key: cord-0042684-ls98i0x4 authors: Dato, Virginia; Shephard, Richard; Wagner, Michael M. title: Outbreaks and Investigations date: 2007-09-02 journal: Handbook of Biosurveillance DOI: 10.1016/b978-012369378-5/50004-1 sha: 5d11cc6da84dd7b8930024ffc0fda1e561e5b1db doc_id: 42684 cord_uid: ls98i0x4 nan In Ernest Hemingway's novel The Sun Also Rises, when Mike Campbell, a Scottish expatriate and World War I veteran, is asked how he went bankrupt, he replies, "gradually, then suddenly." Often, this is how outbreaks of disease appear. Outbreaks can wreak much havoc before they are noticed, and they can grow at an exponential rate before they are brought under control. Some outbreaks spread so far we call them epidemics, or pandemics if they encompass the entire planet. Some outbreaks have never been brought under control. The only certainty is that an outbreak becomes more difficult to stop through human intervention the longer it goes unnoticed. Chapter 2 presents many examples of outbreaks that differ in their origins and in how they were detected, characterized, contained, or continued to develop. Some of these outbreaks have impacted not only health but history itself. These examples illustrate the basic goals, tasks, and activities of biosurveillance and provide a sense of how the methods of biosurveillance have evolved over time. The lives of humans, animals, and microbial organisms have been irrevocably intertwined throughout evolution. Humans rely on these organisms to perform some of the basic functions of life; for instance, the organisms that reside in the gastrointestinal tract of humans participate in the digestion of food. Mitochondria, which provide the energy that fuels our cell processes (Penniston, 1997) , evolved from bacteria that were incorporated into primitive cells during the early stages of evolution. Of course, not all interactions between microbial organisms and humans are favorable. Human (and animal and plant) populations have been battling these unseen living organisms throughout the course of history and, in many instances, losing. William H. McNeill (1989) , in his book Plagues and Peoples, summarizes the scientific evidence of disease outbreaks that predate recorded history. Hippocrates wrote some of the oldest surviving descriptions of disease outbreaks. He described an outbreak of mumps on the island of Thasos, now present-day Greece. Hippocrates also described what appear to be outbreaks of malaria, diphtheria, tuberculosis, and influenza (McNeill, 1989) . Thucydides, a contemporary of Hippocrates, described an outbreak that decimated the Athenian army and many civilians in 430 to 429 BC (McNeill, 1989) . When the outbreak ended, it left a weakened Athenian empire that soon fell to Sparta. The Black Plague killed 25 % to 50% of Europe's population between 1348 and 1351 (EyeWitness to History.com, 2001) . Smallpox wiped out a large portion of the native population of Hispaniola (now Haiti and the Dominican Republic) and spread from there to Mesoamerica (present-day Mexico), contributing to the demise of the Aztecs (McNeill, 1989) . Until the 20th century, the world's urban population was so routinely devastated by infectious diseases that only constant in-migration from the countryside could maintain the population of growing cities (McNeill, 1989) . The 20th century brought technological and medical advancementsmimproved sanitation, vaccines, and antibioticsm that quickly reduced mortality due to infectious disease. Figure 2 .1 demonstrates the steady decline in the death rate in the United States as infectious diseases were gradually controlled with these tools. The death rate reaches its lowest point in 1980, just after natural smallpox was eradicated and just before the appearance of AIDS. By the spring of 1918, when American forces joined the conflagration overseas, Europe had already endured four grinding years of trench warfare. When the tide turned in favor of the Allies in the fall of 1918, it appeared that the unimaginable carnage and devastation consuming the world's Great Powers would finally cease. Then a new scourge appeared. Influenza caused a sudden increase in mortality in the United States (see Figure 2 .1) and other countries (Reid et al., 2004) . This outbreak was termed a pandemic because of its worldwide scope. It killed at least 14 HANDBOOK OF BIOSURVEILLANCE F I 6 U R E 2.1 Crude death rate for infectious diseases--United States, 1900 -1996 . (Graph from CDC, 1999 21.5 million individuals, a number that dwarfs the combat casualties of World War I. A U.S. military facility was an early victim of this outbreak and played an important role in the spread of disease. In Camp Funston (now Fort Riley,) Kansas, on March 11, 1918, 100 soldiers reported sick to the infirmary before noon (Barry, 2004) . Figure 2 .2 is an undated picture of the emergency hospital in Camp Funston. Although ravaged by this outbreak, Camp Funston continued to train troops who then embarked to domestic and F ! G U R E 2.2 Emergency hospital during influenza epidemic, Camp Funston, Kansas. (Photo from the National Museum of Health and Medicine, Armed Forces Institute of Pathology, Washington, DC.) overseas assignments, carrying with them a virus more deadly than their arms. Virus spread to the civilian populations of Europe and North America (Public Broadcasting Service, n.d.) . The disease became known as "Le Grippe" or "Spanish flu" because Spain was not at war, and its domestic press reported on the outbreak. Figure 2 .3 shows the annualized weekly death rates in London, Paris, New York, and Berlin for October and November of 1918. All four cities experienced high mortality rates nearly simultaneously. There was another wave of mortality in early 1919 before this largest of all known epidemics finally burned out on its own, presumably having induced immunity in sufficient numbers of those who had survived. Where did the outbreak in Camp Funston begin? After seven years of study, Barry (2004) concluded that it began in Haskell County, Kansas, located 300 miles to the west, where an outbreak of severe influenza was underway. Military recruits from Haskell County were inducted into the military at Camp Funston. What made the 1918 influenza outbreak so deadly? To understand, it is necessary to know a little about influenza. Influenza is actually a family of viruses with three different types (A, B, and C) and many strains. Scientists create names for influenza strains in the A type based on two proteins (called antigens because they induce immunity in victims) that appear on the surface of the influenza virus and can be measured. Each antigen can take different forms, which are referred to as subtypes: Hemagglutinin (H) antigen with subtypes 1 to 15 and neuraminidase antigen (N) with subtypes 1 to 9. The 1918 virus was named H1N1 because it had on its surface subtype 1 of the hemagglutinin antigen and subtype 1 of the neuraminidase antigen. All influenza A strains infect birds (and, for this reason, influenza A is also known as avian influenza), but only some of these strains are able to infect humans and other mammals and subsequently be passed directly from person to person (or animal to animal). There are two ways that a strain of influenza A can develop the ability to spread from person to person: (1) mutation in one or more genes, and (2) reassortment of genes. Reassortment is simply the exchange of genes between or among two or more different viruses to give birth to a hybrid virus. A prerequisite for reassortment is that the same cell in a bird or mammal must be simultaneously infected with two or more strains of influenza A. If a "parent" strain was capable of being transmitted from person to person, the descendant strain may inherit that ability. Reassortment is a common occurrence in influenza, and it is the key reason that influenza remains a major world health concern to this day. To elucidate whether the 1918 strain was a product of reassortment or mutation, over the past decade, researchers have searched from the frozen tundra of Alaska to the archives of the Smithsonian Institution to find preserved tissues of birds and humans who died in 1917 and 1918. By using modern techniques of molecular biology, they isolated snippets of genetic material from influenza A viruses isolated from these specimens and compared them with each other. They found that the virus taken from individuals known to have died from the pandemic strain was not a direct descendant from the viruses that they found in birds from that period.The best theory is that the 1918 strain was the result of a mutation, a reassortment of an influenza A virus or viruses circulating in mammals such as horses or swine, or both (Reid and Taubenberger, 2003) . Haskell County, Kansas, where animals outnumbered humans by a large factor, was just the type of location where influenza A strains from different mammalian species could converge to develop into the deadliest strain of influenza yet known to humankind (Barry, 2004) . Pandemics of influenza A occurred in 1957 and 1968. The virus strains causing these outbreaks were reassortments of genetic material between human and avian influenza virus strains circulating at the time (Reid and Taubenberger, 2003 ). An H2N2 strain caused the 1957 pandemic. An H3N2 strain caused the 1968 pandemic and is still circulating today (with gradual mutations over the years). Recently, the 1957 H2N2 strain was mistakenly included in a set of test strains sent to thousands of laboratories worldwide that participate in influenza monitoring for purposes of calibration. This error was potentially catastrophic because human beings born since the late 1960s do not have immunity to this strain (CDC, 2005) . The threat of future pandemics of influenza A is ever present because of the propensity of influenza to reassort or mutate into new forms for which humans do not have immunity. The influenza virus (as well as its control and treatment methods, such as vaccination, quarantine strategies, and antiviral treatments) remains an important area of research and development. Our knowledge is accelerating so rapidly that no textbook can remain current for long. Most of what is known about the 1918 influenza virus has been discovered in the past 5 years. Interested readers should consult the resources listed at the end of the chapter. By the 1950s, scientists were optimistic that advances in disease control would conquer the problem of communicable diseases (Lasker, 1997) . Subsequent events, however, awakened a realization that infectious diseases will never be fully controlled (Lederberg J., 1992; CDC, 1998) , as the outbreaks we describe next illustrate dramatically. In the town of Lyme, Connecticut, in 1975, two children were diagnosed with the same rare diseasemjuvenile rheumatoid arthritis. Their mothers became aware of other similarly affected children in their community (American Museum of Natural History, 1998) and notified the local health department about this unusual circumstance. The local health department, suspecting the emergence of a new infectious disease, asked Dr. Allen Steere to investigate. His study of the children of Lyme produced several clues: the disease did not appear to spread from one person to another, it occurred most often in the summer when insect-borne disease was more common, and a rash often appeared before children developed arthritic symptoms, suggesting a tick-borne disease. In 1981, entomologist Willy Burgdorfer found the cause by looking at the digestive tracts of Ixodes ticks under a microscope. The bacterium he found, Borrelia burgdorferi, was named in his honor. We now know that B. burgdorferi, and other closely related organisms, exist on many continents and likely have been causing disease in humans for hundreds of years. One reason for the unusual number of cases in Lyme was the fashionable practice of building new homes in wooded locations. This practice brought mice (a carrier of B. burgdorferi) and deer, which are necessary for tick survival, and humans (tick food) into proximity and created conditions in which the bacteria could infect humans in large numbers. Lyme disease in humans is an example of a vector-borne disease. Malaria, the most prevalent of the vector-borne diseases, causes 1.5 to 2.7 million deaths annually, mostly in third world countries, and remains a major world health problem (Southwest Foundation for Biomedical Research, n.d.). Biosurveillance for vector-borne diseases is complex and involves monitoring the interactions of humans, animals, and insects. One Sunday in 1976, an American Legion official contacted Dr. Lewis D. Polk, director of the Philadelphia Health Department to report the deaths of eight veterans who had participated in a recent American Legion convention in the city (Lewis D. Polk, personal communication). The initial investigation found neither a causative organism nor a common source of exposure, and attendees of the convention continued to die (CDC, 1976) . Philadelphia was celebrating the nation's bicentennial, leading to speculation that a chemical or biologic attack had occurred. The strongest clue available was the Bellevue Stratford Hotel, one of the convention hotels. Many victims visited the hotel during the course of the convention or had walked within a single block of the hotel. However, it was puzzling that individuals who worked at the hotel did not get sick. Investigators compared individuals, both sick and healthy, who had some contact with the hotel. This analysis revealed only that the attack rate was higher in smokers and individuals who spent more time in the hotel lobby. The cause of this outbreak was not found until 6 months later, when, in January 1977, researchers at the Centers for Disease Control and Prevention (CDC) discovered a new class of bacteria by examining microscopic slides of guinea pigs injected with lung tissue from deceased patients. They named the bacteria Legionella pneumophila. Investigators believe that the water cooling tower on the roof of the hotel was the source of bacteria for the Philadelphia outbreak. Water from cooling towers sprays into the air as microdroplets, which may enter the body by inhalation. In the end, this outbreak caused an estimated 180 cases and 29 deaths (CDC, 1997) . Subsequent research has demonstrated that L. pneumophila had been causing outbreaks of pneumonia throughout the United States for years. Researchers thawed and tested serum samples saved from earlier outbreaks of pneumonic illness for which a cause had never been found. They found that L. pneumophila caused the outbreak of "Pontiac fever" in Pontiac, Michigan, in 1968 (CDC, 1997 .A second large outbreak occurred in 1966 in a psychiatric hospital, causing 94 cases and 15 deaths (CDC, 1997) . Today, we know that L. pneumophila exists in nature as a common colonizer of water systems but rarely infects people. The American Legion convention brought together a large number of people whose lung defenses were weakened by age and the effects of cigarette smoking. Effective measures to prevent, detect, and treat Legionnaire's disease now exist, so an outbreak from this organism with this degree of mortality is unlikely to occur again. However, outbreaks and sporadic cases secondary to aspiration of drinking water or inhalation of contaminated aerosols continue to occur (Pedro-Botet et al., 2002; Yu, 2002) . In April 1979, people, and many animals, were dying in the Soviet city of Sverdlovsk from an unknown illness (Guillemin, 1999) . The first clue that the organism causing the illness was Bacillus anthracis came from a pathologist, who found that the brain of a victim showed a cardinal's cap--bleeding at the top of the brain. A cardinal's cap is a pathognomic finding (a finding that allows a physician to conclude a diagnosis with certainty) for the disease anthrax (Mangold and Goldberg, 2000) . Soviet authorities maintained that the cause was consumption of contaminated meat. Although the Soviet Union had signed the Convention on the Prohibition of the Development, Production, and Stockpiling of Bacteriological (Biological) and Toxin Weapons and on their Destructionmeffective March 26, 1975 (Goldblat, 1997 --experts in the West remained suspicious of the official explanation. More than a decade later, a team lead by Mathew Meselson (Meselson et al., 1994) visited Sverdlovsk (then renamed Yekaterinburg), to interview survivors, witnesses, and pathologists. They reviewed tissue samples of lung and intestinal tract taken from victims of this outbreak. The tissue samples were more consistent with an inhalational form of anthrax rather than a gastrointestinal form, which would be expected if the infection were acquired by eating contaminated meat. They, therefore, postulated that the cause was airborne release of anthrax. To test this hypothesis, they analyzed the geographical distribution of sick individuals and the known wind conditions, concluding that the outbreak was most likely due to an airborne release of anthrax from a single location. In 1992, Russian authorities admitted that there had been an accidental release of B. anthracis (Kirov strain) from Soviet Biological Weapons Compound 19. During a shift change, a laboratory technician had removed an air filter from a testing chamber, which the subsequent shift failed to replace (Israelyan, 2002) . As a result, this outbreak was caused by an accidental release of material being tested for use in biological weaponry. This outbreak highlights the difficulties of controlling disease in a world where bureaucratic organizations reward secrecy and restrict information. It is an interesting but unanswered question as to what extent their attempts to cover up the truth affected the morbidity and mortality of this outbreak. Because anthrax is not contagious, secrecy did not result in dissemination of disease outside of Sverdlovsk. However, in the words of Victor Israelyan, former Soviet ambassador, "Such a lack of transparency can have dire consequences in this new era of terrorism" (Israelyan, 2002) . In 1981, doctors in Los Angeles, San Francisco, and New York City began to encounter homosexual patients with rare infections and diseases, including cytomegalovirus, Pneumocystis carinii, and Kaposi's sarcoma (CDC, 1981a,b; Drew et al., 1981) . These rare diseases tend to occur in immunocompromised patients, a clue that pointed investigators to look for an infection or chemical exposure that damaged or interfered with cellular immunity (CDC, 2001) . A CDC team formed in June 1981. They named the disease acquired immunodeficiency syndrome (AIDS) and developed a working case definition. They used the working case definition to find infected individuals to interview and examine. They compared the behaviors and histories of these individuals with those of non-infected individuals, and concluded that AIDS could be contracted from blood transfusion, intravenous drug use, or sexual intercourse or could be passed from mother to child in utero. This information was the basis for the March 1983 recommendations on how to prevent infection, disseminated well before the actual cause of the diseasemthe human immunodeficiency virus (HIV)mwas discovered in 1984 (Srikameswaran, 1999) . Subsequent research has elucidated that HIV existed long before AIDS was first recognized in 1981. The evidence indicates that HIV developed through mutation or recombination in monkeys before crossing over into humans. The earliest known human case, as determined by testing stored serum and tissue, was an adult living in the Democratic Republic of Congo in 1959 (Kanabus and Allen, 2005) . In the absence of international travel and high-risk behaviors (multiple sex partners and sharing of needles), which produced clusters of cases in San Francisco and New York City, HIV could have remained undetected for many years, with the resultant deaths blending in with many infectious-disease deaths in areas with little health care. The AIDS pandemic is an example of an outbreak that has never been brought under control. The Joint United Nations Program on HIV/AIDS estimates that 20 million people have died from AIDS, and an additional 38 million people are living with HIV. During 2003--19 years after the virus was isolated-an estimated five million people were newly infected with HIV (UNAIDS, 2004) . Two highly prevalent human infectious diseases--HIV and hepatitis C (Koop, 1998 )--pose difficult biosurveillance problems because they have a long period of infectivity before the onset of symptoms. It is hoped that future advances in biotechnology will yield better methods for detecting infections during their asymptomatic periods. In 1986, veterinary pathologists at the Central Veterinary Laboratory in Weybridge, United Kingdom, became suspicious that a new disease was killing cattle (Donnelly et al., 1999; Matravers et al., 2000) . Their suspicions were aroused by the microscopic appearance of the brain from a cow that died after exhibiting progressive abnormalities of behavior and movement that resembled those of sheep affected with the disease scrapie. Because of the unnerving signs of this disease, it came to be known as mad cow disease. When pathologists saw similar microscopic findings in two more cattle, they feared that a scrapie-type disease had emerged in cattle. The head veterinary epidemiologist for the United Kingdom, John Wilesmith, commissioned studies to find the origin of this new disease. As a starting point, investigators assumed the new disease was caused by an organism similar to the one that causes scrapie in sheep. Moreover, they hypothesized that an unusual transmission pathway--the eating of brains from infected animals--caused the spread of the disease. In the cattle industry, carcasses of livestock that are not fit for human consumption wcre rendered (cooked) into meat-andbone meal, which was fed to animals as a protein supplement. Their methods involved a series of observational studies and computer simulations. These studies suggested that a mass exposure of the cattle population to a new organism was occurring--most likely beginning in winter 1981/1982. They found that the risk of exposure was 30 times greater for one-month-old dairy calves than for adult cattle. This discovery, coupled with knowledge that dairy farmers remove calves from their mothers at one day of age and feed them powdered milk and high-protein supplements based on meat-and-bone meal, confirmed their conjecture about the route of exposure. The incidence of affected dairy herds also increased as herd size increased. Larger herds require more supplement feeds than do smaller herds, thereby increasing the risk of exposure. Although cattle had been resistant previously to scrapie, it is now believed that a cow became infected with a mutant strain of the scrapie agent some time during the 1970s. The sick cow was recycled into meat-and-bone meal, resulting in the exposure of a large number of animals to the newly adapted scrapie agent. Mad cow disease (more properly referred to as bovine spongiform encephalopathy) remained undetected for many years after the initial mutation in the 1970s. The delay in detection allowed the disease to establish within the cattle population. The conditions for disease transmission were broken in 1988, when regulators banned the use of animal protein sources for animal feeds, and the epidemic in cattle gradually abated. For many years, however, cattle that were infected, but not yet symptomatic, entered the human food supply, resulting in a mass exposure of the human population to this new agent. This exposure set up conditions that allowed the disease to cross from cattle into humans. The public were aware of possible exposure to the agent through consumption of contaminated beef; therefore, when a new variant of Creutzfeldt-Jakob disease (vCJD) first appeared in humans in the United Kingdom during the 1990s, people saw the similarity to mad cow disease in cattle (Nathanson et al., 1997) . The total number of confirmed cases of human vCJD, from first identification to 2005, now approaches 150. The exact number of humans who will develop the disease is unknown. Additional routes of disease transmission (e.g., person to person through blood transfusion) are contributing to uncertainty in disease projections. Figure 2 .4 shows a bovine spongiform encephalopathy epidemic curve. The story of mad cow disease and vCJD demonstrates the need for better methods of biosurveillance of animals for the protection of humans. Although the investigation of mad cow disease occurred at breathtaking speed, the initiation of this F I G U R E 2.4 Bovine spongiform encephalopathy (BSE) epidemic curve for the United Kingdom (UK) and other countries. (Modified from European Commission, 2004.) investigation only occurred in 1986, after the first discovery of the disease within the cattle population. It is very likely the disease existed undetected within the cattle population for at least a decade prior to this discovery. This prolonged period of cover allowed the outbreak to proceed unchecked, resulted in significant exposure of the human population, and contributed to movement of the disease into humans in the form of vCJD. Earlier discovery of the outbreak in cattle would have limited its economic impact and prevented it from spilling over into the human population. The 1993 outbreak of cryptosporidiosis that occurred in Milwaukee is a striking example of how difficult it is for current biosurveillance systems to detect outbreaks in a timely manner. This outbreak, caused by a breakdown in the water filtration process at a water supplier, sickened an estimated 403,000 individuals (Mac Kenzie et al., 1994) . Many individuals were sick by the time that public health authorities initiated an investigation, based on reports of widespread absenteeism among hospital employees, students, and schoolteachers owing to gastrointestinal illness. On April 7, laboratory tests confirmed the cause to be the parasite Cryptosporidium parvum (Mac Kenzie et al., 1994) , and a boil-water advisory was issued. Retrospectively, earlier indicators were an increase in sales of diarrhea remedies, noticed by a pharmacist on April 1 (also apparent in sales figures for sales of such products), and an increase in diarrhea-related calls to area nurse hotlines on April 2 (Rodman et al., 1997 (Rodman et al., , 1998 . Attention to water treatment surveillance could have prevented this outbreak. The investigation discovered an improperly installed streaming current monitor and turbidity readings that were clearly elevated during the period when contaminated water was being supplied to the population (Mac Kenzie et al., 1994) . Corso et al. (2003) estimated the total economic impact of this outbreak to be $96 million. This largest of all U.S. waterborne outbreaks (Mac Kenzie et al., 1994) points to the need to augment current biosurveillance methods with methods that can detect large numbers of sick individuals who may not seek medical care. Cryptosporidiosis is a self-limited disease in immunecompetent hosts. Most people do not get sick enough to go to a physician, the traditional discovery point for cases of diseases in biosurveillance. In 1998, a province in Malaysia began reporting to Malaysian health authorities what were then felt to be cases of Japanese encephalitis. When control measures for Japanese encephalitis were less effective than expected, authorities became suspicious that the disease might not be Japanese encephalitis: The mortality from this disease was higher than expected (approximately 30%), cases occurred predominantly in adults instead of children, and there was seemingly no protection provided from vaccination for Japanese encephalitis or from mosquito control. Then, two additional clusters of disease developed--one in another region of Malaysia and one in abattoir workers in Singapore. At the same time, swine within Malaysia were also becoming ill. Veterinary authorities suspected the disease in swine to be classical swine fever (Chua, 2003) . Medical investigators observed an apparent association between the human disease and the swine disease. Many people affected by the disease worked on pig farms, and the infected abattoir workers in Singapore had recently processed pigs from one of the affected regions of Malaysia. These clues prompted investigators to undertake viral isolation studies from human victims. The emergence of a new disease was confirmed when a novel paramyxovirus was isolated from the brain of a human patient in 1999. By this time, the disease had caused illness in 300 people and more than 100 fatalities. Further epidemiological studies indicated that the sick humans contracted their disease directly from swine. There was no evidence of person-to-person spread (Heymann, 2004) . The commercial movement of infected pigs allowed the disease to establish within the second region of Malaysia and transfer into humans in Singapore. Authorities believe this outbreak arose from the spillover of virus from its normal victims--the Pteropid fruit bat--into swine, and then from swine into man. No fundamental change to virus pathogenicity is believed to have preceded swine and human infection, just a change in circumstance that provided opportunity for swine to become exposed. The opportunity for infection to cross two species arose because a reduction in native forest caused by drought and slash-and-burn deforestation practices caused the migration of large numbers of fruit bats into orchards. At the same time, there was an increase in the number of orchards that were also used for swine farming. Swine were housed under the trees and fed fruit not suitable for marketing. This colocation of fruit bats and swine allowed this previously undescribed paramyxovirus virus to infect swine and then the human population (Chua, 2003) . Foot-and-mouth disease (FMD) is a highly contagious viral disease of cloven-hoofed animals such as cattle, deer, sheep, and swine. It is endemic in many parts of Asia, South America, Africa, and the Middle East. The virus can persist in contaminated material for prolonged periods. Outbreaks of FMD in regions previously free of the virus occur regularly around the world, resulting in significant threats to susceptible livestock production systems and requiring expensive, disruptive, and complex eradication programs. Fourteen countries from South America, the Middle East, Africa, Asia, and Europe have had or are experiencing a FMD outbreak. One outbreak of FMD occurred in Korea in 2000. In early April, animals on a farm in North Korea grew lame rapidly, developed vesicles of the feet and mouth, and stopped eating. Veterinarians were concerned that FMD may have re-entered South Korea after an absence of nearly 70 years, and testing was undertaken. The positive FMD laboratory results led to movement restrictions for all livestock within a 20-km radius of an affected farm, the closure of all animal sale yards and abattoirs within the country, and the veterinary inspection of all farms within the affected region for signs of disease. Then slaughter of all animals from affected farms began. In addition, authorities took the controversial step of vaccinating animals from neighboring farms without disease in order to eliminate the infection and reduce its ability to spread from the region. Despite these interventions, over the next two months, the disease spread to two beef cattle farms situated 100 km away and to a dairy farm 150 km away from the initial outbreak. These events intensified fears that disease would soon enter the swine population and, with the presence of vaccinated animals, evade detection, thereby allowing FMD to become endemic within South Korea. Control activities intensified. The army was deployed to operate checkpoints and to control animal movements; veterinary experts from around the world were employed and vaccination programs expanded. The slaughter of more than 2,000 cattle and pigs, vaccination of more than 1.5 million cattle and pigs, and the employment of 600 veterinarians restricted the outbreak. The inspection in 2000-2001 of 650,000 animals outside the vaccination zone did not find disease. The virus causing FMD does not currently infect humans. The impact on human health is felt through its economic impact on human livelihood and trade. A recent outbreak of FMD in the United Kingdom in 2001 received enormous press attention and had severe economic impact on many industries, including agriculture and tourism (Scott et al., 2004) . The organism causing FMD can be carried by the wind for distances up to 100 km, as discussed in Chapter 19. When Johnny Chen ~--a Chinese-American businessman based in Shanghai--arrived in Vietnam on February 24, 2003, there was no indication this routine business trip would be different from any other. Chen worked for Gilwood Company, a small New York garment firm, and went to Hanoi to inspect the work on the blue jeans being manufactured by a local contractor (Cohen et al., 2003) . To all appearances, Chen was the picture of health. By February 26, the 49-year-old Chen was so gravely ill his colleagues rushed him to the Hanoi French Hospital. At the same time, Liu Jianlun, a 64-year-old Chinese medical professor, was already dying in a hospital in Hong Kong. The two unrelated and unacquainted men were suffering from a virulent respiratory ailment that resembled pneumonia and was characterized by high fever, cough, and body aches. Jianlun had traveled to Hong Kong on February 20 to attend a wedding. While there, he stayed on the ninth floor of the Metropole Hotel. So had Johnny Chen. Jianlun died in a hospital isolation ward on March 4, 2003. On March 5, after a week of ineffective treatment and at his family's request, Chen was moved to a facility in Hong Kong. He died eight days later. What their doctors and the world health authorities did not know then was that Chen and Jianlun represented index cases in the outbreak of a new and lethal disease, later known as severe acute respiratory syndrome (SARS). Figure 2 .5 shows the chain of transmission linking these index cases with outbreaks of this disease that occurred throughout the world. Perhaps the most important chain is the Hanoi chain. On February 28th, the Hanoi French Hospital contacted Dr. Carlo Urbani, an infectious disease specialist with the World Health Organization (WHO), because physicians suspected Chen was infected with avian influenza (Reilley et al., 2003) . Dr. Urbani and the staff at the hospital worked swiftly, instituting isolation measures and collecting respiratory and blood samples. Nevertheless, by March 10, 22 hospital workers in Hanoi had contracted the illness (Heymann, 2003) . On March 12, the WHO issued an unprecedented global alert regarding cases of atypical pneumonia in Vietnam, Hong Kong, and China. As a result of the alert, Toronto hospital emergency and infectious disease physicians (Varia et al., 2003) recognized that they had a case of SARS in their hospital, the son of case F (Figure 2 .5), an older women who died at home on March 5. The son had been admitted to the hospital on March 7 and placed under isolation with contact and droplet precautions on March 10. He died shortly after the alert was issued. Family members who visited him in the hospital became ill and were admitted to three Toronto hospitals on March 13. These relatives were placed under airborne, droplet, and contact precautions; these isolation measures were effective and no further disease transmission from these individuals occurred. What doctors did not realize was that the son of case F had received nebulization treatment in the emergency room on March 7 that had facilitated the infection of a number of other patients. No one realized that these patients had SARS when they began developing fever and cough. Infection control experts 1 As a general practice, public health professionals do not reveal the names of victims or businesses involved in outbreaks unless necessary to prevent morbidity and mortality. In most cases confidentiality is protected by law and in others it is a professional commitment. An exception was made in this chapter for those names that are independently a part of the historical public record. No information from confidential investigations is included in this chapter. F I G U R E 2.5 Chain of transmission among guests at Hotel M, H0ng Kong, 2003 . (From CDC, 2003c only gradually realized the extent of the problem when these patients infected additional patients, visitors, and hospital staff. On March 22, the hospital infection control practitioners (ICPs) implemented contact and droplet precautions for all patients in the intensive care unit (ICU); the next day the ICU and emergency department were closed. By March 24, ICPs realized that SARS was potentially anywhere in the hospital and closed the hospital to new admissions, discharged patients, and quarantined off-duty staff at home. ICPs considered every person in the hospital as potentially infectious. Staff wore equipment such as special masks at all times, even when interacting with other healthy-appearing staff. ICPs monitored the health of the hospital patients and staff to identify who was infected, how they became infected, and at what point in the course of the illness they were most infectious. This important information was quickly shared with the rest of the world. The Toronto investigation ultimately identified a total of 128 persons as probable or suspected cases of SARS, 17 of whom died. Singapore (Gamage et al., 2005) , Hong Kong (Lee and Sung, 2003; Joynt and Yap, 2004) , and Taiwan (Hsieh et al., 2004) all experienced high rates of transmission of infection in healthcare facilities. Figure 2 .6 is a picture of a Taiwanese emergency room taken several months after the end of the SARS outbreak, showing the level of precaution that existed. By April 17, 2003, a pan-national research effort involving health care, academia, and governments identified a previously unknown coronavirus as the cause of SARS (Heymann, 2003) Isolation of the organism was the first step in developing a diagnostic test for SARS. By the time this pandemic was brought under control (July 2003) there had been 8096 cases of SARS with 774 deaths (WHO, 2003b) . Dr. Urbani, one of 1076 healthcare workers infected with SARS, died on March 29,2003 (Reilley et al., 2003 . This outbreak highlights several important aspects of biosurveillance. First, hospitals may be agents for the spread of infectious diseases because they welcome all patients, including those who are infectious, immune compromised, or both. By concentrating individuals with communicable diseases and individuals who are especially susceptible to communicable diseases, hospitals provide an ideal environment for the spread of these diseases. Effective infection control procedures are the first step in preventing transmission of infection. However, infection control measures sometimes break down or may simply be ineffective for novel agents. Surveillance for infections transmitted in hospitals (nosocomial) is an important component of biosurveillance. Second, to its credit, the WHO had issued, on February 11, 2003, a routine communicable disease surveillance report about an outbreak of acute respiratory syndrome with 300 cases and five deaths in Guangdong Province (WHO, 2003a) This report was widely disseminated because of the capabilities of world telecommunication, and information about the SARS outbreak was shared quickly among scientists, public health officials, hospital infection control personnel, and clinicians. Communication technology played an important role in disseminating biosurveillance information worldwide. Finally, the downside of technology is that every corner of the world is accessible to an infectious agent. Airplanes are capable of unintentionally carrying infectious agents half way around the world in less than a day. And because one day is less than the incubation period of most infectious diseases, it is exceedingly difficult, with presently available techniques, to prevent individuals infected in one city from infecting any other city on the planet. The implications of this fact for the organization of biosurveillance activities is profound. During the week of October 26, 2003, Dr. Marcus Eubanks, an emergency room physician in Beaver County, Pennsylvania, treated six patients who had symptoms of hepatitis. The wife of the sixth patient told him that she was aware of three other individuals with similar symptoms with whom she had dined at a local restaurant. Dr. Eubanks notified the Pennsylvania Department of Health of this unusual event (Snowbeck, 2003) . Figure 2 .7 shows the epidemic curve for this outbreak. A case-control study found that most of the infected restaurant patrons ate food items containing green onions (CDC, 2003a) , and most were just becoming ill at the time the outbreak was detected. By the time the investigation was completed, 660 cases and three deaths were associated with the outbreak. The Pennsylvania Department of Health provided hepatitis A immune globulin to more than 9400 restaurant patrons and close contacts of infectious individuals in order to prevent additional cases of hepatitis A (Hersh, 2004) . The Food and Drug Administration conducted a formal trace-back investigation (Figure 2.8) , which led to farms in Mexico (Food and Drug Administration, 2001) . The investigation team found multiple sanitation problems on these farms (Food and Drug Administration, 2003) . This outbreak illustrates the need for monitoring that extends internationally to encompass the global food chain and the difficulty of ensuring high standards thousands of miles from the final consumers of food. The SARS story did not end in 2003. On April 5, 2004, a 20-year-old Beijing nurse developed a cold, a fever, and a cough (China, 2004) . By April 7, she was sick enough to be admitted to a hospital. She did not improve, and on April 14, she was transferred to a second hospital, where she was placed into the ICU, and a SARS test was ordered. On April 22, an initial test returned positive. Hospital and public health staff did not wait for a confirmatory test to act. This nurse had been in two hospitals, and she could have infected many individuals in those hospitals. ICPs traced every person who had contact with the nurse to determine the source of her infection and to identify individuals who might be incubating the disease. One hundred seventyone people were placed under observation (WHO, 2004) . One of the nurse's patients had been a medical student, who traveled to another province--Anhui--after discharge. Investigators found that the mother of this medical student had died in Anhui on April 19, 2004, after caring for the sick medical student. The medical student had recently worked with what was ostensibly inactivated SARS virus at the national research laboratory (ProMED-mail, 2004) . Three other workers in her laboratory were tested and found to be infected. This outbreak, which originated in a laboratory, is not unique. The last two cases of smallpox were the result of a laboratory exposure (Hogan et al., 2005) , and the Boston Public Health Commission recently investigated a November 2004 outbreak of tularemia that originated in a laboratory (Barry, 2004) . These and other outbreaks point to the need for enhanced surveillance of all individuals who work in laboratories where highly infectious agents are used or stored. So far in this book, we have used the terms outbreak and epidemic without definitions because they are commonly understood terms and a technical definition was not necessary. However, for completeness, here we provide more technical definitions. Turnock (2001) defines an epidemic as "The occurrence of a disease or condition at higher than normal levels in a population." Last's Dictionary of Epidemiology defines an outbreak as "An epidemic limited to localized increase in the incidence of a disease, for example, in a village, town, or closed institution; upsurge is sometimes used as euphemism for outbreak" (International Epidemiological Association, 1995) . Teaching material from the CDC considers the terms outbreak and epidemic synonymous but notes that public health practitioners might consider using the term outbreak in communications with the public to avoid causing panic (CDC, 2003b) . In this book, we use the term outbreak. We note that all definitions of outbreak (or epidemic) that we have encountered in published sources include a subjective element--"higher than normal levels in a population." In public health practice, it seems that an investigator or a health department will classify an exceedance as an outbreak when the expected impact on the health of a human or animal population-if the exceedance is not investigated--is greater than the cost and effort of investigation (ideally) or is greater than the priority of using those resources in some other way. This determination seems to depend not only on the magnitude of the exceedance but on the nature of the illness and other information that is available about the set of affected individuals. Thus, the current published definitions of outbreak and epidemic are necessary (i.e., there must be an exceedance) but not sufficient (some exceedances do not qualify) conditions for labeling an exceedance an outbreak. Scientific readers may feel somewhat uncomfortable to realize that a key concept in this area of scientific study is not defined in unambiguous terms. In our experience, this ambiguity does not undermine the foundations of research. It is simply something to be aware of. Microbial organisms knowno artificial boundaries of human society, and neither do many outbreaks. Novel and/or previously unknown organisms can come from a wide range of reservoirs (e.g., animal, insect, water, or soil). Organisms can mutate and jump from one animal species to another and result in outbreaks that can quickly spread around the world. The outbreaks that we described identify many of the challenges of biosurveillance. HIV and mad cow disease illustrate the difficulty in detecting outbreaks of disease for which there is a long period of asymptomatic transmission of infectious agents. The hepatitis A and Nipah virus outbreaks demonstrate how infectious agents can be transmitted across national borders via the complex global food distribution system. SARS illustrates the problems faced by hospitals and other facilities housing sick and vulnerable individuals. The cryptosporidiosis outbreak shows the importance of water surveillance and how there can be delays in detection even for an extremely large outbreak when many individuals are not sick enough to go to hospitals. Finally, the anthrax outbreak demonstrates what can go wrong when humans intentionally manipulate organisms and, in addition, suppress information needed to control the outbreak. Detecting and characterizing outbreaks requires enormous amounts of resources, skill, and knowledge. Mitigation of the dire consequences of outbreaks depends on rapid detection and characterization. The initial detection or key clue to understanding how to respond to the outbreak can come from many sources--astute citizens, physicians, veterinarians, laboratory investigations, autopsies, and pharmacists. In many cases, detection occurs late, with substantial cost in human suffering. The need for global cooperation and support for individual countries cannot be overstated because some countries simply do not have the resources to participate in biosurveillance. The mortality curve in Figure 2 .1 and the success in controlling recent outbreaks, such as SARS, tell a story about the developed world's success in combating microbes. There is little doubt that if the many individuals involved in biosurveillance worldwide were to abruptly cease in their efforts, a spike in mortality at least as large as that experienced in 1918 would be sure to follow. We need only look at developing countries to see the carnage that would result. Better methods are both necessary and possible. 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Using Nurse Hot Line Calls for Disease Surveillance Impact of the 2001 Foot-And-Mouth Disease Outbreak in Britain: Implications for Rural Studies How Sixth Hepatitis Case Put Focus on Chi-Chi's SFBR Scientists Part of Team that Offers New Explanation for the Intercontinental Spread of Drug-Resistant Malaria Timeline: Moments in HIV/AIDS History Public Health: What It Is and How It Works Investigation of a Nosocomial Outbreak of Severe Acute Respiratory Syndrome (SARS) in Toronto Acute Respiratory Syndrome in China Summary of Probable SARS Cases with Onset of Illness from 1 SARS: One Suspected Case Reported in China Legionella Surveillance: Political and Social Implications-A Little Knowledge Is a Dangerous Thing For information about current or recent outbreaks, consult the following resources.9 ProMEDmail (http://www.promedmail.org) is the best source for up-to-the-minute information from around the world. Sign up for e-mail alerts. 9 The Clinician Registry for Terrorism and Emergency Response Update ( http : //www. bt. cdc. gov/clinregistry/index.asp ) delivers timely e-mails on emergent issues, including infectious diseases, from a CDC service. We would like to thank Daphne Henry for her patience, editing, and enhancing the readability of this chapter by providing the quote from Ernest Hemingway, as well as historical information for the SARS section. We would also like to thank William Hogan and Marian Pokrywka ICP for assistance with outbreak descriptions.