Download Outbreak of Coccidioidomycosis in Washington State Residents

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Outbreak of Coccidioidomycosis in Washington State Residents Returning
from Mexico
Lisa Cairns,1,3 David Blythe,1,2 Annie Kao,4
Demosthenes Pappagianis,5 Leo Kaufman,4
John Kobayashi,1 and Rana Hajjeh4
From the 1Section of Communicable Disease Epidemiology,
Washington State Department of Health, and 2University
of Washington School of Public Health and Community Medicine
Preventive Medicine Residency, Seattle, Washington; 3Epidemic
Intelligence Service, Division of Applied Public Health Training,
Epidemiology Program Office, and 4Division of Bacterial and Mycotic
Diseases, National Center for Infectious Diseases, Centers for Disease
Control and Prevention, Atlanta, Georgia; and 5Department
of Medical Microbiology and Immunology, School of Medicine,
University of California at Davis, Davis, California
In July 1996 the Washington State Department of Health (Seattle) was notified of a cluster
of a flulike, rash-associated illness in a 126-member church group, many of whom were
adolescents. The group had recently returned from Tecate, Mexico, where members had assisted with construction projects at an orphanage. After 1 member was diagnosed with coccidioidomycosis, we initiated a study to identify further cases. We identified 21 serologically
confirmed cases of coccidioidomycosis (minimum attack rate, 17%). Twenty cases (95%) occurred in adolescents, and 13 patients (62%) had rash. Sixteen symptomatic patients saw 19
health care providers; 1 health care provider correctly diagnosed coccidioidomycosis. Coccidioides immitis was isolated from soil samples from Tecate by use of the intraperitoneal
mouse inoculation method. Trip organizers were unaware of the potential for C. immitis
infection. Travelers visiting regions where C. immitis is endemic should be made aware of the
risk of acquiring coccidioidomycosis, and health care providers should be familiar with coccidioidomycosis and its diagnosis.
Coccidioidomycosis is caused by inhalation of the airborne
arthroconidia of Coccidioides immitis, a dimorphic fungus
found in the topsoil of certain semiarid regions of the Americas
[1]. Symptomatic disease occurs in ∼40% of infected persons
and is characterized by flulike symptoms, such as headache,
fever, cough, myalgias, and rash [2]. Coccidioidomycosis is usually a self-limited disease; however, in !1% of cases, it can
disseminate and be fatal [3]. A higher rate of dissemination
exists among pregnant women, immunocompromised persons,
and certain racial groups [2]. Outbreaks of coccidioidomycosis
have been linked to events that favor production [4] and dispersion of arthroconidia in dust, such as earthquakes [1], dust
storms [5], and archaeological digs [6, 7].
In July 1996 the Washington State Department of Health
(Seattle) was notified that at least 15 persons from a church
Received 6 April 1999; revised 25 August 1999; electronically published
21 December 1999.
This work was presented in part at the 37th Interscience Conference on
Antimicrobial Agents and Chemotherapy held on 28 September–3 October
1997 in Toronto, Canada, and the 41st annual meeting of the Coccidioidomycosis Study Group held on 5 April 1997 in San Diego, California.
Reprints or correspondence: Dr. Lisa Cairns, MS E-10, Centers for
Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333
([email protected]).
Clinical Infectious Diseases 2000; 30:61–4
q 2000 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2000/3001-0013$03.00
group, including many adolescents, had developed an unidentified, rash-associated, flulike illness. One of these cases was
eventually recognized as coccidioidomycosis. The group had
recently returned from a 6-day stay at an orphanage ∼15 miles
south of Tecate, Mexico, a town in the Sonoran Desert adjacent
to the United States–Mexico border. To determine the extent
of the outbreak and risk factors for disease, we conducted an
investigation, the results of which are summarized in this article.
Methods
Epidemiological studies. We conducted a retrospective cohort
study, which included the administration of a questionnaire, a skin
test survey, and serological testing.
Questionnaire. The church office provided the names of group
members who participated in the trip to Tecate. A standard questionnaire was administered to all available group members; information obtained included demographic data, information on previous travel to areas where C. immitis is endemic, and pertinent
medical history. Information about activities while in Tecate, presence and duration of any symptoms of illness since leaving Mexico
until the time of interview (∼7 weeks), and medical care received
for these symptoms was also obtained.
Skin test survey. Spherulin skin tests (Berkeley Biologicals,
Berkeley, CA) were administered to all available consenting church
group members. Tests were performed by professional nurses experienced in skin testing. Group members received intradermal in-
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Cairns et al.
jections of 0.1 mL of intermediate-strength (1 : 100) spherulin, except for 4 people whose history was consistent with erythema
nodosum. Of these 4, 3 received 0.1 mL of dilute (1 : 1000) spherulin; the fourth was skin tested through her private physician and
received a reduced volume of intermediate-strength spherulin. The
results were read at 48 h after intradermal injection. A skin test
was considered positive if an induration at 48 h was >5 mm [2].
Serological studies. Serum specimens were obtained from people with any flulike symptoms since leaving Mexico or from those
with a positive skin test. These samples were tested at the Centers
for Disease Control and Prevention (Atlanta, GA) for the presence
of antibodies to C. immitis by use of quantitative complement
fixation (CF) tests for coccidioidomycosis and 2 qualitative immunodiffusion tests: immunodiffusion tube precipitin (IDTP),
which gave results corresponding to those obtained with the tube
precipitin test for IgM antibody to C. immitis; and immunodiffusion complement fixation (IDCF), which gave results corresponding to those obtained with the CF test for IgG antibody to
C. immitis [8]. Twenty specimens were also sent to the Coccidioidomycosis Serology Laboratory at the University of California at
Davis School of Medicine (Davis, CA) for repeated IDTP with use
of concentrated serum [9]. In the event of discrepancies in IDTP
results, those obtained through use of concentrated serum were
considered conclusive. We defined a case of acute C. immitis infection as serology positive for C. immitis by IDTP, IDCF, or CF
testing.
Environmental studies. Soil specimens were collected by one of
us (D.P.) from 3 sites at the orphanage in Tecate: loose soil excavated for the construction of a wading pool, the proposed site for
a swimming pool, and the tent site where the church group had
camped. The soil was mixed with sterile saline in a sterile graduated
cylinder. The coarse soil was allowed to settle, and the supernatant,
which should contain the lighter arthroconidia of C. immitis, was
decanted and centrifuged to sediment arthroconidia. The supernatant was discarded, and the sediment was injected intraperitoneally into female Swiss-Webster mice that were killed at 7–10 days.
The lungs, liver, and spleen were cultured on Mycobiotic medium
(Difco, Detroit). Mold growth from these organs was inoculated
intraperitoneally into a second set of mice.
Data analysis. Risk ratios were calculated for each exposure.
Univariate risk ratios, P values, and 95% CIs were determined by
the x2 method with use of Epi-Info Version 6.0 [10].
CID 2000;30 (January)
themselves as white. None of the 59 members reported being
immunocompromised or pregnant.
Twenty-seven (46%) of the 59 church group members had a
positive skin test. Serological testing for 21 of these members
was positive for C. immitis; therefore these 21 met the case
definition for coccidioidomycosis. The attack rate for the 59
members who responded to the questionnaire was 36%, and
the minimum attack rate for the entire 126-member group was
17%. Of the 21 members who met the case definition, 20 (95%)
were adolescents aged 14–18 years (median, 16 years; range,
14–43 years), and 18 (86%) were female. Four patients (19%)
had negative skin tests.
Clinical characteristics and laboratory findings.
Twenty
(95%) of the 21 patients were symptomatic; the date of the
onset of symptoms ranged from 15 to 28 July 1996 (figure 1).
Assuming that exposure occurred on 8 July 1996, the average
incubation period was 12 days (range, 7–20 days). Patients
started developing symptoms 1–3 weeks after arrival in Tecate;
these symptoms included fever (85% of patients), headache
(81%), chest pain (76%), body aches (71%), cough (66%), fatigue (66%), rash (62%), muscle pain (52%), nausea (43%), and
joint pain (33%). Rash was described as initially papular; it
progressed to a confluent maculopapular rash, with lesions on
the trunk, at times the palms and soles, and, in some instances,
the buccal mucosa. Four patients reported lesions consistent
with erythema nodosum. At the time our investigation was
conducted, no patients had persistent rash, and no additional
clinical information about this rash was available. None of the
patients developed disseminated disease, and none died.
Of the 21 patients, 15 were positive for C. immitis by both
IDTP and IDCF, 4 were positive by IDCF but negative by
IDTP, and 2 were negative by IDCF but positive by IDTP. Of
the 4 patients with negative skin tests, 1 had a positive IDCF
with a titer of CF antibody of 1 : 16 and a negative IDTP; the
Results
Case identification and demographic characteristics. One
hundred twenty-six church group members participated in the
trip to Tecate, which occurred from 8 to 13 July 1996. Of 100
members (79%) who were contacted, 59 (47% of 126) completed
questionnaires, underwent skin tests, and had the results read.
Forty members had serological testing done; blood samples
were obtained from 95% of these 40 between 5 and 11 weeks
after the day of arrival in Tecate. Of the 59 members who
completed the questionnaire and skin testing, 35 (59%) were
female, and 51 (86%) were aged 14–18 years (median, 16 years;
range, 14–71 years). All except 1 trip participant identified
Figure 1. Date of the onset of symptoms of coccidioidomycosis in
church group members from Washington State in 1996 who returned
from Tecate, Mexico, where they had assisted with construction of an
orphanage (information available for 19 of 20 symptomatic patients).
Rr, dates of stay in Mexico.
CID 2000;30 (January)
Outbreak of Coccidioidomycosis in Washington State
other 3 had a positive IDCF, a positive IDTP, and titers of CF
antibody ranging from 1 : 4 to 1 : 16.
Sixteen symptomatic patients saw a total of 19 health care
providers, most of whom we believe were aware of the patient’s
travel history. Health care providers ranged from physician’s
assistants to infectious disease specialists. Only 1 health care
provider, an infectious disease physician trained in California,
diagnosed coccidioidomycosis after seeing a patient with erythema nodosum. Other reported diagnoses included bacterial
bronchitis, contact dermatitis, and viral infection. Of 11 patients who were prescribed medication, 7 could identify the
medications by name; of these patients, 6 had received antibiotics, and 1 was treated with prednisone for contact dermatitis. None of the patients received antifungal therapy.
Risk factors. While in Tecate, trip participants had excavated ground for 2 swimming pools, assisted in construction
projects such as roofing, cooked for group members, played
outdoors, and traveled by bus and foot on dirt roads. Most of
them had slept in tents. They did not routinely follow procedures that might have protected them from infection, such as
wearing dust masks or sleeping upwind from construction sites
[11]. Univariate analysis revealed that digging 1 of the swimming pools was significantly associated with an increased risk
of acute coccidioidomycosis (RR, 2.5; 95% CI, 1.0–6.6). No
other activities were associated with an increased risk of disease.
Environmental study results. No lesions were detected in
killed mice after the initial intraperitoneal inoculation with supernatant. However, the second set of inoculated mice became
ill and had visible lesions. These lesions contained microscopic
endosporulating spherules characteristic of C. immitis.
Late report of coccidioidomycosis. In January 1998 we were
notified that a 17-year-old church member who had traveled
to Tecate in July 1996 and to San Diego in July 1997 was being
treated for a coccidioidal pulmonary cavitary lesion that had
been identified in November 1997. This person had reported
being asymptomatic after returning from Mexico, had refused
skin testing, and was not serologically tested during the 1996
investigation. Clinical specimens that could be cultured for
comparison with C. immitis isolated from soil were not obtained.
Discussion
Our results highlight that exposure to C. immitis carries significant risk for people who are susceptible and that physicians
are not aware of coccidioidomycosis in areas where C. immitis
is not known to be endemic. It also demonstrates that C. immitis
is endemic in the region of Tecate. The church has been sending
groups to Tecate for several years and has received anecdotal
reports of flulike illnesses after these trips; however, the 1996
trip organizers and participants were not aware of the potential
for C. immitis infection. Although the earliest case was detected
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by an infectious disease specialist in early August 1996, in most
cases, the health care providers did not consider coccidioidomycosis in the differential diagnosis (despite, we believe, being
aware of the patient’s travel history). This may have been because they saw patients individually (i.e., without being aware
that that several people had had a common exposure), but also
because coccidioidomycosis mimics other diseases [12]. Other
studies have also pointed out that the diagnosis of coccidioidomycosis can be missed because physicians are not familiar
with the disease in areas where it is not endemic [13]. This point
is of particular importance for immunocompromised patients
who have a higher risk of developing severe disease [14, 15].
The high incidence of rash in our study is an interesting
finding. Although erythema nodosum or erythema multiforme
is estimated to occur in 20% of clinically diagnosed adults [16],
the incidence of rash among children and adolescents is uncertain but suspected to be higher [17]. In a study of college
students at an archaeological dig, Werner and Pappagianis [7]
noted a 52% incidence of rash among persons with laboratoryproven disease, a rate approaching the incidence that we observed. Children and young adults can have a clinical presentation different than older adults when they develop acute
coccidioidomycosis. Another interesting finding is the high incidence of headache, ranging from 26% [18] to 74% [7] in other
reports. The incidence of headache in our study is closest to
that reported by Werner and Pappagianis [7], which may reflect
the higher levels of exposure to C. immitis–contaminated soil
in these settings. Finally, the relatively high number of patients
with coccidioidomycosis for whom skin tests were negative (although all tests were administered by experienced personnel)
is an unexpected finding for which there is no obvious
explanation.
These results emphasize the need to increase the awareness
of coccidioidomycosis among physicians and travelers to
regions where C. immitis is endemic. Awareness could be increased through publications in both primary care and specialty
medical journals, presentations at national and regional professional meetings, posting information on coccidioidomycosis
on the Internet, and adding coccidioidomycosis to lists of other
known travel-related health risks in bulletins and books. Prevention of coccidioidomycosis in visitors to areas of endemicity
may be difficult; however, early suspicion of and diagnostic
testing for disease may reduce health-related costs, minimize
patient anxiety, and limit progression to severe disease. People
at high risk for infection may be best served by the eventual
development of a vaccine [19].
Acknowledgments
We acknowledge the assistance of Karen Mottram, Jan Bigelow,
Richard Tucker, Alan Tice, Philip Craven, James DeMaio, Jim
Schwarz, Carey Snow, Marcia Goldoft, Daniel Jernigan, Andy Pelletier,
C. R. Zimmermann, and the members of the church group studied.
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