parts of the body, causing a rash, fever, fatigue, arthritis, or hemorrhaging in some instances.

The 1999 outbreak in the New York City area, where of course the virus had never been seen before, followed the recent pattern of centering in an urban area and of causing severe neurological disease in many patients. Once the virus arrived in the United States, it showed no inclination to leave and in fact began spreading out of the New York area. By 2000, West Nile virus had affected people in New York, New Jersey, and Connecticut. In addition, by this time veterinarians had identified the virus in many birds, horses, bats, rodents, rabbits, cats, raccoons, and skunks throughout the East Coast region.

By 2001, West Nile virus had infectand animals in nearly every state in the continental United States. Most of these cases have occurred in Illinois, Louisiana, Michigan, and Ohio. The federal Centers for Disease Control and Prevention (CDC) reports that as of late 2002, there were more than 3,500 people infected with noticeable symptoms and more than 200 West Nile virus–related deaths in this country. Public health officials estimate that there are hundreds more people who do not know they are infected because they never have symptoms.

Varying Degrees of Sickness

According to the CDC, anyone in an area where West Nile virus is present can get infected; however, how sick someone gets depends on several factors. One is age. "All residents of areas where virus activity has been identified are at risk of getting West Nile encephalitis, but persons over 50 years of age have the highest risk of serious disease,"⁴ says the CDC. Older people are also at higher risk of developing lasting disability related to the disease and of dying from West Nile virus infection; about 20 percent of older adults die from the disease, whereas only 4 to 13 percent of the rest of the population succumbs.

Another factor that influences how sick an infected individual becomes is the presence of chronic medical conditions such as diabetes, high blood pressure, cancer, or diseases of the immune system. Such individuals are at high risk of getting severely ill and of dying from West Nile virus infection. This is mostly because people with chronic or debilitating diseases are less able to fight off the virus and keep it from overwhelming the immune system.

Recent research suggests that genetics may play a role in determining who gets very sick and who gets a mild form of the disease. Genes are the part of a DNA molecule that transmits hereditary information from parents to offspring. The genes that a person inherits determine the function and operation of each cell in the body. They play an important role in moderating how an individual responds to various internal and external forces.

Researchers at the Pasteur Institute in Paris, France, tested different strains of laboratory mice to see if genetics might determine which mice were most likely to die from a West Nile virus infection. The investigators found that one strain of mice in particular died within two weeks after becoming infected. They figured out which gene was responsible for this phenomenon and named it the West Nile gene. The scientists discovered that this gene blocks a protein that would usually prevent the virus from reproducing, inducing severe disease. No one has ascertained whether or not a similar genetic flaw is responsible for serious instances of West Nile virus illness in humans, but research is under way to find out.

Other researchers have shown that some strains of mice show no symptoms at all when infected with West Nile virus; it appears that these animals' genes prevent the virus from replicating, thereby preventing serious illness. Again, no one has proven that a similar process exists in humans who do not experience symptoms after being infected with the virus, but scientists believe such factors are likely to play a role in humans as well.

Tracking the Disease

Tracking a disease like West Nile virus involves doctors reporting to public health agencies on instances of infection that are confirmed in a laboratory. Thus, the actual number of cases in a particular area may be under-reported because many people with mild symptoms may never go to see a doctor.

Experts also rely on reports of ill or dead birds and of infected mosquitoes to keep track of where the virus is active. Scientists analyze bird and mosquito tissue samples for evidence of West Nile virus, and if it is found, this information can be used to predict and prepare for new cases of the disease in humans and animals in the area.

Besides the influence of age, overall health, and genetics, the severity of West Nile virus symptoms can also be affected by how common the virus is to the locale, by the subject's nutritional state, and by how much of the virus enters the nervous system. In places where the virus is endemic, infected persons are likely to experience only mild disease. This is because most people in such areas are exposed to the virus yearly from the time they are very young; thus, they are able to build up resistance. Conversely, in places where it is new or uncommon, as in the United States, it is more likely to result in serious illness because the population has not developed resistance to it. Nutritional state, of course, refers to how well nourished an individual is. In general, people who consume a well-balanced diet have better resistance to infections and to life-threatening complications from these infections. How much of the virus gets into the nervous system depends on individual characteristics like genetics and overall resistance to infection, as well as on the particular strain of the West Nile virus the person contracts.

How virulent, or potent, the strain of the virus is also determines the severity of a person's sickness. Different viral strains result from the virus mutating, or changing its genetic structure; sometimes these mutations can make a virus more or less aggressive, or more or less likely to produce serious illness. Experts have discovered that the strain of West Nile virus involved in the 1999 New York City outbreak was a very aggressive strain, which at least partly explains the large number of affected patients with severe neurological disease.

West Nile Fever and More Serious Illnesses from West Nile Virus

Even with extremely aggressive strains of West Nile virus, public health officials say most infected people do not show any symptoms; in fact, only about 20 percent exhibit signs of the disease. Once someone is infected, the incubation period before they show symptoms, if any, is from three to fifteen days. Experts divide those patients who do show symptoms after the incubation period into two groups. The first group, who are referred to as having West Nile fever, has mild symptoms that resemble influenza, including fever, headache, body aches, and sometimes nausea, vomiting, a rash, and swollen lymph nodes. Symptoms generally last for a few days and disappear with no lasting effects.

The second group of patients with symptoms from West Nile virus become sicker than those with West Nile fever. This category of patients represents about 1 percent of those infected with the virus. They are said to suffer from West Nile encephalitis, West Nile meningitis, or West Nile meningoencephalitis. Encephalitis is an inflammation of the brain; depending on which part of the brain is inflamed, the person will show varying symptoms. For example, if the cerebral cortex, the part of the brain involved mostly in thinking and reasoning, is affected, the individual may exhibit mental confusion, disorientation, and memory loss. These symptoms, of course, would be in addition to the fever, headache, and other typical West Nile symptoms such as lethargy, nausea, vomiting, and body aches. If the cerebellum, a part of the brain involved in movement, is inflamed, the patient is more likely to be unable to walk or to move other muscles in the body. Inflammation in other areas of the brain may produce convulsions, weakness, or even coma.

In rare cases, the inflammation in the brain triggered by West Nile virus infection can lead to a condition called Guillain-Barré syndrome, characterized by sudden weakness or paralysis in the face, arms, legs, and breathing muscles. Guillain-Barré happens when antibodies and white blood cells the body produces in response to an infection damage the cells that protect nerve cells. This disrupts the transmission of nerve signals from one part of the body to another. One patient infected during the August 1999 outbreak in New York City developed Guillain-Barré syndrome and was hospitalized. Extreme weakness, pain, numbness, and tingling in his arms and legs progressed to partial paralysis and the inability to walk. Soon the man needed a mechanical ventilator to breathe. Although these complications are rare in West Nile virus infections, several patients have experienced them during the outbreak in this country. As a result, public health officials recommend that anyone with symptoms of Guillain-Barré syndrome during the late summer or early fall months be tested for West Nile virus.

In contrast to encephalitis, meningitis, the second disorder experienced by many West Nile virus patients, is an inflammation of the meninges—the membrane around the brain and spinal cord. It can produce symptoms of fever, headache, stiff neck, nausea, vomiting, sensitivity to light, and sleepiness. Sometimes seizures are present. It is often difficult for doctors to differentiate meningitis from encephalitis because the symptoms can be very similar, although mental confusion, other changes in thought processes, weakness, and paralysis are generally associated with encephalitis rather than with meningitis. When both the brain and meninges are inflamed, the condition is known as meningoencephalitis. A definitive diagnosis of encephalitis, meningitis, or meningoencephalitis requires laboratory tests that study the cerebrospinal fluid and other tests that take pictures of the brain, in addition to looking at an individual's symptoms. These tests are performed as part of the diagnostic workup when a patient visits a doctor or is admitted to a hospital with suspicious symptoms.

Diagnosing West Nile Virus

When a patient goes to a doctor or is brought into a hospital, a physician first studies the person's medical history to find out whether other medical problems might explain his or her symptoms. The doctor then orders blood tests to be analyzed in a laboratory. If the doctor suspects West Nile virus, he or she can specifically order antibody, DNA, or virus-culture tests to confirm the diagnosis. If the individual is infected with West Nile virus, the blood sample will probably show a rising level of antibodies to the virus, a positive DNA test for the virus, or a positive culture of the virus grown in a culture dish. A positive culture means that the West Nile virus appears when a sample of the patient's blood is incubated in a laboratory dish used for this purpose.

Persons with neurological symptoms indicating encephalitis, meningitis, or meningoencephalitis will also undergo a spinal tap, also known as a lumbar puncture, to obtain a sample of cerebrospinal fluid. A physician performs a spinal tap by giving the nserting a long, hollow needle between two lower vertebrae and into the spinal column. Then the doctor withdraws a sample of cerebrospinal fluid. If the person has West Nile virus, laboratory DNA and immune-chemical tests will indicate the presence of the virus and an increased white blood cell count in response to the infection.

In addition to the spinal tap, persons with neurological symptoms may be given an electroencephalogram (EEG). Here, electrodes attached to the head and to a machine known as an electroencephalograph record the brain waves on a moving sheet of paper. The test can help doctors determine whether the source of certain neurological symptoms is a seizure disorder or another type of illness.

Brain imaging techniques such as computerized tomography (CT) scans or magnetic resonance imaging (MRI) may also be employed to reveal inflammation and swelling in the brain and meninges. These diagnostic tools help physicians determine whether a West Nile virus patient has encephalitis or meningitis. CT scans are X rays that produce more-detailed images of internal organs than do traditional X rays. These scans can pinpoint infections or inflammation deep within the brain.

MRI uses a magnetic field and radio waves to create images of the inside of the body. An MRI machine is a large, cylindrical magnetic tube. When a person is placed inside the machine, radio waves produced by a coil in the machine cause the body to emit faint signals. The machine picks up these signals and processes them through a computer that creates corresponding images from the person's insides. Specially trained doctors can then analyze certain body tissues by the electronic characteristics they display. In this manner, a physician can determine whether the individual has encephalitis, meningitis, or other characteristic symptoms of West Nile virus.

A Complicated Process

With the wide variety of symptoms and the similarities among the various classifications of West Nile virus infection, it can be difficult for physicians to differentiate among the subtypes and to actually diagnose the disease at all unless the correct tests are performed. Now that experts are aware of the presence of West Nile virus in the United States, doctors have been alerted to watch for suspicious symptoms and to perform appropriate tests. However, it is still often difficult to decide when one is dealing with West Nile virus as opposed to influenza or to encephalitis or meningitis brought on by other causes.

The fact that West Nile virus looks very similar to other flaviviruses when viewed under an electron microscope and in DNA and immune protein tests also complicates the diagnostic process. This was illustrated in the 1999 New York City–area West Nile virus outbreak in which physicians originally thought the affected patients were suffering from Saint Louis encephalitis virus. However, recent improvements in methods of laboratory identification of West Nile virus have made it easier for experts to pinpoint exactly which pathogen is responsible for a patient's symptoms.

Public health officials have gone to great lengths to educate both doctors and the public about the virus so that it will be considered in diagnosis of anyone with suspicious symptoms, particularly during the summer and early fall months. But in some places with moderate climates where mosquitoes are active year-round, it is possible for people to be infected at any time, so experts emphasize that West Nile should always be considered as a possibility. "Severe neurological disease due to WNV [West Nile virus] infection has occurred in patients of all ages. Year-round transmission is possible in some areas. Therefore WNV should be considered in all persons with unexplained encephalitis and meningitis,"⁵ say authorities at the CDC.

After the Diagnosis

Once someone is diagnosed with West Nile virus, the illness is reported to local, state, and federal public health officials as part of a concerted effort to track the spread of the disease throughout the nation. Data on when and where West Nile virus infections occur is then used to track down the immediate causes of the disease in hopes of gaining control over the rapidly spreading menace.