1. Detecting and Investigating Foodborne Outbreaks Ian Williams PhD, MS Chief, Outbreak Response and Prevention Branch Centers for Disease Control and Prevention, USA Dubai, February 2014

2. Objectives At the end of this lecture, you will be able to:  Describe how outbreaks are detected  Explain the steps in investigating an outbreak  Identify the necessary collaborators for an outbreak investigation, including epidemiologists, laboratorians, environmental health specialists, among others

3. Last meal bias: A common problem When people develop an enteric (diarrheal) illness that might be caused by food, most people think the last meal they ate is what made them sick This is not true in most instances, especially for bacterial pathogens (like salmonella) In a outbreak that is suspected to be related to food, it is important to understand and follow certain steps in the investigation Requires collaboration between laboratorians, epidemiologists, and environmental health specialists

4. Successful outbreak investigation depends on collaboration

5. Experts on surveillance and investigating illness in humans Experts on testing samples from humans and food Experts on food preparation and food production

6. What is an outbreak? The occurrence of cases of an illness clearly in excess of the normal expectancy Where you work, how are outbreaks detected?

7. Laboratory confirmed cases are the tip of the iceberg Lab-confirmed case reported

8. Laboratory- based surveillance Laboratory- based surveillance Pyramid (iceberg) of laboratory-based surveillance Person has symptoms Person goes to doctor Doctor requests sample Sample submitted to lab Lab identifies pathogen Lab-confirmed case reported Public complaints Syndromic surveillance Outbreak detection and interventions can occur at all levels

9. Is it an outbreak? Causes of an increased number of cases  Artificial increase  Change in lab methods  Change in reporting  Data entry errors  Real increase  Increased population size  Change in population characteristics  Random variation  Outbreak

10. Why investigate foodborne outbreaks? Immediate goal: prevent more illnesses from this outbreak Longer-term goals – identify pathogens that often cause outbreaks – identify food vehicles that often cause outbreaks – Identify common settings and contributing factors – identify gaps in the food safety system to take action to prevent future outbreaks and illnesses

11. Steps in investigating an outbreak 1. Detect the outbreak and assemble a team 2. Gather descriptive information 3. Generate hypotheses 4. Test hypotheses 5. Determine how and where contamination occurred 6. Prevent more illnesses 7. Communicate

13. Step 1. Detect the outbreak and assemble a team  Ways outbreaks are detected  informal reports, e.g., physician, ill persons, clinical laboratory  notifiable disease surveillance  laboratory-based surveillance subtyping results, e.g., Salmonella serotyping antibiotic resistance pattern pulsed-field gel electrophoresis (PFGE) phage typing Step 1: Detect the outbreak and assemble a team

14. Types of foodborne outbreaks Traditional Scenario  Cases clustered in time and space  Common meal or event  Result of food handling error New Scenario  Seemingly unlinked cases  Widely distributed foods  Foods with long shelf-life, or ready-to-eat, or that require no or little consumer handling Step 1: Detect the outbreak and assemble a team

15. Traditional scenario “point source” foodborne outbreak

16. New scenario “ongoing exposure” foodborne outbreak E. coli O157 outbreak Step 6: Prevent more Illnesses

17. Example: United States, 2009  On May 19, PulseNet identified 17 human Escherichia coli O157 isolates with a particular pulsed- field gel electrophoresis (PFGE) pattern uploaded in May  On average, 6 to 7 isolates with this pattern uploaded each month Step 1: Detect the outbreak and assemble a team

18. Shiga toxin-producing E. coli O157  Causes diarrhea, often bloody  can be severe in children and elderly  hemolytic uremic syndrome (HUS) is a complication causes kidney failure Usual food vehicles: ground beef, leafy greens, unpasteurized milk Step 1: Detect the outbreak and assemble a team

19. Assemble a team  Contact key groups  local, regional, national  laboratory, epidemiology, health inspectors, food regulators, communicators, clinicians, others  Determine responsibilities  collect and analyze data  implement control measures  communicate Step 1: Detect the outbreak and assemble a team

20. Successful outbreak investigation depends on collaboration

21. Steps in investigating an outbreak 1. Detect the outbreak and assemble a team 2. Gather descriptive information 3. Generate hypotheses 4. Test hypotheses 5. Determine how and where contamination occurred 6. Prevent more illnesses 7. Communicate

22. Step 2: Gather descriptive information 2a: Determine the etiology 2b: Describe the outbreak by time, place, and person 2c: Write a case definition 2d: Look for more cases The order of these steps can vary depending on the investigation

23. 2a: Determine the etiology  If the outbreak was detected by public complaint or syndromic surveillance, determine the etiology  use symptoms, incubation period, etc, to determine possible etiologies  decide which lab tests are needed (eg, bacterial stool culture)  collect specimens from ill persons and test them Step 2: Gather descriptive information. Step 2a: Determine the etiology

24. Food testing does not determine the etiology  Collect food samples for laboratory testing  IF preliminary data points to certain foods  epidemiologists, food regulatory authorities, and laboratorians discuss and then decide appropriate tests on food  be aware of limitations of food testing Do not expect to learn the etiology from laboratory testing of food! Do not delay investigation awaiting tests on food! Step 2: Gather descriptive information. Step 2a: Determine the etiology Talk to lab!

25. False negative tests of food Why might the lab not identify the etiologic agent in a food that caused the outbreak? Step 2: Gather descriptive information. Step 2a: Determine the etiology

26. Why the laboratory may not find the etiologic agent in food  Collection reasons  sample was improperly collected or transported  the actual food that caused illness was not sampled  Food reasons  all the food that caused illness was consumed  only some parts of the food were contaminated  the etiologic agent did not survive in the food  Lab reasons  the laboratory does not test for the agent  the lab test is not sensitive enough to detect the agent  there is no lab test for the agent Step 2: Gather descriptive information. Step 2a: Determine the etiology Talk to lab!

27. False positive tests of food Why might lab identify a pathogen in a food that did not cause the outbreak? Step 2: Gather descriptive information. Step 2a: Determine the etiology

28. False positive tests on food The lab may identify a pathogen that did not cause the outbreak  Food reasons  foods may be contaminated with pathogens unrelated to the outbreak  especially true for raw meat and poultry  Lab reasons: false positive results, errors In most diarrheal outbreaks, you will learn more by collecting specimens from ill people than from food Step 2: Gather descriptive information. Step 2a: Determine the etiology

29. Step 2: Gather descriptive information 2a: Determine the etiology 2b: Describe the outbreak by time, place, and person 2c: Write a case definition 2d: Look for more cases

30. Step 2b: Describe outbreak by time, place, person  When did the illnesses occur?  Where did illnesses occur?  Who was affected?  age, sex  symptoms and signs  number ill, hospitalized, died Step 2: Gather descriptive information. Step 2b: Describe by time, place, person

31. Step 2b: Describe outbreak by time, place, person  When did the illnesses occur?  Where did illnesses occur?  Who was affected?  age, sex  what were the symptoms and signs?  % hospitalized  % died Make a map Step 2: Gather descriptive information. Step 2b: Describe by time, place, person Draw an epidemic curve Summarize in a table

32. Epi curve made at start of investigation Step 2: Gather descriptive information. Step 2b: Describe by time, place, person

33. Map made at start of investigation Step 2: Gather descriptive information. Step 2b: Describe by time, place, person

34. Table of patient characteristics Step 2: Gather descriptive information. Step 2b: Describe by time, place, person Characteristicn (%)* Age < 19 years50 (66) Female53 (71) Median age (range): 15 years (2 – 65 years)

35. Step 2: Gather descriptive information 2a: Determine the etiology 2b: Describe the outbreak by time, place, and person 2c: Write a case definition 2d: Look for more cases

36. 2c: Write a case definition  Components: illness, pathogen, time, place  Case types: possible, probable, confirmed Step 2: Gather descriptive information. Step 2c: Write a case definition Include the lab in the discussion

37. Example: Confirmed case definition, US outbreak of E. coli O157 infections  E. coli O157 infection, and  PFGE pattern indistinguishable from outbreak strain, and  multi-locus variable-number tandem repeat analysis (MLVA) pattern indistinguishable from outbreak strain pattern and  illness began (or isolation date if date illness began is not available) on or after March 1, 2009 Step 2: Gather descriptive information. Step 2c: Write a case definition Talk to lab! Some outbreaks also have definitions for probable and possible cases

38. What is MLVA?  DNA sequence-based subtyping technique  During outbreak investigations  PFGE alone might not differentiate between outbreak-associated and unrelated cases  adding MLVA information can help Step 2: Gather descriptive information. Step 2c: Write a case definition

39. Step 2: Gather descriptive information 2a: Determine the etiology 2b: Describe the outbreak by time, place, and person 2c: Write a case definition 2d: Look for more cases

40.  Purpose of case finding  treat ill persons  prevent secondary cases  determine location and magnitude of outbreak  find clues about source Why does finding more cases increase the likelihood of a successful investigation? Step 2: Gather descriptive information. Step 2d: Look for more cases What can you do to find more cases?

41. 2d: Ways to look for more cases  Request information from health care providers  Review calls to health department from ill persons  Request information from clinical laboratories  Review notifiable disease reports to health department  Contact nearby health departments to see if they have similar illnesses  Assure strong communication between epidemiology and laboratory groups  In special circumstances, request information directly from the public, via the media Step 2: Gather descriptive information. Step 2d: Look for more cases

42. Steps in investigating an outbreak 1. Detect the outbreak and assemble a team 2. Gather descriptive information 3. Generate hypotheses 4. Test hypotheses 5. Determine how and where contamination occurred 6. Prevent more illnesses 7. Communicate

43. 3: Generate hypotheses  Promptly, thoroughly interview some cases to  identify common exposures  eliminate uncommon exposures  Alternative interview methods  one investigator conducts open-ended interviews with 5-10 ill persons, or  one or more investigators conduct interviews with some ill persons using a detailed “hypothesis-generating” questionnaire

44. Example: US outbreak of E. coli O157 infections First, used “hypothesis-generating” questionnaire to interview cases  several epidemiologists did interviews Step 3: Generate hypotheses Possible vehicles ground beef strawberries ice cream Unlikely vehicles spinach unpasteurized dairy animal contact Findings (no strong hypothesis emerged):

45. Example: US outbreak of E. coli O157 Infections Then, they tried a different approach  One investigator interviewed 5 people with recent illness from one state (Washington)  open-ended, conversational interviews conducted during June 13 - 16  asked about exposures during week before illness Step 3: Generate hypotheses

46. Open-ended interview results What patients reported:  5 of 5 ate ground beef  3 of 5 ate strawberries  5 of 5 ate raw cookie dough  4 of 5 ate Brand X raw cookie dough On June 16, presented these data to investigation group  Maryland, Iowa, Illinois, and Minnesota reported that patients they interviewed also ate raw cookie dough! Step 3: Generate hypotheses Raw cookie dough documented in notes from first interview

47. Finally, a hypothesis! Raw cookie dough as a vehicle?  some questioned biological plausibility  never before linked to E. coli outbreak Based on epidemiologic evidence, raw cookie dough became a leading hypothesis Step 3: Generate hypotheses

48. Steps in investigating an outbreak 1. Detect the outbreak and assemble a team 2. Gather descriptive information 3. Generate hypotheses 4. Test hypotheses 5. Determine how and where contamination occurred 6. Prevent more illnesses 7. Communicate

49. Step 4: Test hypotheses  4a: Gather data relevant to the hypothesis  4b: Design a study  4c: Analyze the study Do a study only after you have a strong hypothesis!

50. Step 4a. Gather data relevant to the hypothesis  Discuss possible steps with food safety agencies  For point source outbreaks, restaurant inspection history, etc.  For dispersed outbreaks, product distribution what regions of country, which stores could the product come from one factory?  Consider collecting data from patients  information on food packages  leftover food Step 4: Test hypothesis. Step 4a: Gather data relevant to hypothesis

51. Step 4b: Design a study  Basic strategy: compare exposures of ill and well persons  Two standard methods  Cohort study illness in a defined group interview everyone possible  Case-control study interview ill persons and similar well persons (controls)  Both methods use a standard questionnaire use hypothesis to decide what questions to ask Step 4: Test hypotheses. Step 4b: Design a study

52. Step 4b: Design a study Comparison groups to consider  persons who attended the event the ill persons attended  persons from the same community as the ill persons  persons previously interviewed in surveys of food consumption in the general population  persons with illness caused by the same pathogen who are not part of the outbreak  persons with illness caused by a different pathogen Step 4: Test hypotheses. Step 4b: Design a study

53. Step 4c: Analyze the study  Determine whether each exposure (food, water, etc.) is associated with illness  calculate the appropriate measure of effect for the study design (relative risk, odds ratio)  determine the statistical significance of results (95% confidence intervals, p-values)  interpret results in light of the power of the study  if the study is too small, findings may not be statistically significant Step 4: Test hypotheses. Step 4c: Analyze the study

54. Example: US outbreak of E. coli O157 infections  Hypothesis: Raw cookie dough was the source  Study design: case-control study  controls from health department databases of persons with other enteric illnesses  controls matched 1:1 on age, sex, and state of residence  questionnaire asked about 20 food items, including raw cookie dough, ground beef, and strawberries Step 4: Test hypotheses

55. Results: US outbreak of E. coli O157 Infections  94% (33/36) of cases but only 11% (4/37) controls ate raw cookie dough  matched odds ratio = 42.8 95% confidence interval 7.6 – ∞ p < 0.0001  No other exposure associated with illness Step 4: Test hypotheses

56. Other evidence implicating raw cookie dough  93% of patients who ate raw cookie dough ate Brand X  Brand X made by Company X, which produced only ~40% of U.S. market share of cookie dough  No cases in Canada  Company X did not ship Brand X to Canada Step 4: Test hypotheses

57. Really? Raw cookie dough? We learned that, although cookie dough is sold to be baked, some people, especially young girls, love to eat it raw!

58. Steps in investigating an outbreak 1. Detect the outbreak and assemble a team 2. Gather descriptive information 3. Generate hypotheses 4. Test hypotheses 5. Determine how and where contamination occurred 6. Prevent more illnesses 7. Communicate

59. Step 5: Determine how and where contamination occurred  Obtain details about implicated food  When and where prepared?  Where purchased, brand, lot number  Contaminated in the kitchen? cross-contamination by a food handler? inadequate cooking?  Contaminated before the kitchen? at the processing plant? on the farm?  Food regulatory authorities, environmental health specialists, epidemiologists, laboratorians (as needed) should discuss all findings

60. Step 5: Determine how and where contamination occurred  Trace the contamination back as far as possible  Talk to owners and employees  Examine invoices  Ensure that the inspection of facilities is directed at understanding the outbreak (that is, not like a routine inspection)  look for unrecognized problems in procedures  use epidemiologic information to guide facility investigation

61. Example: US outbreak of E. coli O157 Infections Product testing  State public health laboratories tested open packages from homes and unopened packages from stores  FDA tested finished product retained by Company X Step 5: Determine how and where contamination occurred

62. Cookie dough culture results  157 packages from stores: negative  2 packages from patient homes: non-O157 Shiga toxin-producing E. coli  Unopened package retained by Company X: E. coli O157  PFGE and MLVA patterns were different from outbreak strain Step 5: Determine how and where contamination occurred

63. Cookie dough ingredients Step 5: Determine how and where contamination occurred

64. Food facility inspections Food and Drug Administration (FDA) inspected Plant X and flour supplier  E. coli O157 not isolated from  cookie dough plant environment  cookie dough production line  Non-O157 Shiga toxin-producing E. coli isolated from flour mill Step 5: Determine how and where contamination occurred

65. Steps in investigating an outbreak 1. Detect the outbreak and assemble a team 2. Gather descriptive information 3. Generate hypotheses 4. Test hypotheses 5. Determine how and where contamination occurred 6. Prevent more illnesses 7. Communicate

66. Step 6: Prevent more illnesses  Institute short-term prevention  Institute long-term prevention  What questions remain unanswered?  What technological, regulatory, or human behavior changes would prevent future illnesses from this food?  Evaluate effectiveness of prevention measures

67. Short-term prevention Product recall  On June 18, CDC and FDA informed Company X about investigation  On June 19, Company X recalled all refrigerated cookie dough products  47 flavors  3.6 million packages Photo: Bill Keene, Oregon Department of Health Step 6: Prevent more Illnesses

68. Short-term prevention E. coli O157 Infections, by Week of Onset of Illness, March 1—July 31, 2009 (n=70)* *Onset date missing for 7 cases. Step 6: Prevent more Illnesses

69. Long-term prevention Company made a new label with more visible warning Before RecallAfter Recall Photos courtesy of Bill Keene, Oregon Department of Health Step 6: Prevent more Illnesses

70. Long-term prevention  After the outbreak was long over, Plant X continued to test product  on January 13, 2010, 2 samples of finished raw cookie dough tested positive for E. coli O157  none had been shipped  Company X switched to heat-treated flour Step 6: Prevent more Illnesses

71. Long-term prevention Step 6: Prevent more Illnesses

72. Successful outbreak investigation depends on collaboration

73. Steps in investigating an outbreak 1. Detect the outbreak and assemble a team 2. Gather descriptive information 3. Generate hypotheses 4. Test hypotheses 5. Determine how and where contamination occurred 6. Prevent more illnesses 7. Communicate

74. Step 7: Communicate  Needed throughout all steps!  During investigation  among all investigators, e.g., lab, epi, regulators  with stakeholders, e.g., press, health care providers, industry  After investigation  present findings at meetings  write a report  make practical recommendations  Report essential information to national outbreak surveillance Step 7: Communicate

75. Example: US outbreak of E. coli O157 Infections http://www.cdc.gov/ecoli/2009/0630.html Clin Infect Dis. (2011) doi: 10.1093/cid/cir831 Step 7: Communicate

76. Steps in investigating an outbreak 1. Detect the outbreak and assemble a team 2. Gather descriptive information a. determine etiology b. describe the outbreak by time, place, and person c. write a case definition d. conduct surveillance for more cases 3. Generate hypotheses 4. Test hypotheses a. gather data relevant to the hypothesis b. design a study c. analyze the study 5. Determine how and where contamination occurred 6. Prevent more illnesses 7. Communicate

77. Final thoughts  Most outbreaks are local  Most information about foodborne illness comes from investigation of local outbreaks  Investigation of local outbreaks can lead to identification of widespread problems and result in widespread improvements  Widespread outbreaks  Demonstrate the power of subtyping combined with the epidemiologic method  When solved, can result in widespread improvements  Finding a local cluster that is part of a widespread outbreak increases the chance of solving the widespread outbreak

78. Food commodities implicated in US outbreaks, 1998-2010 (n=3565)

79. Objectives At the end of this lecture, you will be able to:  Describe how outbreaks are detected  Explain the steps in investigating an outbreak  Identify the necessary collaborators for an outbreak investigation, including epidemiologists, laboratorians, environmental health specialists, among others

80. Acknowledgements: E. coli and cookie dough investigation Arizona California Colorado Connecticut Delaware Georgia Hawaii Iowa Illinois Kentucky Ohio Oklahoma Oregon Pennsylvania South Carolina The findings and conclusions in this presentation are those of the author and do not necessarily represent the views of the Centers for Disease Control and Prevention Virginia Department of Agriculture Minnesota Department of Agriculture Food and Drug Administration USDA Food Safety Inspection Service Enteric Diseases Laboratory Branch Enteric Diseases Epidemiology Branch Outbreak Reponse and Prevention Branch State and local health departments Massachusetts Maryland Maine Minnesota Missouri Montana North Caroline New Hampshire New Jersey Nevada New York Texas Utah Virginia Washington Wisconsin Karen Neil Kathryn MacDonald Carlota Medus Kirk Smith Bill Keene Nicole Comstock Eija Hyytia-Trees Gerry Gomez Patricia Lafon Mike Humphrys Steven Stroika Gwen Ewald Mark Sotir Jack Guzewich Bonnie Kissler Patricia Griffin Special Thanks

81. Thank you! iwilliams@cdc.gov The findings and conclusions in this presentation are those of the author and do not necessarily represent the views of the Centers for Disease Control and Prevention