Identified in 1937 and named after the Ugandan province where its discovery took place, West Nile virus has a widespread distribution in Africa, West Asia, and the Middle East, occasionally causing epidemics also in Europe. Many people infected with the virus do not become ill or show symptoms, and even when they do, symptoms may be limited to a headache, sore throat, backache, or fatigue. Because no effective antiviral drugs have been discovered, treatment for those who do become seriously ill can only attempt to address symptoms such as swelling of the brain (encephalitis) and other complications such as bacterial pneumonia. Fatality rates—the percentage of people with confirmed infections who have died—have ranged from 3 to 15 percent for West Nile and are highest in the elderly. The virus that was originally misidentified as the cause of the New York outbreak is called St. Louis virus. Both West Nile and St. Louis encephalitis viruses are in a group called “flaviviruses,” and can be spread when mosquitoes bite birds (often a natural host for the virus), acquire the virus, and then pass it on to humans (see fig. 1). St. Louis encephalitis is found in nature through much of the lower 48 states and is the most common mosquito-borne virus causing outbreaks of human disease in the United States. About 30 confirmed cases occur on average each year during non- outbreak years. St. Louis encephalitis is also similar to West Nile in that most people infected with it show no symptoms, but for those who become seriously ill, no effective antiviral drugs are available. St. Louis encephalitis has a slightly higher fatality rate than West Nile, ranging from 3 to 30 percent of confirmed cases. Rapid and accurate diagnosis of disease outbreaks is essential for many reasons. It can help contain an outbreak quickly by allowing health officials to implement appropriate control or prevention measures and provide the most effective treatment for those who are affected. Rapid and accurate diagnosis is essential not only for the public at large, but also for health care workers and others who work with patients and laboratory samples. Accurate diagnosis is also important in providing information that could help determine whether the outbreak could have been deliberate—an act of bioterrorism. Public health officials use the term “surveillance” to denote the ongoing effort to collect, analyze, and interpret health-related data so that public health actions can be planned, implemented, and evaluated. Local health personnel are likely to be the front line of response. Local and state health departments might be the first to recognize unusual patterns of illnesses. For example, an epidemiologist (a health official trained to investigate diseases of unknown origin) in a city health department might receive phone calls from nurses, doctors, or emergency room personnel about increasing numbers of patients with similar symptoms. If the problem is thought to be widespread or suspicious in origin, the local health department is likely to involve the state health department, which is responsible for statewide surveillance and investigations involving multiple locations. The local and state response may also involve emergency management personnel. Current protocols recommend that law enforcement officials be notified if a case or series of cases have a suspicious origin. Local, state, and federal laboratories also play a vital role. Initially, this role may be to determine whether the unusual cases have the same pathogen (the specific causative agent for the disease), and if so, to identify it. Once an outbreak is established, laboratories may be called upon to test samples such as blood or spinal fluid from persons with similar symptoms, to determine who has the illness and the extent of the problem. At the federal level, CDC, an agency of the Department of Health and Human Services (HHS), is available upon request to help state and local officials investigate the nature and origin of disease outbreaks. For example, CDC maintains several laboratories that identify unusual or exotic viruses and other pathogens when other laboratories are unable to do so. One such laboratory, at the Division of Vector-Borne Infectious Diseases in Fort Collins, Colorado, deals with viral and bacterial diseases transmitted by vectors such as mosquitoes and ticks. It is part of CDC’s National Center for Infectious Diseases. Besides providing laboratory services, this division also develops ways to diagnose vector-borne pathogens more quickly and helps develop and evaluate approaches to preventing and controlling outbreaks. CDC is also the lead agency in HHS for bioterrorism preparedness. In recent years, the President and Congress have been increasingly concerned about the threat of terrorists using weapons of mass destruction, including biological agents.Part of CDC’s National Center for Infectious Diseases, the Bioterrorism Preparedness and Response Program is responsible for public health preparedness for potential acts of bioterrorism. In fiscal year 2000, HHS received $278 million of the $10.2 billion in counterterrorism monies allocated to federal agencies. Of the HHS funding, CDC received approximately $155 million for bioterrorism preparedness programs in fiscal year 2000, approximately $40 million of which is to be awarded to state and local health departments for surveillance, epidemiology, laboratory, and communications. During the first recognized outbreak of West Nile virus in the United States, infection of animals preceded the first human cases by at least 1 to 2 months. Large numbers of dying birds and an unusual cluster of human cases were at first viewed as separate events. Gradually, as an increasing number of laboratories became involved to conduct further testing on human, animal, and mosquito samples, the linkages became clear, resulting in the identification of the West Nile virus (see fig. 2). The scale of these efforts was substantial, involving participants around the country. Since the end of the outbreak, various local, state, and federal agencies have taken actions to address the potential ongoing consequences of the virus’s introduction into North America. The identification of a newly emerging infectious diseasewithin a few months was due to the combined, considerable efforts of scores of individuals and several agencies in the animal and the human public health fields and in academia. Here is an overview of the key events that occurred. Appendix II contains a more detailed chronology. No one is sure exactly when or how birds became infected. By late June a veterinarian at an animal health clinic in the New York City borough of Queens had examined and treated several birds that appeared to have nervous system disorders, releasing those that survived. Reports of dead birds increased through July and into August. By mid-August, dead birds were being sent to the wildlife pathologist at the New York State Department of Environmental Conservation. The wildlife pathologist was able to determine that the birds were not dying from any of several common problems, but he could not identify a clear cause. By late August, veterinarians at the Bronx and Queens zoos had joined the effort to identify the disease, after several wild and caged birds died on zoo property. Meanwhile, near the end of August, a specialist in infectious diseases in a community hospital in Queens noticed that the hospital had an abnormally large number of suspected cases of encephalitis or meningitis (diseases involving inflammation of the brain or spinal cord) and that several of the patients had developed an unusual pattern of muscle weakness. When the hospital’s doctors were unable to find a clear cause or an effective treatment, the specialist called the Bureau of Communicable Disease within the New York City Department of Health.After a quick but careful investigation, city health officials contacted the state health department and CDC for additional help. Blood and spinal fluid specimens from hospital patients were rapidly tested at state and CDC laboratories. On September 3, CDC announced that the test results were positive for St. Louis encephalitis, a virus known in the United States but never before known to occur in New York City. That same day, the city, assisted by the state and CDC, launched a massive campaign to prevent people from being bitten by mosquitoes and to determine the extent of the St. Louis encephalitis outbreak. Within the next week, however, the State Department of Health obtained what appeared to be conflicting test results for St. Louis encephalitis, raising doubts among some health officials about whether the exact cause of the outbreak in humans had been determined. In addition, CDC officials were questioned by city and state health workers and the public as to whether the deaths of large numbers of birds and the human encephalitis cases might be connected. Because St. Louis encephalitis had not been known to kill its bird hosts, CDC officials said they considered the two outbreaks to be unrelated. The cause of the outbreak in birds remained unidentified, and, to help identify it, the zoo veterinarians and the state wildlife pathologist enlisted the help of federal veterinary laboratories at the U.S. Department of Agriculture (USDA) and the U.S. Geological Survey (USGS). By mid-September, both laboratories concluded that the bird disease was caused by a virus, that it did not appear to be any strain of St. Louis encephalitis or other avian virus they had previously tested, and that they had insufficient laboratory capabilities to identify it more specifically. The USDA veterinary laboratory sent its virus samples to the CDC laboratory for further analysis. The test results in birds, along with repeated negative test results in human samples in the state health department laboratory, increased the doubts of some state health officials about whether the human disease agent had been correctly identified as St. Louis encephalitis. On September 15, they invited a visiting academic researcher from California to try out some new testing methods on tissue specimens from human patients. The following week, a Connecticut agricultural laboratory involved in that state’s routine mosquito surveillance reported isolating St. Louis encephalitis virus from both a dead bird and mosquitoes collected near the outbreak area. This finding was significant in implying that, if the virus was St. Louis encephalitis, it was killing birds and possibly could be connected to the human outbreak. At about the same time, CDC had begun testing and retesting mosquito, bird, and human specimens against a wider variety of flaviviruses in order to rule out the possibility of another closely related virus.