1. Outbreak Investigation HSPH Infectious Disease Epidemiology April 29, 2015 Natasha Hochberg, MD, MPH Boston University School of Medicine Boston University School of Public Health Boston Medical Center

3. Recent/Current Outbreaks H5N2 in turkeys in United States Leptospirosis in Argentina Undiagnosed fatal blinding illness in Nigeria Chikungunya in the Americas Measles from Disney theme parks (US)  Sign up for daily alerts at http://www.promedmail.org http://www.promedmail.org

4. Outbreaks are not new

6. Learning Objectives Describe real and artificial reasons for an increase in case numbers Report the steps taken in an outbreak investigation Create a case definition and understand how different case definitions serve different purposes Interpret epidemic curves and identify likely date of exposure Understand factors that affect choice of study design in an outbreak

7. Factors affecting outbreaks Changes in environment Agriculture/food processing International transport Changes in human behavior Density of populations Underlying medical problems

8. Why investigate an outbreak? Agent-related –1983: Is AIDS caused by an infectious agent? –2004: How infective is SARS? Source-related –2003: How did monkeypox get to the Midwest? Vehicle-related –2001: Can anthrax spores leak out of a sealed envelope? –2007: What widely distributed food is contaminated with Salmonella? Control-related –1990s: Do “safe cooking” directions actually do anything to help protect consumers from E. coli O157:H7 infection? –2006: Are two doses of mumps vaccine better than one?

9. What is an outbreak?

10. 3389 cases of West Nile virus infection. Is this an outbreak? A. Yes B. No C. It depends

11. Is this an outbreak?  3389 cases of West Nile virus infection In 2002 in the United States Compared with 149 in 1999 through 2001

12. Is this an outbreak?  2820 cases of tuberculosis In 1999 in Guatemala Compared with 3059 in 1998

13. Definitions  Epidemic: “The occurrence of cases of an illness clearly in excess of the normal expectancy.”  Outbreak: Same as epidemic but more limited geographical area (really a political distinction)  Cluster: Aggregation of cases in a given area over a particular period without regard to whether the number of cases is more than expected

14. Is this an outbreak?  48 E. coli O157:H7 infections In June and July 1994 in New Jersey, Compared with 4 cases in June and July 1993

15. Causes of an increased number of cases Artificial increase Real increase

16. Source: Mead et al, Arch Internal Med, 1997:157:204-8.

17. Sometimes it’s not so clear 2001 (4) (3) (5) (3) (9) 0 0.5 1 1.5 2 2.5 20022003Jan-Oct 2004 Nov 04- Feb 05 Period of Lumbar Puncture Incidence per 100,000 Person Years

18. Steps in outbreak investigation Confirm outbreak and diagnosis Define a case Find and count cases Descriptive epidemiology Generate hypotheses Design and conduct epi study Laboratory and environmental investigation Implement and evaluate control measures Communicate findings Consider additional studies

19. June,1995 Arizona Department of Health Services reports to CDC: 19 cases of Salmonella serotype Stanley infection in Arizona residents in April and May, 1995. By comparison: –1992—0 cases –1993—1 case –1994—1 case Concurrent outbreaks in other states, Canada, Finland

20. Steps in outbreak investigation Confirm outbreak and diagnosis Define a case Find and count cases Descriptive epidemiology Generate hypotheses Design and conduct epidemiologic study Laboratory and environmental investigation Implement and evaluate control measures Communicate findings Consider additional studies

21. Confirm outbreak and diagnosis No change in lab procedures at ADHS No known change in clinical practices in AZ or elsewhere No change in reporting

22. Steps in outbreak investigation Confirm outbreak and diagnosis Define a case Find and count cases Descriptive epidemiology Generate hypotheses Design and conduct epidemiologic study Laboratory and environmental investigation Implement and evaluate control measures Communicate findings Consider additional studies

23. Define a case Definition always includes: –Person Clinical criteria –Place –Time Definition sometimes includes: –Laboratory criteria –Epidemiologic criteria

24. By including a laboratory component to a case definition, one would A.Increase sensitivity B.Increase specificity C.Not sure

25. Using Multiple Case Definitions Confirmed or definite –Most specific, least misclassification –Useful for analytic study Probable: –Symptoms without lab confirmation Possible –Most sensitive –Use for gauging overall impact of outbreak

26. What case definition would you use?

27. Arizona Salmonella Stanley outbreak case definition An illness occurring in 1995 in a person who was in Arizona for the 3 days before illness onset and in which S. Stanley was isolated.

28. June,1995 Arizona Department of Health Services reports to CDC: 19 cases of Salmonella serotype Stanley infection in Arizona residents in April and May, 1995. By comparison: –1992—0 cases –1993—1 case –1994—1 case

29. Steps in outbreak investigation Confirm outbreak and diagnosis Define a case Find and count cases Descriptive epidemiology Generate hypotheses Design and conduct epidemiologic study Laboratory and environmental investigation Implement and evaluate control measures Communicate findings Consider additional studies

30. Find and count cases During an outbreak, enhanced surveillance is needed. –Usually, active surveillance is used In Arizona, active surveillance included: –Letters to clinical laboratories –Telephone calls to laboratories of large hospitals –Letters to all infection control practitioners 22 cases identified

31. Steps in outbreak investigation Confirm outbreak and diagnosis Define a case Find and count cases Descriptive epidemiology Generate hypotheses Design and conduct epidemiologic study Laboratory and environmental investigation Implement and evaluate control measures Communicate findings Consider additional studies

32. Epidemic Curves An epidemic curve (epi curve) is a graph of the number of cases by date of illness onset Can provide information on the: –Pattern of spread (Common source, point source, propagated) –Magnitude –Outliers –Time trend (peak of outbreak, date of first/last case) –Exposure and/or disease incubation period

33. Epidemic Curves (Epi curves) Two-dimensional graph of the number of cases by date of illness onset Simple display of an epidemic's magnitude and time course

34. Drawing an Epi Curve - Histogram with time on X axis and number of cases on Y axis - Include title and axis labels Date of symptom onset Number of cases

35. Drawing an Epi Curve Changing the time interval can markedly change the shape of the curve: - Intervals between ¼ to ½ of an incubation period work best at revealing the time pattern Date of symptom onset Number of cases

36. Drawing an Epi Curve Begin before the onset of the outbreak to show -the background number of cases and/or -the source case for propagated outbreaks Date of symptom onset Number of cases

37. Pattern of Spread Point Source: A group of persons are all exposed to an infectious agent or a toxin from the same source –Exposed over a relatively brief period so everyone who becomes ill does so within one incubation period Common-source outbreak: Exposed from same source –Period of exposure is prolonged –Can be intermittent Propagated: Transmission from person to person (“secondary transmission”)

38. Point Source Steep upslope More gradual decline Cases occur within one incubation period

39. Common source continuous exposure: Salmonella Salmonella incubation period 1-3 days

40. Propagated outbreak: Measles Propagated = secondary transmission One case = source for subsequent cases Series of peaks separated by the incubation period

41. Assuming a 1 day incubation period, what type of transmission pattern does this epi curve represent? A.Propagated B.Common Source C.Point source D.Hmmm....

42. Bonus Points What are some problems with this epi curve?

43. Pay attention to the outliers

44. Point source outbreak: Rubella Epi curve can be used to estimate: Point source/ exposure for a disease with known incubation period or Incubation period of disease with known date of exposure

45. Point source outbreak: Rubella Usual incubation period 14-21 days 17.5 days before peak of curve Time of exposure: count back the median incubation period from the peak of the outbreak

46. Point source outbreak: Rubella Usual incubation period 14-21 days 14 days before first case Time of exposure: count back the minimum incubation period from the first case

47. 21 days before last case Point source outbreak: Rubella Usual incubation period 14-21 days Time of exposure: count back the maximum incubation period from the last case

48. likely time of exposure Point source outbreak: Rubella Usual incubation period 14-21 days

49. Descriptive epidemiology Arizona S. Stanley epidemic curve

50. Descriptive epidemiology TIME –Epidemic curves PERSON –Age –Sex –Race/ethnicity –Health status –Etc. PLACE –Residence –Work/school –Travel, events –Etc.

51. Descriptive Epi: Line Lists

52. Descriptive epidemiology Arizona S. Stanley outbreak PERSON –Age: 25 years median (2 months to 81 years) –Sex: 68% female –Race: 91% white PLACE –Cases in the 3 most populous counties –No obvious geographic clustering

53. Steps in outbreak investigation Confirm outbreak and diagnosis Define a case Find and count cases Descriptive epidemiology Generate hypotheses Test hypotheses Laboratory and environmental investigation Implement and evaluate control measures Communicate findings Consider additional studies

54. Generate hypotheses Sources of hypotheses regarding vehicles of exposure: Descriptive epidemiology Existing scientific knowledge--“the usual suspects” Open-ended patient interviews –4 patients, all ate lots of salad –1 vegetarian –3 ate alfalfa sprouts –1 with animal contact Outliers

55. Steps in outbreak investigation Confirm outbreak and diagnosis Define a case Find and count cases Descriptive epidemiology Generate hypotheses Design and conduct epidemiologic study Laboratory and environmental investigation Implement and evaluate control measures Communicate findings Consider additional studies

56. Epidemiologic Study: Outcome & Determinant Outcome (case definition) –Laboratory test? –Clinical symptoms? –Confirmed, probable, possible? –May have small number of cases Determinant (aka exposure): characteristic upon which the outcome depends –Can be a behavior (e.g. food consumption, injection) or environmental exposure (e.g. water, air) –Often several suspected possible determinants (e.g. food items in the case of common vehicle; contacts in hospital setting)

57. What is the determinant? Think about what you ate for lunch two weeks ago...

58. Cohort vs. Case-Control Retrospective Cohort – –Retrospective – study begins after cases have occurred –Source population defined and enumerated –Good if outbreak suspected to have occurred at a specific event (party) or place (cruise ship) –Can try to include all persons or selection Case control – –Include persons based on their disease status –For large event (state fair), community-wide or uncommon diseases reported from a population –Include all or select group of cases –Most common study type in outbreaks

59. Arizona case-control study Cases (outcome): A person with onset of illness in which a clinical specimen yielded S. Stanley from routine serotyping of Salmonella isolates submitted to the Arizona Health Dept laboratory Controls: –2 per case, matched on neighborhood and age  1 year if  5 years of age to  20 years if >60 years of age –Found by systematic telephone dialing (adding or subtracting to case’s telephone number) –Excluded if had symptoms since April 25 –Interviewed about most recent same 3 days of week as case Possible determinants: Medical history, 24 specific foods, environmental exposures –In 3 days before illness for cases –Most recent same 3 days of the week for controls

60. Arizona study results ExposureMatched ORp-value Alfalfa sprouts12.000.02 Applesauce0.500.87 Chicken1.400.91 Egg0.740.84 Lettuce1.000.74 Onion1.171.00 Roast beef0.330.50 Turkey1.850.43 Reptile contact1.250.91 And many others, none associated with illness

61. Other evidence Investigations in other outbreak sites –Independent case-control studies conducted in Michigan and Finland –Both found associations with alfalfa sprouts and only alfalfa sprouts Case interviews in other states –95 people interviewed in 16 states –82% said they definitely or probably ate alfalfa sprouts before illness

62. Other evidence cont’d Traceback of alfalfa seeds in the US

63. Other evidence cont’d Traceback of alfalfa seeds for 50 patients in 6 states to both a US and Finnish supplier

64. Steps in outbreak investigation Confirm outbreak and diagnosis Define a case Find and count cases Descriptive epidemiology Generate hypotheses Design and conduct epidemiologic study Laboratory and environmental investigation Implement and evaluate control measures Communicate findings Consider additional studies

65. Laboratory Investigation Can include: –1. identification of agent –2. environmental testing –3. molecular analysis of isolates from cases and environment

66. Molecular subtyping of S. Stanley isolates (Pulsed Field Gel Electrophoresis) Outbreak isolates Non-outbreak isolates

67. Environmental Investigation Can include: traceback, culturing Can support epidemiologic findings, but –Samples may not be available from time of exposure –Where to sample may not be straightforward –Finding an organism in an environmental sample does not always mean that was the source –Some organisms are hard to culture or test for –Patient may have contaminated environment, rather than vice-versa

68. Steps in outbreak investigation Confirm outbreak and diagnosis Define a case Find and count cases Descriptive epidemiology Generate hypotheses Design and conduct epidemiologic study Laboratory and environmental investigation Implement and evaluate control measures Communicate findings Consider additional studies

69. Implement control measures Wash sprouts? Decontaminate seeds?

70. Steps in outbreak investigation Confirm outbreak and diagnosis Define a case Find and count cases Descriptive epidemiology Generate hypotheses Design and conduct epidemiologic study Laboratory and environmental investigation Implement and evaluate control measures Communicate findings Consider additional studies

71. Communicate findings Volume 175 · Number 4April 1997 Sprouts are now one of the “usual suspects” –Recognized as vehicle for many foodborne outbreaks –Salmonella, E. coli O157:H7, and other agents –Alfalfa, mung, radish, other sprouts

72. Steps in outbreak investigation Confirm outbreak and diagnosis Define a case Find and count cases Descriptive epidemiology Generate hypotheses Design and conduct epidemiologic study Laboratory and environmental investigation Implement and evaluate control measures Communicate findings Consider additional studies

73. Jaquette et al, Applied Environmental Microbiol 1996;62:2212-5 Growth of S. Stanley on alfalfa seeds during soaking (1), germination (2), and sprouting (3), and survival during storage (4)

74. Steps in outbreak investigation Confirm outbreak and diagnosis Define a case Find and count cases Descriptive epidemiology Generate hypotheses Design and conduct epidemiologic study Laboratory and environmental investigation Implement and evaluate control measures Communicate findings Consider additional studies

75. Summary Describe real and artificial reasons for an increase in case numbers –Artificial: __________________ Report the steps taken in an outbreak investigation Case definition consists of ________________________________

76. Summary Epi curves: –Point source: All cases occur within _________________ –Propagated: See evidence of person-person transmission from ____________________ Can count back to find likely date of exposure in point source outbreak: –From peak of epidemic, count back _____ –From first case, count back ________ –From last case, count back _________ Considered study design types

77. Thank You