outbreak investigation hsph infectious disease epidemiology april 29, 2015 natasha hochberg, md, mph...
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Outbreak Investigation
HSPH Infectious Disease Epidemiology
April 29, 2015
Natasha Hochberg, MD, MPHBoston University School of Medicine
Boston University School of Public Health
Boston Medical Center
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)
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Outbreaks are not new
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
Factors affecting outbreaks
• Changes in environment
• Agriculture/food processing
• International transport
• Changes in human behavior
• Density of populations
• Underlying medical problems
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?
What is an outbreak?
3389 cases of West Nile virus infection. Is this an outbreak?
• A. Yes
• B. No
• C. It depends
Is this an outbreak?
3389 cases of West Nile virus infection
• In 2002 in the United States• Compared with 149 in 1999 through 2001
Is this an outbreak?
2820 cases of tuberculosis
• In 1999 in Guatemala• Compared with 3059 in 1998
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
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
Causes of an increased number of cases
• Artificial increase
• Real increase
Source: Mead et al, Arch Internal Med, 1997:157:204-8.
Sometimes it’s not so clear
2001
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1.5
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2.5
2002 2003 Jan-Oct2004
Nov 04-Feb 05
Period of Lumbar Puncture
Incidence per
100,000 Person Years
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
June,1995Arizona 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
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
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
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
Define a case
• Definition always includes:– Person
• Clinical criteria
– Place– Time
• Definition sometimes includes:– Laboratory criteria– Epidemiologic criteria
By including a laboratory component to a case definition,
one wouldA. Increase sensitivity
B. Increase specificity
C. Not sure
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
What case definition would you use?
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.
June,1995Arizona 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
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
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
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
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
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
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
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
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
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”)
Point Source
• Steep upslope
• More gradual decline
• Cases occur within one incubation period
Common source continuous exposure: Salmonella
Salmonella incubation period 1-3 days
Propagated outbreak: Measles
• Propagated = secondary transmission
• One case = source for subsequent cases
• Series of peaks separated by the incubation period
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. . ..
Propagated
Common Source
Point source
Uh, yeah
0% 0%0%0%
Bonus Points
• What are some problems with this epi curve?
Pay attention to the outliers
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Date of Onset of Illness
Nu
mb
er o
f C
ases
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
0
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6
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9
10N
um
ber
of
Cas
es
Date of Onset of Illness
Point source outbreak: RubellaUsual 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
0
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Date of Onset of Illness
Nu
mb
er o
f C
ases
Point source outbreak: RubellaUsual incubation period 14-21 days
14 days before first case
Time of exposure: count back the minimum incubation period from the first case
0
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Date of Onset of Illness
Nu
mb
er o
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ases
21 days before last case
Point source outbreak: RubellaUsual incubation period 14-21 days
Time of exposure: count back the maximum incubation period from the last case
0
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Date of Onset of Illness
Nu
mb
er o
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ases
likely time of exposure
Point source outbreak: RubellaUsual incubation period 14-21 days
0
2
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10
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Epidemiologic week, 1995# ca
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kDescriptive epidemiology
Arizona S. Stanley epidemic curve
Descriptive epidemiology
TIME – Epidemic curves
PERSON– Age– Sex– Race/ethnicity– Health status– Etc.
PLACE – Residence– Work/school– Travel, events– Etc.
Descriptive Epi: Line Lists
Descriptive epidemiologyArizona 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
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
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
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
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)
What is the determinant?
Think about what you ate for lunch two weeks ago. . .
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
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
Arizona study results
Exposure Matched OR p-value
Alfalfa sprouts 12.00 0.02
Applesauce 0.50 0.87
Chicken 1.40 0.91
Egg 0.74 0.84
Lettuce 1.00 0.74
Onion 1.17 1.00
Roast beef 0.33 0.50
Turkey 1.85 0.43
Reptile contact 1.25 0.91
And many others, none associated with illness
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
Other evidence cont’dTraceback of alfalfa seeds in the US
Other evidence cont’dTraceback of alfalfa seeds for 50 patients in 6
states to both a US and Finnish supplier
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
Laboratory Investigation
• Can include:– 1. identification of agent – 2. environmental testing – 3. molecular analysis of isolates from cases
and environment
Molecular subtyping of S. Stanley isolates (Pulsed Field Gel Electrophoresis)
Outbreak isolates Non-outbreak isolates
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
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
Implement control measures
• Wash sprouts?
• Decontaminate seeds?
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
Communicate findings
Volume 175 · Number 4 April 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
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
Consider additional studies
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)
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
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 ________________________________
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
Thank You