**A Multistate Outbreak of Cyclosporiasis**

#### A Classroom Case Study

**INSTRUCTOR'S VERSION**

+-----------------------------------------------------------------------+
| **Original investigators:**                                           |
|                                                                       |
| Barbara L. Herwaldt, MD, MPH^1^, Marta-Louise Ackers, MD^1^, Michael  |
| J. Beach, PhD^1^, and the Cyclospora Working Group                    |
|                                                                       |
| ^1^Centers for Disease Control and Prevention                         |
|                                                                       |
| **Case study and instructor's guide created by:** Jeanette K.         |
| Stehr-Green, MD                                                       |
|                                                                       |
| **Reviewed by:** Charles Haddad, Robert Tauxe, MD, MPH, Roderick C.   |
| Jones, MPH                                                            |
+-----------------------------------------------------------------------+

> *NOTE: This case study is based on real-life investigations undertaken
> in 1996 and 1997 in the United States and abroad that were published
> in the [Morbidity and Mortality Weekly Report]{.underline}, the [New
> England Journal of Medicine]{.underline}, and the [Annals of Internal
> Medicine]{.underline}. The case study, however, is not a factual
> accounting of the details from these investigations. Some aspects of
> the investigations (and the circumstances leading up to them) have
> been altered to assist in meeting the desired teaching objectives.
> Some details have been fabricated to provide continuity to the
> storyline.*

**Target audience:** students with minimal knowledge of basic
epidemiologic concepts who are interested in learning more about the
practice of epidemiology including participants in the Knight Journalism
Fellowship Program.

**Level of case study:** basic

**Teaching materials required:** none

**Time required:** approximately 3 hours

**Language:** English

**Training materials funded by:** John S. and James L. Knight Foundation
and the Centers for Disease

Control and Prevention

**August 2004**

**U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES**

**Public Health Service**

**Centers for Disease Control and Prevention**

**Atlanta, Georgia 30333**

# INSTRUCTOR'S VERSION

# A Multistate Outbreak of Cyclosporiasis

+-----------------------------------------------------------------------+
| **Learning objectives:**                                              |
|                                                                       |
| After completing this case study, the participant should be able to:  |
|                                                                       |
| 1)  use the modes of transmission and incubation period for a disease |
|     to focus the search for the source of an outbreak                 |
|                                                                       |
| 2)  describe the two most common types of epidemiologic studies       |
|     routinely used to investigate outbreaks                           |
|                                                                       |
| 3)  interpret the results of an epidemiologic study                   |
|                                                                       |
| 4)  consider potential sources of error in designing or carrying out  |
|     an epidemiologic study                                            |
|                                                                       |
| 5)  apply the criteria for causation to the results of an outbreak    |
|     investigation                                                     |
|                                                                       |
| 6)  list considerations in implementing control measures before       |
|     confirmation of the source of an outbreak                         |
|                                                                       |
| 7)  describe the occurrence, signs and symptoms, and control of       |
|     cyclosporiasis                                                    |
+-----------------------------------------------------------------------+

# Part I -- Background 

On May 20, 1996, the following article appeared on the front page of the
Toronto Sun:

+----------------------------------+-----------------------------------+
| **Exotic Parasite Sickens        | microorganism *Cyclospora         |
| Canadian Businessmen**           | cayetanensis.* *Cyclospora*       |
|                                  | infects the small bowel and       |
| By Xavier Onnasis                | usually causes watery diarrhea,   |
|                                  | with frequent, sometimes          |
| TORONTO -- Public health         | explosive, bowel movements.       |
| officials today confirmed that   | Symptoms can include bloating,    |
| three Canadian businessmen, two  | increased gas, stomach cramps,    |
| from Toronto and one from        | nausea, loss of appetite, and     |
| Ottawa, were diagnosed with      | profound weight loss. The illness |
| cyclosporiasis, a parasitic      | is diagnosed by examining stool   |
| disease seen only in tropical    | specimens in the laboratory.      |
| countries and overseas           |                                   |
| travelers. The three men, who    | Dr. Schabas declined to identify  |
| had recently traveled to the     | a source of infection for the     |
| United States, became seriously  | three businessmen but indicated   |
| ill with diarrhea over the       | that the parasite is transmitted  |
| weekend (May 16-18). One of the  | through contaminated food or      |
| men was hospitalized at Princess | water but not by direct           |
| Margaret Hospital when he        | person-to-person spread. The time |
| collapsed due to severe          | between exposure to the parasite  |
| dehydration.                     | and becoming sick is usually      |
|                                  | about 7 days.                     |
| Dr. Richard Schabas, Ontario's   |                                   |
| Chief Medical Officer, reported  | Dr. Schabas reported that all     |
| that cyclosporiasis was          | three men had attended a meeting  |
| exceedingly rare in North        | in Texas on May 9-10. He said     |
| American and that much was still | Ontario Health Department staff   |
| unknown about this disease.      | would be investigating leads      |
| Cyclosporiasis is caused by the  | locally and in Texas.             |
+----------------------------------+-----------------------------------+

See Appendix 1 for "Cyclosporiasis Fact Sheet".

**Question 1:** What is the incubation period for cyclosporiasis? How
will it be used in the investigation?

*The incubation period is the **time between exposure to an infectious
agent or toxin and the first appearance of symptoms** suggestive of the
infection or intoxication. The incubation period of a disease can help
investigators identify the agent causing an illness. For example, an
incubation period of a few minutes or hours is suggestive of a preformed
toxin (e.g., heavy metal, paralytic shellfish poisoning,
[Staphylococcus]{.underline} [aureus]{.underline}); a few days, a viral
or bacterial infection (e.g., norovirus, salmonellosis, [E]{.underline}.
[coli]{.underline} O157:H7 infection), a week or more, a parasitic
infection (e.g., cyclosporiasis, giardiasis). If the causative agent is
known, the incubation period can help determine the most likely period
of exposure to the agent (i.e., one incubation period before the onset
of illness).*

*The **average** incubation period for cyclosporiasis is about 1 week
but can range from 2-10 days.*

NOTE TO INSTRUCTORS: Students should be reminded of two good resources
on the epidemiology of infectious diseases (including incubation period,
modes of transmission, common sources of infection, and period of
communicability):

-   *CDC Health Topics A to Z at <http://www.cdc.gov/az.do>*

-   *[Control of Communicable Diseases Manual]{.underline} published by
    American Public Health Association.*

**Question 2:** On what sources of infection should public health
officials focus for the three cases of cyclosporiasis? Is it possible
that one of the men was the source of infection for the others? Do you
think that it is likely that the businessmen became infected with
cyclosporiasis in Texas?

*[Cyclospora]{.underline} is spread by ingesting something that has been
contaminated with stool containing the parasite (i.e., the **fecal-oral
route**). [Cyclospora]{.underline} **needs time** (days or weeks),
however, after being passed in a bowel movement **to become
infectious**. (The parasite, which is passed in the stool as an
"oocyst," must change forms and "sporulate" to become infectious.). As a
result, food or water contaminated with unsporulated oocysts shortly
before consumption should not cause infection and direct
person-to-person spread is unlikely. In addition, exposure of the
parasite to temperatures less than --20ºC for 24 hours or above 60ºC for
1 hour inactivates the oocysts. No documented outbreaks have been
associated with cooked or commercially frozen foods.*

*In investigating the source of these cyclosporiasis cases, public
health officials should focus on **foods, water, or beverages** that
were consumed by the three men approximately **one incubation period**
(i.e., about a week) **before becoming ill**. Officials may want to
focus on uncooked foods and foods that have not been frozen (e.g., fresh
produce) since cooking and freezing inactivate the parasite.*

*Since all three men had onset of symptoms around the same time, it is
unlikely that one was the source of infection for the others.*

*The onset of symptoms among the three men was reported to be May 16-18.
Counting back the average incubation period for cyclosporiasis (i.e.,
one week), the **period of exposure** for the three men was about May
9-11 (i.e., around the time they were in Texas). If they shared no other
common exposures around that time period (e.g., meals on airlines,
drinks at airport lounges), it is very likely that they became infected
with cyclosporiasis in Texas.*

# Part II -- Outbreaks in Texas

The chief medical officer of the Ontario Health Department notified the
Texas Department of Health (TDH) about the *Cyclospora* infections in
the three Canadian businessmen. The businessmen had attended a meeting
at a private club in Houston, Texas on May 9-10.

A total of 28 people had attended the Houston business meeting.
Participants came from three U.S. states and Canada. Meals served during
the meeting were prepared at the restaurant operated by the private
club. Rumors among restaurant staff suggested that other attendees at
the meeting had also become ill.

TDH, the Houston Health & Human Services Department, and the Centers of
Disease Control and Prevention (CDC) initiated an epidemiologic
investigation to identify the source of the cyclosporiasis outbreak.

**Question 3:** What are the two most common types of epidemiologic
studies used to investigate the source of an outbreak (or other public
health problem)? Which would you use to investigate the source of the
cyclosporiasis outbreak in Texas? Why?

*In some outbreak investigations, laboratory, environmental, and/or
epidemiologic information available at the outset so clearly supports a
particular source for the outbreak that all that is needed is to
carefully examine the established facts. In most investigations,
however, the circumstances are not that straightforward and an
**analytic study** (which includes a comparison group) must be
undertaken. An analytic study allows investigators to quantify
relationships between a suspected exposure and disease, test hypotheses
about causal relationships, and explore the role of chance.*

*In outbreak investigations, two types of analytic studies are commonly
used:*

-   ***case-control study** -- in a case-control study, subjects are
    enrolled based on whether they have (or had) the disease of interest
    (i.e., are a "case") or not (i.e., are a "control").
    Characteristics, such as previous exposure to some factor, are then
    compared between cases and controls to see if there is a
    relationship between the disease and the exposure.*

> ![](media/image1.jpeg){width="3.879861111111111in"
> height="2.564583333333333in"}

-   ***cohort study** - in a cohort study, subjects are enrolled based
    on exposure (or lack of exposure) to a factor of interest (e.g.,
    whether or not they smoked cigarettes, took a particular medication,
    ate a particular food) or if they were a member of a particular
    group (e.g., were a guest at a wedding banquet, were a patient on a
    particular hospital ward). The occurrence of disease is then
    ascertained and compared between people with exposure to the factor
    of interest and those without the exposure to see if there is a
    relationship between exposure and disease.*

![](media/image2.jpeg){width="4.1in" height="2.5479166666666666in"}

*When do you use which type of study? A case-control study is typically
used when the population at risk is not known, when the disease under
investigation is rare, when the exposure is common, or if the time
between exposure and onset of the disease is long. A cohort study is
typically used when illness occurs among a well-defined group or
population, when exposure is rare, or when the disease is common.*

*The cyclosporiasis outbreak in Texas appears to be associated with a
business meeting that involved a small, well-defined group of attendees.
Therefore, it makes sense to undertake a **cohort study** to identify
the source of the outbreak. Because the study was initiated after the
outbreak occurred and will rely on the collection of exposure
information after the fact (i.e., after disease has developed), the
study is called a **retrospective cohort study**.*

Because the outbreak appeared to affect a small, well-defined group of
individuals (i.e., meeting attendees), investigators undertook a
retrospective cohort study to investigate the source of the
cyclosporiasis.

Investigators first surveyed people who attended the meeting to
characterize the illness associated with the outbreak. (Twenty-seven of
the 28 meeting attendees were interviewed.) All ill people experienced
severe diarrhea and weight loss. In addition, 87% reported loss of
appetite; 87% reported fatigue; 75% reported nausea; 75% reported
stomach cramps; and 25% reported fever. Five ill people had stool
specimens positive for *Cyclospora*.

Based on this information, investigators defined a case of
cyclosporiasis for the cohort study as diarrhea of at least 3 days
duration in someone who had attended the business meeting. Laboratory
confirmation of *Cyclospora* infection was not required.

![](media/image3.jpeg){width="3.55in" height="2.6783464566929136in"}Of
the 27 meeting attendees who were interviewed, 16 (59%) met the case
definition for cyclosporiasis. Onsets of illness occurred from May 14
through

May 19. (Figure 1)

Investigators questioned both ill and well meeting attendees about
travel history and food and water exposures during the meeting.

**Question 4:** Why would you question people who did not become ill
about possible sources of infection with *Cyclospora*?

*Analysis of exposures among ill people (i.e., cases) alone is
insufficient to determine the relationship between an exposure and a
disease. Exposures common among cases may be related to the disease or
may just be common in the group at large.*

***A comparison group is needed to determine how common exposure is in
the group at large**. The comparison group provides a baseline for the
level of exposure to the factor of interest (i.e., what you would expect
to find in the group at large if the exposure were not associated with
the disease). In the Texas cohort study, people who attended the Houston
meeting and did not become ill served as the comparison group.*

Restaurant management at the private club refused to take calls from
investigators or cooperate with the investigation. As a result, a list
of foods served at meals during the meeting was obtained from the
meeting organizer. No menu items were confirmed by restaurant staff.

Twenty-four meeting attendees provided information on foods eaten during
the meeting. (Four attendees, including three cases, did not provide the
information.) Investigators examined the occurrence of illness among
people who ate different food items.

Twelve (92%) of 13 attendees who ate the berry dessert became ill. Only
one (9%) of 11 attendees who did not eat the berry dessert became ill.
The relative risk for eating berries was 10.2 (p-value \<0.0001). No
other exposures were associated with illness.

Case-patients reported that the berry dessert contained strawberries.

**Question 5:** In your own words, interpret the results of the cohort
study.

*The following statements can be made based on the results of the cohort
study:*

-   *The attack rate for cyclosporiasis was **high among people who ate
    the berry dessert** (92%).*

-   *The attack rate for cyclosporiasis was **low among people who did
    not eat the berry dessert** (9%).*

-   *As a result, **the relative risk** (which compares the attack rate
    among people who ate the berry dessert with the attack rate among
    people who did not eat the berry dessert) **was high**. People who
    ate the berry dessert were over 10 times more likely to develop
    cyclosporiasis than those who did not.*

-   ***Most** (12 out of 13) **of the cases of cyclosporiasis** (who
    provided food histories) **were exposed** to the berry dessert so
    that the exposure could "explain" almost all cases.*

-   *There was a less than one-in-10,000 chance that the observed
    relative risk was due to chance alone.*

Students interested in examining the calculation of the relative risk
should be directed to Appendix 2.

# Question 6: What problems in study design or execution should you consider when reviewing the results of this study (or any epidemiologic study)? 

*In reviewing the results of an epidemiologic study, one should always
play devil's advocate and consider other possible explanations for the
findings. The following items/questions should be routinely considered
in interpreting any study results:*

-   ***selection bias** (i.e., who got into the study) - Was
    participation in the study good? Were ill and well persons who
    participated in the study representative of all ill and well
    persons? (In the Texas study: Participation in the study was good
    with 24 \[86%\] of 28 meeting attendees providing food exposure
    information.)*

-   ***information bias** (i.e., the validity of the information
    collected) - Was the information provided on exposure or disease
    development likely to reflect the truth? Did the exposures actually
    occur? Were cases really cases? Were individuals in the comparison
    group really well (i.e., could they have been asymptomatic or
    minimally symptomatic cases)? (In the Texas study: Only 5 \[31%\] of
    16 cases were laboratory confirmed; however, the case definition
    \[diarrhea lasting at least three days\] reflected a fairly serious
    illness and probably identified true cases of cyclosporiasis. Since
    [Cyclospora]{.underline} infection can be asymptomatic, some "well"
    persons may have actually been infected, but the proportion is
    unknown. Study participants had to recall what they ate a week
    earlier and may have had some difficulty providing accurate food
    histories from the meeting. In addition, it appears that food items
    served during the meeting were not confirmed with restaurant
    management.)*

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-   ***confounding** (i.e., other explanatory factors) - Is there
    another factor that is independently associated with both the
    exposure and the disease of interest that may distort the
    exposure-disease relationship? Is there an item consistently served
    with the implicated food that was actually the source of the
    infection? (In the Texas study: We do not know what analyses were
    performed to search for confounding.)*

-   ***investigator error** - Were there problems with the execution of
    the study? Were enrollment criteria followed? Were case definitions
    consistently applied? Were data entry and calculations verified
    making investigator error remote? (In the Texas study: We do not
    know if there were problems in executing the study or with data
    entry or analysis.)*

On June 4, before the first investigation had been completed, TDH was
notified of another outbreak of cyclosporiasis involving physicians who
attended a dinner on May 22 at a Houston, Texas restaurant. A second
cohort study was undertaken. Nineteen attendees were interviewed. Ten
met the case definition for cyclosporiasis (i.e., diarrhea of at least 3
days duration).

Attendees who ate dessert at the dinner were more likely to become ill
than attendees who did not. Illness, however, was not associated with
eating a particular type of dessert. No other exposures were associated
with illness.

All desserts were garnished with either one fresh strawberry (for
regular patrons) or with a strawberry, blackberry, and raspberry (for
VIPs). Of the 7 attendees who reported eating a strawberry, all seven
became ill. Of the eight attendees who reported not eating a strawberry,
only one became ill (relative risk = 8.0, p-value = 0.001). (Note: four
attendees, including two cases, could not recall whether they had eaten
a strawberry and were excluded from this analysis.)

Based on the results of the two cohort studies, investigators
hypothesized that strawberries were the source of the cyclosporiasis
outbreaks in Houston.

**Question 7:** What additional studies might confirm (or refute) the
hypothesis that strawberries were the source of the cyclosporiasis
outbreaks?

*Studies that might help confirm (or refute) the strawberry hypothesis
include:*

-   *collection and testing of the implicated strawberries for
    [Cyclospora]{.underline}*

-   *traceback of the strawberries from the two events to the
    producer/distributor*

-   *a search for additional cases of the disease (and their likely
    source)*

*At the time of the outbreak, there was no effective testing procedure
for [Cyclospora]{.underline} on produce, so the likely utility of that
action is questionable. If a traceback investigation of the strawberries
from the two events found that the strawberries originated from the same
producer/distributor or had specific places in common during
production/distribution, that information would support the hypothesis
that the strawberries were the source of the outbreak. Conversely, if
the strawberries from the two events did not have any specific places in
common, it would suggest that the strawberries were not the source of
these outbreaks. Finally, because it is unlikely that the implicated
strawberries were only distributed to the two restaurants in Houston
associated with these outbreaks, other persons probably consumed them.
And if the strawberries were the source of the outbreak, there would be
other cases of cyclosporiasis in the community. A search for additional
cases would be most beneficial in further exploring the source of the
infection*

TDH staff examined invoices and other records from the two restaurants
involved in the Texas cyclosporiasis outbreaks. The strawberries
consumed at both the May 9-10 business meeting and the May 22 physician
dinner were grown in California. The individual producers/distributors
of the strawberries, however, were not determined.

On May 31, TDH released a public health advisory about the presumed link
between the consumption of California strawberries and the
cyclosporiasis outbreak. The State Health Officer advised consumers to
wash strawberries \"very carefully\" before eating them, and recommended
that people with compromised immune systems (e.g., people with HIV
infection, patients on cancer chemotherapy) avoid them entirely.

A few days later, Ontario\'s chief medical officer reported on an
outbreak of cyclosporiasis in the Metro Toronto area affecting 40
people. Ontario public health officials believed California strawberries
were also the source of the Toronto outbreak. A public health advisory,
similar to the one from Texas, was issued.

Concurrent with the announcements from Texas and Ontario, CDC encouraged
physicians from across the United States to report cases of
cyclosporiasis to their local or state health department so that the
source of the *Cyclospora* could be investigated further.

**Question 8:** You are writing a newspaper article about the
cyclosporiasis outbreaks in Texas and Ontario. It is thought that the
cyclosporiasis problem is ongoing. Four people are available for
interview: the CDC expert on cyclosporiasis, one of the Canadian
businessmen who became ill following the meeting in Houston, the owner
of the private club in Houston where the first outbreak occurred, and
the attorney for the California Strawberry Grower's Association. Your
deadline is looming. You have time to ask each of these people only
three questions. What would you ask them?

# 

# 

# 

# 

# 

#  

# Part III -- Outbreaks in Other States 

Despite recommendations by health departments in Texas and Ontario to
wash strawberries carefully before eating them, cases of cyclosporiasis
continued to occur nationwide. By the end of June, over 800
laboratory-confirmed *Cyclospora* infections were reported to CDC from
20 states, the District of Columbia, and two Canadian provinces. (Figure
2)

![](media/image4.jpeg){width="4.320078740157481in"
height="3.0291338582677168in"}Discrepancies began to appear in the link
between California strawberries and the *Cyclospora* infections.
Investigations undertaken by the New York City Health Department and
South Carolina Department of Health and Environmental Control pointed
toward raspberries as the source of the cyclosporiasis outbreaks in
their jurisdictions.

In late June, the New Jersey Department of Health and Senior Services
(NJDHSS) initiated an epidemiologic investigation to identify the source
of infection among cyclosporiasis cases in New Jersey residents. The
cases to be included in the New Jersey study were not linked together by
a common event and did not occur in a well-defined group of people.

**Question 9:** Would you undertake a case-control or a cohort study to
investigate the source of the cyclosporiasis cases in New Jersey? Why?

*The cases are "sporadic". They **do not arise from a well-defined group
of people** (i.e., the population at risk is not known). Furthermore,
the disease (i.e., cyclosporiasis) is relatively rare in the general
population and there are several exposures of interest (e.g.,
strawberries, raspberries). As a result, it would make most sense to
undertake a **case-control study** to explore the source of infection
among the sporadic cases of cyclosporiasis in New Jersey.*

To assess possible risk factors for infection among the cases of
cyclosporiasis in New Jersey, NJDHSS conducted a case-control study. In
contrast to the Texas investigation, a case of cyclosporiasis for this
study was defined as a patient with laboratory-confirmed *Cyclospora*
infection and a history of diarrhea.

**Question 10:** How might you identify cases of cyclosporiasis for the
case-control study? Who would you use as controls?

*There are many sources that can help investigators identify cases of a
particular disease. These include:*

-   *passive surveillance (if the disease is notifiable)*

-   *laboratory reports*

-   *requests to health care providers*

-   *chart reviews at hospitals or health care provider offices*

-   *surveys of known cases*

-   *surveys of the affected population*

-   *requests to the public through the media*

Since the New Jersey study focuses on laboratory-confirmed cases, review
of laboratory records would be most appropriate.

*Controls should be people without the health problem under
investigation who are representative of the population from which the
cases originated. They should be at risk for the health problem (i.e.,
they can develop the problem), have the potential for exposure to the
factor(s) of interest, and be selected independent of their exposure to
the factor(s) of interest. For the New Jersey study, investigators would
want to use people with access to the same food sources as the cases.
Therefore, they might use members of the case's family who are well or
people living in the same neighborhood.*

For the New Jersey case-control study, cases were identified by
reviewing laboratory records from all clinical laboratories in the
state. Forty-two cases were identified. Two controls were identified for
each case through telephone calls to randomly selected households in the
community. To be eligible for the study, controls could not have had
loose stools during the previous 30 days.

Investigators interviewed 30 case-patients and 60 controls by telephone
using a standardized questionnaire that asked about possible exposures
(including consumption of 17 fruits and 15 vegetables, water and soil
exposures, and animal contact) during the period of interest.

Case-patients and controls were similar with respect to age, sex, and
level of education. Twenty-one (70%) of 30 case-patients and four (7%)
of 60 controls had eaten raspberries. The odds ratio for eating
raspberries was 32.7 (p-value \<0.000001). No other exposures (including
strawberries) were associated with illness.

**Question 11:** In your own words, interpret the results of the New
Jersey case-control study.

*The **odds of exposure to raspberries was over 32 times higher** among
cases of cyclosporiasis than among controls. The probability that this
finding was due to chance alone was less than one-in-a-million (i.e.,
the finding was statistically significant). In addition, this exposure
could explain 70% of cases.*

*If investigators can rule out selection bias, information bias,
confounding, and investigator error, the findings suggest that eating
raspberries was a risk factor for cyclosporiasis in New Jersey.*

Studies from other states and Canada supported the results from New
Jersey, New York City, and South Carolina. A total of 725 cases of
cyclosporiasis associated with 55 different events (e.g., wedding
receptions, parties, buffets) were investigated. The only exposure
consistently associated with cyclosporiasis was the consumption of
raspberries.

Raspberries were served at 54 of the 55 events and were the only berries
served at 11 events. (Reexamination of the events associated with the
initial outbreaks in Texas and Ontario indicated that raspberries were
included among the implicated berry items served at those events.) The
median attack rate for cyclosporiasis among persons who ate items that
contained raspberries at the different events was 93%. Furthermore, for
27 of the 41 events for which adequate data were available, the
associations between the consumption of raspberries and cyclosporiasis
were statistically significant (p-value\<0.05).

The origin (i.e., producer) and mode of contamination of the raspberries
served at the events were unknown. Due to the large number of raspberry
producers at the time of the outbreaks (both domestic and
international), public health officials could not recall the implicated
raspberries or remove them from the marketplace. Traceback
investigations were planned.

**Question 12:** Would you alert the public of this possible public
health threat? Defend your answer.

*NOTE TO INSTRUCTORS: Have students vote on this question. Then select a
few voting for and against to defend their opinions. (There is no right
or wrong answer. It is largely a matter of judgment.)*

Public health officials often struggle with decisions similar to this
one (called the "Grey Zone" in the business). Going public at this point
means that you will tell people about a problem without being able to
tell them what to do about it. And, broad/vague warnings can
unnecessarily harm products not responsible for the problem and
undermine the public's confidence in the public health system.

######### Pros

Alerting the public to the linkage between raspberries and
cyclosporiasis will result in consumers avoiding raspberries, in
general. If the exposure is ongoing (i.e., contaminated raspberries are
still available), this will prevent additional cases of cyclosporiasis
from occurring as well as the morbidity, mortality, and costs associated
with those cases. Avoidance of infection would be particularly critical
for individuals at risk for serious complications of the illness (e.g.,
children under five years of age, the elderly, immunocompromised
individuals).

######### Cons

*Without specification of the producer, consumers will avoid all
raspberries, resulting in an economic hardship for the entire raspberry
industry. Consumers may continue to avoid raspberries even after the
specific source of the problem is identified and corrected, taking
months for individual producers and the industry to recover. In
addition, vague or nonspecific warnings will heighten the public's
anxiety but not provide them with a means to do anything about it. If
warnings continue to be non-constructive, the public will eventually
stop listening to them.*

# Part IV -- Traceback and Environmental Investigations

To identify the sources of raspberries served at the 54 events linked to
outbreaks of cyclosporiasis, CDC, the U.S. Food and Drug Administration
(FDA), and health departments from the affected states obtained
information on the place and dates of purchase of the implicated
raspberries. Distributors and importers of the raspberries were
identified through invoices and shipping documents. Airway bill numbers
and importation documents (e.g., Custom's forms), supplied by importers,
were used to identify overseas shipments and exporters.

By the third week of July, investigators had documented the source of
the raspberries for 29 of the 54 cyclosporiasis-associated events. For
21 of these events, the raspberries definitely came from Guatemala. For
8 events, the raspberries could have originated there. No commonalities
were found in the U.S. ports of entry for the implicated raspberries.

During the outbreak period, raspberries had been imported from a number
of countries. Based on monthly data from the U.S. Department of
Agriculture, Guatemalan raspberries represented 4-20% of fresh
raspberries (domestic and imported) shipped within the United States in
April-June of 1996.

**Question 13:** Does the traceback information support raspberries as
the source of the cyclosporiasis outbreak?

*The fact that a large proportion of the raspberries associated with the
outbreaks were linked to a common place (i.e., Guatemala) is strong
evidence that they were the source of the outbreak. This finding is even
more notable given that only 4-20% of raspberries shipped within the
United States during that time period came from Guatemala.*

*NOTE TO INSTRUCTORS: The implicated food item was fresh produce which
is notoriously difficult to trace due to the short shelf-life, multiple
possible shipments, and lack of brand-name recognition. Although glossed
over in the above description, much time and effort went into the
documentation of the source of the raspberries.*

At the time of the investigation, seven Guatemalan exporters, of which A
and B were the largest, shipped raspberries to the United States. The
raspberries for 25 of the 29 events were traced to only one Guatemalan
exporter per event:

-   18 of 25 (72%) to Exporter A

-   5 (20%) to Exporter B

-   1 (4%) to Exporter C

-   1 (4%) to Exporter D

Using exporter records, the raspberries were traced back to the farm
where they were grown. Because exporters typically combined raspberries
from multiple farms in a shipment, investigators could identify only a
group of contributing farms (an average of 10 farms with a range of 2 to
30) rather than one source farm per event. More than 50 farms could have
contributed to implicated shipments of raspberries.

To investigate how raspberries were grown and handled in Guatemala, CDC
and FDA investigators visited Exporters A, B, C, and D and the seven
most commonly implicated raspberry producing farms (six supplying
Exporter A and one supplying Exporter B).

**Question 14:** Given what you know about the transmission of
cyclosporiasis, on what cultivation or harvesting practices would you
focus in the investigation of the raspberry-producing farms?

*One would want to focus on activities that could allow the raspberries
to become contaminated with feces containing [Cyclospora]{.underline}.
This would include:*

-   *irrigation water (and source wells)*

-   *proximity of fields or irrigation water to sources of human fecal
    material (e.g., pit latrines, outhouses, privies, and septic
    systems)*

-   *substances added to the soil which could contaminate the
    raspberries (e.g., manure, fertilizer)*

-   *substances applied to the raspberries (e.g., insecticides,
    fungicides, and liquids used to dilute these substances)*

-   *harvesting or processing equipment or surfaces that might come in
    contact with the raspberries*

-   *human handling of raspberries*

-   *storage containers*

-   *shipping trucks*

*NOTE: The focus of the investigation was on contamination of
raspberries with human feces. However, it was not and is still not known
if animals can become infected with Cyclospora or be a source of
infection for humans. Therefore, this focus may not have been
appropriate.*

The six most commonly implicated farms supplying Exporter A were in the
same region of Guatemala. All six began harvesting for the first time in
1996 and often had raspberries in the same shipment. Five of the farms
obtained agricultural water from wells. These wells varied in
construction, depth, and quality. Two of the five farms also stored well
water in reservoirs constructed of concrete blocks and covered with
concrete. The sixth farm used river water. The farm that supplied
raspberries to Exporter B was 25 km from the closest of the six farms
that sold raspberries to Exporter A. That farm used well water, which
was stored in a mesh-covered, plastic-lined, man-made reservoir.

At all seven farms, ground-level drip irrigation was used (primarily
during the dry season) to avoid direct contact between raspberries and
water. Agricultural water was also used to mix insecticides and
fungicides that were sprayed directly onto raspberries, sometimes as
late as the day they were harvested. At all farms, the raspberries were
picked and sorted by hand, packed in plastic containers, and flown to
the United States within 36 hours of picking.

Agricultural water at the seven farms (and on Guatemalan raspberry
farms, in general) was filtered to remove debris but not microbes.
Testing of agricultural-water samples from the seven farms indicated at
least intermittent contamination with bacteria commonly found in sewage
and human wastes (i.e., "coliforms" such as *Escherichia coli*). No
*Cyclospora* were found.

No *Cyclospora* were found in samples of Guatemalan raspberries obtained
from the farms during the traceback investigation.

**Question 15:** *Cyclospora* were not found in any Guatemalan
raspberries or water samples. If the Guatemalan raspberries were the
source of the cyclosporiasis outbreaks, list plausible explanations for
this finding.

*There are several possible explanations for not finding
[Cyclospora]{.underline} on Guatemalan raspberries or water samples at
the time of the traceback investigations:*

-   ***Testing methods** for [Cyclospora]{.underline} were
    **insensitive**. A small number of [Cyclospora]{.underline}
    organisms is probably enough to make people sick but the available
    methods for testing food for [Cyclospora]{.underline} were not
    adequately sensitive to detect low levels of contamination. At the
    time of the outbreak, [Cyclospora]{.underline} had never been
    isolated from any food item or water.*

-   The water and raspberries from the farms were **collected after the
    outbreak period**. Leftover raspberries from the
    cyclosporiasis-associated events in the United States and Canada
    were not available for testing. If contamination was temporary or
    intermittent (e.g., associated with environmental conditions such as
    excessive rain and flooding), one might not expect to find
    contaminated raspberries or water at the time of the traceback
    investigations.

-   *The contamination of the raspberries could have occurred **during
    transport and/or shipping**.*

> *Of course, some might interpret this finding to mean that the
> raspberries were not the source of the outbreak of cyclosporiasis.
> (But this is an unlikely explanation given the rest of the evidence!)*

Investigators hypothesized that the raspberries became contaminated
through spraying with insecticides and fungicides that had been mixed
with contaminated water from improperly constructed or maintained wells
near deep pit latrines or seepage pits. The wells may have been
particularly vulnerable to contamination during the rainy season (e.g.,
from surface-water runoff), when the 1996 outbreak occurred. Once
contaminated, the raspberries remained contaminated until eaten because
they were too fragile and covered with crevices to be washed thoroughly.

By July 18, 1996, CDC and FDA declared that raspberries from Guatemala
were the likely source of the *Cyclospora* outbreak.

**Part V -- Control and Prevention Measures**

Although skeptical of study findings and suspicious of potential trade
barriers, the government of Guatemala, Guatemalan raspberry growers and
exporters, and the Guatemalan Berries Commission (a growers'
organization) collaborated with CDC and FDA to decrease the risk of
contamination of Guatemalan raspberries during growth, harvest, and
packaging.

**Question 16:** What specific measures would you suggest to decrease
the likelihood of contamination of raspberries from the Guatemalan
farms?

*The following measures will help decrease the likelihood of
contamination of raspberries with [Cyclospora]{.underline} at the
Guatemalan farms:*

-   Renovate (or construct new) wells and reservoirs so that potable
    water supplies are consistently safe for drinking and not vulnerable
    to contamination during periods of excessive surface-water runoff.

-   *Use potable water for drinking, handwashing, cleaning surfaces that
    touch berries, and mixing substances sprayed onto berries (e.g.,
    insecticides, fungicides).*

-   *Instruct workers on personal hygiene and the need to wash hands
    after going to the bathroom and before handling the raspberries or
    touching surfaces that will come into contact with the berries.*

-   *Provide adequate sanitary and handwashing facilities for workers to
    decrease the potential for direct or indirect contamination of
    berries.*

-   *Work with applied food safety researchers to identify methods
    to: 1) decrease cross-contamination of berries on surfaces used to
    sort and inspect them and 2) inactivate [Cyclospora]{.underline}
    oocysts on raspberries using a treatment that does not affect the
    quality or taste of the berries (e.g., gamma irradiation).*

-   *If contaminated raspberries are identified, undertake traceback
    investigations to identify the source farm. To facilitate these
    traceback investigations in the future, distributors should indicate
    the source farm on all containers (e.g., clamshell containers) used
    to package the raspberries for sale and invoices.*

The Guatemalan raspberry growers voluntarily improved employee hygiene,
sanitation, and water quality. They implemented systems to monitor the
production of the raspberries so that potential points of contamination
could be identified and addressed (i.e., Hazard Analysis and Critical
Control Point systems). The Guatemalan Berries Commission established a
farm classification system (with only farms in the best class permitted
to export) in an attempt to minimize the exportation of
*Cyclospora*-contaminated raspberries to the United States.

During the fall and winter of 1996, no outbreaks of cyclosporiasis in
the United States were linked to Guatemalan raspberries. In the spring
of 1997, however, another multistate outbreak occurred. By the end of
May, more than a thousand new cases of cyclosporiasis had been reported
from18 states and two provinces in Canada. Consumption of raspberries
was strongly associated with the outbreaks and the preponderance of the
traceback data implicated Guatemala as the source of the raspberries,
suggesting either some farms did not fully implement the control
measures or the contamination was associated with a source against which
these measures were not directed.

In the face of warnings by U.S. public health authorities on the danger
of eating Guatemalan raspberries, the government of Guatemala and the
Guatemalan Berries Commission voluntarily suspended exports of fresh
raspberries to the United States on May 30, 1997. (See "FDA Talk
Paper".) The interruption of exportation caused large economic losses
for the producers, especially small and medium-sized ones.

+-----------------------------------------------------------------------+
| # FDA TALK PAPER                                                      |
|                                                                       |
| > *Food and Drug Administration\                                      |
| > U.S. Department of Health and Human Services\                       |
| > Public Health Service 5600 Fishers Lane Rockville, MD 20857*        |
| >                                                                     |
| > T97-22 June 10, 1997                                                |
| >                                                                     |
| > OUTBREAKS OF CYCLOSPORIASIS AND GUATEMALAN RASPBERRIES              |
| >                                                                     |
| > We have been receiving inquiries about recent U.S.                  |
| >                                                                     |
| > outbreaks of cyclosporiasis, a diarrheal illness resulting from     |
| >                                                                     |
| > ingestion of the *Cyclospora* parasite. The following may be        |
| >                                                                     |
| > useful for answering questions.                                     |
| >                                                                     |
| > According to the U.S. Centers for Disease Control and               |
| >                                                                     |
| > Prevention, fresh raspberries from Guatemala are the likely cause   |
| >                                                                     |
| > of outbreaks of cyclosporiasis that have occurred since mid-April   |
| >                                                                     |
| > in at least seven states including California, Maryland,            |
| >                                                                     |
| > Nebraska, Nevada, New York, Rhode Island and Texas. CDC and FDA     |
| >                                                                     |
| > are cooperating in investigating the outbreaks, examining           |
| >                                                                     |
| > epidemiological evidence and tracing the source of implicated       |
| >                                                                     |
| > raspberries.                                                        |
| >                                                                     |
| > FDA and CDC were informed by the Guatemalan government and          |
| >                                                                     |
| > the Guatemalan Berries Commission on May 30 that the country\'s     |
| >                                                                     |
| > growers voluntarily suspended shipment of fresh raspberries to      |
| >                                                                     |
| > the United States. FDA is working with CDC, the Guatemalan          |
| >                                                                     |
| > government and the Guatemalan Berries Commission to determine       |
| >                                                                     |
| > when the country may resume shipment of fresh raspberries to the    |
| >                                                                     |
| > United States.                                                      |
| >                                                                     |
| > FDA believes that few if any fresh raspberries from                 |
| >                                                                     |
| > Guatemala remain on the U.S. market due to the short shelf life     |
| >                                                                     |
| > of the commodity. However, if any consumers, distributors,          |
| >                                                                     |
| > caterers, restauranteurs or retail establishments are holding       |
| >                                                                     |
| > fresh raspberries labeled as Product of Guatemala, they should      |
| >                                                                     |
| > not serve, sell or eat them.                                        |
| >                                                                     |
| > FDA is advising consumers who have recently eaten fresh             |
| >                                                                     |
| > raspberries from Guatemala and who are suffering diarrheal          |
| >                                                                     |
| > illness to see a doctor for diagnosis and possible treatment for    |
| >                                                                     |
| > cyclosporiasis.                                                     |
| >                                                                     |
| > *Cyclospora* infects the small intestine and causes watery          |
| >                                                                     |
| > diarrhea with frequent, sometimes explosive bowel movements.        |
| >                                                                     |
| > Other symptoms include loss of appetite, substantial loss of        |
| >                                                                     |
| > weight, bloating, increased gas, stomach cramps, nausea,            |
| >                                                                     |
| > vomiting, muscle aches, low-grade fever and fatigue. Symptoms       |
| >                                                                     |
| > usually develop about a week after consuming contaminated           |
| >                                                                     |
| > product. *Cyclospora* infection can be successfully treated with    |
| >                                                                     |
| > appropriate antibiotics.                                            |
| >                                                                     |
| > FDA will convene a public meeting in July to review the             |
| >                                                                     |
| > science on *Cyclospora* on fresh produce and its control. The       |
| >                                                                     |
| > date and other details of that meeting will be made public when     |
| >                                                                     |
| > they are available.                                                 |
| >                                                                     |
| > \####                                                               |
+-----------------------------------------------------------------------+

CDC and FDA continued to work with the government of Guatemala and the
Berries Commission to determine when the safety of Guatemalan
raspberries could be assured and exports could resume. The exportation
of raspberries resumed in mid-June; however, U.S. public health
authorities continued to warn of the dangers of eating Guatemalan
raspberries.

In December 1997, amid objections from the Guatemalan government, FDA
announced that it was blocking imports of raspberries from Guatemala for
1998. Before this time, FDA rarely denied imports without physical
evidence, and this ban was based only on epidemiological evidence about
past outbreaks and FDA observations on current raspberry production
practices. Congressional representatives and supporters of free trade
railed about protectionism and questioned the science behind the
decision since *Cyclospora* had not been identified on any raspberries
from Guatemala.

**Question 17:** Do you believe that the raspberries were the source of
the multistate outbreaks of cyclosporiasis? Which of the criteria for
causality (i.e., strength of association, biological plausibility,
consistency with other studies, exposure precedes disease, and
dose-response effect) have been satisfied in the linkage between
raspberries and cyclosporiasis? How would you convince others on the
validity of these findings?

*Although no smoking gun was found (i.e., raspberries contaminated with
[Cyclospora]{.underline}), there is good epidemiologic, laboratory, and
environmental evidence that the raspberries were the source of the
outbreak:*

-   ***strength of association** - The median attack rate at the
    cyclosporiasis-associated events in North America was high among
    persons who ate items that contained raspberries. A statistically
    significant association between raspberries and cyclosporiasis was
    determined for a large proportion of the investigations of these
    events. Data from case--control studies of sporadic cases of
    cyclosporiasis in New York City, New Jersey, and Florida also
    demonstrated strong associations between illness and raspberries
    (large odds ratios).*

-   ***biological plausibility** - The possibility of foodborne
    transmission of [Cyclospora]{.underline} had been considered in
    previous outbreaks including an outbreak that occurred in Florida
    in 1995. Environmental investigations identified several potential
    sources of contamination during growth, harvest, and packaging of
    the raspberries. Water supplies at a number of the Guatemalan farms
    (used for irrigation and dilution of insecticides and fungicides)
    were found to be contaminated with [E]{.underline}.
    [coli]{.underline}, and could have contained other contaminants from
    human wastes. The timing of the outbreaks occurred during the rainy
    season when surface-water runoff would have been at its greatest,
    increasing the risk of contamination of suboptimally constructed or
    maintained wells near deep pit latrines or seepage pits.*

-   ***consistency with other studies** - Multiple investigations (by
    different investigators) identified raspberries as the source of the
    cyclosporiasis outbreaks associated with events in North America.
    Traceback investigations of raspberries served at these events
    repeatedly led to Guatemalan raspberries. The timing of cases
    coincided with rising and falling imports of raspberries from
    Guatemala and the outbreaks ended after suspension of raspberry
    exports from Guatemala.*

-   ***exposure precedes disease** -- Exposure to raspberries preceded
    illness in both event-associated and sporadic cases in North
    America. The median incubation period for cases associated with
    events in North America was 7 days and ranged from 1 to 14 days (by
    definition, \<15).*

-   ***dose-response effect** -- No information/data supporting this
    criterion for causation was reported in the literature.*

The U.S. ban on importation of Guatemalan raspberries became effective
on March 15, 1998 and continued through August 15, the normal Guatemalan
raspberry exporting season. With the ban in place, outbreaks of
cyclosporiasis did not occur in 1998 in the United States.

Canadian officials decided not to block the importation of Guatemalan
raspberries in 1998. In May and June, a multicluster outbreak of
cyclosporiasis occurred in Ontario involving over 300 people.
Investigations linked the outbreak to raspberries from Guatemala.

Beginning in the spring of 1999, the United States allowed entry of
raspberries from farms that complied with a detailed program of food
safety practices and successfully passed Guatemalan government
inspections and FDA audits. That spring, there were several
cyclosporiasis outbreaks in the United States and Canada; however,
Guatemalan raspberries were not implicated as a source for any. In 2000,
two outbreaks of cyclosporiasis were linked to raspberries traced to one
Guatemalan farm. That farm discontinued exportation of raspberries.

As of June 2004, no further outbreaks of cyclosporiasis have been
associated with Guatemalan raspberries. However, only three of the
original 85 Guatemalan raspberry growers continue to export raspberries.

**Epilogue**

Announcements by Texas and Ontario public health officials implicating
California strawberries as the source of the cyclosporiasis outbreaks in
May of 1996 had a devastating effect on the strawberry industry.
Supermarket chains took California strawberries off their shelves, in
response to pressure from consumers. Consumers stopped buying
strawberries from all sources. Truckloads of strawberries headed for
market rotted as they were turned away by produce and grocery store
managers. Strawberry sales around the United States and Canada crashed,
causing \$40 million in losses for the industry and the loss of 5,000
jobs.

And, in the end, the actual vehicle for the outbreak turned out to be
Guatemalan raspberries, not strawberries.

**Question 18:** To prevent additional cases of a health problem (and
possible hospitalizations and deaths), public health authorities are
often required to make decisions on control measures when data are
suggestive of the source of the problem but are, perhaps, not
conclusive. What criteria would cause you to implement control measures
for a health problem before you were absolutely certain of the source?

![](media/image5.jpeg){width="2.479861111111111in"
height="0.9506944444444444in"}*In making timely decisions to implement
control measures, public health officials must **balance** the potential
public health impact of a problem with the known quality of available
data and the potential damage to business or industry.*

*Information that might lead officials into taking action when data are
suggestive of the source but insufficient to make a definitive call
include:*

-   ***the severity of the disease** (e.g., [E]{.underline}.
    [coli]{.underline} O157:H7, botulism) (i.e., one may be moved to act
    more quickly with a very serious or potentially fatal disease than
    one which is mild or self-limiting)*

-   ***the population at risk** (e.g., infants, immunocompromised
    persons, the elderly) (i.e., if the population at risk includes
    persons who are highly likely to have poor outcomes from the
    infection/intoxication, then one may be moved to act more quickly)*

-   ***whether exposure is suspected to still be occurring***

-   ***the quality of available data** (e.g., use of a controlled study
    of sufficient size to detect differences, low probability of
    selection or information bias or confounding, consistency with other
    studies)*

-   ***potential impact on business/industry** (e.g., is the decision
    likely to impact an entire industry or a single business or
    foodhandler?)*

*So what went wrong in Texas? In actuality, public health officials had
data that **properly** implicated "berry dessert items" served at the
two Houston events linked with the cyclosporiasis outbreaks. However,
their results could not distinguish between the ingredients in the
dessert and reports were inconsistent concerning the types of berries in
the dessert. Based on information from case-patients from the Houston
business meeting (who recalled that the dessert contained strawberries)
and under pressure to act quickly, Texas investigators declared that the
source of the outbreak was strawberries from California. If Texas
investigators had considered results from other investigations occurring
at the same time (New York City and South Carolina) or completed
tracebacks of the California strawberries (which probably would not have
led to the same producers/distributors), they may have been able to
clarify the potential risk from the strawberries, raspberries, or other
ingredients in the desserts.*

**References**

CDC. Outbreaks of *Cyclospora cayetanensis* infection \-- United States,
1996. *Morbidity and Mortality Weekly Report* 1996;45(25):549-551.

CDC. Update: Outbreaks of *Cyclospora cayetanensis* infection \-- United
States and Canada, 1996. *Morbidity and Mortality Weekly Report*
1996;45(28):611-612.

CDC. Outbreaks of cyclosporiasis \-- United States, 1997. *Morbidity and
Mortality Weekly Report* 1997;46(20):451-452.

## CDC. Update: Outbreaks of cyclosporiasis \-- United States, 1997. *Morbidity and Mortality Weekly Report* 1997;46(21):461-462.

CDC. Update: Outbreaks of cyclosporiasis \-- United States and Canada,
1997. *Morbidity and Mortality Weekly Report* 1997;46(23);521-523.

Herwaldt BL, Ackers ML. An outbreak in 1996 of cyclosporiasis associated
with imported raspberries. The Cyclospora Working Group. *N Engl J Med*
1997;336:1548-56.

## Herwaldt BL, Beach MJ. The return of *Cyclospora* in 1997: Another outbreak of cyclosporiasis in North America associated with imported raspberries. *Annals of Internal Medicine* **1999;130:210-220.** 

Herwaldt BL. *Cyclospora cayetanensis*: A review, focusing on the
outbreaks of cyclosporiasis in the 1990s. *Clin Infect Dis*
2000;31:1040-57.

Texas Department of Health. Outbreaks of *Cyclospora* infection.
*Disease Prevention News* 1997;57 (11):1-4.

**APPENDIX 1: CDC Cyclosporiasis Fact Sheet** (available at
http://www.cdc.gov/az.do)

*Cyclospora* *cayetanensis* (SIGH-clo-SPORE-uh KYE-uh-tuh-NEN-sis) is a
parasite composed of one cell, too small to be seen without a
microscope. The first known human cases of illness caused by
*Cyclospora* infection (i.e., cyclosporiasis) were reported in 1979.
Cases began being reported more often in the mid-1980s. In the last
several years, outbreaks of cyclosporiasis have been reported in the
United States and Canada.

#### 

#### How is *Cyclospora* spread?

*Cyclospora* is spread by people ingesting something, for example, water
or food that was contaminated with infected stool. For example,
outbreaks of cyclosporiasis have been linked to various types of fresh
produce. *Cyclospora* needs time (days or weeks) after being passed in a
bowel movement to become infectious. Therefore, it is unlikely that
*Cyclospora* is passed directly from one person to another. It is
unknown whether animals can be infected and pass infection to people.

#### 

#### Who is at risk for infection?

People of all ages are at risk for infection. In the past, *Cyclospora*
infection was usually found in people who lived or traveled in
developing countries. However, people can be infected worldwide,
including the United States.

#### 

#### What are the symptoms of infection?

*Cyclospora* infects the small intestine (bowel) and usually causes
watery diarrhea, with frequent, sometimes explosive, bowel movements.
Other symptoms can include loss of appetite, substantial loss of weight,
bloating, increased gas, stomach cramps, nausea, vomiting, muscle aches,
low-grade fever, and fatigue. Some people who are infected with
*Cyclospora* do not have any symptoms.

#### 

#### How soon after infection will symptoms begin?

The time between becoming infected and becoming sick is usually about 1
week.

#### 

#### How long will symptoms last?

If not treated, the illness may last from a few days to a month or
longer. Symptoms may seem to go away and then return one or more times
(relapse).

#### 

#### What should I do if I think I may be infected?

See your health care provider.

#### 

#### How is *Cyclospora* infection diagnosed?

Your health care provider will ask you to submit stool specimens to see
if you are infected. Because testing for *Cyclospora* infection can be
difficult, you may be asked to submit several stool specimens over
several days. Identification of this parasite in stool requires special
laboratory tests that are not routinely done. Therefore, your health
care provider should specifically request testing for *Cyclospora*. Your
health care provider may have your stool checked for other organisms
that can cause similar symptoms.

#### 

#### How is infection treated?

The recommended treatment for infection with *Cyclospora* is a
combination of two antibiotics, trimethoprim-sulfamethoxazole, also
known as Bactrim\*, Septra\*, or Cotrim\*. People who have diarrhea
should rest and drink plenty of fluids.

#### 

#### I am allergic to sulfa drugs; is there another drug I can take?

No alternative drugs have been identified yet for people who are unable
to take sulfa drugs. See your health care provider for other treatment
recommendations.

#### How is infection prevented?

Avoiding water or food that may be contaminated with stool may help
prevent *Cyclospora* infection. People who have previously been infected
with *Cyclospora* can become infected again.

#### 

#### For more information:

1.  CDC. Outbreak of cyclosporiasis \-- northern Virginia-Washington,
    D.C.-Baltimore, Maryland, metropolitan area, 1997. *MMWR* 1997;
    46:689-91.

2.  Herwaldt BL, et al. An outbreak in 1996 of cyclosporiasis associated
    with imported raspberries. *N Engl J Med* 1997;336:1548-56.

3.  Herwaldt BL, et al. The return of *Cyclospora* in 1997: another
    outbreak of cyclosporiasis in North America associated with imported
    raspberries. *Ann Intern Med* 1999;130:210-20.

4.  Hoge CW, et al. Placebo-controlled trial of co-trimoxazole for
    cyclospora infections among travellers and foreign residents in
    Nepal. *Lancet* 1995;345:691-3.

5.  Hoge CW, et al. Epidemiology of diarrhoeal illness associated with
    coccidian-like organism among travellers and foreign residents in
    Nepal. *Lancet* 1993;341:1175-9.

6.  Huang P, et al. The first reported outbreak of diarrheal illness
    associated with *Cyclospora* in the United States. *Ann Intern Med*
    1995;123:409-14.

7.  Ortega YR, et al. Cyclospora species - a new protozoan pathogen of
    humans. *N Engl J Med* 1993;328:1308-12.

8.  Soave R. *Cyclospora*: an overview. *Clin Infect Dis*
    1996;23:429-37.

9.  Soave R, et al. Cyclospora. *Infect Dis Clinics N Amer*
    1998;12:1-12.

# APPENDIX 2: Calculating Measures of Association

# Cohort studies

The **relative risk** is the measure of association for a cohort study.
It tells us how much more likely (or less likely) it is for people
exposed to a factor to develop a disease compared to people not exposed
to the factor.

The relative risk is the **ratio of the attack rates** of a disease
among people exposed to the factor and those not exposed to that factor.
(The **attack rate** is the incidence of disease in a group \[i.e., the
number of people in the group who became ill divided by the total number
of people in the group\].)

> attack = [\# ill people in group]{.underline}
>
> rate \# people in group
>
> relative = [attack rate for exposed persons]{.underline}
>
> risk attack rate for unexposed person

A relative risk of:

-   **1.0** (or close to 1.0) means the risk of disease is similar in
    the exposed and unexposed group and exposure is not associated with
    disease.

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```
-   **Greater than 1.0** means the risk of disease is greater in the
    exposed than the unexposed group and the exposure could be a risk
    factor for the disease.

-   **Less than 1.0** means the risk of disease is less in the exposed
    group than the unexposed group and the exposure could be a
    protective factor.

In the Texas cohort study:

Twelve of 13 attendees who ate the berry dessert became ill. Only one of
eleven attendees who did not eat the berry dessert became ill. Inserting
these numbers into the 2x2 table:

  ------------------------------- ------------ ----------- --------------
  Ate Berry Dessert               Ill          Well        TOTAL

  Yes                             12           1           13

  No                              1            10          11

  TOTAL                           13           11          24
  ------------------------------- ------------ ----------- --------------

attack rate ~(ate\ berries)~ = [\# people who ate berries who became
ill]{.underline}

> \# people who ate berries
>
> = 12/13 = 92%

attack rate ~(did\ not\ eat\ berries)~ = [\# people who did not eat
berries who became ill]{.underline}

> \# people who did not eat berries
>
> = 1/11 = 9%

relative risk ~(eating\ berries)~ = [attack rate for people exposed to
berries]{.underline}

> attack rate for people not exposed to berries

= 92%/9% = 10.2

Interpretation: People exposed to the berry dessert were 10 times more
likely to develop illness than people not exposed to the berry dessert.

# Case-control studies

The **odds ratio** is the measure of association for a case-control
study. It tells us how much higher the odds of exposure is among cases
of a disease compared with controls.

The odds ratio compares the **odds of exposure** to the factor of
interest **among cases** to the odds of exposure to the factor **among
controls**. (The **odds** is the probability that an event will happen
divided by the probability that it won't happen.)

For an unmatched case-control study, the data look like this:

  ------------------------------- ------------ ----------- --------------
  Exposed                         Case         Control     TOTAL

  Yes                             a            b           a+b

  No                              c            d           c+d

  TOTAL                           a+c          b+d         a+b+c+d
  ------------------------------- ------------ ----------- --------------

odds of = [number of cases with the exposure]{.underline} =
[a]{.underline}

exposure ~(cases)~ number of cases without the exposure c

odds of = [number of controls with the exposure]{.underline} =
[b]{.underline}

exposure ~(controls)~ number of controls without the exposure d

odds ratio = [odds of exposure (cases)]{.underline} = [ad]{.underline}

odds of exposure (controls) bc

An odds ratio of:

-   **1.0 (or close to 1.0)** means that the odds of exposure among
    cases is the same as the odds of exposure among controls. The
    exposure is not associated with the disease.

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-   **Greater than 1.0** means that the odds of exposure among cases is
    greater than the odds of exposure among controls. The exposure may
    be a risk factor for the disease.

-   **Less than 1.0** means that the odds of exposure among cases is
    lower than the odds of exposure among controls. The exposure may be
    protective against the disease.

In the New Jersey case-control study:

Twenty-one of 30 case-patients and four of 60 controls had eaten
raspberries. Inserting these numbers into the 2x2 table:

  ------------------------------- ------------ ----------- --------------
  Ate Raspberries                 Case         Control     TOTAL

  Yes                             21 (a)       4 (b)       25

  No                              9 (c)        56 (d)      65

  TOTAL                           30           60          90
  ------------------------------- ------------ ----------- --------------

odds of exposure ~(cases)~ = 21/9 = 2.3

odds of exposure ~(controls)~ = 4/56 = 0.07

odds ratio = [odds of exposure (cases)]{.underline} = [2.3]{.underline}
= 32.7

odds of exposure (controls) 0.07

or

odds ratio = [ad]{.underline} = [(21) (56)]{.underline} = 32.7

bc (4) (9)

Interpretation: The odds of exposure to raspberries was over 30 times
higher among cases than controls.