KU Version March 2011
At the end of the case study, the scholar will be able to:
Identify the steps of the investigation of an outbreak;
Describe the characteristics of an outbreak in terms of time, place and person;
Use descriptive epidemiological data to generate hypotheses;
Use analytical epidemiological data to test hypotheses;
Formulate recommendations for the control of an outbreak.
Part A cluster of acute hepatitis in Provo, Utah
Provo is a large municipality located in the North of Utah, close from the border with Wyoming and Idaho. The population of Provo was 6,185 in year 1901. The city developed fast after World War II and some of the urbanization has been difficult to keep under control. In the late 1990s, the population size exceeded 100,000.
On 8 February 2004, a number of physicians from Provo, Utah, called the Assistant District Medical Officer (Public Health) to report large numbers of patients suffering from acute jaundice in the city. These practitioners reported that these cases of acute jaundice tended to cluster by households. At the same time, clinical laboratories established in the city of Provo reported a large number of specimen submitted for analysis with a working diagnosis of acute hepatitis.
On 9 February 2004, a team of public health workers and supervisors led by Dr Susan Swain, Field Epidemiologist reached the city of Provo to investigate the outbreak. On the day of the arrival of the team, 21 reports of acute jaundice had been received so far.
Question 1. A.
What are the key steps of the investigation of an outbreak?
Answer: According to the Centers of Disease Control and Prevention, following are the steps for investigation of an outbreak:
Preparing for the field work
Establishing the existence of the diagnosis
Verification of the diagnosis
Construction of a working case definition
Finding cases systematically and recording the information
Performing descriptive epidemiology
Epidemiological evaluation of the hypothesis
If required, reconsideration, refining and re evaluation of the hypotheses
Comparison and reconciliation between the environmental and laboratory studies
Implementation of the control and preventive measures
Initiation or maintenance of surveillance
Communicating the findings (Centers for Disease Control and Prevention, 2015)
Question 1. B.
Can the team determine whether or not they are dealing with an outbreak at this stage? What additional information would they need?
Answer: No, the team cannot determine whether they are dealing with an outbreak at this stage. There are only 21 cases that they have recorded. They need to verify the outbreak through laboratory investigations. Furthermore, they need to correlate the symptoms of the patients with each other. They need to know about the prevalence of the disease in the region every year and then they must compare with the current rate. They should investigate if the people who have been diagnosed with jaundice are migrants or they originally belong to that particular place.
Part Confirming the diagnosis
The steps of an outbreak investigation include (1) determining the existence of the outbreak, (2) confirming the diagnosis, (3) defining a case, (4) searching for cases, (5) using descriptive epidemiological data to generate hypotheses, (6) testing hypotheses using an analytical epidemiological study, (7) drawing conclusions, (8) comparing the findings with established facts, (9) communicating the findings and (10) executing prevention measures.
Reaching the field, the lead investigator and his team attempted to determine whether they were dealing with an outbreak or not. First, they checked that the population of the city had not changed recently because of massive population migration. The absence of such event reassured them about a change in the denominator. Second, they enquired about a potential recent change in the case definition or reporting mechanism. They could not find any artifact that would have lead to an increase in the numerator. Third, they enquired about the background rates of acute jaundice in the city and were told that under normal circumstances, about eight to 10 cases of such diseases were reported in the city each year. On the basis of these findings, they concluded that the outbreak was real.
When they arrived in Provo, the team went to the hospital to see some of the affected case-patients and discuss with the clinicians who had been managing them. They learned that patients presented with fever, malaise and then with acute jaundice. Urines were dark. All patients experienced severe symptoms and 36 presented signs and symptoms of fulminant liver failure. Five deaths occurred in February 2004. None of the patients had any history or signs of pre-existing chronic liver disease. Laboratory investigations conducted among some of the hospitalized patients indicated high levels of aminotransferases, Serum bilirubin, and alkaline phosphatase. Two case-patients who had been tested were negative for IgM antibodies to hepatitis A virus (HAV) and to the hepatitis B virus surface antigen (HBsAg).
What are the possible agents that could be causing this outbreak? For each, list the clinical and epidemiological elements that are compatible with the diagnosis and those that go against it.
Answer: The possible agents that can be the cause of the outbreak are:
Hepatitis A virus or HAV: Hepatitis A is seen to progress to liver failure or fulminant hepatitis in some patients. So it could be a cause of the same in the given case. But two patients tested negative for this, hence the diagnosis is not confirmed.
Hepatitis B or HBV: Like Hepatitis A, Hepatitis B is also known to cause liver failure (Clark, 2015). Hence it could be another agent leading to the severe condition of the patients. However, two patients reported negative tests, thus the diagnosis cannot be believed completely.
Hepatitis C or HCV: This form of hepatitis is known to result in maximum number of acute hepatic failure cases, more than the other two forms of hepatitis discussed above, however they are not known to cause outbreaks. But the test has not been conducted, so the diagnosis is doubtable (Davis, 2014).
Hepatitis E or HEV: This form of virus is known to cause outbreaks of the disease mainly in the developing countries. It can also result in fulminant hepatitis (Fujiwara et al., 2013).
Toxic substances: If all the above mentioned causes of the disease are found be non confirmatory, then it could be due to some toxic substances.
How would it be possible to confirm the diagnosis?
Answer: All the patients must undergo IgM test against HAV, HBsAg test for HBV and anti- HCV test to diagnose the cause. If all the tests are negative, then the cause could be toxic hepatitis in this case. There could be a probability that all the patients were exposed to some form of toxic substance that lead to the development of hepatitis in them. In order to confirm the diagnosis of toxic hepatitis, liver biopsy will be required (Mayo Clinic Staff, 2015). For hepatitis E the patients should be tested for specific IgG and IgM antibodies against Hepatitis E virus. If special laboratory facilities are available, then the patients may undergo RT- PCT test to detect the presence of Hepatitis E virus RNA in the blood or stool of the affected patients (World Health Organization, 2014). Drug induced hepatitis cannot lead to an outbreak. So it can be ruled out.
Part Defining cases
After reviewing the clinical information, the investigators listed the agents that could have caused this outbreak. This included viruses and toxic substances. A number of severe infections can lead febrile jaundice (e.g., leptospirosis, malaria), but the clinical picture was different in this case. The sequence of fever followed by jaundice is suggestive of viral hepatitis. Among viral hepatitis viruses, HAV is a real possibility and hepatitis A can lead to fulminant liver failure. However, high levels of herd immunity tend to make community-wide outbreaks uncommon in Utah. HBV or hepatitis D virus (HDV) could cause that kind of clinical picture, but large outbreaks in the community are uncommon. Acute hepatitis C virus (HCV) infection usually does not cause marked clinical symptoms, is not associated with fulminant liver failure and outbreaks in the community are uncommon. Hepatitis E virus infection can cause disease of that kind and may occur as large community wide outbreaks. The initial negative serological tests for HAV and HBV infection need to be checked but could suggest HEV as the causal agent.
The investigators are now about to look for cases so that they can describe the characteristics of the outbreak.
What kind of elements should be contained in a case definition?
Answer: A case definition should consist of the clinical criteria including the signs and symptoms of the disease, the time, place and persons involved (Principles of Epidemiology, 2015).
What case definition could be suggested to look for cases?
Answer: In this particular case, the case definition should consist of a) presence of skin discoloration & yellow discoloration of the urine b) Positive result for hepatitis E tests c) time of the symptoms should be after 25th of January 2004 d) the patient must be resident of Provo.
Part Searching for cases of acute hepatitis in Provo
During an outbreak investigation, a case definition should contain time, place and person criteria. Sometimes, case definitions may be formulated at various levels of sensitivity and specificity so that they can be used for different purposes. For examples, possible cases are used to screen patients or members of the population, probable cases are used for case finding and confirmed cases are used for analytical studies.
During the Provo investigation, the investigators decided to define a case as a combination of (1) loss of appetite with (2) yellow coloration of conjunctiva or colored urine that occurred suddenly since 19 January 2004 in a resident of Provo.
The investigators are now about to search for cases systematically in the city of Provo so that they can constitute their line listing and describe this outbreak in terms of time, place and person.
What are the potential options available to search for cases during an outbreak investigation?
Answer: The following options can be used to search for cases during an outbreak investigation:
Regular surveillance reports should be reviewed.
The local physicians should be asked to inform about the diagnosis of the disease as soon as they find someone suffering from the disease.
Emergency departments should be reviewed regularly in order to detect any one suffering from the disease
The groups that have been exposed to the disease should be reviewed
The physicians of that particular area should report any case that they may suspect to be related to the illness (Centers for Disease Control and Prevention, 2015).
What case finding strategy could be adapted to this specific situation?
Answer: All the people of the specific area must be examined for screening of the disease. The patients who exhibit the symptoms of the disease should undergo the confirmatory test for Hepatitis E virus or HEV. IgG or IgM antibody against Hepatitis virus must be tested.
What minimum information will be required for each case? How should this information be organized?
Answer: The patient should present with the symptoms of jaundice. He or she should test positive for HEV. He should be having the symptoms after 25th of January 2004 and must be a resident of Provo. The data should be organized in a tabular form along with the names of the patients indicated against the above mentioned criteria. The criteria should then be marked as ticked for the presence and crossed out for simultaneous absence of the same.
How would you analyze the data?
Answer: the data will give the number of affected patients in the area. It will help in determining the severity of the disease.
Part Using descriptive epidemiological findings to raise hypotheses
A number of case finding strategies may be used during an outbreak as long as they are applied uniformly in the whole population being investigated. This ensures that the strategy leads to the identification of cases that are representative of all cases. The simplest way to identify cases is to take cases passively reported through the surveillance system. The next option is stimulated passive surveillance, which consists in investigators reminding reporting units to notify cases through the routine surveillance system. If a more extensive search is needed, active surveillance may be used. In this case, investigators actively collect information from reporting sites or laboratories (e.g., through phone calls or visits). Finally, door-to-door case search is the most exhaustive option if resources are available and other mechanisms are potentially insufficient. During this outbreak, investigators conducted an active door-to-door case search in seven days with the help of 44 field workers and collected information regarding age, sex, date of onset, signs and symptoms and potential exposures.
The investigators have now completed the search that led to the identification of 538 cases among which five deaths for a population of 105,801 persons (attack rate: 5,1 per 1,000 population, case fatality ratio: 0.9%). They constructed a line-listing. They also completed a report with the descriptive epidemiology findings, by time (Figure 1), place (Figure 2) and person (Table 1). Interviews of the case-patients did not allow identifying any common events among them, but the environmental health specialists of the district mentioned that the workers involved with all the sources of water supply in the city had been on strike from 2 to 10 January on the same year.
Figure 1: Cases of acute hepatitis by week of onset, Provo, Utah, India. January-March 2004
Figure 2: Attack rate of acute hepatitis in the various areas of Provo municipality, Utah, February March 2004
How can the epidemiological information contained in these figures and this table be described?
Answer: The cases were recorder over a period of 35 days, ranging from 19th January 2004 to 23rd February 2004. Maximum numbers of cases were recorded in the mid of February. Also deaths occurred during the same phase, which shows the maximum severity of the disease at that time. The occurrence of the disease following the strike indicates the link between contaminated water and the disease occurrence. It is also evident that the areas which received water supply from the nearby underground water supply had more number of affected patients than the rest of the area. People in the age group of 15 to 44 years were the most affected, males showed a higher prevalence rate than the females.
How can this information be interpreted?
Answer: This information can be interpreted as the disease is the result of water borne infection which occurred following the strike, it affected the people from 15 to 44 years the most with a higher predilection for the males.
What are the potential hypotheses that could be generated on the basis of these data?
Answer: The hypothesis that can be formulated is that the disease is a result of the water borne infections that occurred following the strike by the officials.
How could these hypotheses be tested?
Answer: The hypothesis can be tested by examining the water for the presence of harmful contaminants. After this, the people should be suggested to drink purified or boiled water and then they should be examined for occurrence of the infection. Absence of infection would prove the hypothesis true.
Part An analytical study to test the main hypothesis
Cases were reported from 19 January to 1 March 2004 with a peak around the 14 February 2004. With respect to the geographical distribution, the incidence was higher in one part of the city that is close to a specific source of water supply for which water was pumped from the nearby river. In the rest of the city where the attack rate was lower, there were a number of sources of water all supplied with underground water. With respect to the attack rate by age and sex, there was a higher attack rate among persons from 15 to 44 years of age and a slightly higher attack rate among male.
The shape of the epidemic curve suggested a persisting common source outbreak. Given the incubation period for HEV infection (about one month), the exposure probably occurred early in January. The geographical distribution of the cases suggested a clustering around the source of water supply pumped from the riverbed. The attack rate by age and sex suggested that the exposure affected the whole population although young adults were at higher risk to develop symptoms. The timing of the strike among the employees of the municipal water system coincided with the probable time period during which the exposure took place. This led the team to investigate how the strike affected the source of water supply pumped from the riverbed. It turned out that (1) while the water pumped from the river was usually treated, the treatment was interrupted during the strike in January and (2) the distribution of this source of water supply corresponded to the distribution of the areas with higher attack rates in the city. None of the other hypothesis-generating interviews led to suspect any other event nor factor that could explain the outbreak.
At this stage of the investigation, the leading hypothesis was that the discontinuation of the water treatment during the strike of the employees of the municipal water supply system led to the supply of un-treated river water to the population between 2 to 10 January 2004, which led to the outbreak. The investigators have now decided to test this hypothesis in an analytical epidemiological study.
What are the options available to the investigators in terms of study design? Which one may be preferable? Why?
Answer: The investigators may go for case control study or cohort study. Both the studies are types of observational studies. But case control study should be the preferred study design as the numbers of affected people are quite less and for cohort studies a larger affected population is needed (Song & Chung, 2010).
What kind of study participants should be recruited for this study? What criteria should be used to select them?
Answer: The study should consist of two groups of people, the case and the control group. The case group should include the affected patients and the control group should be of those who are unaffected.
What kind of data should be collected among study participants?
Answer: These case and the control group patients should be asked about the source of water supply in their houses. These data then should be analyzed by dividing the number of people who are affected by drinking the contaminated water and the number of people who are not. And another would consist of the affected and unaffected people by drinking uncontaminated water.
Part Identifying the source of the outbreak
The investigators had the choice between a case-control study and a cohort study to test the main hypothesis of this outbreak. Because the incidence in the population was low, even in the parts of the city where the attack rate was at its highest, a case-control study was preferable. Thus, they decided to conduct a case control study in the city to compare cases and control in terms of their use of the suspected source of water supply.
The investigators used the case definition they had formulated at the case search stage for the case control study (See: Part 4. Searching for cases of acute hepatitis in Provo, Page 5). For the controls, they selected healthy persons from the general population at random in the various areas affected. Within each area, they selected as many controls as they were cases. Then, they used standardized questionnaires to collect information from case-patients and control-subjects about demographic characteristics and about the source of water they were using in the house.
The investigator have now completed their fieldwork and finished tabulating the data (Table 2).
How should the data be analyzed? What measure of association need to be calculated? How?
Answer: The data should be analyzed by odds ratio as the selected study design was case control study. Odds ratio is the “ratio of the odds of an exposure in the case group to the odds of an exposure in the control group” (Lewallen & Courtright, 1998). In the above mentioned case the confidence interval is not one. this shows that the occurrence is not by chance.
Question 7. B
Calculate the appropriate measure of association. How do you interpret the results?
Answer: By using the odds ratio, it can be said that there is some association between the contaminated water and the occurrence of the disease.
Question 7. C
Would you conduct additional investigations?
Answer: Further investigation if required, would consist of reconfirming the results with the help of the obtained data. Investigations should also be carried out to determine the water contaminants.
Part Examining this outbreak in the context of what is known of hepatitis E
Because the investigators made the choice to use a case control design, the appropriate measure of association to calculate for the analysis is the odds ratio. Applying the formula of the odds ratio to the 2x2 table generates an odds ratio of (493 x 404) / (45 x 134) which comes to 33. The 95% confidence interval of this odds ratio is spread from 23 to 47. Because it does not include one, it is reasonable to say that the association observed was not caused by chance. This result suggests that the null hypothesis – that there was no association between the pipeline water and hepatitis E - can be rejected.
Figure 3: Site where the river water was pumped for the supply to the city, Provo, 2004
At this stage, it is necessary to better document the circumstances that may have led to the contamination of the water. The investigators enquired about the normal treatment that is applied to the river water after pumping (Figure 3) before distribution. They learned therefore from the water supply department of the city that under normal conditions, the water from the river goes through a process that includes flocculation, sedimentation, rapid graded filtration and chlorination.
Question 8. A
Are the results of this investigation compatible with what was already known about hepatitis E outbreaks?
Answer: Yes, the results are compatible. Hepatitis E is believed to cause outbreaks by spread through water (Hepatitis Australia, 2013) .
Question 8. B
Did we learn new features of hepatitis E through this outbreak investigation?
Answer: Yes. We learned that chlorination alone is not sufficient to remove contamination water. Added steps of filtration are required in order to make the water suitable for human consumption. Also it was clear from the outbreak that there can be pathogens that can lead to Hepatitis E at places where they were never found before.
Part Communicating the findings
The conclusion of the investigation is that a large hepatitis E outbreak occurred in Provo, Utah, from February to March 2004. This outbreak was caused by the delivery of contaminated water to the population through the municipal water supply. The discontinuation of the water treatment during a strike of the employees of the municipal water supply system between 2 and 10 January 2004 lead to the supply of untreated surface water to the population. This conclusion is compatible with what is known of HEV, including its usual mode of transmission and incubation period.
The investigation of this outbreak adds to the knowledge about HEV. First, infections with this virus had never been reported in the State of Utah. Hence, this episode suggests that careful laboratory testing should be done during hepatitis outbreak to spot unusual pathogens. Second, the occurrence of the outbreak one incubation period after the window during which treatment was interrupted is compatible with the fact that the water treatment usually applied to the water was effective to some extend. To date, this evidence was not available. There was evidence that chlorination alone at the usual doses is not effective, but the fact that the combined steps applied in municipal water treatment plants may be effective is of practical public health interest.
At this stage, the investigation team needs to report back the results of the investigation.
Question 9. A
Answer: The investigation should first be reported to the public health managers. Then it should be reported to the epidemiologists or laboratory specialists followed by political leaders, the people of the community and the scientific community in the mentioned order.
Question 9. B
What do you expect of the various audiences to whom the results of this outbreak investigation will be reported?
Answer: the public health manager will provide recommendations to confirm that adequate actions are taken. The epidemiologists or the laboratory specialists will reconfirm the results at their levels. The political leaders will ensure that the disease is being tackled the way it should have been. The people of the community should know about the disease in order to take necessary steps to prevent themselves. The scientific community needs to know about the disease in order to help in the advancement of medical knowledge in the world.
Question 9. C
What media will you be using to reach each of these audiences?
Answer: The public health managers should be informed orally. The laboratory scientists and the epidemiologists should get the reports in the form of documented evidences containing the results of the investigation. The political leaders can be informed through summaries given by the public health managers or directly by the epidemiologists. The people of the community can be informed by press releases. Finally, the scientists can be informed by presentations or written manuscripts containing the required scientific evidences.
Question 9. D
What are should be the short term, medium term and long-term recommendations following this outbreak?
Answer: Short term recommendations can only include reassuring the community about the decline in the disease and that sufficient steps have been taken to ensure safety and proper health of the people. Medium term recommendations involve ensuring proper treatment of water before that reaches the houses of the general public. Long term recommendation will include ensuring a backup plan in case of such strikes among the officials again.
Question 9. E
What this outbreak investigated too late?
Answer: No, the investigation started as soon as the disease started flaring up. It could not have been done any earlier than this.
Part Epilogue: Executing prevention measures
Reporting the results of this investigation is important. Different audiences might need to be targeted according to the circumstances. First, the investigators should report to public health managers, preferably in the form of an oral briefing, so that the recommendations can be proposed to ensure that action is taken. Second, they should report to epidemiologist colleagues and laboratory specialist in the form of a report containing the epidemiological evidence that documents the conclusion of the investigation. Third, may need to report back to political or administrative leaders, either directly or through the local public health manager, in the form of talking points and / or a summary. This will be important for the authorities to understand that the situation is being handled, as it should. Fourth, they could have needed to report to the community through press releases and / or interviews health education message to help the public in taking active steps towards prevention. However, in the case of this investigation, the evidence was generated at a time when it was too late to usefully inform the public. Finally, the scientific community needs to know about this investigation through presentations and / or manuscripts containing new scientific information that may advance public health.
In terms of recommendation, the investigators did not make particular recommendations for the short term other than reassuring the population as the exposure has been discontinued. However, they took good care to avoid the spread of unnecessary measures that would not be supported by the evidence and that could direct the attention away from the real issues. For the medium term and long term, the investigators worked with the district health authorities to initiate a dialogue with the municipal water supply about (1) quality assurance measures that could ensure the continuous quality of the water supply and (2) the type of minimum service that could be put in place in the case of strikes.
This outbreak was investigated as soon as the report was made available. While a better surveillance system might have captured the outbreak earlier, none could have identified the cluster in time to do anything about the event that led to the exposure. Despite the impossibility to intervene in time on the source of infection, this investigation was useful in documenting a process by which prevention opportunities were missed. It also allowed knowing more about HEV and its epidemiology. It is never too late to investigate an outbreak, delays just make the problem slightly more difficult to solve.
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