Analysis of disease occurrence by person, place, and time is used to deter- mine whether an outbreak or epidemic is occurring. A disease outbreak is the occurrence of cases of disease in excess of what would normally be expected in a given area or among a specific group of people.38 Outbreaks are synonymous with epidemics, though the former often describes a localized as opposed to a widespread epidemic.39 Additionally, though infectious disease outbreaks are most common, outbreaks may also be from noninfectious causes. Determining what is “in excess of normal”
varies by disease, season, and area, and there is no hard-and-fast rule for defining an outbreak. As an example, the World Health Organization (WHO) defines the occurrence of three or more confirmed measles cases in a population of 100,000 in a month as a confirmed outbreak in the United States.40 Alternatively, for influenza, the U.S. Centers for Disease Control and Prevention (CDC) calculates the typical proportion of pneu- monia and influenza deaths during a season and defines an epidemic as an increase of 1.645 standard deviations above this typical level.41
Outbreak investigations are an essential and challenging activity of epidemiologists that helps identify the source of ongoing outbreaks and prevent new ones. Even if an outbreak is over by the time an investigation begins, it is still valuable for developing strategies to prevent future ones.
Outbreaks are often recognized by a clinician or clinical laboratory worker who notices an unusual disease or a sudden increase in a disease and alerts public health officials. Increasingly, Internet surveillance has contributed to the early identification of disease outbreaks, including
searches of global media sources such as news wires. The WHO Global Outbreak Alert and Response Network relies on these data for day- to- day surveillance activities. According to the WHO, more than 60% of initial outbreak reports come from unofficial sources and require verifi- cation.42 The usefulness of these aggregator networks was demonstrated in 2002 when Health Canada’s Global Public Health Intelligence Network identified the outbreak of severe acute respiratory syndrome (SARS) in Guangdong Province, China, more than 2 months before the WHO released details on the new disease.43
The general approach to conducting an outbreak investigation is described below. After initial recognition of an outbreak, a thorough investigation includes (1) formulating case definitions, (2) conducting case confirmation, (3) establishing the background rate of disease and finding cases, (4) examining the descriptive epidemiology of the out- break cases, (5) generating and testing hypotheses about the causes of the outbreak, (6) collecting and testing environmental samples, (7) imple- menting control measures, and (8) interacting with the press and public to disseminate information.44,45
Case definition and confirmation: In many outbreak investigations, multiple case definitions are used. For example, cases from an outbreak of gastroenteritis caused by Salmonella infection may be defined using a culture-confirmed infection with Salmonella for the laboratory case definition and new onset of diarrhea for the clinical case definition.44 For an emergent disease with an unknown range of clinical manifestations, however, defining a case may be more complicated. Often, establish- ing a case definition is a fine balance between crafting a simple defini- tion and ensuring there are enough cases available for the investigation while also maintaining strict enough exclusion criteria to reduce the chance of including cases of unrelated illness as outbreak-related cases.
For example, the WHO uses the following criteria for defining a case of measles. A clinically confirmed case is (1) any person with fever and a nonvesicular rash and either a cough, runny nose, or conjunctivitis or (2) any person in whom the clinician suspects measles because of his or her exposure history. (For example, the person may be a close contact of a confirmed measles case.) In addition, a laboratory-confirmed case is a person with a positive blood test for measles-specific antibodies.40 Of course, one would have the most confidence in the accuracy of cases defined by both clinical and laboratory criteria. In many outbreaks, case confirmation is also necessary given certain clinical findings may be from laboratory error. Case confirmation usually comprises detailed medical record review and discussion with healthcare providers, espe- cially when a new disease appears to be emerging.
Finding cases and background rate: Another essential element of out- break investigation involves finding all cases in a given population (based on the case definition) over a specific time period before the outbreak began and using these cases to establish a background rate. This analysis should prove that the number of cases is truly in excess of what might
Disease Clusters and Epidemics 107
be expected based on the historical level of disease and can also help to define the geographic and temporal scope of the outbreak. Substan- tial effort is often required in outbreaks of new diseases to determine whether cases have gone unrecognized. An outbreak can also be difficult to identify when there are fluctuations in patient care-seeking behavior and access to care, provider referral patterns and test-ordering practices, diagnostic tests used by laboratories, and the prevalence of underlying immunosuppressive conditions or other characteristics of the population.
Descriptive epidemiology: These case finding and background rate generation exercises all contribute to the descriptive epidemiologic fea- tures of the outbreak. Investigators can plot an “epidemic curve,” with date or time of illness onset among cases along the x-axis and number of cases along the y-axis. From an epidemic curve, investigators may be able to discern the distribution of cases over time, an outbreak’s magnitude, pattern of spread, and most likely time of exposure.45(pp436-442)
The shape of an outbreak curve can also be used to make inferences about an outbreak’s most likely mode of transmission. In a point source outbreak, persons are exposed over a brief time to the same source, such as a single meal or an event. The number of cases rises rapidly to a peak and falls gradually. The majority of cases occur within one incubation period, that is, the time interval between infection and clinical onset of the disease (see FIGURE 5-2). On the other hand, in a continuous common source outbreak, persons are exposed to the same source but exposure is prolonged over a period of days, weeks, or longer. The epidemic curve rises gradually and might plateau. It eventually falls off when the expo- sure ends (see Figure 5-2). Finally, in a propagated outbreak, there is no common source because the outbreak spreads from person to person.
The epidemic graph will cycle through progressively taller peaks that are often one incubation period apart (see Figure 5-2).
Generating and testing hypotheses: Extrapolations from the epidemic curve and examination of the characteristics of cases often lead inves- tigators to the next step in the investigation process: generating ideas about the cause of the outbreak. Generating these ideas is challenging when the cause of an outbreak is entirely unknown and even in those instances when the cause seems relatively obvious. In 2014 for instance, 864 foodborne disease outbreaks were recorded by the CDC. These out- breaks resulted in 13,246 illnesses and 21 deaths, but a single cause was confirmed in only 53% of outbreaks.46 A literature review can provide background for what is already known about a particular disease, but it is not always helpful in investigating new diseases or unsuspected sources of exposure. When a literature review and the descriptive epidemiology do not give rise to a definitive source or route of exposure, open-ended interviews of cases can be useful.
If the initial investigation finds no association between hypothe- sized source and risk of disease, several steps may be taken. First, it is essential to consider whether the number of cases was large enough to find an association. Second, the accuracy of the available information
concerning the exposures should be carefully considered. For example, generally, it is quite difficult to remember every food eaten in a day, espe- cially when that day is several weeks past. Finally, it is possible the true source of the outbreak was not investigated.
Environmental and/or laboratory investigation: When environmental exposures, such as contaminated food or water, are found to be the cause of an outbreak, laboratory testing of environmental samples is the ideal next step. The epidemiological, environmental, and laboratory arms of an investigation complement one another, and often environmental and laboratory testing confirm the source of an outbreak. In many cases, how- ever, it may be too late to collect such samples. For example, if the cause of an outbreak is contaminated food, the food source may no longer be
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FIGURE 5-2 Types of outbreak curves.
Time of Onset (Days) Point Source Outbreak
Continuous Common Source Outbreak
0 5 10 15 20 25
0 5 10 15 20 25
0 5 10 15 20 25 30
Number of Cases
Time of Onset (Days) 0
5 10 15 20 25 30
Number of Cases
0 0 2 4 6 8 10
Number of Cases
5 10
Time of Onset (Days) Propagated Outbreak
15 20 25
available, or if interventions have already been implemented to alter the environment, samples will be of little use. Even if an environmental sam- ple is obtained, many laboratory tools are not sensitive enough to detect a contaminant or, in the case of a new disease or exposure, laboratory methods or tests for the cause may not yet exist.47(pp463-464)
Control measures: Outbreak investigations require the timely imple- mentation of appropriate control and prevention measures to minimize further disease. Control measures are usually directed against one or more segments in the path from the exposure source to cases of disease that are amenable to intervention. For example, a product recall or processing plant shutdown after a foodborne outbreak targets the source of illness, bed nets block mosquitos carrying malaria from biting susceptible people, and flu vaccinations aim to increase a person’s defenses against illness.
The timing and nature of implementing such measures are complex.
Although results of the epidemiological investigation should guide imple- mentation of control measures, waiting for these results can delay preven- tion of exposure to a suspected source, making it difficult to defend from a public health perspective. Conversely, acting too quickly and harshly is also problematic considering control measures may have a negative effect on a given food product or restaurant, in the case of foodborne illnesses, or on the lives of individuals who may be unnecessarily quarantined in the case of infectious diseases. If an outbreak investigation is premised on incorrect information, there may also be damaging legal implications. Therefore, control measure implementation is often a balancing act between timely interventions to prevent further spread of disease and deferring action until accurate information regarding the source of disease is available.
Dissemination of information: Finally, media attention and public concern often become part of outbreak investigations, and dissemination of information to the public is critical. Sometimes, the media learn about incidents and reports on events as they unfold and before much is known about the disease or source of exposure. For example, in 2008, the Pub- lic Health Agency of Canada coordinated communication of a national response to an incident involving passengers on a train in northern Ontario. One death, one medical evacuation, and influenza-like illnesses had occurred on board the train, and the media reported the events live on television. It turned out that three unrelated health events had occurred, none of which posed an active public health threat.43 Even though media reports can be inaccurate, media outlets are a powerful means of sharing information about an investigation with the public and disseminating timely information about control measures.
▸ Ebola Outbreak and Its Investigation
The Ebola virus outbreaks in Central and West Africa have been among the most devastating infectious disease outbreaks in recent times. Fol- lowing, we describe the course of these outbreaks and the response of
the public health and medical communities. You will see that, even in the most difficult circumstances, investigators used the epidemiological principles described previously to identify the cause and mode of trans- mission and implement control measures.
Nzara, South Sudan, 1976: In 1976, the first Ebola virus outbreaks occurred in two remote villages in Central Africa, one in what is now Nzara, South Sudan (formerly Sudan), and the other in Yambuku, Democratic Republic of Congo (formerly Zaire).48-50 The first cases occurred in Nzara, where cotton factory workers were affected with an unknown and fatal disease. Though the early symptoms of Ebola virus are nonspecific—fever, muscle pain, severe headache, weakness, diar- rhea, vomiting, and abdominal pain—later stages of the disease are unique and often dramatic. Internal bleeding may cause broken capil- laries, which appear as a raised rash, and organ failure. The worst cases cause individuals to vomit blood, have bloody diarrhea, and bleed from their nose and mouth.48,49
In August 1976, one of the first cases was transferred to the district hospital of Maridi. Within 4 weeks, one-third of the 220 staff at the hospital had acquired infection and 41 died.48,51 At this time, the mode of transmis- sion of this disease was unknown, and therefore no effective form of infec- tion control was utilized. Before the disease was recognized, most wards of the hospital had hemorrhaging Ebola patients with no protective measures in place, and at the height of the epidemic, the hospital was in chaos. After the adoption of protective clothing, the number of cases declined in early October. A considerable increase in the number of cases was observed in late October and early November after protective clothing supplies ran out. By the time a WHO investigative team arrived in late October, there were almost no patients left in the Maridi district hospital, and very few nurses were reporting for duty. It was readily apparent to the community that the hospital was a prime source of the outbreak.48
The first step for the WHO and Sudanese outbreak investigators was to develop a case definition. The late-stage presentation of most cases was clinically unique; therefore, a case definition based on clinical signs or merely on the hospital physician’s judgment was deemed suf- ficient. Moreover, the causative agent of the disease was still unknown, and therefore a laboratory-confirmed case definition was not feasible.
Thus, investigators developed the following case definition: any person
“(1) having fever and headache lasting for at least 2 days with diarrhea or vomiting or chest pain; or (2) diagnosed by a physician in a hospital.”48
Given the sudden onset, rapid transmission, and deleterious effects of the disease, control measures were immediately necessary and imple- mented before a thorough epidemiological investigation was conducted.
The disease affected those in very close contact with patients with active disease, and therefore it was safe to postulate that the illness was infec- tious and spread by direct contact from person to person. Contact trac- ing was used to identify cases, leading to isolation of cases. Contact tracing involves finding everyone who has close contact with infected
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individuals and watching for signs of sickness for a given period of time.
If any of these contacts shows symptoms of the disease, they are isolated and cared for. Then, the process is repeated by tracing the contacts’ con- tacts.52 While in isolation, patients were cared for by hospital staff who had had the infection and had now fully recovered. Protective clothing and careful training regarding the use of protective clothing and its sub- sequent decontamination were provided.
A surveillance team of 30 individuals was dispatched to visit every home in Maridi to find active cases. Each case was reported to Sudanese officials, and an ambulance was sent to the house. Patients were per- suaded to enter the isolation wards at the hospital, though some refused.
In addition to tracing all active cases of infection, the surveillance teams sought out recovered cases, who were approached regarding the possi- bility of obtaining immune plasma. Within 3 weeks, blood samples had been obtained from 51 recovered individuals.
The high mortality rate and alarmingly high rate of infection among Maridi hospital staff left medical staff understandably reluctant to carry out any postmortem examinations. Two limited postmortem exams were carried out by WHO investigation team members, and tissues were removed for study. By the end of the outbreak in October, there were 284 cases and 151 deaths.48
Yambuku, Zaire, 1976: One month after the initial case presented with signs of infection in Sudan, a similar disease became apparent roughly 500 miles southwest of Maridi in Yambuku, Zaire. The first case in Zaire is believed to have been a 44-year-old teacher who sought treat- ment for what was thought to be malaria at Yambuku Mission Hospital on August 26, 1976. At least nine other cases occurred during the first week of September, all among people who had received treatment for other diseases at the outpatient clinic at the mission hospital.49
Two Zairean doctors who traveled to the Bumba region, the main epidemic area in northwest Zaire, containing Yambuku, diagnosed the illness as yellow fever. However, in addition to high fever, headache, and vomiting, the patients began to suffer violent hemorrhagic symp- toms, including extensive bleeding from the anal passage, nose, and mouth, symptoms quite unusual in yellow fever. With shocking rapidity, 11 of the 17 hospital workers died, and the hospital was forced to close on September 30. Specimens were collected and sent out to labs across the world, and within several weeks, three external labs discovered the new illness was similar to Marburg virus. In fact, one of the labs tested samples from the outbreak in Sudan, meaning three labs independently identified the same new virus that was the probable cause of two simul- taneous, deadly epidemics.
In mid-October, an International Commission was formed in Zaire by the Minister of Health to investigate the cause, clinical manifes- tations, and epidemiology of the new disease and to advise and assist with control measures. Implementation of several control measures occurred promptly within the outbreak investigation timeline, and the
entire Bumba Zone was quarantined in early October, just 2 days after the hospital closure. The quarantine was put into place so early largely because of the fear caused by such a grisly and devastating disease. The first visit by a commission subgroup to Yambuku almost did not occur because terrified pilots, having heard stories of birds dropping out of the sky, sick with fever, and of human bodies being found by the roadsides, at first refused to fly the team to the closest airfield in Bumba. Once they arrived in Yambuku, the team found the nuns of the mission and hospital had posted a sign around the guesthouse where they were sleeping that warned “anybody who passes this fence will die.”53(p38) They also found no effective communication between the isolated city of Yambuku and the capital city of Kinshasa. The mission hospital had little electricity, no diesel fuel, no functional laboratory, and no protective clothing for staff.
A report from the International Commission described the members’
work as being carried out “under circumstances which at times seemed to us those of a small war.”49 Applying the same case definition as used in Sudan, in just over a week, the team found a disconcerting number of cases and deaths from the disease across at least 20 villages.
The next step was for the investigative team to determine how the virus was moving from person to person—by air, in food, by direct con- tact, or spread by insects. The team members mapped out the number of infections in each village, piecing together data from their notes and interviews, and they were able to discern two key elements linking almost every victim of the epidemic. First, people were becoming ill after attend- ing funerals. Second, the outbreak was closely related to areas served by the mission hospital, with nearly every early case having attended the outpatient clinic a few days before becoming symptomatic. The team drew epidemic curves showing the number of cases by location, age, and gender and found that more women, particularly those between the ages of 18 and 25, were likely to have the disease.53(pp48-49) It turned out that many of the women in this age group were pregnant and had attended an antenatal clinic at the hospital. This provided an important clue as to the mode of transmission.
Pregnant women in Yambuku attended the mission hospital where nuns administered vitamin shots reusing infected needles. If transmis- sion occurred through blood or bodily fluids, this explanation was com- patible with cases becoming ill after attending to their deceased relatives.
As part of the funeral ritual, cadavers were thoroughly cleaned, often by family members working bare-handed. The bodies of Ebola victims were usually covered in blood, feces, and vomit, and therefore any direct con- tact, such as washing or preparation of the deceased without protection, was a serious risk. Though it was difficult, investigators tried to convince locals not to attend to their diseased relatives. After this first visit, the Commission determined that mobilization of all available resources was necessary to cope with such a major threat.
The case definitions used for any future surveillance visits to Zairean villages were different from the definition created in Sudan. First, the
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