**A Multistate Outbreak of Cyclosporiasis**

#### A Classroom Case Study

**STUDENT'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**

# STUDENT'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?

**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?

# 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?

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.

![](media/image1.jpeg){width="3.55in"
height="2.6783464566929136in"}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.

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*?

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.

# 

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

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?

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/image2.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?

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?

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.

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.

# 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?

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?

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.

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 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?

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?

**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.

```{=html}
<!-- -->
```
-   **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.

```{=html}
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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.