1. Outbreak Investigation
Dr. Rajaa M. Al-Raddadi
MBBS,ABCM,RICR

2. Outbreaks: The basics Definition
Occurrence in a region/community of a disease/healthrelated event clearly in excess of normal expectancy
Relative to usual frequency
Goals of an outbreak investigation
To identify the source of illness
To guide public health intervention
Ways to recognize an outbreak
Routine surveillance activities
Reports from physician and laboratories

3. Why investigate an outbreak?
Characterize the problem
Extent, impact (including economic)
Identify preventable risk factors
New research insights into disease

4. Case Study

5. Initial Call
Late June, 2007: Calls from 4 Doctors reporting 6 patients with bloody diarrhea and E. coli O157:H7 infection
So what do you make of this?

6. Initial Call
Late June, 2007: Calls from 4 Doctors porting 6 patients with bloody diarrhea and E. coli O157:H7 infection
1 day later: Call from Department of preventive medicine in Jeddah
Increase in laboratory reports of E. coli O157:H7
June 2007 = 52
So what do you make of this?

7. Steps in Outbreak Investigation
1. Verify the Diagnosis

8. 1. Verify the Diagnosis
Escherichia coli O157:H7 first identified as a human pathogen in 1982 in the US
Sporadic infections and outbreaks since reported from many parts of the world (e.g., N. America, Western Europe, Australia, Asia, and Africa)
Cattle are the primary reservoir for E. coli O157:H7
Implicated foods are typically those derived from beef, hamburger, raw milk
Infection has also been transmitted through contact with infected persons, contaminated water, and other contaminated food products.
The first identification followed an outbreak of bloody diarrhea associated with contaminated hamburger meat.
Other animals are capable of carrying and transmitting the infection,

9. 1. Verify the Diagnosis
Infection with E. coli O157:H7 is diagnosed by detecting the bacterium in the stool.
Most laboratories that culture stool do not routinely test for E. coli O157:H7, but require a special request from the health care provider.
That’s what happened in the vast majority of these cases; tested because it was suspected.

10. Steps in Outbreak Investigation
1. Verify the Diagnosis

11. Steps in Outbreak Investigation
Verify the diagnosis
Confirm the outbreak

12. Trends in E. Coli O157 Cases
There were 52 cases in the current month of June compared with 18 the prior year.

13. What could account for the increase in cases?

14. What could account for the increase in cases?
Real increase
Increase in population size
Changes in population characteristics
Random variation
Outbreak
Artificial increase
New testing protocol
Changes in reporting procedures
Changes in population characteristics such that there are now more people at high risk
New testing protocol such that lab now testing for it when it hadn’t before

15. Initial Investigation
No substantial changes in population size
No appreciable changes in the population characteristics
No laboratory based changes
Surveillance / testing
Reporting protocol

16. Initial Investigation
Any other way to see if there is a relationship between these E. coli isolates?

17. Molecular Epidemiology
DNA fingerprinting
Pulsed Field Gel Electrophoresis (PFGE) most common in outbreak investigations
A cluster of isolates with the same PFGE pattern suggests they arose from the same parent (same source)
Still need an epidemiologic investigation

18. Steps in Outbreak Investigation
Verify the diagnosis
Confirm the outbreak

19. Steps in Outbreak Investigation
Verify the diagnosis
Confirm the outbreak
Case definition
Person, place, time

20. 3. Develop a Case Definition
Incubation period for E. coli O157:H7 ranges from 3-8 days with a median of 3-4 days.
The infection often causes severe bloody diarrhea and abdominal cramps, but can also cause a non-bloody diarrhea or result in no symptoms.
In some persons, particularly children under 5 years of age and the elderly, infection can be complicated by hemolytic uremic syndrome (occurs in about 2-7% of infections)

21. Case Definition?
A case definition is a standard set of criteria for deciding whether an individual should be classified as having the disease of interest.
A case definition includes clinical criteria (e.g., signs, symptoms, and laboratory tests) and restrictions on time, place, and person.

22. Case Definition 2. resident of Jeddah
Outbreak investigation definition:
1. diarrhea (>3 loose bowel movements a day) and/or abdominal cramps
2. resident of Jeddah
3. onset of symptoms between June 15 and July 15
4. stool culture yielding E. coli O157:H7 with the outbreak strain PFGE pattern.

23. Steps in Outbreak Investigation
Verify the diagnosis
Confirm the outbreak
Case definition

24. Steps in Outbreak Investigation
Verify the diagnosis
Confirm the outbreak
Case definition
Descriptive Epidemiology
Describe the person place and time of the outbreak

25. Characterization of Cases
Of the initial 38 persons who met the case definition, 26 (68%) were female with a median age of 31 years.
Table 1. Age group and gender distribution for persons with E. coli O157:H7 infection (with PFGE pattern), Jeddah, June 15 - July 15, (N=38)
SO what does this tell you?
You might to compare this to national data.

26. Cases

27. Epidemic Curve
Figure 1. Date of illness onset for persons with E. coli O157:H7 infection and the outbreak PFGE pattern, June 15 - July 15, (N=38)

28. Epidemic Curves How to set it up What it tells you
Mode of transmission
Propagated
Common source
Timing of exposure
Course of exposure

29. Epidemic Curve
Figure 2. Date of illness onset for persons with E. coli O157:H7 infection and the outbreak PFGE pattern, June 15 - July 15, (N=38)

30. Steps in Outbreak Investigation
Verify the diagnosis
Confirm the outbreak
Case definition
Descriptive epidemiology
Person, place, time

31. Steps in Outbreak Investigation
Verify the diagnosis
Confirm the outbreak
Case definition
Descriptive Epidemiology
Develop a hypothesis
Person, place, time

32. Developing a Hypothesis

33. Determining the Probable Period of Exposure
Mean/Median incubation period
Minimum/maximum incubation period

34. Estimating date of exposure
Peak
One incubation period
Rubella = 18 days
Probable time of exposure

35. Estimating date of exposure
Maximum incubation
21 days
Probable time of exposure
Minimum incubation
14 days

36. E. Coli Epidemic Curve
Figure 3. Average incubation period = 4 days ( range 3-8 days)

37. Findings
The median age of patients is 31 years (range 2-76); 68% of cases are among females.
Factors present in over 50% of cases:
Female, milk, hamburger, lettuce, alfalfa sprouts
water exposure?

38. Hypothesis?

39. Hypothesis of Investigators
Lettuce and/or parsley consumption is associated with E. coli infection

40. Steps in Outbreak Investigation
Verify the diagnosis
Confirm the outbreak
Case definition
Descriptive epidemiology
Develop a hypothesis

41. Steps in Outbreak Investigation
Verify the diagnosis
Confirm the outbreak
Case definition
Descriptive epidemiology
Develop a hypothesis
Test the hypothesis

42. Pick a Control Group
Controls should be individuals without the disease in question who are representative of the population from which the cases originated. In addition:
•controls should be at risk for the disease (i.e., they can develop the disease)
•controls (and cases) should have the potential for exposure to the risk factor of interest, and
•selection of controls (and cases) should be independent of their exposure status
In this outbreak, controls should be from the same communities as the cases. Controls should not have had symptoms suggestive of E. coli O157:H7 infection (i.e., diarrhea consisting of $3 unformed stools per day or bloody diarrhea) during the outbreak period.

43. Age group Sex Controls Selected
2 controls selected for every case
Matched to the case by:
Age group
(0-<2 years, 2-<5 years, 5-<12 years, 12-<18 years, 18-<60 years, and 60+ years)
Sex
Matching generally refers to a case-control study design in which controls are intentionally selected to be similar to cases on one or more characteristics. The characteristics most appropriately specified for matching are those which are potential confounders of the exposure-disease association of interest (e.g., age, gender, geographic area). By matching, the distribution of the selected characteristics will be identical among cases and controls and, therefore, will be eliminated as potential confounders in the analysis. Given the unique age and gender distribution of cases, it might be a good idea to match on these characteristics in the study design, but there are arguments for and against matching.
Advantages of matching:
Matching on factors such as neighborhood, friendship, or sibship (or even age and gender) may control for confounding by numerous social factors that would be otherwise impossible to measure and control.
•Matching may be cost- and time-efficient, facilitating enrollment of controls, when the control knows the case and, therefore, is more likely to participate.
•Appropriate matching increases statistical efficiency of an analysis and, thus, provides narrower confidence intervals.
Disadvantages of matching:
•Matching on a factor prevents one from examining its association with disease.
•Matching may be cost- and time-inefficient, if considerable work must be performed to identify appropriately matched controls.
•Matching on a factor that is not a confounder or having to discard cases because suitable controls could not be found decreases statistical efficiency and results in wider confidence intervals (i.e., decreases precision).
•Matching complicates analyses, particularly if confounders are present.

44. Selection of Controls
Exposure information among cases was collected for the 7 days before onset of illness.
For controls, exposure information was collected for the 7 days before the interview and for the 7 days before the onset of illness in the matching case.
Twenty-seven case-control sets were interviewed; the remaining case-patients could not be reached.

45. Interview Results

46. E. Coli and parsley?
Variable Cases Controls OR (95%CI)
15 (56%) 4 (7%) (4-528)
No other food item was significantly associated with
illness.

47. Steps in Outbreak Investigation
Verify the diagnosis
Confirm the outbreak
Case definition
Descriptive epidemiology
Develop a hypothesis
Test the hypothesis

48. Steps in Outbreak Investigation
Verify the diagnosis
Confirm the outbreak
Case definition
Descriptive epidemiology
Develop a hypothesis
Test the hypothesis
Refine hypothesis / Execute additional studies

49. Steps in Outbreak Investigation
Verify the diagnosis
Confirm the outbreak
Case definition
Descriptive epidemiology
Develop a hypothesis
Test the hypothesis
Refine hypothesis / Execute additional studies
Implement control and prevention measures
Person, place, time

50. Steps in Outbreak Investigation
Verify the diagnosis
Confirm the outbreak
Case definition
Descriptive epidemiology
Develop a hypothesis
Test the hypothesis
Refine hypothesis / Execute additional studies
Implement control and prevention measures
Communicate findings
Person, place, time

51. Conclusions
Importance of applying the multi-step approach in outbreak investigation
Utility of new subtyping methods such as PFGE
Importance of disease reporting
Flexibility of hypothesis generation
New vehicle for the transmission of E. coli O157:H7
Increasing geographic dissemination of outbreaks