Most enteric illness
is spread by the fecal-oral route, and the history of these diseases
mirrors changes in
the social, economic, and physical environments in which we live. By one
estimate, nearly 90%
of the global burden of diarrheal disease is attributable to unsafe water
supplies (19).
Improved basic sanitation, medical care, and diagnostic capabilities have
helped substantially
reduce both the risks for foodborne and waterborne diseases and the
frequency of
complications overall. That said, new problems emerge that reflect changes in
both human and
microbial populations—not to mention nonhuman reservoir species and the
environment. For
example, the population of vulnerable persons is growing as people live
longer or live with
immunosuppressive conditions. The rapid international movement of
people and
foodstuffs, shifts in food production methods and eating habits, and other
factors
all change patterns
of food exposure and hence patterns of foodborne disease. Improved
diagnostic tests
identify new or newly described pathogens. Many pathogens considered
important sources of
morbidity today were unheard of even 40 years ago, including
noroviruses,
rotaviruses, Cryptosporidium, Campylobacter, and Escherichia coli O157:H7.
Acute gastroenteritis
and other foodborne diseases can be caused by bacteria, viruses,
protozoa, fungi,
helminths, prions, and biological or environmental toxins. People are
exposed to these
pathogens or toxins in contaminated food or water, by person-to-personcontact,
and by direct contact
with animals. Many foodborne and waterborne diseases are
self-limited and
characterized by gastrointestinal symptoms such as vomiting and diarrhea.
Others, however, may
manifest with or progress to include systemic or neurological disease
that can result in
substantial morbidity and mortality, e.g., infection with E. coli O157:H7
(causing
hemolytic-uremic syndrome), Helicobacter pylori (linked to gastric
cancers), Listeria
(meningitis and miscarriage), Salmonella(increased risk of reactive
arthritis), and Toxoplasma
gondii (birth defects).
DISEASE SURVEILLANCE
Enteric disease
surveillance is generally the province of public health agencies. Surveillance
includes the
collection and analysis of information about disease occurrence and leads to
taking considered
action based upon those data. Disease surveillance often is based on
mandatory reporting
laws, whereby diagnostic laboratories or clinicians are required to notify
public health
agencies about individuals with specified conditions, e.g., salmonellosis or
hepatitis A, as well
as unusual clusters of illness.
While conceptually
simple, disease surveillance can be a daunting logistical challenge that
places demands on
legal, medical, communications, transportation, scientific, and social
infrastructure.
Unless otherwise noted, the following discussion pertains to enteric disease
surveillance and
outbreak investigation in the United States.
In the United States
and many other countries, public health workers collate notifiabledisease
reports in search of
broader patterns, often collecting additional information from
patient interviews
and other sources. The general public may also contact public health
agencies directly
with concerns about individual or apparently clustered illnesses, and these
reports too must be
considered for potential significance.
While definitions and
usage vary, disease outbreaks in general are comprised of individual
illnesses that can be
connected by webs of transmission or by exposures to common sources.
For example, we can
refer to an outbreak of norovirus infections at a nursing home, an
outbreak of cholera
affecting the population of a region or country, or an outbreak of
salmonellosis resulting
from consumption of contaminated peanut butter. In the United
States, over 95% of
reported enteric illnesses are not recognized to be part of outbreaks
(12).
That said, outbreak-related cases play a disproportionately large role in our
understanding of
pathogen transmission and attempts to control it.
Since 1938, the U.S.
Public Health Service has collated reports on foodborne and waterborne
disease outbreaks
from public health agencies (4). What was once a flow of
paper has largely
become an electronic
reporting system. From 2004 to 2006, the CDC received~1,200 reports
of foodborne
outbreaks involving at least 24,000 people annually
(http://www.cdc.gov/outbreaknet/).
Examples of forms, an electronic database used for
foodborne disease
outbreaks, and recent data are accessible online
(http://www.cdc.gov/outbreaknet/).
Summary information about foodborne and waterborne
outbreak
investigations is typically reported to the CDC, which periodically summarizes
these
data.
It should be
emphasized that the quality of these data is highly variable, which complicates
our ability to
summarize them meaningfully. Most outbreaks are probably never recognized
or reported, much
less investigated, and those that are reported nationally are likely to be a
biased sample of the
whole. For example, large outbreaks or outbreaks involving more
severe illnesses or
deaths are much more likely to get a thorough investigation. In the
United States, over
half of reported foodborne disease outbreaks are associated with food
eaten outside the
home (6). Many investigations are inconclusive, and different people may
summarize similar
situations in different ways.
Pathogens most
commonly identified in outbreaks reported from 2001 to 2006 are shown
in Fig.
1. It is noteworthy that no etiology was identified for almost
one-third of foodborne
outbreaks during that
period. Noroviruses were the leading cause of half of those with a
confirmed etiology,
and bacteria were responsible for 38%.
There are many
reasons to investigate outbreaks. The most obvious is to arrest an ongoing
problem. Recalling a
contaminated product from the marketplace or excluding a typhoid
carrier from work as
a food handler can prevent illness and even save lives. Given the
inherent delays in
disease reporting, many outbreaks are over before public health agencies
learn about them; the
benefits of investigating these clusters are more indirect.
Investigations often
reveal systemic problems that could cause illness in the future;
correction of these
problems reduces those risks. Examples might include substandard
operation of a
drinking-water treatment facility or inadequate temperature control in a
peanut roasting
operation. Outbreaks also provide an opportunity for public health
education—education
that may be targeted to the individual who manages a restaurant or to
the broader community
through media contacts. The identification or better characterization
of the root causes of
outbreaks, often assessed as aggregate data from many investigations,
also helps drive the
agenda of regulatory agencies, businesses, and others trying to develop
more effective
practices and regulations.
Public health
agencies in most countries have a legal authority and responsibility to
investigate certain
kinds of diseases and most clusters of illness (i.e., outbreaks) (Table
1).
In the United States,
that legal authority rests primarily at the local and state levels, and the
vast majority of
outbreaks are investigated by agencies at those levels. Suspected disease
outbreaks must be
reported to the public health department in most states, though this
requirement is often
unappreciated or ignored by clinicians and others.
a This
table provides a general outline of typical responsibilities for different
agencies
involved in
investigating food- and waterborne outbreaks. All states have unique food and
water safety laws,
policies, and organizational structures that will affect investigations, and
many other agencies
and organiza-tions may play important roles in certain situations.
Additional information
is available at the “Gateway to Government Food Safety Information”
(http://www.foodsafety.gov/)
and the Environmental Protection Agency website
(http://www.epa.gov/ebtpages/water.html).
To thoroughly
investigate an outbreak, epidemiologists need to collect a diverse range of
information. Public
health authorities have substantial legal authority to gather such data
that usually goes
hand in hand with state laws protecting the confidentiality of information
collected in the
context of an investigation. In practice, however, sweeping legal authorities
are rarely invoked;
epidemiological investigations typically rely on the voluntary cooperation
of all parties.
Regulatory agencies such as the FDA and the USDA have clearer police powers
that can be utilized
when circumstances demand them, but these powers typically apply only
to commercial
entities.
The capacity to
conduct public health investigations varies with the resources, experience,
and interest of the
agencies involved and in practice is highly variable. Moreover, some
states are hobbled by
a cumbersome legal structure that makes it difficult to move quickly in
a coordinated
fashion. The success of many multistate investigations in the United States
depends to a
surprising degree on the involvement of one or more of a small number of
states with expertise
in outbreak investigation. Realistically, not all clusters merit a thorough
investigation;
resources are always finite. One must consider the severity of the disease, the
community affected,
and the likelihood that useful data can be obtained from an
investigation. Basic
laboratory testing and interviews of a limited number of ill persons may
provide sufficient
information to identify the source of the outbreak and take appropriate
control measures. In
many cases, however, more extensive epidemiological investigation is
indicated.
Outbreak Detection
A foodborne outbreak
can be defined as “the occurrence of two or more cases of a similar
illness resulting
from ingestion of a common food” (4).
There are analogous surveillance
definitions for
outbreaks due to drinking or recreational water (23, 24).
In practice, most
intrahousehold
clusters are not pursued unless the disease is severe. To recognize unusual
clusters of illness,
public health officials must have knowledge of what “normal” or baseline
rates of a disease
are in the affected community. These may be available from historical
surveillance data.
In general, potential
outbreaks come to the attention of health authorities through one of
three routes. First,
people often contact public health agencies directly to report illness
clusters, e.g., after
a common restaurant meal or a wedding, or among persons at a nursing
home, school, or
prison. These reports come from physicians, infection control practitioners,
institutional staff,
and often from private citizens. Second, public health agencies identify
clusters through
review and follow-up of routinely collected surveillance information,
including reports of
legally notifiable diseases and subtyping of specimens submitted to
public health
laboratories. Third, recognition may come in response to queries from other
public health
agencies doing “case finding” as part of investigations in their jurisdictions.
One of the first
responses to the recognition of a potential outbreak is assessing whether
something “real” has
actually occurred. Surveillance reports are often incomplete,
misleading, or
erroneous, and many “clusters” dissolve under scrutiny. Outbreak clusters are
often obvious, but
sometimes it is difficult to separate minor fluctuations in rates (i.e.,
“noise”) from true
increases due to a common-source outbreak (“signal”).
Laboratory Investigation
The response to
preventive measures and the treatment of clinical infections varies markedly
depending on the
etiologic agent involved. It is therefore concerning that the etiologic agents
were not identified
for half of foodborne disease outbreaks reported to the CDC from 2004 to
2006. While many
factors can impede an investigation, laboratory testing is usually
necessary to confirm
an etiology. Stool specimens were not collected for laboratory testing in
two-thirds of
foodborne disease outbreaks of unknown etiology occurring at seven sites in
1998 and 1999 (12).
To meet most
definitions of a confirmed outbreak, the etiologic agent should be isolated
from
the stool of two or
more ill persons or from the epidemiologically implicated food (Table
3).
In a few situations,
such as mushroom poisoning, ciguatera fish poisoning, or other chemical
intoxications, it is
sufficient to document the clinical syndrome among affected
persons. Staphylococcus
can also be problematic because the organism may not be viable in
stool or food
samples, and most laboratories cannot test for enterotoxin. Thus, investigators
must collect
sufficient numbers of specimens (potentially including stool and other clinical
specimens and also
food, water, or environmental specimens) and handle them appropriately
to ensure that
laboratory testing identifies the etiologic agent. Investigators should consult
early with their
public health laboratory regarding appropriate collection and testing of
samples.
Most private clinical
laboratories currently cannot test specimens for norovirus, which is the
most common cause of
foodborne disease in the United States. Most state health department
laboratories offer
PCR (reverse transcriptase PCR [RT-PCR]) testing for norovirus and can
help coordinate
appropriate testing of specimens if this agent is suspected as the cause of an
outbreak. Likewise,
few private laboratories can serotype Salmonella isolates or
definitively
identify
enterotoxigenic E. coli, non-O157:H7 Shiga-toxigenic E. colistrains,
or staphylococcal
enterotoxin.
Guidelines for
collecting appropriate specimens during an outbreak investigation are listed
in Table
4. It can be difficult to collect adequate specimens for laboratory
testing. In general,
the concentration of
etiologic agents decreases with time after onset, putting a premium on
prompt specimen
collection, but many pathogens are sometimes detectable days or even
weeks after symptoms
resolve. Investigators may need to convince reluctant persons of the
social benefits of
providing stool specimens and will need to arrange the necessary logistics,
including
distribution of collection materials, aliquoting, and transportation.
Investigators
should promptly
contact private laboratories that may have received specimens from
outbreak-associated
patients to ask that the original material be held for possible additional
testing.
b Wrap
the packaged samples in sealed, waterproof containers (i.e., plastic bags).
Label each
specimen container in
a waterproof manner. Batch the collection and send in overnight mail
to arrive at the
testing laboratory on a weekday during business hours unless other
arrangements have
been made in advance with the testing laboratory. Contact the testing
laboratory before
shipping, and give the testing laboratory as much advance notice as
possible so that
testing can begin as soon as samples arrive. When etiology is unclear and
syndrome is
nonspecific, consider collecting all four types of specimens.
c For
more detailed instructions on how to collect specimens for specific parasites,
please go
tohttp://www.dpd.cdc.gov/dpdx/.
d For
more detailed instructions on how to collect specimens for viral testing,
please go
tohttp://www.cdc.gov/mmwr/PDF/RR/RR5009.pdf.
e The
containers have been tested for the presence of the chemical of interest before
use.
f Unused
specimen collection containers that have been brought in to the field and
subjected
to the same field
conditions as the used containers. These containers are then tested for
trace amounts of the
chemical of interest.
Where applicable,
samples of suspected vehicles of infection (e.g., food or water) should be
collected as soon as
possible after an outbreak is recognized. Actual testing is not always
practical, but
getting specimens preserves the option of later testing. Ideally, investigators
will collect
specimens from the batches or lots of food or water that patients actually ate
or
drank before becoming
ill. If this is not possible (as is often the case), products as similar as
possible are the next
best thing. If investigators suspect that the source of an outbreak is
contaminated packaged
food, they should collect unopened packages from the implicated lot.
Positive (and
sometimes negative) specimens are often critical evidence in outbreaks caused
by commercial
products.
Laboratory subtyping
is critical to many outbreak investigations, particularly those with
bacterial etiologies.
“Subtyping” is a generic term referring to any method that improves the
specificity of the
description of an etiologic agent. For example, a Salmonella isolate
could be
characterized by
serotype (e.g., Enteritidis or Heidelberg), pulsed-field gel electrophoresis
(PFGE) or other
restriction fragment length polymorphism patterns, multilocus variable
number tandem repeat
analysis (MLVA) pattern, DNA sequence, or other characteristics.
When methodologies
are standardized, subtyping data can be shared to identify potential
matches between
isolates at different laboratories. PulseNet
(http://pulsenetinternational.org) is
an example of an international network that effectively
shares such
information. Specific subtyping can be invaluable: two salmonellosis reports in
the same week may be
normal, but two Salmonella enterica serovar Hvittingfoss cases in the
same week in most
jurisdictions would be an unlikely coincidence. On closer inspection,
those matching
isolates might turn out to be from the same household (or even from the
same individual), but
such matches are often the first indication of an outbreak. Subtype
matches not only help
link scattered cases but also can provide a way to exclude similar but
perhaps unrelated
cases (Fig. 4). Refining case definitions in this manner can greatly
increase the
statistical power of an analytic epidemiological study.
Some outbreaks
involve multiple variants of a pathogen. Investigations may start because of
an increase in one
PFGE pattern, but multiple patterns may eventually be recognized to be
part of the same
cluster, reflecting the genetic diversity or microevolution of the etiologic
agent in vivo.
Outbreaks that involve gross environmental contamination may even include
multiple species (13, 18).
EPIDEMIOLOGICAL APPROACHES TO OUTBREAK
INVESTIGATIONS
While there is much
variation in practice, there is a general logic that underlies most
successful outbreak
investigations. These steps are outlined in Table 5.
Depending on
circumstances, some
steps may be more implicit than explicit, and they do not necessarily
occur in a neat
sequence.
In any investigation,
the most immediate priorities are to implement appropriate measures
to control the
outbreak, mitigate associated morbidity, and prevent recurrences. When
outbreaks appear to
be ongoing, public health officials may institute substantial and
occasionally
controversial control measures before the investigation is complete and before
all desired data are
available. Such measures may include ordering (or recommending)
product recalls,
confiscating products, excluding food handlers or ill persons from work,
closing retail food
establishments or implicated venues, and publicly notifying persons who
may have been
exposed. Because such interventions can have important medical, emotional,
and economic
implications, the larger investigative team must assimilate available data
rapidly and
communicate effectively with each other and the public. Such collaboration is
imperative to ensure
that the public health benefits are maximized while the collateral
damage is minimized.
Good communication
among epidemiologists, laboratorians, environmentalists, and other
partners is essential
to successful investigations. Most health department jurisdictions have
environmental health
specialists (also known as sanitarians or environmentalists) or
regulatory staff with
expertise in the technical aspects of food handling, inspection of food
establishments,
tracing of food distribution, environmental specimen collection, water safety,
and other issues that
are often critical to successful investigations.
Epidemiologists use
case definitions to consistently include or exclude people from a cluster
or study group. Case
definitions typically include criteria for symptoms, time of onset, and
the time and place of
potential exposure, e.g., “any person reporting vomiting or diarrhea
within 5 days of
consuming food from restaurant A from 2 to 5 March” or “any U.S. resident
with an isolate of Salmonella
enterica serovar Rissen and PFGE pattern XYZ1234 reported in
2010.” Case
definitions are investigative constructs, not biological verities, and may be
modified during the
course of an investigation as the need arises; there can even be multiple
case definitions
serving different purposes.
Epidemiologists
collect clinical information about potential cases, including signs and
symptoms, onset time,
and indices of severity such as duration of illness, hospitalization, and
fatalities.
Individual case data are often displayed in a spreadsheet or database layout as
a
“line list,” and
epidemiologists pore over these in search of patterns. When outbreaks
manifest by matching
laboratory isolates (e.g., E. coli O157:H7 cases with the same PFGE
pattern), the
pathogen is known at the outset, and there may be less interest in some
clinical details.
Investigations that stem from citizen reports, on the other hand, often rely on
thorough symptom
profiles to classify potential cases.
After confirming the
existence of an outbreak, investigators interview affected persons to
identify demographic
characteristics of cases, the nature and timing of symptoms, and
potential exposures
of interest. Systematically collected information is much more useful
than desultory
anecdotes. Well-designed forms and questionnaires—and skilled
interviewers—provide
structure to that information and are essential to transforming raw
reports into
analyzable data. Good questionnaire design requires training, insight, and
experience and can be
surprisingly time-consuming. Outbreak investigations often move
quickly, and template
questionnaires developed in advance that can be quickly modified to fit
a given situation can
be very useful. The best templates allow for quick and flexible
modification,
deployment in multiple modes (e.g., paper and electronic) for a variety of
audiences, rapid data
entry, and easy abstraction of data for tabulation and statistical
analyses.
A careful
consideration of the cases’ demographics (age, sex, race, and ethnicity) can
narrow
the range of plausible
vehicles. For example, salmonellosis outbreaks caused by fresh
produce (e.g.,
lettuce, spinach, and sprouts) typically manifest with disproportionate
numbers of female
patients in the age group from 20 to 50. Outbreaks focused among young
children are less
likely to be caused by vegetables. The spatial and temporal distribution of
cases also is
instructive. Illnesses scattered across the country are unlikely to be caused
by
products with local
or regional distribution (e.g., milk). Products with a short shelf life (e.g.,
fresh produce) tend
to cause shorter-lived outbreaks than processed foods with a long shelf
life (e.g., peanut
butter).
Different kinds of
outbreaks call for different types of questionnaires. Even in a single
investigation, more
than one questionnaire may prove useful as things progress. The desire
to be comprehensive
must be balanced by practical considerations, including ease of use and
acceptability to
interviewees and interviewers. Complete answers to reasonably limited
questions are
generally preferred over incomplete answers to an unreasonable number.
Questionnaire
designers should be mindful of the population for which it is intended, the
mode of
administration, the sophistication of those collecting the data, and —often
overlooked—how data
will be entered and analyzed. Questionnaires can be deployed via
telephone, in a
face-to-face interview, or as self-administered paper or electronic forms;
each choice has
advantages and disadvantages. Interviewers must know how to introduce
the study to
participants and answer questions about it. Data collectors must also be given
guidelines for
obtaining data and be familiar with standard definitions so that information is
elicited consistently
and completely, thereby minimizing errors and potential bias.
Simple event-centric
outbreaks (e.g., church suppers, wedding receptions, and many
restaurant clusters)
lend themselves to short questionnaires. Menus are obtained, other
exposures (e.g.,
water) are assessed, and with a good template, questionnaire design is
often
straightforward. When cases are more scattered in place and time, suspicions
may
arise about
commercially distributed food products. These can be complex,
multijurisdictional
investigations with
large public health and economic consequences. Such investigations often
evolve over weeks or
even months, with different questionnaires used at different stages of
the process. Broad
hypothesis-generating questionnaires may be used initially to identify
food items or other
exposures that deserve additional scrutiny. There are several models for
approaching these
kinds of outbreaks that have proven effective in practice (8, 21).
Interviews with
persons who were not sick (controls) are often necessary to provide a
comparison group. If
the population affected by the outbreak is well defined, such as
attendees of a church
picnic or patrons of a single restaurant within a 3-day period, a
retrospective cohort
study can be performed. In this situation, all members or a
representative sample
of the affected group (the cohort) are interviewed to assess whether
they were ill and
what items they consumed. Rates of illness among persons with and
without certain
exposures are compared with appropriate statistical methods to identify
exposures associated
with illness (3,10). If the affected population is not well defined or a
cohort study is not
practical, a case-control study may be performed. In such outbreaks,
persons with the
illness of interest (cases) are compared to those without it (controls). In the
absence of formal
control data, other information may be better than nothing in assessing
case exposure data:
restaurant service records (e.g., how many people got salads on
Monday night), brand
name market share data, or even available survey data (<3% of
people drink
unpasteurized milk in any given week).
To keep the
investigation focused, data about cases should be regularly organized,
summarized, and
shared with colleagues. The occurrence of new cases over time (usually by
day or week of
symptom onset) can be represented graphically as an “epidemic curve” (Fig.
5 and 6),
and the geographic distribution of cases can be plotted on a map. The line
list, the
epidemic curve, and
the map can give the investigator clues about the source of an
outbreak. Localized
cases may reflect an exposure at a single time and place (a “point
source” outbreak),
e.g., patrons of a restaurant on a single day; such outbreaks are often
associated with
mishandling, undercooking, cross-contamination, or poor hygiene locally. In
contrast, cases
widely scattered geographically suggest the distribution of a commercial
product (or a
convergence at a national meeting, event, or vacation venue).
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