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The differential diagnosis of a sudden, large increase in flulike illness includes the first 11 agents.

The differential diagnosis of a sudden, large increase in flulike illness includes the first 11 agents.

likely epidemiologically to be causing the illness. We discuss the full range of laboratory tests in Chapter 8.

The causative biological agent for some outbreaks is never found. Causative agents were not identifed for 16 outbreaks associated with burritos that affected approximately 1,700 individuals (CDC, 1999c). These outbreaks were eventually (epidemiologically) traced to two companies, resulting in the recall of two million pounds of burritos. In the study by Ashford et al. (2003), the causative biological agent was not found in 41 of the 1,099 (3.7%) investigations studied.

4.3.2. Characterizing the Disease

If the biological agent is unknown or if the disease itself is unusual in its presentation or severity, then characterizing the disease process becomes a priority for investigators. They will develop a working case definition, as was done by CDC and WHO for both AIDS and SARS, to enable additional case finding and to use in case-control studies. They will measure the incubation and infectious periods of the disease to bracket the period in which to search for causative factors and contacts.

Incubation Period. The incubation period is the time from infection of an individual to onset of clinical illness (Figure 3.9). The incubation period may vary from individual to individual based on health status and the dose of the biological agent to which the individual was exposed; therefore, investigators measure the average and range of the incubation period.

If the source or route of transmission of the infection is known, investigators measure the incubation period as the time from exposure to onset of symptoms. For contagious diseases, the time of exposure is the date at which an individual was exposed to an index case. For infections caused by contaminated materials, the time of exposure is the date that the contaminated material was ingested or otherwise entered the body of the victim.

The incubation period may provide a weak clue to the identity of the organism. Some classes of organisms such as HIV have long incubation periods.

Infectious Period. The infectious period is the time during the course of an individual's illness when he or she can transmit the disease to another individual. It usually does not provide a clue to the biological agent. Its importance is as a basis for developing guidelines for isolating infected individuals to prevent further infections. The beginning of the infectious period usually coincides with onset of symptoms because many diseases are transmitted by coughing, sneezing, diarrhea, or weeping skin lesions. There are exceptions, however, and the infectious period may begin before or after the onset of symptoms.

Investigators establish the beginning of the infectious period by analysis of dates of contact between infected individuals. In particular, investigators compare the dates of contact between an index case and the secondary cases that likely resulted from

FIGURE 3.9 Incubation and symptomatic periods for 10 cases of inhalational anthrax. The incubation period is the time from infection or exposure to onset of symptoms (white bars to the left of the vertical line denoting day of onset of symptoms). The symptomatic period is the time from onset of symptoms to recovery or death (bars to the right of the vertical line). The infectious period may begin before of after the onset of symptoms. The infectious period for anthrax ends when the host develops sufficient antibodies to clear the infection, when the infection is eradicated through treatment, or when the body is cremated (Jernigan et al., 2001).

FIGURE 3.9 Incubation and symptomatic periods for 10 cases of inhalational anthrax. The incubation period is the time from infection or exposure to onset of symptoms (white bars to the left of the vertical line denoting day of onset of symptoms). The symptomatic period is the time from onset of symptoms to recovery or death (bars to the right of the vertical line). The infectious period may begin before of after the onset of symptoms. The infectious period for anthrax ends when the host develops sufficient antibodies to clear the infection, when the infection is eradicated through treatment, or when the body is cremated (Jernigan et al., 2001).

contact with that index case. The beginning and end of the infectious period for an index case are roughly the dates when that individual starts and stops infecting other individuals, respectively. As with the incubation period, investigators compute the average and range of the infectious period over many cases.

Another method of establishing the end of the infectious period is laboratory testing for agent-specific antibodies. When antibodies appear, the person is usually no longer infectious.

The term source refers to the starting point in the path via which a biological agent is eventually conveyed into the body of a victim (Table 3.2). The source is critically important because removal or isolation of a source prevents further infections. In Hong Kong in 1997, an outbreak of avian influenza due to the H5N1 strain led to a small number of human cases with a high fatality rate. Fearing that the avian influenza would lead to a human pandemic, authorities sacrificed millions of chickens harboring the H5N1 strain (Sims et al., 2003).

There are many possible sources for outbreaks. The most common sources are food, water, other people, and animals.3 We note that the source is simply the starting point in a path of transmission. Investigations seek to understand the entire path because it may contain many points at which they can apply disease control measures. We also note that the source attributed to an outbreak may not be the ultimate source. For example, the nominal source of the hepatitis A outbreak described in Chapter 2 was green onions from farms in Mexico. The source of contamination of the green onions is unknown. Operationally, the search for a source ends when a common early point in the path of transmission of the disease is found at which control measures can be applied to halt the outbreak.

Sometimes a source is never identified. The source was never identified for three outbreaks involving group A rotavirus (CDC, 2000b), E. coli O111:H8 (CDC, 2000a), and Norwalk-like virus (CDC, 2000f). Table 3.3 provides examples of potential sources and routes of transmission for microbes.

4.3.4. Route of Transmission

The term route of transmission refers to the path that connects a source of biological agent to sick individuals.4 The route of transmission for the U.S. 2001 postal anthrax attack, for example, started in an unknown facility or facilities that manufactured the anthrax powder (the source) (Jernigan et al., 2002). Unknown individuals then transferred the powder into

TABLE 3.3 Examples of Sources and Routes of Transmission

Source

Route of

Transmission (Path)

Hosts

^ Terrorist ^ envelop ^ mail Postal workers, system ^ air recipients of mail, people in buildings in which envelops were opened

^ Green onions ^ food ^ system ^ restaurant Restaurant patrons ^ Contaminated ^ water treatment plant Consumers of tap source water ^ water distribution system water (reservoir)

Poultry ^ air ^ persons ^ air Close contacts of infected individuals

An arrow before the source means that there may be more proximate sources that remain unknown.

envelops and deposited them in mailboxes in or around Trenton, New Jersey. Mail sorting machines in postal processing and distribution centers compressed the envelops, thus expressing spores, which were sufficiently light to float in the air. The air carried the spores into the lungs of individuals working in the processing centers. After an incubation period, some of these individuals developed the disease inhalational anthrax. Postal workers delivered the envelopes to the addressees, who opened them, allowing the spores to float into the air in buildings. The addressees and other occupants of the buildings inhaled spores, and some developed inhalational anthrax. The spores infected the skin of other individuals, who developed the disease cutaneous anthrax. Investigators believe that cross-contamination of bulk mail resulted in a case of inhalational anthrax in a woman in rural Connecticut (Griffith et al., 2003). Figure 3.10 shows the route of transmission identified by investigators for the 2001 postal attack.

The final step in a route of transmission is always the point of entry into the host, which is biologically possible through only a finite number of entry points. Biological agents can enter humans (and other animals) through the respiratory tract (breathing or sniffing), the gastrointestinal tract (eating or per rectum), the skin, the eyes, sexual contact, medical procedures (surgical incision, transfusion, intubation), and non-medical intravenous injections.

In contrast, the paths by which a biological agent can arrive at an entry point of an individual are virtually infinite. They include the air, any water (bottled water, city water supply, temporary water supplies at public events, swimming pools, hot tubs, dental office water), any food, the mail, manufactured products,

3 The term reservoir is somewhat synonymous with source, although it only refers to sources in which an organism lives and multiplies. The human body is a reservoir for many viruses and bacteria as are animals. Bats are a reservoir for rabies, and sheep a reservoir for anthrax. Human diseases that have an animal reservoir are called zoonotic diseases.

4 Epidemiologists use the term 'route of transmission' or 'mode of transmission' to refer to generic transmission patterns such as airborne, sexual, person-to-person, and food borne. When characterizing an outbreak, however, the goal is to elucidate in detail the particular path by which biological agents 'travel' from a source to a host (host is the term for an individual who is sick).

FIGURE 3.10 Cases of anthrax associated with mailed paths of implicated envelopes and intended target sites. NY indicates New York;NBC, National Broadcasting Company; AMI, American Media; USPS, United States Postal Service; and CBS, Columbia Broadcasting System. *Envelope addressed to Senator Leahy, found unopened on November 16,2001, in a barrel of unopened mail sent to Capitol Hill. **Dotted line indicates intended path of envelope addressed to Senator Leahy. (From Jernigan et al., 2002.)

FIGURE 3.10 Cases of anthrax associated with mailed paths of implicated envelopes and intended target sites. NY indicates New York;NBC, National Broadcasting Company; AMI, American Media; USPS, United States Postal Service; and CBS, Columbia Broadcasting System. *Envelope addressed to Senator Leahy, found unopened on November 16,2001, in a barrel of unopened mail sent to Capitol Hill. **Dotted line indicates intended path of envelope addressed to Senator Leahy. (From Jernigan et al., 2002.)

legal drugs, illegal drugs, medical instruments (surgery, endoscopic examinations, intravenous lines), blood products, another person, or an animal (including insects, snakes, and fish). With the advent of bioterrorism, the path is limited only by the ingeniousness of man, as evidenced by the murder of the expatriate Bulgarian writer and broadcaster Georgi Ivanov Markov by the Bulgarian secret police, who used an umbrella tip to inject a tiny platinum ball filled with the toxin ricin (http://en.wikipedia.org/wiki/Georgi_Markov).

4.3.5. Methods to Elucidate Source and Route of Transmission

Elucidating the source and route of transmission may be labor and time intensive. For example, the investigation that elucidated the source of the listeriosis outbreak described earlier involved a case-control study of 17 cases conducted by five states, two local health departments, and the CDC to identify potential common sources. The root source—a supplier of processed deli meat—was identified by visiting 13 stores to identify the supplier that they had in common (CDC, 2000c).

Environmental Investigations. Much of the dramatic decrease in U.S. crude death rate in the early part of the 20th century can be attributed to sanitary improvements in water, food, and sewage management (CDC, 1999a). Outbreaks may result when these practices break down or are not adhered to.

An environmental investigation may examine water and food sanitation, underground water, surface water, agriculture, and domestic or wild animals. When there is reasonable possibility that a facility may be involved in an outbreak, investigators request that sanitarians conduct an inspection or review of a facility. Sanitarians (also known as environmental health specialists), using a body of science developed through the past century, routinely inspect and advise food service facilities and recreational and potable water facilities to ensure that environmental safeguards are in place to prevent outbreaks and a return to 19th-century rates of infectious diseases. The sanitarian can quickly determine whether the facility is operating with no violations or practices that would cause an outbreak. If stronger evidence becomes available that a facility or specific environment is involved, the investigators may initiate a more extensive environmental investigation (Massachusetts Department of Public Health, 2005a,b).

More generally, an environmental investigation, depending on the problem at hand, explores the environments that provide reservoirs where agents can reside and multiply. When the causative biological agent and the source are unknown, as was the case during the 1976 Legionnaire's outbreak, an environmental investigation can be far-ranging.

Food service inspection and investigation methods are well developed as the result of accumulated experience with thousands of foodborne outbreaks. Hazard analysis critical control point (HACCP) is a "science based method to identify or prevent hazards which contribute to foodborne disease" (Massachusetts Department of Public Health, 2005a). Critical control points include the appropriate heating and cooling of food. The value of the HACCP method is that it can identify likely points in a path of transmission well in advance of full characterization of an outbreak. A malfunctioning refrigerator, for example, is both a clue to the potential source of an outbreak (staphylococcus can elaborate a toxin, which is heat stable and therefore not neutralized by subsequent cooking) as well as a point for immediate correction to prevent future problems. If a specific food is implicated by survey methods or microbiological analysis, the sanitarian will look very carefully at food preparation steps.

The investigators of the 2001 anthrax outbreak conducted environmental investigations in postal processing and distribution centers, offices, and homes to determine the presence of Bacillus anthracis and the paths by which it spread. For the environmental investigation related to the most unusual case-the 94-year-old woman in Connecticut discussed earlier-specialists assessed the patient's activities in her home and searched for letters she received in the prior two months, in addition to conducting sampling in and on the periphery of her home by using swabs on surfaces and high-efficiency particu-late air vacuums (Griffith et al., 2003). Molecular sub typing identified the isolate from the 94-year-old woman as matching the isolates from the other anthrax patients infected through mail. The investigators did not find matching isolates in the woman's home or in any of the places she regularly visited.They did learn by going through her garbage that she regularly tore her bulk mail in half before discarding. And they found that bulk mail that was processed and delivered by her local mail distribution center had been processed in another post office in the 24 hours after heavily contaminated letters. Evidence that at least some of that bulk mail was cross-contaminated came when matching isolates were found on her local bulk mail processing machines. Investigators believe this woman's advanced age, medical condition, and habit of ripping junk mail in half before discarding it contributed to infection from a very low level of contamination of the mail she received.This explanation was the simplest and most biologically plausible.

The anthrax environmental investigations led to routine use of biohazard detection systems (BDSs) (Military Postal Service Agency, 2004) to identify mail contamination before mail distribution to the public.

Food Chain Investigation (Trace-Back and Trace-Forward).

When investigators suspect or find a contaminated food item (based on microbiological analysis of a sample of the food or as the result of a case-control study), they trace backward through the food supply to identify the root source of the contamination. The trace-back begins when a sanitarian collects information about a product or food item from the restaurant, consumer, or retail seller. The necessary information includes brand name, product name, code/lot number, expiration/sell by/use by date, size/weight, package type, date of purchase, manufacturer and address, distributor name and address, and retail food establishment where purchased or consumed (Massachusetts Department of Public Health, 2005).

The U.S. Food and Drug Administration (FDA) conducted a trace-back study that led to green onions grown on farms in Mexico as the source of the hepatitis A outbreak in Pennsylvania (CDC, 2003a). The FDA then conducted an environmental investigation at the farms: "The investigation team identified issues of concern from interviews and observations at all four firms visited including items such as poor sanitation, inadequate hand washing facilities, questions about worker health and hygiene, the quality of water used in the fields, packing sheds, and the making of ice, any of which can have a role in the spread of infectious diseases such as hepatitis A" (FDA, 2003).

The complexity of a trace-back is evident from Figure 3.11. The Public Health Security and Bioterrorism Preparedness and Response Act of 2002 (FDA, 2004) requires that food producers, retailers, and restaurants maintain records to facilitate trace-back investigations. We discuss these regulations in more detail in Chapter 10.

Trace-forward investigations similarly track a product through the supply chain, but they do so in the forward direction; that is, from a starting point that may have been discovered by the trace-back process through the distribution system to the consumer. U.S. Department of Agriculture (USDA) and other entities conduct trace-forward investigations to find and remove contaminated products before they are distributed to consumers. Trace-forward can also identify people who have already been exposed, who are sick, or who may already have recovered or died from the illness.

Readers interested in more details about food-chain investigation should consult The Guide to Trace Back of Fresh Fruits and Vegetables Implicated in Epidemiological Investigations at http://www.fda.gov/ora/inspect_ref/igs/epigde/epigde.html. An example of a trace-forward protocol used by the USDA (for a plant disease) is at http://www.aphis.usda.gov/ppq/ispm/ pramorum/pdf_files/traceforwardprotocol.pdf.

FIGURE 3.11 A hypothetical trace-back investigation involving four different points of service (POSs). POSs are restaurants or other retail stores (e.g., produce store) that sell or serve food or products believed to have caused an outbreak. In this example grower B was the ultimate source of produce for all four points of services. (From The Guide to Trace Back of Fresh Fruits and Vegetables Implicated in Epidemiological Investigations http://www.fda.gov/ora/inspect_ref/igs/epigde/epigde.html.)

FIGURE 3.11 A hypothetical trace-back investigation involving four different points of service (POSs). POSs are restaurants or other retail stores (e.g., produce store) that sell or serve food or products believed to have caused an outbreak. In this example grower B was the ultimate source of produce for all four points of services. (From The Guide to Trace Back of Fresh Fruits and Vegetables Implicated in Epidemiological Investigations http://www.fda.gov/ora/inspect_ref/igs/epigde/epigde.html.)

Vector Investigation. A vector is an animal that can transmit a disease to humans. Many vectors are insects that depend on specific ecological conditions for survival. If the biological agent causing an outbreak is known and if it is known to be associated with vector-based transmission, an investigator will interview the patients and ask questions related to exposure to vectors, insect bites, animal bites, use of prophylaxis such as antimalarial drugs, and travel history before onset of illness. If travel is involved, the investigator may consult CDC travel advisory documents for current information on levels of vector-borne disease around the world.

If investigators suspect an exposure to a vector as responsible for disease, they will consult with environmental health specialists to discuss methods to identify the vector habitat and control the vector, especially for prevalent vector-borne diseases such as malaria that have no vaccine. A full investigation of a vector-borne disease normally requires rapid exchange of data and information among a multidisciplinary team of environmental health specialists, veterinarians, and epidemiologists. Environmental health expertise is needed to understand the complex transmission cycles involving a number of vectors (and usually reservoir hosts) and complex environmental controls (World Resources Institute, 1998).

In the spring of 2002, an outbreak of monkeypox in humans produced 71 cases (Ashford et al., 2003). The investigation was initiated based on the report of a three-year-old girl with a history of a prairie dog bite. Investigators used sales invoices to link all cases to a shipment of 38 prairie dogs sold at pet stores or at a swap meet (it is often difficult for investigators to obtain invoices transacted at venues such as a swap meet). A trace-back investigation (Figure 3.12) elucidated the path by which monkeypox was introduced into the United States. A shipment of exotic rodents from Africa made its way via an importer in Texas to its final destination in the midwest. The rodents were colocated temporarily with a colony of prairie dogs. Once the original shipment was identified, trace-forward investigations identified additional animal vendors and owners who purchased prairie dogs during the time frame of the suspect shipment.

4.3.6. Number of People Ill and Number of Persons at Risk

Early during an investigation, the investigators have considerable uncertainty about the number of sick individuals in the population and the number that are infected but not yet symptomatic. The investigators may have very worrisome questions about whether they have enough investigators, vaccine, or antibiotics on hand to manage the outbreak, and they may worry whether their control measures are sufficiently aggressive.

They must estimate the true spatial distribution and true epidemic curve, based on the information available (current set of cases identified, contacts, and known outbreak characteristics). To do this, they must understand the limitations of the biosurveillance systems in place (e.g., the notifiable

Includes two persons *tio ware emplcyees atlL-1.

FIGURE 3.12 Result of a trace-back and trace-forward investigation of the 2003 Monkeypox outbreak. (From CDC,2003b.)

Includes two persons *tio ware emplcyees atlL-1.

FIGURE 3.12 Result of a trace-back and trace-forward investigation of the 2003 Monkeypox outbreak. (From CDC,2003b.)

disease system, any electronic laboratory reporting systems, and their screening procedures) and of their investigation. In particular, they must understand what fraction of cases their methods detect and what time delay may be present from date of infection. Their decision making related to logistics and control measures depends on an accurate assessment of both the state of the outbreak at the moment as well as projections of the future number of cases and their geographic distribution.

At present, the state of the art in real-time estimation of the magnitude and geographic scope of an outbreak is primitive. In current practice, investigators simply do their best to intensify surveillance to identify all cases so that the observed number of cases is as close to the real number of cases as possible. Any delays in case detection in the biosurveillance system compound the estimation problem. Mathematical models that can estimate the true parameters from observed parameters and knowledge of the delays and sampling efficiency of surveillance methods would likely be very useful, but this topic is an open area of research.

5. LEGAL, ETHICAL, AND PUBLIC RELATIONS ISSUES_

Although the immediate purpose of a field investigation is to characterize and control an outbreak, investigators are cognizant that outbreaks often generate legal proceedings (Gregg, 2002).5 Outbreak investigators and police investigators often talk to the same individuals and visit the same locations. They may even come into conflict over who gets to speak to an individual first or who has authority over a contaminated building. Police investigators depend on outbreak investigators for many of the clues that they need to identify and successfully prosecute the culprit. Biosurveillance systems must track chain of custody of evidence, especially in the laboratory. For these reasons, the public health workforce receives training in forensic epidemiology to handle legal issues that arise in the setting of joint investigations.

Investigators also must disclose information to the public about outbreaks. Ethical conduct of investigations includes the protection of individual information and confidentiality against disclosure of information (Coughlin and Beauchamp, 1996). Investigators understand that they depend on the public's trust to obtain cooperation and truthful answers to sensitive medical and behavioral questions in future investigations.

The public, politicians, and lawyers can influence the conduct of an investigation, especially investigations of outbreaks of a large number of people or in connection with sudden, mysterious illness with high mortality. The early HIV epidemic highlighted the complex bureaucracy and social agendas that come into play when an epidemic is investigated in an atmosphere charged with fear and prejudice (Shilts and Greider, 1987).

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