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Coccidioidomycosis in Human Immunodeficiency Virus-Infected Persons in Arizona, 1994–1997: Incidence, Risk Factors, and Prevention

  1. Christopher W. Woods1,2,a,
  2. Cheryl McRill3,
  3. Brian D. Plikaytis2,
  4. Nancy E. Rosenstein2,
  5. David Mosley3,
  6. Denise Boyd3,
  7. Bob England3,
  8. Bradley A. Perkins2,
  9. Neil M. Ampel4 and
  10. Rana A. Hajjeh2
  1. 1Epidemic Intelligence Service, Epidemiology Program Office
  2. 2Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia
  3. 3Arizona Department of Health Services, Phoenix
  4. 4University of Arizona College of Medicine and Medical and Research Services, VA Medical Center, Tucson, Arizona
  1. Reprints or correspondence: Dr. Rana A. Hajjeh, Mycotic Diseases Branch, MS C-09, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Rd. NE, Atlanta, GA 30307 (rfh5{at}cdc.gov).

  1. Presented in part: 36th annual meeting, Infectious Diseases Society of America, Denver, November 1998 (abstract 344-Sa).

  • ↵a Present affiliation: Division of Infectious Diseases, Duke University Medical Center, Durham, NC.

 
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Abstract

From 1 January 1995 through 31 June 1997, 153 cases of coccidioidomycosis in human immunodeficiency virus (HIV)—infected persons were identified in Arizona (incidence, 41/1000 persons living with AIDS). A case-control study was conducted to evaluate risk factors for coccidioidomycosis in HIV-infected persons. A case was defined as laboratory-confirmed, incident coccidioidomycosis in a person infected with HIV for ⩾3 months, and each case patient had 3 control patients matched by county, age group, sex, HIV/AIDS status, and CD4 lymphocyte count. Multivariable analysis identified black race and a history of oropharyngeal or esophageal candidiasis to be associated with increased risk of coccidioidomycosis; protease inhibitor therapy was associated with a reduced risk. In persons with previous history of oropharyngeal or esophageal candidiasis, having received an azole drug was associated with a reduced risk (odds ratio, 0.4; 95% confidence interval, 0.2–0.9; P = .04). Physicians may need to consider azole chemoprophylaxis for HIV-infected persons who live in areas of endemicity, have CD4 cell counts <200/μL, are black, or have a history of thrush.

Coccidioidomycosis is caused by the dimorphic fungus Coccidioides immitis, which is endemic in the southwestern United States. The south-central region of Arizona has one of the highest incidences in the country [1, 2]. Among immunocompetent persons, ∼40% of those infected with the fungus develop symptoms [3]. Symptomatic coccidioidomycosis has a wide clinical spectrum, ranging from a mild febrile illness to more severe pulmonary manifestations and disseminated extrapulmonary disease [4]. Although disseminated disease is rare, it occurs more frequently in blacks, Filipinos, pregnant women, and immunocompromised persons [2, 5, 6].

Early in the human immunodeficiency virus (HIV) epidemic, coccidioidomycosis was recognized as an opportunistic infection that caused significant morbidity and mortality among HIV-infected persons living in areas of endemicity [7–9]. Recently, analysis of surveillance data from Arizona during 1990–1995 documented a substantial increase in the incidence of coccidioidomycosis. This increase in incidence disproportionately affected residents aged ⩾65 years and HIV-infected persons [10, 11]. During the same period, the prevalence of AIDS in Arizona increased by at least 79% [10]. Analysis of hospital discharge data from 1993 revealed that 98 HIV-infected persons were hospitalized with coccidioidomycosis in Arizona, constituting 10% of all HIV-related hospitalizations. One-third of these HIV-infected persons died, compared with 15% of HIV-infected persons hospitalized for other reasons [10, 11].

The majority of coccidioidomycosis cases in Arizona, as well as cases of HIV infection, are reported from 2 southern counties: Maricopa (population 2,611,327) and Pima (population 767,873). By January 1995, ∼4000 HIV-infected persons were living in both counties. Previous studies suggest that up to 27% of HIV-infected persons in southern Arizona may develop symptomatic coccidioidomycosis each year [9, 12] and that between 5% and 10% develop disseminated disease [13]. Before this study, the only identified risk factors for developing symptomatic coccidioidomycosis in these persons were a diagnosis of AIDS and a CD4 lymphocyte count <250 cells/μL [12].

HIV-infected persons with acute coccidioidomycosis can be treated with either amphotericin B or fluconazole but require lifelong suppressive treatment [14]. Although azole drugs have been proven effective for preventing certain systemic mycoses (e.g., histoplasmosis and cryptococcosis) in HIV-infected persons [15–17], the role of prophylactic antifungal therapy in coccidioidomycosis has not been evaluated.

To estimate the incidence of coccidioidomycosis among HIV-infected persons in southern Arizona, we reviewed the surveillance data for coccidioidomycosis reported from 1 January 1995 through 1 July 1997 from 2 urban counties. Concurrently, we conducted a case-control study to identify risk factors for disease and to assess the effect of azole use in the development of coccidioidomycosis in this population.

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Methods

HIV cohort

Beginning in August 1997, cases for both the surveillance and the case-control studies were retrospectively identified by use of the HIV and AIDS Registry (HARS) of Arizona. HARS is a database that includes basic demographic and clinical information on all HIV-infected residents of Arizona, as mandated by state law. The HARS data were used to generate the denominators necessary to calculate incidences of coccidioidomycosis among all HIV-infected persons and among persons with AIDS in Maricopa and Pima counties.

Case patient definition

A case patient was defined as a resident of Pima or Maricopa County with symptomatic, laboratory-confirmed [18], incident (i.e., first diagnosis of) coccidioidomycosis diagnosed from 1 January 1995 through 1 July 1997.

Case finding

In Arizona, HIV infection, AIDS, and coccidioidomycosis are reportable to the Arizona Department of Health Services. To identify coccidioidomycosis cases, the Arizona surveillance data were reviewed, and a list was generated of all cases of C immitis infection that were diagnosed and reported from 1 January 1995 through 1 July 1997. This list was supplemented with additional cases identified through the Arizona Hospital Discharge Database by use of coccidioidomycosis-specific International Classification of Diseases-9 codes (114.0–114.5 and 114.9) during 1995–1996. Private, university, and state laboratories that performed coccidioidal culture and serologic tests for the medical communities of Pima and Maricopa Counties were also contacted, to identify any coccidioidomycosis cases that had not been found in the Arizona state surveillance system or hospital discharge database. Beginning 1 January 1997, all positive coccidioidal cultures, antigen tests, and serology were required to be reported to the state laboratory. A final list of all HIV-infected persons with coccidioidomycosis was then generated by cross-matching the list of coccidioidomycosis cases with the HARS database. All cases were confirmed through review of inpatient and outpatient charts.

Case-control study, case patient eligibility, and enrollment

To be eligible for enrollment in the case-control study, a case patient with coccidioidomycosis had to be diagnosed with HIV infection for ⩾90 days before the diagnosis of coccidioidomycosis. This 90-day “buffer” period was chosen to ensure that case and control patients had the opportunity to receive some medical care for their HIV infection. The date of diagnosis of coccidioidomycosis for case patients (outpatient) or the date of admission to the hospital (if diagnosis occurred after admission) was used as a case reference date. A reference period was defined as the 90 days before the case reference date. Persons with a history of coccidioidomycosis before 1 January 1995 were excluded.

Control patient selection

Three HIV-infected control patients from the HARS database were randomly selected for each case patient. Control patients were matched to case patients by county, sex, age group (<25, 25–40, and >40 years), clinical status of HIV infection (HIV vs. AIDS) during the reference period, and CD4 lymphocyte count (<100, 100–200, and >200 cells/μL). The most recent CD4 lymphocyte count obtained within the 6 months preceding the reference date was used for matching. Control patients with a history of coccidioidomycosis or with a positive serologic result for coccidioidomycosis before the reference date or persons whose HIV infection was not diagnosed before the first day of the case buffer period were not included in the study.

Data collection

Medical and pharmacy records of all case and control patients were reviewed to collect demographic information, medical history, risk factors for HIV infection, CD4 lymphocyte count, prior coccidioidal serology, and azole drug or other prescription medication (e.g., antiretroviral) use in the 3 months preceding the reference date. We were unable to determine patient compliance with prescribed medication.

Patient confidentiality

This case-control study did not involve any direct patient contact. All information was obtained by medical record or chart review. The Arizona Revised Statutes mandate access to medical or laboratory records for Arizona Department of Health Services and local health departments investigating reportable diseases.

Data management and analysis

Chart abstraction was done by a physician familiar with the care of HIV-infected patients and was validated by review of patient materials by a second investigator for a randomly selected 10% of case and control patients. There was a 99% concordance between the data recorded by each investigator. Epi Info (version 6.0) and SAS (release 6.12; SAS Institute, Cary, NC) were used for data entry and analysis [19, 20].

Univariate and multivariable analyses were done by use of conditional stepwise logistic regression. The multivariable model included factors found to be univariately significantly associated with or suggested by previous studies, as well as potential confounders. Interaction terms were created to assess effect modification and to allow for evaluation of specific effects at individual levels of variables being modeled. The multivariable model was evaluated for multicolinearity, to judge whether there were strong correlations among ⩾2 factors in the model. We defined population attributable risk as the proportion of coccidioidomycosis cases occurring in the general population that can be attributed to a given exposure factor.

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Results

Surveillance

Medical record review was attempted for the 297 persons identified from both the HARS database and the coccidioidomycosis list resulting from review of the Arizona coccidioidomycosis surveillance system, the hospital discharge database, and the state, private, and university laboratory records from 1 January 1995 through 1 July 1997. After medical record review, 153 HIV-infected persons were found to have incident coccidioidomycosis. Eighty-six persons who did not have confirmed coccidioidomycosis and 43 persons who had been diagnosed with coccidioidomycosis before 1 January 1995 were excluded. The medical records for 15 of these patients could not be accessed.

Incidence

A total of 77 cases of coccidioidomycosis in HIV-infected persons were identified in 1995, 61 in 1996 (figure 1), and 15 in 1997. As expected, average annual incidences of coccidioidomycosis in Maricopa and Pima Counties were substantially higher for persons with a diagnosis of AIDS than for HIV-infected persons without AIDS (4.1% vs. 0.2%; P<.001) [21]. The incidences of coccidioidomycosis in HIV-infected persons were similar for Maricopa and Pima Counties (1.5% vs. 2.0%; P = .2).

Figure 1
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Figure 1

Annual incidences of coccidioidomycosis among human immunodeficiency virus (HIV)—infected persons (all HIV-infected persons, persons with AIDS, and persons without AIDS) in Maricopa and Pima counties, Arizona, 1995–1996.

Diagnostic and clinical characteristics

Of the 153 HIV-infected persons diagnosed with coccidioidomycosis between 1 January 1995 and 1 July 1997, 88 (58%) were diagnosed by isolation of C. immitis in culture (71 from a pulmonary source [44 bronchoalveolar lavage specimens and 27 sputum], 4 from blood, 1 from cerebrospinal fluid, and 12 from other sterile sites). The majority of case patients (146 [95%]) had serologic testing done. Of the 110 (75%) case patients with a positive serologic test, 6 (5%) were positive for IgM by ELISA; 55 (50%) were positive for IgM by immunodiffusion; 81 (74%) were positive for IgG by immunodiffusion; and 90 (82%) were positive for IgG by complement fixation, 78 with a titer ⩾8. Although 46 case patients had C. immitis identified on pathologic study, only 4 had a diagnosis based on histopathologic findings alone, whereas 54 (35%) had their disease diagnosed on the basis of serology alone, 46 (86%) by complement fixation.

Of the 153 HIV-infected persons with incident coccidioidomycosis, 134 (88%) were men, with a median age of 37 years (range, 23–62 years). CD4 lymphocyte counts were low (median, 54 cells/μL; range, 1–1235 cells/μL), with 135 (88%) having a CD4 lymphocyte count <200 cells/μL. Coccidioidomycosis was the AIDS-defining illness for 27 case patients (18%). The most common symptoms of acute coccidioidomycosis were fever in 115 (75%), cough in 104 (68%), and dyspnea in 63 (41%). Of the 115 case patients (75%) who were hospitalized, 29 (20%) required intensive care. Chest radiographic reports were reviewed for 146 cases (95%). Diffuse pulmonary infiltrates (i.e., infiltrates involving multiple lobes in both lungs) were the most common finding (in 80 [52%]), and 43 (28%) had a focal infiltrate. Sixty-four case patients (42%) were considered by their physicians to have disseminated disease, although only 43 had documented extrapulmonary disease, sometimes from >1 site (central nervous system [19], lymph nodes [9], skin [7], blood [4], bone [5], genitourinary [2], and gastrointestinal [1]). The remaining 21 had diffuse pulmonary infiltrates.

All patients with recorded treatment regimens (132 [86%]) received antifungal therapy for their infection. Fluconazole was the most common antifungal drug used for treatment, with 130 (98%) receiving it, 105 (80%) at ⩽400 mg/day (maximum, 800 mg). Among hospitalized patients, 74 (75%) received oral rather than intravenous fluconazole. Itraconazole (4 [3%]) and ketoconazole (2 [2%]) were infrequently used for treatment. A total of 50 (38%) received amphotericin B as part of their initial regimen. Despite antifungal therapy, of the 116 whose outcome was known, 29 (25%) died within 90 days of the diagnosis of coccidioidomycosis.

Case-control study

Of all 153 HIV-infected persons with incident coccidioidomycosis, 40 (26%) did not have an adequate buffer period (⩾90 days) between diagnosis of HIV and diagnosis of coccidioidomycosis, suggesting that coccidioidomycosis was the presenting HIV-associated illness for these persons. These persons were not eligible for enrollment in the case-control study. A total of 113 persons (74%) were enrolled as case patients in the case-control study. All met the case definition for incident coccidioidomycosis and had an adequate buffer period. The median age was 38 years (range, 23–62 years), and 96 (85%) were men. The median CD4 lymphocyte count was 54 cells/μL (range, 1–730 cells/μL). Two-thirds (66%) lived in Maricopa County at the time of coccidioidomycosis diagnosis. Case patients enrolled in the case-control study were similar to all cases identified through surveillance (table 1). The 333 control patients (of >2500 screened) were similar to matched case patients by county, age, state of HIV infection, and CD4 lymphocyte cell count (table 1).

Table 1
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Table 1

Selected characteristics of human immunodeficiency virus-infected persons with coccidioidomycosis, including all cases detected through surveillance and case and control patients enrolled in a coccidioidomycosis risk-factor study, Arizona, 1995–1997.

Univariate analysis

The results of univariate analysis are summarized in table 2. Blacks had an increased risk of developing coccidioidomycosis (odds ratio [OR], 4.1; 95% confidence interval [CI], 1.8–8.9]. Injection drug users also had an increased risk of disease (OR, 2.0; 95% CI, 1.3–3.3). Markers of socioeconomic status, such as employment and type of medical insurance, were not associated with increased risk of coccidioidomycosis. Having recently moved to the state of Arizona was not associated with an increased risk for disease; however, that information was not always available in the medical records (available for 86 case patients [76%] and 267 control patients [80%]).

Table 2
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Table 2

Results of matched univariate analysis of risk factors for coccidioidomycosis in human immunodeficiency virus (HIV)-infected persons, Arizona, 1995–1997.

Previous history of any opportunistic infection was not associated with increased risk for coccidioidomycosis; however, persons with a history of oropharyngeal or esophageal candidiasis were almost 2 times as likely to develop coccidioidomycosis (OR, 1.9; 95% CI, 1.2–2.9).

We also evaluated the effect of taking certain medications during the reference period. Not taking any medications was associated with an increased risk of disease (OR, 5.4; 95% CI, 2.5–11.5). The 43 persons (23 case and 20 control patients) not receiving medications were more likely than persons receiving medications to be black (P = .04), unemployed (P = .03), and homeless (P = .007). However, the median CD4 lymphocyte count was significantly higher than that for persons receiving medications (166 vs. 44 cells/μL; P<.001), and they were much less likely to have had a previous opportunistic illness (P = .008). The use of any antiretroviral drug was associated with a reduced risk of coccidioidomycosis (OR, 0.5; 95% CI, 0.3–0.8). Although few persons were taking protease inhibitors during the period under study (10 case patients [9%] and 65 control patients [20%]), use of this class of antiretroviral agents was associated with a reduced risk of disease (OR, 0.3; 95% CI, 0.1–0.8). Use of systemic azole drugs during the reference period appeared to reduce the risk of developing symptomatic coccidioidomycosis but did not reach statistical significance.

Multivariable analysis

The results of multivariable analysis after controlling for possible confounders and effect modifiers are shown in table 3. Blacks (OR, 4.9; 95% CI, 1.9–12.4) and persons with a history of oropharyngeal or esophageal candidiasis (OR, 2.3; 95% CI, 1.4–4.1) were at increased risk of disease. Persons who were not receiving any medications also continued to be at increased risk for disease (OR, 3.3; 95% CI, 1.3–8.4). Protease inhibitor use was associated with a reduced risk of coccidioidomycosis (OR, 0.4; 95% CI, 0.1–1.0). The population attributable risk for developing coccidioidomycosis was 16% for blacks and 31% for persons with a prior history of oropharyngeal or esophageal candidiasis.

Table 3
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Table 3

Results of multivariable analysis of risk factors for coccidioidomycosis in human immunodeficiency virus-infected persons, Arizona, 1995–1997.

By both univariate and initial multivariable analyses, systemic azole use for 21 days (the mean number of days of azole therapy received by persons in the study) during the reference period was associated with a reduced risk of invasive coccidioidomycosis, but the association was not significant (tables 2 and 3). In an attempt to identify a group of high-risk persons who may benefit from antifungal prophylaxis, the data were analyzed by use of a model that included an interaction term between oropharyngeal or esophageal candidiasis and azole therapy for ⩾21 days in the 3 months before the reference date. Systemic azole therapy was associated with a significant decrease in risk of disease (OR, 0.4; 95% CI, 0.2–0.9) for persons with a previous history of oropharyngeal or esophageal candidiasis. There was no effect for those persons without a history of oropharyngeal or esophageal candidiasis.

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Discussion

This study provides a population-based estimate of the incidence of coccidioidomycosis among HIV-infected persons in Arizona and defines the demographic and clinical risk factors for disease in this population. The identification of a subgroup of HIV-infected persons who are at increased risk for coccidioidomycosis, such as blacks and persons with a previous history of opportunistic fungal infection, may help target prevention measures, including azole chemoprophylaxis.

Among persons living with AIDS in Arizona, the incidence of symptomatic coccidioidomycosis was ∼4% per year during the study period. Although the rate among HIV-infected persons without AIDS was substantially lower (0.2%), this was still much higher than the incidence among ArizonA's general population in 1995 (14.9/100,000) [10]. This study did not evaluate the rate of overall infection with C. immitis (which would include asymptomatic infection) among HIV-infected persons in Arizona. However, earlier reports have found that HIV-infected persons have more severe disease (higher rates of disseminated illness, hospitalization, and case fatality) than are observed in the general population [3, 9, 12, 22].

More than one-third of the patients identified in the study met the case definition on the basis of only clinical presentation and results of serologic tests (EIA, complement fixation, and immunodiffusion). Each of these serologic methods has demonstrated a high sensitivity and specificity for acute coccidioidomycosis and are part of the laboratory-confirmed definition suggested by the Centers for Disease Control and Prevention and the Council of State and Territorial Epidemiologists [18, 23]. However, in HIV-infected patients with disseminated coccidioidomycosis, serologic tests have demonstrated a reduced sensitivity because of decreased antibody production by these persons [24]. Therefore, for diagnostic purposes, physicians should not rely only on serologic methods.

Studies performed earlier during the HIV epidemic documented rates of coccidioidomycosis as high as 27% among persons with AIDS in Arizona when a similar case definition was used [9, 12]. The much lower rate found in our study is consistent with the decreasing trend in incidence of most AIDS-related opportunistic infections and may be due to various factors, including introduction of highly active antiretroviral therapy (HAART) and an increasing frequency of azole use among HIV-infected persons [25]. As in most parts of the country, HAART was not standard therapy during the first 2 years of this study. However, persons receiving the newer antiretrovirals (particularly protease inhibitors) had a significantly reduced risk of developing coccidioidomycosis. Of note, though, is that 18% of all case patients in this study had coccidioidomycosis as their AIDS-defining illness, and 40 (26%) of 153 as their HIV-presenting illness, suggesting that many of these persons had a late diagnosis of HIV and, therefore, lack of access to medical care.

Persons not receiving any medications during the reference period were 3 times more likely to develop symptomatic coccidioidomycosis than were other HIV-infected persons. Although similar in age and sex, the persons not receiving medications were more likely than persons receiving medications to be black, unemployed, and homeless, suggesting that the increased risk may result from reduced access to care or other socioeconomic, educational, or overall health status issues. Although these persons may have been somewhat healthier than the rest of the group (as reflected by a higher median CD4 cell count and a lower frequency of opportunistic infections), they had missed a chance for preventing not only coccidioidomycosis but probably other opportunistic infections and should have more access to routine care and antiretroviral therapy.

In our study, a history of oropharyngeal or esophageal candidiasis was associated with an increased risk for developing coccidioidomycosis. An earlier review of coccidioidomycosis in AIDS found that coccidioidomycosis was more likely to occur in persons who had a previous opportunistic infection [13]. Additionally, a history of thrush has been shown to be a predictor for Pneumocystis carinii infection [26]. Although thrush seems to be a general indicator of an accelerated course of HIV infection [26, 27], specific defects of antifungal immune factors may account for the increased risk of invasive fungal diseases [28]. Further study of the predisposing genetic and immunologic risk factors for coccidioidomycosis, as well as other systemic fungal infections, will improve our understanding of the pathogenesis of this disease and have a significant impact on its treatment and prevention.

Although blacks represent only a small percentage of both case and control patients in this study, they were 5 times more likely to develop symptomatic coccidioidomycosis. This association was persistent even after socioeconomic status and HIV risk factors were controlled for. Although black race has been previously associated with disseminated coccidioidomycosis [3, 29], this is the first time that it has been determined to be a risk factor for symptomatic disease in general (one-third of all black case patients [9/25] had extrapulmonary disseminated disease). The number of HIV-infected persons of other races known to be at increased risk, particularly Asians, was small, and this study could not evaluate the risk of coccidioidomycosis in these groups.

Primary antifungal prophylaxis with systemic azole drugs for selected opportunistic fungal infections has previously been shown to be effective for preventing disease [15–17]. In a prospective randomized controlled trial, oral fluconazole (200 mg/day) for the prophylaxis of invasive fungal infections was found to be very effective against cryptococcosis, but it had no effect on survival of these patients [16]; although this study included 3 institutions in Southern California, only a single case of coccidioidomycosis was recorded; therefore, the impact of fluconazole chemoprophylaxis could not be assessed for coccidioidomycosis. Similarly, another recent study evaluated the effect of oral itraconazole (200 mg/day) for preventing invasive fungal infections [17]. This regimen was effective in preventing histoplasmosis and cryptococcosis, although, again, no survival benefit was demonstrated. No cases of coccidioidomycosis were recorded in this study, which did not include institutions from areas in which coccidioidomycosis is endemic. Before initiating our study, a randomized controlled trial was attempted; however, low enrollment rates prevented its successful completion. However, antifungal chemoprophylaxis, despite multiple studies showing its effectiveness, has not been routinely recommended, because of the relative infrequency of systemic fungal infections in HIV-infected persons, the lack of survival benefit, and the possibility of drug interactions [30].

The population attributable risk estimates for blacks (16%) and persons with a previous fungal infection (31%) account for nearly half of the HIV-infected persons who develop coccidioidomycosis in Arizona. Although we could not evaluate the association of azole therapy with the development of coccidioidomycosis in HIV-infected blacks because of small numbers, use of azole therapy for ⩾21 days during our reference period appears to confer a 60% reduction in disease incidence in HIV-infected persons with a history of fungal infection. Given the substantial risk of coccidioidomycosis in HIV-infected blacks and the high frequency of disseminated disease in these persons, antifungal prophylaxis needs to be considered for all HIV-infected blacks with CD4 lymphocyte counts <200 cells/μL who live in Arizona. Similarly, physicians may consider azole prophylaxis for Arizona residents with HIV infection who have a history of oropharyngeal or esophageal candidiasis. Prophylaxis could also be considered for similar persons in other areas where coccidioidomycosis is endemic or when disease has become epidemic, such as after large outbreaks [31]. Fluconazole was the most frequently used drug in this group of persons and the most commonly used azole for treating coccidioidomycosis; however, itraconazole has also been recently determined to have an adequate therapeutic efficacy for nonmeningeal coccidioidomycosis [32]. Future studies need to address the efficacy of different agents in a prospective fashion and to keep in mind the cost-effectiveness of such an approach and its potential effect on the development of antifungal resistance in Candida species.

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Acknowledgments

We gratefully acknowledge the many people without whom this study would not have been possible: Mark Fickes and Heather Norman (Arizona Department of Health Services); Neil Gershman (Sonora Laboratory Sciences, Phoenix, AZ); John Post and staff (McDowell Clinic, Phoenix, AZ); Ken Fisher and staff (Lee Hood, VA Medical Center, Phoenix, AZ); Kevin Carmichael and staff (El Rio Special Immunology Associates, Tucson, AZ); Elizabeth Graham (VA Medical Center, Tucson, AZ); and Colin Shepard (Wake Forest School of Medicine, Winston-Salem, NC).

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Footnotes

  • This study obtained the approval from the Centers for Disease Control and Prevention and the Arizona Department of Health Services institutional review board.

  • Received October 13, 1999.
  • Revision received December 17, 1999.
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  1. J Infect Dis. (2000) 181 (4): 1428-1434. doi: 10.1086/315401
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