Coccidioidomycosis (valley fever) is a disease caused by Coccidioides spp., dimorphic fungi that thrive in the alkaline soil of warm, arid climates ( 1 ). Infection may occur when conidia in disrupted soil are inhaled. Coccidioidomycosis-endemic areas include the southwestern United States, parts of Mexico, and Central and South America. In the United States, these areas include parts of Arizona, California, New Mexico, Nevada, Texas, and Utah ( 1 ). The clinical manifestations of coccidioidomycosis have been well established ( 2 – 4 ); 1–3 weeks after a person inhales the spores, most persons with symptomatic infection will have a clinical syndrome consistent with community-acquired pneumonia (CAP) ( 3 ). Serologic testing is the most frequently used method for diagnosis of primary pulmonary coccidioidomycosis ( 3 , 5 ). For most patients, serologic reactivity ends after a few months unless infection is active. Although 95% of symptomatic pulmonary infections are self-limiting and resolve after several weeks or months without antifungal therapy, ≈5% progress to asymptomatic residua, such as pulmonary nodules or cavities ( 2 ). Among all recognized infections, extrapulmonary disease involving the meninges, bones and joints, skin, and soft tissues occurs in 18 years vs. 14 days, as well as other demographic or clinical symptom characteristics. A final multivariable model was chosen by using the stepwise selection procedure. Independent variables that remained significant (α 65 years of age also had high incidence rates (65–74 years, 161/100,000; 75–84 years, 147/100,000; >85 years, 153/100,000). Figure Coccidioidomycosis cases reported by month, Maricopa County, Arizona, 1999–2004. Retrospective Cohort Studies Participants In system A, 619 visits for “pneumonia, organism unspecified” were identified, from which 132 (21%) were sampled for chart review. From the 132, 66 (50%) were excluded: 11 had no charts available, 21 were miscoded or did not have a clinical diagnosis of pneumonia, 30 were initially hospitalized, and 4 had been residents of long-term care facilities or hospitalized within the 14 days before symptom onset. The remaining 66 patients were confirmed by chart review to have CAP and were included. In system B, 14,695 visits for “pneumonia, organism unspecified” were identified, from which 159 (1%) were sampled for chart review. From the 159, 72 (46%) were excluded: 6 had no charts available, 25 did not have clear documentation of pneumonia, 37 were initially hospitalized, 1 had been hospitalized within 14 days before symptom onset, and 3 had a history of coccidioidomycosis. The remaining 87 patients were therefore included. Patient Characteristics and Clinical Description (Table 2) Table 2 Demographic and clinical characteristics of patients with community-acquired pneumonia included in retrospective cohort studies, Maricopa County, Arizona, January 2003–December 2004* Patient characteristic System A (% or range),
n = 66 System B (% or range),
n = 87 Absolute difference in percentages (95% CI)* Evaluated initially in emergency department 17 (26) 5 (6) 20 (7–33)† Median age, y (range) 54 (6–90) 37 (0–86) Age 21 d at time of 1st visit 4 (9) 6 (7) NS Symptoms Fever 22 (33) 50 (58) NS Chills 5 (8) 12 (14) NS Night sweats 0 4 (5) NS Myalgias 2 (3) 3 (3) NS Fatigue 4 (6) 4 (5) NS Cough 54 (82) 69 (79) NS Dyspnea 18 (27) 23 (26) NS Chest pain 10 (15) 11 (13) NS Wheezing 8 (12) 9 (10) NS Signs Temperature >100.4°F 10 (15) 24 (28) NS Tachycardia 8 (12) 11 (13) NS Focal lung examination 37 (56) 44 (51) NS Hypoxia 0 0 NS Rash 0 0 NS Immunosuppressive medication 2 (3) 1 (1) NS Coexisting conditions Asthma 10 (15) 23 (26) NS Chronic obstructive pulmonary disease 13 (20) 12 (14) NS Diabetes mellitus 25 (38) 7 (8) 30 (16–43)† HIV infection 0 1 (1) NS Pregnancy 1 (2) 0 NS Transplant 1 (2) 0 NS Malignancy 1 (2) 3 (3) NS Diagnostic testing, noncoccidioidal Chest radiograph 23 (35) 83 (95) 61 (47–72)† Radiographically proven pneumonia 18 (27) 67 (83) 50 (35–63)† Treatment and outcome Antibacterial drugs 66 (100) 87 (100) NS Follow-up visits None 17 (26) 27 (31) NS 1 34 (52) 27 (31) NS 2 5 (8) 13 (15) NS >3 10 (15) 20 (23) NS Hospital admissions 2 (3) 6 (7) NS Died 0 (0) 2 (2) NS Coccidioides spp. serologic testing At any visit 1 (2) 11 (13) 11 (3–20)‡ During follow-up visit 0 4 (5) NS Reactive results 0 1 (1) NS Median no. days before testing 12 27 (1–99) – Symptoms >14 days before testing 0 7 (64) NS Diagnosis of coccidioidomycosis, any technique 0 1 (1) NS CI, confidence interval; NS, not significant. CIs on difference in percentages were performed by using an exact method with 2 independent binomial proportions.
†p 14 days (OR 5.8, 95% CI 2.1–15.7) were significantly more likely to have been tested (Table 3). Additionally, patients >18 years of age (OR 5.5, 95% CI 2.1–15.3) and those who had diabetes or were receiving an immunosuppressive medication (OR 3.6, 95% CI 1.0–16.5) were significantly more likely to have been tested. Table 3 Characteristics of patients with community-acquired pneumonia (CAP) who were tested for coccidioidomycosis, Maricopa County, Arizona, January 2003–December 2004* Characteristic Case-patients, no. (%), n = 60 Controls, no. (%), n = 76 Odds ratio (95% CI) Adjusted odds ratio† (95% CI) Age >18 y 53 (88) 44 (58) 5.5 (2.1–15.3)‡ 5.3 (1.5–24.0) Male 28 (55) 40 (53) 0.9 (0.5–1.9) NS Chest pain 19 (32) 7 (9) 4.6 (1.8–11.8)‡ 3.9 (1.2–13.8) Rash 5 (8) 0 Undefined (1.2–Undefined)‡ 21.1§ (2.2–undefined) Diabetes mellitus or immunosuppressive condition 10 (17) 4 (5) 3.6 (1.0–16.5)‡ NS Symptoms >14 d 20 (33) 6 (8) 5.8 (2.1–15.7)‡ 4.1 (1.3–14.2) *CI, confidence interval; NS, not significant. Case-patients were patients who had CAP and had received Coccidioides spp. serologic testing, regardless of test result; controls were patients who had CAP but had not received Coccidioides spp. serologic testing.
†Adjusted odds ratios and exact 95%CI from a multivariable logistic regression model.
‡Significant (p 14 days (adjusted OR 4.1, 95% CI 1.3–14.2). The Hosmer-Lemeshow goodness-of-fit test showed no evidence of a lack of fit (p = 0.8). Of the 60 case-patients who were tested for Coccidioides spp., 9 (15%, 95% CI 8%–26%) had positive results. Of these 9, 3 had immunoglobulin (Ig) M by enzyme immunoassay alone, 3 had IgM and IgG by enzyme immunoassay (IgG titers 4, 8, and 8 by complement fixation), 1 had IgM and IgG by immunodiffusion, 1 had a single high IgG titer (128), and another had a rising IgG titer (<2 initial; 16 at 4 weeks). Discussion Our study directly measured serologic testing practices for coccidioidomycosis. The proportion of ambulatory patients with CAP who were tested for Coccidioides spp. was low in this coccidioidomycosis-endemic area. Because incidence rates of CAP in this area of the United States are not available, the number of CAP patients who do not receive serologic testing for Coccidioides spp. cannot be estimated. However, if incidence rates are comparable to those in other parts of the country ( 6 ), the number of patients with CAP who are not tested for coccidioidomycosis would be high. If CAP is the result of coccidioidomycosis in as many as 10%–15% of these untested patients, then large numbers of patients would remain undiagnosed. According to recently published Infectious Disease Society of America (IDSA) guidelines, the benefit of antifungal therapy for uncomplicated respiratory Coccidioides spp. infection is unknown ( 6 ). However, treatment is more likely to benefit groups at risk for severe or disseminated infection ( 6 ). Although these groups are especially likely to benefit from early testing for coccidioidomycosis, other benefits of early diagnosis may exist for all patients with coccidioidomycosis, regardless of risk for severe disease. Such benefits may include avoidance of unnecessary use of antibacterial agents, earlier identification of complications, decreased need for further expensive diagnostic studies, and reduction of patient anxiety ( 3 ). Reasons that CAP patients may not be tested for Coccidioides spp. are unclear but are likely complex. First, professional consensus for optimal testing practices may have been lacking. Although guidelines developed by national professional organizations for the management of CAP were available during the study period ( 11 – 13 ), these guidelines did not directly address the best strategy for Coccidioides spp. serologic testing ( 11 – 13 ). IDSA guidelines for the treatment of coccidioidomycosis also did not clearly recommend serologic testing for patients with CAP ( 6 , 14 ). The most recent IDSA/American Thoracic Society guidelines for CAP, published after the study period, now recommend evaluating travel history or exposure to disease-endemic area during the initial assessment rather than waiting for a failed response to therapy ( 15 ); these guidelines may lead to increased testing for coccidioidal CAP. Second, physicians may be unaware of the benefits of early testing or the possible high prevalence of coccidioidomycosis in those with CAP in Arizona and therefore may not understand the utility of testing. Regardless of the reasons, the lack of testing in the presence of widespread disease hampers epidemiologic understanding of this disease and subsequently may affect public health decisions related to resource allocation to control disease, educate physicians, and develop a vaccine. Our data also illustrate the marked differences in process of care for ambulatory patients with CAP in different health systems. Patients in the uninsured population, system A, were less likely to be tested than patients in the primarily insured population, system B. This disparity is evidenced by the higher proportion of CAP patients in the insured system who received chest radiography in addition to serologic testing. Public health officials may be able to address these disparities by providing general recommendations for diagnostic testing of patients with CAP in coccidioidomycosis-endemic areas; process-of-care measures such as chest radiography and Coccidioides spp. serologic testing may help determine effectiveness of such interventions. Of the tested CAP patients in system B, 15% had serologic evidence of recent Coccidioides spp. infection; this proportion is much lower than that (29%) found in a recently reported study ( 8 ). Several differences may explain this discrepancy. First, our study population was located in a different area of Arizona. Second, our definition of CAP differed from the definition used in the other study and is likely more representative of actual CAP found in outpatient practices ( 8 ). However, our proportion may overestimate the true proportion of CAP caused by coccidioidomycosis because testing in our cohort was subject to a decision made by the treating physician. Nevertheless, the high proportion could signify that a large number of pulmonary coccidioidomycosis diagnoses are likely missed in Maricopa County alone and that the overall extent of pulmonary coccidioidomycosis is higher than that indicated by reportable disease data. Further studies are needed to better quantify the extent of disease. Our study has several limitations. First, in contrast to definitions used in many studies, our definition of CAP included patients whose diagnosis was made by a clinician without a chest radiograph or with a negative chest radiograph. However, although some patients may not have truly had CAP, our definition reflects what clinicians actually believed they were treating, which is clinically relevant to whether a diagnostic test is ordered. Second, although the study populations were geographically dispersed throughout metropolitan Phoenix and included varied population segments, they may not be generalizable to populations in health systems in other areas of Arizona. Third, at system B, controls were inadvertently oversampled during 2003, so we were unable to include visit year in our analysis. However, it is unlikely that the biased selection based on year led to substantial bias for other variables such as age, sex, clinic location, signs, symptoms, coexisting medical conditions, or testing. Fourth, data on socioeconomic status were not available for either system, and race or ethnicity data were not available from system B. Fifth, because our study evaluated ambulatory rather than hospitalized patients with CAP, our conclusions cannot be generalized to the hospital, where testing practices are likely to differ. Our study shows that testing for Coccidioides spp. among ambulatory patients with CAP is infrequent in metropolitan Phoenix. Providers in metropolitan Phoenix and other coccidioidomycosis-endemic areas should consider testing patients with CAP for coccidioidomycosis. Further epidemiologic studies are needed to better determine the true extent of pulmonary coccidioidomycosis.
