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FIGURE 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.

4.6. Cryptosporidiosis Outbreak (1993)

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., 1997,1998).

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 immune-competent 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).

4.8. Foot-and-Mouth Disease (2000)

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.

4.9. Severe Acute Respiratory Syndrome (2003)

When Johnny Chen1—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.

FIGURE 2.5 Chain of transmission among guests at Hotel M, Hong 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.

FIGURE 2.6 Photo of a Taiwanese emergency room taken several months after the end of the SARS outbreak.

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.

4.10. The Largest U.S. Food-borne Hepatitis A Outbreak (2003)

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.

4.11. Severe Acute Respiratory Syndrome (2004)

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 seventy-one 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.

FIGURE 2.7 Number of hepatitis A cases by date of eating at restaurant A and illness onset, Monaca, Pennsylvania, 2003. (From CDC, 2003a.) * N = 206. Excludes one case-patient whose illness onset date was not available. Dining dates for three persons who ate at Restaurant A on October 15 (n=one) and October 17 (n=two) are not shown.

FIGURE 2.7 Number of hepatitis A cases by date of eating at restaurant A and illness onset, Monaca, Pennsylvania, 2003. (From CDC, 2003a.) * N = 206. Excludes one case-patient whose illness onset date was not available. Dining dates for three persons who ate at Restaurant A on October 15 (n=one) and October 17 (n=two) are not shown.

FIGURE 2.8 Sample trace-back investigation. (From Food and Drug Administration, 2001.)

5. DEFINITIONS OF "OUTBREAK" AND "EPIDEMIC"_

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.

6. SUMMARY_

Microbial organisms know no 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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