12.1 Background
Initial detection of outbreaks
An outbreak is an epidemic or upsurge of cases in a defined geographic region or easily defined subpopulation. Outbreaks come to the attention of public health agencies in two primary ways: either through surveillance systems or by notification of public health departments by citizens or health care providers.
Epidemiologic surveillance systems are organizations and structures set in place to collect and analyze outcome-specific health data. Surveillance systems are distinguished by their practicability, uniformity, and rapidity at which they receive and process information. As a result, information from surveillance systems is often limited in scope, and often requiring supplementation. (See Section 4.1 for additional background on surveillance systems). The other way to become aware of an outbreak is by direct notification by an affected individual, their family, or their care givers. See Illustrative Example 4.1 for a discussion about the initial detection of HIV/AIDS.
The decision whether to mount an investigation of an apparent outbreak is based on the numerous factors, including: (a) the ability to confirm that the observed number of cases is significantly greater than expected, (b) the scale and severity of the outbreak, (c) whether the outbreak disproportionally affects an identifiable subgroup, (d) the potential for spread, (e) political and public relations considerations, and (f) availability of resources. Ultimately, the decision comes down to the authorities at the local health department made in consultation with the Centers for Disease Control and Prevention or other comparable agency outside of the United States.
The responsibility of investigating outbreaks usually falls on the shoulders of the local county or city health department. However, if the investigation requires additional resources, attracts substantial public concern, or is associated with a high attack rate and serious complications (hospitalization or death), state and federal agencies are called in. Outbreaks of national importance are investigated by the CDC. In fulfillment of this responsibility, the CDC has prepared excellent outbreak investigation training materials. Much of the remaining discussion in this chapter is based on these materials.
Goals and methods of outbreak investigations
Outbreak investigations have both diagnostic and directed action components. The objectives of the investigation may include:
- To assess the range and extent of the outbreak.
- To reduce the number of cases associated with the outbreak by identifying and eliminating the source of the problem.
- To identify new disease syndromes.
- To identify new causes of known disease syndromes.
- To assess the efficacy of currently employed prevention strategies.
- To address liability concerns.
- To train epidemiologists.
- To provide for good public relations and educate the public.
To successfully conduct any type of epidemiologic investigation, Evans (1982, p. 7) offers these helpful actions:
The CDC (1992a) prescribes these specific steps:
The CDC prescribed steps are discussed in the next section.
12.2 CDC prescribed investigatory steps
Step 1: Prepare for field work
Preparation for an investigation includes completing the administrative and personal measures required to begin the inquiry. Travel preparations must be made, supplies and equipment readied, knowledge updated, and administrative and scientific contacts established. Investigators must have a clear understanding of their role in the field and must know the chain of authority involved in the process.
Step 2: Establish the existence of an outbreak
The task of verifying an outbreak is made simple if a common cause can be identified (as might be expected with food-borne illnesses). When this is the case, mechanisms of transmission and means of control will be known, allowing for routine and rapid completion of the investigation.
However, when a common cause cannot be initially identified, the suspected outbreak must be first confirmed. In so doing, the first step in establishing the existence of an outbreak is to confirm that the reported cases actually have the disease that is being reported. After confirming each case using standard diagnostic criteria, the observed rate of occurrence is compared with that which is normally expected. Rates in the absence of an outbreak can often be gleaned from national surveys, special registries (e.g., cancer or birth defect registries), data from neighboring states, and from the published literature. In addressing this issue, the epidemiologist compares the observed number of cases with that which is expected under normal conditions. The comparison must account for random fluctuations in occurrence (see Sections 19.2 and 19.3). It must also account for seasonal variation (e.g., see Figure 4.8) and other phenomena that could conceivably increase the reported number of cases without a concommitent true increase in occurrence in the population. This includes:
Steps 3 and 4: Verify diagnoses of cases and search for additional cases
If the existance of the outbreak is verified, the next task is to review the existing cases and search for additional cases using a standardized case definition. The case definition is the set of standardized criteria used to decide whether an individual should be classified as having the disease in question or not.
The investigation team searches for previously unidentified cases in local hospitals and clinics that are likely to treat cases. In addition, they may screen data in clinical laboratories that are likely to diagnose cases. It often proves useful to directly question those individuals who might treat or encounter the disease. For example, in studying a disease of the blood, the investigator might query hematologists and laboratory personnel who treat or study the disease; in studying neoplastic diseases, the investigator questions oncologists, cancer clinics, cancer support groups, and other people likely to encounter prospective cases. Because direct inquiry may require a fair amount of walking about, it has traditionally been called “shoe-leather” epidemiology. Additional cases may be discovered by issuing a plea for reports through a media appeal or by direct requests for information to physicians. Note, however, that blanket requests such as these may elicit duplicate reports, false-positives, reports of old cases irrelevant to the current outbreak, and other dubious information.
Step 5: Conduct descriptive epidemiologic studies
Descriptive epidemiology is used to explore the general pattern of disease in the affected population. Descriptive epidemiology has the following objectives:
- to learn about the range and extent of the outbreak;
- to assess the possible source of exposure, mode of transmission, incubation period, environmental contributors, host risk factors, and agent characteristics;
- to generate hypotheses about the outbreak.
To begin the process of describing the outbreak, the following information is collected:
- case identification information (name, address, telephone number, and other information that will allow investigators to contact the subjects for notification or follow-up purposes);
- demographic information (age, sex, race, occupation, and other “person” factors that allow for the description of rates);
- clinical information (time of disease onset, time of exposure to the etiologic agent, signs, symptoms, and test results as are relevant to the case definition);
- risk factor information (relevant exposures and extraneous factors that might influence the occurrence of disease, specific items must be tailored to the disease in question);
- reporter information (to allow for further questioning and follow-up, if needed);
- denominator data (census and ad hoc information that might provide reasonable estimates of denominators for prevalence and incidence calculations).
After the data are entered into a database and assessedf for quality and completeness, the investigator describes the outbreak according to epidemiologic variables of time, place, and person. Although principles of descriptive epidemiology have already been considered in Chapter 4, a brief review relevant to outbreak investigation is in order.
Time
An important component of the investigation is the epidemic curve. The y axis of an epidemic curve represents the number (or percentage) of cases. The x axis represents a time line. When drawing the curve, the x axis should begin before the epidemic period and extend to the period after the epidemic is over.
Epidemic curves provide pictorial insights into the source of exposure, the nature of the epidemic (e.g., whether it is a point source epidemic or propagating epidemic), and the future course of the epidemic.
The incubation period of an agent is the time between exposure to the agent and appearance of first signs or symptoms of disease. This period varies considerably by the type of agent, level of exposure, and susceptibility of the host. If the probable time of exposure to the agent is known, the incubation period can be summarized with descriptive statistics, such as the minimum, maximum, and average. The average incubation can be expressed as an arithmetic mean, geometric mean, median, and/or mode. Knowledge of the range and average incubation period is often helpful in identifying the type of agent and its source.
Figure 12.1 exhibits an epidemic curve for an outbreak of hepatitis B in which exposure was from drinking uncholorinated water at a school. Because the exact date of exposure could not be determined, the investigators were able to back-calculate the most likely period of exposure based on the typical one month incubation period of the disease. This yielded a date that was consistent with the period during which water supply at the school was not cholorinated.
Figure 12.1 Epidemic curve, hepatitis A outbreak, Colbert County, Alabama, 1972. (Source: CDC, 1992a, p. 367.).
Epidemic curves are also useful for predicting the future temporal course of an epidemic. For example, Figure 12.2 shows an epidemic curve for famous 1854 Golden Square (Broad Street pump) cholera epidemic investigated by John Snow (see Section 1.4). Ironically, this graph suggests that removal of the handle from the Broad Street pump had little to do with ending this notorious outbreak, thus contradicting the folklore surrounding this decisive (and largely symbolic) act. Sir A. Bradford Hill (1955) eloquently describes the course of events:
Though conceivably there might have been a second peak in the curve, and though almost certainly some more deaths would have occurred if the pump handle had remained in situ, it is clear that the end of the epidemic was not dramatically determined by its removal. (p. 1010)
John Snow (1855), himself, recognized that the epidemic might have burned itself out before the pump handle was removed.
… but the attacks had so far diminished before the use of the water was stopped, that it is impossible to decide whether the well still contained the cholera poison in an active state, or whether, from some cause, the water had become free from it. (pp. 51–52)
The shape of the epidemic curve is useful in determining the type of epidemic in question. Point-source epidemics are caused by exposure to the agent from a single source over a brief period of time. When this is the case, the epidemic exhibits a sudden rise followed by a rapid falloff (Figure 4.6c). Propagating epidemics depend on serial propagation from host to host, or possibly continuous exposure from a single source, and thus exhibit a plateau or continual rise in the number of cases (Figure 4.6d).
Place
Mapping cases according to their place of origin may provide supporting evidence about transmission of the agent responsible for the outbreak. Epidemic maps may take the form of simple dot maps indicating location of origin or maps or area-specific rates.
Dot maps serve to document the geographic extent of the problem and can provide evidence of clustering. Snow’s celebrated map of clustering of cholera deaths around the Broad Street pump (Figure 1.13) provides a well-known historical example. By combining the mapping of cases with other sources of information, John Snow was able to support his theory of the waterborne transmission of cholera.
When the populations in the areas being compared are of unequal size, dot maps can be misleading. To compensate for this inherent weakness of dot maps, the epidemiologist will map rates by region. One such map of an Ebola virus outbreak is shown as Figure 12.3. This figure displays Ebola attack rates per 100 inhabitants in the epidemic zone. The highest attack rates are centered around Yambuku, Zaire, the town where the mission hospital was located. Decreasing attack rates with increasing distance from the hospital supported a hypothesis of iatraogenic spread of the agent.
Person
Description of disease rates by person variables is useful in identifying high-risk groups. Examples of person factors relevant to outbreak investigation include demographic characteristics (age, sex, ethnicity), personal activities and practices (occupation, customs, leisure activities, religious activities, knowledge, attitudes, and beliefs), genetic predispositions, physiologic states (pregnancy, parity, distress, nutritional status), concurrent diseases, immune status, and marital status. At minimum, the frequency of disease should be described by age and sex. Other analyses according to person variables cater to the type of disease being investigated. For example, when investigating AIDS, the epidemiologist is interested in describing disease rates according to sexual practices, intravenous drug use, and exposures to blood transfusions and other biological products of human origin.
Step 6: Develop hypotheses
A hypothesis is a tentative explanation that accounts for a set of facts and that can be tested by further investigation. In the investigation of outbreaks, hypotheses should address the most likely source of exposure to the etiologic agent, the means of transmission, and the next steps in the investigation and future control measures.
Hypothesis generation involves a scientific knowledge of the facts and a bit of intuition. It begins when the first clues that an epidemic might exist come to light and continues until the investigation is complete. Hypothesis development requires an understanding of the disease process and population at risk. It is supported by discussions with patients, health-care providers, local public health officials, community activists, and other interested parties, and should include the review of all relevant clinical, epidemiologic, and laboratory information. In generating and developing hypotheses one should consider what is generally known about the disease, relevant clinical and laboratory findings, what patients say about the disease, and the the descriptive epidemiologic findings
Table 12.1 is a checklist that may be used when generating and developing hypotheses about outbreaks. When generating hypotheses, we search for common characteristics and notable exceptions.
Table 12.1 Hypothesis-generating checklist.
| 1. | Review what is known about the disease itself: | |
| Agent | Reservoir | |
| Mechanisms of transmission | Natural history of disease | |
| Clinical spectrum | Pathogenic mechanisms | |
| Known risk factors | Ecology of the agent | |
| 2. | Study clinical and laboratory findings: | |
| Review clinical and laboratory records (check and confirm accuracy) | ||
| Determine if specialized lab work is necessary (e.g., DNA “fingerprinting”) | ||
| Describe frequency of symptoms, signs, and test results among cases | ||
| 3. | Consider what patients and caregivers say: | |
| Determine potentially relevant exposures | Hear what they think about cause | |
| Gain additional insights into clinical features | See if they are aware of other cases | |
| Determine commonalities and differences in cases | ||
| 4. | Review descriptive epidemiology: | |
| Epidemic curve and pattern | Geographic distribution | |
| Incubation period statistics | Significant host risk factors | |
| Events occurring around the most likely period of exposure for each case | ||
| 5. | Ruminate facts: | |
| Deduction | Intuition | |
| Analogy | Coherence | |
| Credibility of sources | Quality of information | |
| Missing keys and explanations | Exceptions and outliers | |
When searching for common characteristics, the objective is to search for specific exposures that have the strongest association with disease. This is normally done by calculating risk ratios or odds ratios. The exposure associated with the largest risk ratio or odds ratio is a prime suspect as the sources of the agent.
Important clues may also come from investigating notable exceptions. For example, we might investigate why certain people who were exposed to the putative agent did not become ill, and why apparently unexposed people did develope the illness. Such “outliers” can provide clues about the source of infection and mode of transmission. John Snow, in his classic 19th-century cholera investigations, used this technique repeatedly. For example, he pointed out the relative absence of fatal cholera cases in brewery workers living near the epidemic’s center (see Figure 1.13) and attributed this deficiency to avoidance of pump water. (The proprietor of the brewery believed his workers did not drink water at all and most certainly did not obtain water from the pump on the street.) Snow also noted a fatal case in a 59-year-old widow living outside the epidemic area and traced this to water transported from the pump. These notable exceptions provided strong clues in support of the waterborne theory of cholera transmission.
Steps 7 and 8: Evaluate hypotheses; as necessary, reconsider or refine hypotheses and conduct additional studies
Hypotheses developed in step 6 are re-examined, refined, and tested throughout the investigation. The process is iterative, cyclic, and self-correcting, requiring continual hypothesis refinement and testing. The usefulness of the epidemiologic investigation is often dictated by the clarity and quality of its underying hypotheses.
Causal hyoptheses can be tested using qualitative or quantitative methods, depending on underlying circumstances. Here is an example in which the causal hypothesis was solved with qualitative methods (CDC, 1992a, p. 375):
In an outbreak of hypervitaminosis D that occurred in Massachusetts in 1991, it was found that all the case-patients drank milk delivered to their homes by a local dairy. Therefore, investigators hypothesized that the dairy was the source and the milk was the vehicle. When they visited he dairy, they quickly recognized that the dairy was inadvertently adding far more than the recommended dose of vitamin D to the milk. No analytic epidemiology was really necessary to evaluate the basic hypotheses in this setting.
In other instance, quantitative epidemiologic investigations will be necessary to draw inferences about the etiology of the outbreak and source of exposure. Analytic studies may take the form cohort or case–control studies. The choice of a study design depends on whether the outbreak is ongoing or has been resolved, the availability of resources, past experience of the investigator, the size of the population at risk, the prevalence of the exposure, and the incidence of the disease. In general, small, well-circumscribed outbreaks in which the incidence of disease is high are well suited for cohort study. In contrast, outbreaks in large, poorly circumscribed populations in which the disease is rare may be better suited for case–control methods.
Laboratory and environmental studies are used to isolate causal agents from cases and from the environment. Environmental and sanitary conditions should be studied to help explain why the outbreak occurred in the first place and what might prevent it from happening again. Special laboratory tests (e.g., DNA, chemical, or immunologic fingerprinting) can occasionally be used to link the agent isolated from patients to specific environmental sites. When available, laboratory evidence can “clinch the findings” established by the epidemiologic investigation. Note, however, that since many outbreaks are investigated after the fact, collection of specimens may be precluded.
Step 9: Implement control and prevention measures
Two of the main objectives of outbreak investigation are to (a) bring the current epidemic to a halt and (b) to prevent future occurrences. Elements of disease control may be directed toward agent, host, or environmental factors. In foodborne outbreaks, for example, it is important to identify the initial point of contaimination, if possible. In some instances, this may require tracking the agent to its initial agricultural source. Remaining contaminated food should be discarded after specimens are collected for laboratory investigation. Food preparers should be educated on proper handling of food in terms of refrigeration, cooking, cooling, storage and serving techniques in order to prevent future occurrences.
Step 10: Communicate findings
The investigation is not complete until the results are disseminated to the public and the profession. Findings should be reported to initial informants, those involved in the investigation, local, state, and federal public health agencies, and the community of people affected by the outbreak. This is done in the form of oral briefings and written reports. Examples of the “what, why, when, how, where, and who” of reporting are summarized in Table 12.2.
Table 12.2 The “what, why, when, how, where, and who” of outbreak reporting.
| What: oral briefings |
| Why: to disseminate information and defend conclusions and recommendations, to promote good public relations, and to allow for constructive criticism |
| When: at the beginning and end of the investigation and whenever information for prevention and control comes to light |
| How: use scientifically objective language (avoid emotional terms), consider the audience (many people may not be epidemiologists), and explain epidemiologic principles and methods (avoid jargon) |
| Where: the appropriate venue is dictated by the audience; presentations should be given in the locality affected by the outbreak and at the sponsoring agency; findings can also be presented at regional and national professional conferences |
| Who: audience may vary but should include local, state, and federal authorities and people responsible for control and prevention measures |
| What: written reports |
| Why: to document the investigation, to disseminate information and defend conclusions and recommendations, to promote good professional relations, to increase credibility of the work, to allow for constructive criticism, to prevent future occurrences, and to add to the public health information base |
| When: at the conclusion of the investigation |
| How: use standard scientific reporting format with introduction, methods, results, discussion, (± recommendations); sponsoring agency may have additional reporting requirements |
| Where: internal documents should be filed with the local health department and all supporting agencies; if appropriate, a manuscript should be submitted to a general or discipline-specific peer-reviewed journal for publication |
| Who: audiences may vary but might include epidemiologists in training, field epidemiologists, and researchers in the discipline |
Review questions
R.12.1 What federal agency in the United States is primarily responsible for investigating outbreaks of national importance?
R.12.2 Multiple choice (M/C): Select the best response. The x axis of an epidemic curve represents: (a) the number of cases; (b) time since exposure or some other type of time line; (c) the percentage of cases; (d) responses a and c; or (e) all of the above.
R.12.3 M/C: The y axis of an epidemic curve represents: (a) the number of cases; (b) time since exposure; (c) the percentage of cases; (d) responses a and c; or (e) all of the above.
R.12.4 M/C. A notable exception to the observed pattern of occurrence is a(n): (a) outlier; (b) case; (c) control; and (d) exposure.
R.12.5 How do outbreaks come to the attention of public health authorities?
R.12.6 What is an epidemiologic surveillance system?
R.12.7 List four different phenomena that could cause an increase in the number of cases reported to a system without there being a true increase in the rate of occurrence.
R.12.8 The decision whether or not to investigate an outbreak depends on many factors. List several.
R.12.9 Descriptive epidemiology traditionally describes the occurrence of a condition according to three types of “epidemiologic variables”. Name these.
R.12.10 One of the first things to do when investigating an outbreak is to confirm the ___________ of prospective cases.
R.12.11 The observed number of cases is compared with the ___________ number to confirm the occurrence of an epidemic.
R.12.12 What does an epidemiologist mean when they refer to a “case definition”?
R.12.13 True or false? John Snow recognized that the outbreak of cholera in the Golden Square area that was associated with the Broad Street pump might have been burning itself out before the pump handle was removed.
R.12.14 Define “incubation period.”
R.12.15 What is a hypothesis?
R.12.16 True or false? Hypothesis development requires an understanding of the disease process and population at risk
R.12.17 When communicating the findings of an outbreak investigation, we address the ‘who, what, where, when, ___________, and ______________ of what we discovered.
References
Centers for Disease Control and Prevention (CDC) (1992a) Principles of Epidemiology: Self-study Course 3030-G, 2nd edn, U.S. Department of Health and Human Services, Atlanta. GA.
Centers for Disease Control and Prevention (CDC) (1992b) An Outbreak of Hemorrhagic Fever in Africa, 1992 EIS Course, Association of Teachers of Preventive Medicine, Washington, DC.
Evans, A.S. (1982) Epidemiological concepts and methods, in Viral Infections of Humans. Epidemiology and Control (ed. A.S. Evans) Plenum Medical Book Company; New York, pp. 3–42.
Hill, A.B. (1955) Snow—an appreciation. Proceedings of the Royal Society of Medicine, 48, 1008–1012.
Lilienfeld, A.M. (1976) Foundation of Epidemiology, Oxford University Press, New York.
Snow, J. (1936). Snow on Cholera, The Commonwealth Fund, New York. (Originally published as On the Mode of Communication of Cholera in 1855.)
Chapter addendum 1 (case study)
Drug–disease outbreak
Author: Joyce Murat Piper
Background
As your first assignment working for the U.S. Food and Drug Administration (FDA), you are to act as an epidemiologic consultant to the division that reviews and approves the use of endocrinologic and metabolic drugs. One day in late February (1985), a medical officer from the reviewing division comes to you with an unusual problem and asks for your help. The medical officer has just received a report of the death of a 20-year old man with Creutzfeldt–Jakob disease (CJD). It is noted that this case received human growth hormone (hGH) for 13 years as a child, between the ages of 3 and 16 (from 1966 to 1980). You note that hGH is used to prevent pituitary dwarfism when given during the growth years.
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