Medscape, LLC is pleased to provide online continuing medical education (CME) for this journal article, allowing clinicians the opportunity to earn CME credit. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Emerging Infectious Diseases. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians. Medscape, LLC designates this educational activity for a maximum of 0.5 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test and/or complete the evaluation at www.medscapecme.com/journal/eid; (4) view/print certificate.

Upon completion of this activity, participants will be able to:

• Evaluate the impact of coccidioidomycosis on patients and the broader health system

• Evaluate the performance of a laboratory-based system of diagnosis for coccidioidomycosis and incorporate that information into effective diagnostic strategies.

Carol Snarey, MA, Technical Writer-Editor, Emerging Infectious Diseases. Disclosure: Carol Snarey, MA, has disclosed no relevant financial relationships.

Charles P. Vega, MD, Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine. Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.

Disclosures: Clarisse A. Tsang, MPH; Shoana M. Anderson, MPH; Sara B. Imholte, MPH; Laura M. Erhart, MPH; Sanny Chen, PhD, MHS; Benjamin J. Park, MD; Cara Christ, MD, MSc; Kenneth K. Komatsu, MPH; Tom Chiller, MD, MPH; and Rebecca H. Sunenshine, MD, have disclosed no relevant financial relationships.

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• You are seeing a 52-year-old man in Arizona who has a history of cough and intermittent fever for 2 months. He was previously seen in an urgent care center and an emergency department, and he completed one course of azithromycin with little effect.

  • You suspect that this man might have coccidioidomycosis. Which of the following statements regarding the definition of coccidioidomycosis in the current case series is most accurate?

  • A. Only clinical criteria were important in the definition of coccidioidomycosis

  • B. The vast majority of laboratory-diagnosed cases met the clinical criteria for coccidioidomycosis

  • C. Both clinical and laboratory criteria were required to define coccidioidomycosis

  • D. Fungal culture was the sole means of laboratory diagnosis of coccidioidomycosis

• Which additional symptom in this gentleman would support a clinical suspicion of coccidioidomycosis according to the current study?

  • A. Fatigue

  • B. Cough

  • C. Dyspnea

  • D. F ever

• The patient from question 1 is diagnosed with coccidioidomycosis, and he is worried what this diagnosis might cost him financially and in terms of his daily function. Based on the results of the current study, what can you tell him?

  • A. Most patients with coccidioidomycosis do not miss work because of illness

  • B. Three quarters of patients report an impact on usual daily activities

  • C. Less than 10% of patients visit the emergency department

  • D. Hospitalization for coccidioidomycosis is exceedingly rare

• Which of the following factors from the current study had the biggest impact on being diagnosed and treated for coccidioidomycosis earlier?

  • A. Education about coccidioidomycosis from television announcements

  • B. Education about coccidioidomycosis from newspaper campaigns

  • C. Education about coccidioidomycosis from social circles or families

  • D. The presence of sore throat

Coccidioidomycosis, or valley fever, is a fungal disease endemic to the southwestern United States, parts of Mexico, and Central and South America. Infection probably occurs when arthroconidia from disrupted soil are inhaled, causing lung infection (1,2). Signs and symptoms occur 1–4 weeks after exposure and can include fever, cough, fatigue, shortness of breath, headache, joint and muscle aches, and rash. Coccidioides spp. can spread to the central nervous system, skin, joints, or bones in <1% of those infected, resulting in extrathoracic dissemination (3,4).

Each year, an estimated 150,000 persons in the United States become infected with Coccidioides spp., and ≈50,000 of these become ill (5). Most cases are not reported to health departments, resulting in an underestimated number of coccidioidomycosis cases (6). In 2006 in the United States, 8,917 coccidioidomycosis cases were reported, with 5,535 cases reported in Arizona (7). The number of reported coccidioidomycosis cases in Arizona began to increase in 1990. From 1990 through 1995, the annual number of reported coccidioidomycosis cases increased from 255 (7/100,000 population) to 623 (15/100,000 population) (8). This increase led the Arizona Department of Health Services (ADHS) to change its reporting rules to make coccidioidomycosis a laboratory-reportable illness in 1997.

Since laboratory reporting became mandatory, coccidioidomycosis case reports have rapidly increased in Arizona. In 2006, the number of cases peaked at 5,535 cases (89/100,000 population) and decreased to 4,815 cases (75/100,000 population) in 2007 and to 4,768 cases (73/100,000 population) in 2008. During 2006–2008 in Arizona, the median age of patients with coccidioidomycosis was 52 years (mean 51 years). Fifty-four percent of patients with coccidioidomycosis were male (84/100,000 population), and 46% were female (72/100,000 population).

The Council of State and Territorial Epidemiologists (CSTE) and the Centers for Disease Control and Prevention require laboratory and clinical criteria to meet the case definition for coccidioidomycosis. The laboratory criteria consist of culture, histopathologic, or molecular evidence; or immunologic evidence in the form of detection of immunoglobulin M or immunoglobulin G by immunodiffusion, enzyme immunoassay, latex agglutination, tube precipitin, or complement fixation. Clinical criteria require influenza-like signs and symptoms; pneumonia or other pulmonary lesion; erythema nodosum or erythema multiform rash; involvement of bones, joints, or skin by dissemination; meningitis; or involvement of viscera and lymph nodes (9).

Because of Arizona’s large number of cases, ADHS uses only the laboratory component of the CSTE case definition. In 2007, ADHS initiated enhanced coccidioidomycosis surveillance (which included patient interviews) to validate a laboratory-exclusive case definition for coccidioidomycosis and to characterize the effects of the disease on Arizona’s population, healthcare system, and economy. The purpose of this study was to validate this case definition and characterize the effects of coccidioidomycosis in Arizona during January 2007–February 2008.

This investigation provides the largest population-based estimate of the effects of coccidioidomycosis in Arizona. We identified substantial personal and economic costs due to coccidioidomycosis among Arizonans with respect to duration and severity of illness, healthcare use, and healthcare costs. We also found marked delays in diagnosis as well as long duration of symptoms.

In our cohort, persons with coccidioidomycosis had prolonged symptoms for a median of 120 days, substantially longer than previous reports that indicated that coccidioidomycosis symptoms typically last <21 days (fatigue may last longer) (2,13). A study conducted among US Navy SEALS, a presumably healthy and relatively young population, reported median symptom duration of 19 days (range 2–63 days) (14). Our investigation identified a high number of missed workdays (median 14 days, range 0–365 days, IQR 5–30 days) and days during which persons could not perform their daily activities (median 47 days, range 0–1,825 days, IQR 15–120 days). In a study among military members, persons with coccidioidomycosis lost an average of 35 days from work (15). These data support the finding that coccidioidomycosis greatly affects a person’s ability to function and remain productive once the disease develops.

In addition, we found a substantial delay between symptom onset and disease diagnosis. The delay in seeking medical care needs to be addressed by increasing public education about the signs and symptoms of coccidioidomycosis and the importance of seeking care early to obtain an accurate diagnosis. Our data show that the delay between seeking healthcare and ordering a diagnostic test may also be shortened by patient education. Persons who knew about coccidioidomycosis before seeking healthcare were more likely to request coccidioidomycosis testing and were more likely to receive a diagnosis earlier than those who were not familiar with the disease. Our data show that 46% of patients sought medical care without a fever, making recognition of the disease difficult for physicians and patients and possibly contributing to delays in diagnosis. Additionally, the nonspecific manifestation of respiratory illness in coccidioiodomycosis patients is indistinguishable from the manifestation of community-acquired pneumonia, which makes accurate diagnosis even more difficult (16).

Besides the effects on patients, this disease greatly affects the healthcare system. In our investigation, ≈25% of patients visited a healthcare provider >10 times during the course of their illness, and 41% of all interviewed patients were hospitalized. In 1993, a study conducted by Kerrick et al. showed that college students who had coccidioidomycosis visited their doctor an average of 7 times before the disease resolved (17). Similarly, Leake et al. found that patients >60 years of age had a median of 4 medical visits (range 1 to >30 visits) during the course of their illness (18). In this same study, 59% of patients were hospitalized for a median of 7 days. A study among military personnel by Crum et al. found that 22% of those with pulmonary disease and 40% with disseminated disease were hospitalized (15). Our study is consistent with this literature, but, being population-based, is more representative of the disease’s effects on Arizona residents.

In addition to the costs generated by excess healthcare visits, we found the costs associated with hospitalizations to be higher than costs found in previous studies. Our data show hospital charges totaling $86 million (mean $49,000 per hospitalization) among Arizona patients who had primary or secondary diagnoses in 2007. This total is much higher than that found in a previous analysis, which showed total annual hospital charges of $2 million in 1998, increasing to $19 million in 2001 (19). Our data clearly show the growing costs of coccidioidomycosis and its effect on healthcare costs in Arizona.

Persons with a diagnosis of coccidioidomycosis reported living in Arizona for significantly fewer years (median 12) than a sample of the general population (median 22). This finding is consistent with previous studies, which showed that relatively recent relocation to Arizona from a non-disease–endemic area is a risk factor for developing the disease (18,20,21). Leake et al. examined patients >60 years of age and identified a median duration of residence in Arizona of 6.5 years for coccidioidomycosis patients compared with 19.5 years for controls from the same geographic area (18).

We also found that the modified surveillance case definition used by Arizona is appropriate and has a high positive predictive value for the population in this coccidioidomycosis-endemic area. Arizona originally adopted a modified coccidioidomycosis case definition that includes only the laboratory criteria for several reasons. First, clinical information is rarely reported to public health agencies, and with >4,000 cases reported each year, obtaining this information for each case is resource intensive. Second, our experience suggests that most Coccidioides tests are performed on symptomatic patients (i.e., persons sick enough to seek medical attention). The data from this investigation confirm that our modified case definition is highly specific: 95% of cases reported to ADHS met both the laboratory and clinical criteria specified in the CSTE definition; the other 5% either had no symptoms or had symptoms that were inconsistent with the coccidioidomycosis case definition. These findings suggest that eliminating clinical criteria from the coccidioidomycosis case definition allows for simpler surveillance methods and requires fewer resources yet still accurately estimates prevalence and incidence of the disease in endemic regions.

Our investigation has several limitations. Coccidioidomycosis surveillance in Arizona requires a laboratory diagnosis of the disease. Because patients without a laboratory-confirmed diagnosis are missed, the number of reported coccidioidomycosis cases underestimates the actual number of cases. These reports come from outside sources, so a minor chance of error in data collection exists. Additionally, because case-patients reported to the health department are usually persons who are sick enough to seek medical attention for their symptoms and receive testing, this study is biased toward more patients with severe coccidioidomycosis cases and toward those with medical insurance. Furthermore, this enhanced surveillance data relied on self-reporting by patients. Because patients often lack medical knowledge or may refuse to answer questions during the interview, information reported may be missing or inaccurate. For instance, we relied on self-reported use of immunosuppressive medications, and these data were not verified by medical records or by physicians.

Self-reporting is subject to recall bias. However, most case-patients were contacted within a few months of their diagnosis, minimizing recall bias as much as possible. In addition, because telephone interviews were conducted, the data are limited to information from persons who were at home and who had telephones. These factors might explain the underrepresentation of Native American and Hispanics in the enhanced surveillance cohort, although every effort was made to capture information from persons who spoke only Spanish. Table 1 shows that Native Americans were underrepresented in the enhanced surveillance sample compared with the statewide coccidioidomycosis cases reported from January 2007 through February 2008 (2% vs. 5%; p<0.01), a difference possibly caused by lack of telephone contact information in this community. Another possible contributor to the underreporting of Native Americans is the fact that tribal entities are not required to report coccidioidomycosis cases to the state health department; however, most tribes in Arizona do voluntarily report infectious diseases to ADHS. Last, the data from the BRFSS survey may not accurately reflect the general population because respondents tended to be older and were more likely to be female than the Arizona population reported in the US Census 2000 (22).

This population-based cohort investigation illustrates the severe effects that coccidioidomycosis has on patients, the healthcare system, and the economy in Arizona. The data emphasize the need for effective education campaigns aimed at the general public and healthcare providers to decrease delays in diagnosis of coccidioidomycosis, which would probably reduce unnecessary use of antimicrobial drugs, relieve patient anxiety, and enable early recognition and treatment of the disease. Furthermore, the data validate a case definition that uses only laboratory criteria for coccidioidomycosis surveillance in disease-endemic areas. This information could be used to propose changes to the national CSTE coccidioidomycosis case definition in other US disease-endemic areas and thus reduce resources needed for an accurate assessment of the extent of the disease and its effects.