Emerging Infectious Diseases
[Volume 6 No.1 / January - February 2000]

Synopses

Coccidioidomycosis in New York State

Vishnu Chaturvedi,* Rama Ramani,* Sally Gromadzki,*
Birgit Rodeghier,* Hwa-Gan Chang, and Dale L. Morse*

New York State Department of Health, Albany, New York,
USA; and School of Public Health, University at
Albany, SUNY, Albany, New York, USA

--------------------------------------------------------

      Coccidioidomycosis, a systemic fungal
      disease caused by Coccidioides immitis, is
      endemic in the southwestern United States
      and in parts of Mexico and Central and
      South America. Only sporadic cases have
      been reported in areas (including New York)
      where the disease is not endemic. We used
      hospital discharge records and state
      mycology laboratory data to investigate the
      characteristics of C. immitis infections
      among New York State residents. From 1992
      to 1997, 161 persons had hospital discharge
      diagnoses of coccidioidomycosis (ICD9 Code
      114.0 - 114.5, 114.9). From 1989 to 1997,
      49 cultures from patients were confirmed as
      C. immitis; 26 of these patients had
      traveled to disease-endemic areas. Fourteen
      of 16 isolates had multilocus genotypes
      similar to those of Arizona isolates, which
      corroborates the travel-related acquisition
      of the disease. Our results indicate that
      coccidioidomycosis may be more common in
      New York residents than previously
      recognized. Increased awareness among
      health-care providers should improve timely
      diagnosis of coccidioidomycosis and
      prevention of associated illnesses and
      deaths among patients in nondisease-endemic
      areas.

Coccidioidomycosis, a systemic disease caused by the
dimorphic fungus Coccidioides immitis, is endemic in
the southwestern United States and parts of Mexico and
in Central and South America (1,2). The incidence of
this systemic mycosis in disease-endemic areas
increased during the 1990s (3-5). An estimated 100,000
infections occur in the United States annually, and 1
in 200 infections progresses to disseminated disease
(1,6). Sporadic cases of coccidioidomycosis have been
reported among visitors to the Southwest, and one
earlier report recognized coccidioidomycosis as a
serious travel hazard for visitors to that region
(7-9).

C. immitis, a soil fungus, inhabits a unique ecologic
niche in the topsoil of the lower Sonoran life zone
(10). The infectious propagules are arthroconidia,
single-cell fragments of mycelial threads, which become
easily airborne to cause inhalation exposure. In the
alveoli, arthroconidia undergo dimorphic transition to
spherules, which fragment into endospores. When
released from the spherule, each endospore can act as a
new infectious unit in vivo (1). C. immitis, one of the
most virulent and infectious fungal pathogens, poses a
serious occupational hazard for laboratory personnel,
especially in areas where the disease is not endemic
and workers are less likely to practice biohazard
safety level (BSL)-3 containment, which is required for
the handling of this pathogen. The serious biohazard
potential of C. immitis has led to its inclusion among
the biological agents covered under the recently
enacted Anti-Terrorist and Effective Death Penalty Act,
which regulates interstate transport of infectious
materials (11).

The extent and source of C. immitis infections have not
been thoroughly investigated in areas where the disease
is not endemic. In this study we summarize discharge
data from persons with coccidioidomycosis hospitalized
in New York, a nondisease-endemic area with a single
coccidioidomycosis case report (7). In addition, we
tested a proposed set of molecular markers for
multilocus genotyping of C. immitis to determine the
geographic origins of fungal isolates obtained in this
study.

The Study

Data on hospitalization for coccidioidomycosis in the
state of New York from 1992 to 1997 were obtained from
the New York Statewide Planning and Research
Cooperative System, which compiles uniform inpatient
data from all general acute-care hospitals (all public
and private hospitals and hospital-based and
free-standing ambulatory surgery facilities).

Patients were selected if their hospitalizations listed
a primary or secondary discharge diagnosis of
coccidioidomycosis (ICD9 114.0-114.5, 114.9) during
1992 to 1997. Information was collected from hospital
discharge data abstracts and uniform billing forms for
age at admission, sex, race, ethnicity, county of
residence, insurance status, seasonality, disposition
of patient, hospital length of stay, and total hospital
cost.

Hospital medical records were requested from the 16
patients with positive C. immitis cultures available
for multilocus genotyping (1994-1997). These records
were reviewed for travel histories.

Laboratory Methods

All suspect C. immitis isolates were transported and processed with full safety precautions in a BSL-3 facility. The isolates were subcultured on modified Sabouraud's agar and Mycosel agar, morphologic and microscopic features were examined, and cultures were processed for specific nucleic acid detection. The AccuPROBE C. immitis culture identification test (Gen-Probe Inc., San Diego, CA) was used to confirm the fungal identity. Before 1993, most culture identifications were confirmed by using a C. immitis exoantigen test kit (Scott Laboratories Inc., Fiskeville, RI).

The fungal DNA was extracted from mycelial cultures according to the method of Pan et al. (12). PCR-RFLP was done as described by Burt et al. (13), with minor modifications. We studied five of the 10 loci originally used for each C. immitis isolate because analysis showed
these loci to be most useful for strain differentiation (13). The loci/restriction enzymes used included a1/BsrI, bg/DdeI, bl/DdeI, bq/HinFI, and e1/BsmI. Accordingly, California isolates were expected to show polymorphism at e1, and Arizona isolates could be either positive or negative at each locus, while isolates from Texas would be
polymorphic only for the a1, bq, and e1 loci.

Findings

Hospital discharge data from 1992 to 1997 in New York showed 181 hospitalizations with coccidioidomycosis as the primary or secondary discharge diagnoses (Table 1). The yearly distribution of hospitalizations was 30 (1992), 28 (1993), 30 (1994), 33 (1995), and 32 (1996), with no discernible seasonal pattern. Coccidioidomycosis was the primary diagnosis in 75 hospitalizations and the secondary
diagnosis in 106. The clinical diagnoses according to ICD9 Codes included 105 hospitalizations for pulmonary coccidioidomycosis (114.0, 114.5), one with extrapulmonary coccidioidomycosis (114.1), five with coccidioidal meningitis (114.2), 18 with other forms of
coocidioidomycosis (114.3), 19 with chronic pulmonary
coccidioidomycosis (114.4), and 33 with unspecified coccidioidomycosis (114.9). The mean length of stay was 16 days, with an average hospital cost of $22,516.00.

Table 1. Coccidioidomycosis hospital
discharge data, New York State,
19921997
-------------------------------------
Characteristic	N (%)
Total
hospitalizations  181
Total patients    161
Male 			93(58)
Female  		68(42)
Race
White   		128    (79)
Black   		18(11)
Asian/Pacific
Islander 		2 (1)
Other   		 9 (6)
Unknown  		4 (3)
Ethnicity
Hispanic 		4 (2)
Non-hispanic 	151    (94)
Unknown  		6 (4)
Coccidioidomycosis
diagnosis
Primary 		5(41)
Secondary   	106    (59)
Concurrent diagnosis
HIV			32(20)
Cancer  		16(10)
Died while in
hospital		18(11)
Mean length of stay
(days)  16

Age range (yrs)  0-93  (median
58)
Mean hospital charge $22,516.00
-------------------------------------

One hundred sixty-one patients were hospitalized, of whom five had two hospitalizations, two had three, one had four, and one had nine (Table 1). Thirty-two (20%) patients had HIV, 16 patients (10%) had cancer, and 18 patients (11%) died while hospitalized. Overall, 120 (75%) of these 161 patients were either >54 years of age, had cancer, or were
HIV infected.

Table 2. Correlation among clinical history, travel, and multilocus genotypes of Coccidioides immitis isolates from 16 patients, New York, 19941997 (Table not available
in ascii)

Mean and median ages for HIV-infected patients were 36 and 33 years, compared with 66 and 64 years for cancer patients and 59 and 63 years for others. Further comparison of HIV-infected patients with patients who had neither cancer nor HIV infection showed differences in percentages with a primary diagnosis of coccidioidomycosis (22% vs 50%), male sex (81% vs 50%), black race (31% vs 5%), and death during
hospitalization (31% vs 6%).

Forty-nine C. immitis cultures were identifiedFigure
at the state mycology laboratory from 1989 to 1997 (Figure). 
(Figure not available in ascii)

Sixteen patient isolates were available for
multilocus genotyping. The hospital records of
these patients were reviewed to determine the
likely source of infection. All had a history of
travel to the Southwest, with 12 of 16 patients traveling to Arizona. However, date(s) of travel in New York, could not be correlated with onset of the disease. The typing of five alleles allowed unambiguous matches with Arizona genotypes for eight isolates from patients whose histories 
supported this conclusion (Table 2). It was also 
possible to type the respective C. immitis
isolates to Arizona in five instances in which 
patients gave a history of travel to more than 
one disease-endemic area (four with travel to
Arizona). The Arizona genotypes of three
isolates (474-97, 639-97, and 779-97) did not match, as these patients had a history of travel to California, California and Mexico, and California, respectively.

Conclusions

Before 1994, the Centers for Disease Control and Prevention (CDC) definition for coccidioidomycosis relied solely on a physician's clinical diagnosis (5). The current Council of State and Territorial Epidemiologists/CDC surveillance case definition requires the presence of both clinically compatible symptoms and laboratory evidence of
infection (5). The laboratory criteria include a positive culture, positive histopathologic results, molecular evidence of C. immitis, a positive serologic test, or a positive skin test. The retrospective nature of this study and our exclusive reliance on hospital discharge summary data precluded detailed evaluation of diagnostic criteria.
Nevertheless, the average of 30 hospital discharges per year suggests that coccidioidomycosis may be more common in New York residents than previously recognized. The largest number of positive cases was reported from New York City, but the rate was not increased, and cases were reported throughout the state. Furthermore, while information on
travel history was limited, all 16 patients from whom information was obtained had traveled to disease-endemic areas before becoming ill.

Immunocompromised persons, infants, and non-Caucasians are considered at increased risk for coccidioidomycosis (1). The mean age of patients in this series was 54 years, which is in agreement with >40-year age-group most commonly diagnosed in disease-endemic areas (5,6). As expected, a large proportion of patients had other diagnoses consistent with underlying immunosuppression, including a primary diagnosis of HIV in 20% and cancer in 10%. Overall, 75% were 55 years
of age, had cancer, or were HIV infected. The availability of C. immitis cultures from only 10% of cases precluded any definitive investigations of geographic areas in which New Yorkers are at greater risk for infection.

The discovery of recombination in clinical isolates of C. immitis (14) has shown genetic evidence of two sexually distinct taxa in this pathogen, which was previously thought to reproduce asexually (15). A corollary of these investigations was the development of a multilocus
genotyping scheme for determining the geographic origin of clinical isolates. Although the discharge data available for this study did not include travel information, we were able to delineate Arizona isolates in a subpopulation of our study for which cultures and medical record travel data were available. Thus, a patient's travel history was correlated with disease acquisition in a particular area by independently demonstrating the geographic pattern of the patient's isolate in 13 (81%) of 16 patients evaluated. However, the typing scheme could not determine the geographic origin of two C. immitis isolates, which came from patients thought to have traveled to both
California and Mexico. This discrepancy may have resulted from the limited number of alleles used for typing, incomplete travel histories, shortcomings of the typing scheme for California isolates, or the possibility that the two isolates belonged to an outlier group of strains. Further testing is needed on a larger set of isolates from
different geographic areas to evaluate this typing scheme.

As a result of this study, laboratories participating in the New York State Clinical Laboratory Evaluation Program (Mycology) were alerted about the hazards posed by C. immitis. A safe procedure for initial examination of suspect cultures was recommended. The laboratories were also provided with guidelines for safe transport of C. immitis to the state mycology laboratory for confirmation and characterization.

The diagnosis and clinical management of coccidioidomycosis in areas where the disease is not endemic pose unique challenges. The clinical symptoms of the disease mimic those of other infectious diseases, which may result in misdiagnosis and inappropriate treatment (1,16).
Additionally, C. immitis cultures could be easily confused with a number of nonpathogenic fungi by unsuspecting laboratory personnel, who are at risk for infection. Increased awareness among health-care providers is likely to help in the timely diagnosis of coccidioidomycosis and the prevention of associated illness and death among patients in nondisease-endemic areas.

Acknowledgments

This study was partially supported by Centers for Control and Prevention Emerging Pathogens Program funds (DLM) and an unrestricted educational grant from Pfizer, Inc. (VC), and was presented as a poster at the First International Conference on Emerging Infectious Diseases, Atlanta, Georgia, March 8-11, 1998.

Dr. Chaturvedi is director of the Mycology Laboratory, Wadsworth Center, New York State Department of Health, and assistant professor of Biomedical Sciences, School of Public Health, SUNY, Albany. His research interests are molecular epidemiology, fungal pathogenesis, and antifungal drug discovery.

Address for correspondence: Vishnu Chaturvedi, Mycology Laboratory, Wadsworth Center, New York State Department of Health, 120 New Scotland Ave., Albany, NY 12208-2002, USA; fax 518-486-7971; e-mail: vishnu@wadsworth.org.

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Emerging Infectious Diseases
National Center for Infectious Diseases
Centers for Disease Control and Prevention
Atlanta, GA

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