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Synopsis Cost-Effectiveness of a Potential Vaccine for Coccidioides immitisAppendix I: Clinical and Economic BackgroundAmber E. Barnato,* Gillian D. Sanders,† and Douglas K. Owens†‡ We present here detailed information to supplement the methods and results sections of the manuscript. Cost-Effectiveness Ratio FormulaThe incremental cost-effectiveness ratio is calculated as:
where the subscript 1 denotes the intervention under study and subscript 0 the alternative with which it is compared, C1 and C0 are the net present values of costs accrued when the intervention and its alternative are used, and E1 and E0 are their respective health outcomes (1). Thus, C1 - C0 is the incremental cost and E1 - E0 is the incremental effectiveness of the intervention over the alternative. Population CharacteristicsIn the 10 highly coccidioidomycosis-endemic California counties used for our analysis, the annual birth cohort is 90,000 per year and the net annual population growth ranges from 0.3% in Cochise to 3.6% in Pinal (2). Using age-grouped U.S. census data and regional skin test surveys, we calculated a weighted population mean age and mean prior probability of immunity for children (<17: age 8.85, prior 14.5%) and adults (18-65: age 39.51, prior 47.5%). These figures account for population inflow of nonimmune persons from nonendemic regions. Inflow and outflow migration data at the county level are available from the Internal Revenue Service (IRS, unpub. data). For these 10 counties, there is an annual inflow of 5.4% from, and outflow of 4.2% to, nonendemic regions. No data source provides person-level migration data. To account for vaccinees' accruing cost without benefit, we assumed that 0.5% of yet uninfected persons move from highly disease-endemic regions to nonendemic regions each year, corresponding to one third of a birth cohort emigrating by age 65 years. We also used census data to calculate the proportion of whites, blacks, Hispanics, native Americans, and Asians in these 10 counties. We used this information to calculate a composite dissemination rate (see "Disseminated Infection," below). Clinical Manifestations of CoccidioidomycosisPulmonary infectionThe initial respiratory infection with Coccidioides immitis, if symptomatic, is a 2- to 3-week flulike respiratory ailment with cough, fever, and chest pain that may be associated with erythema nodosum. The illness is usually self-limited. If symptoms last longer than 6 weeks, the illness is considered a chronic pulmonary infection (3-7). Among the 40% of infected persons who have symptomatic primary pulmonary infection, from one third to two thirds visit their physicians (8,9), and 1 in 10 patients is serologically diagnosed (John Galgiani, pers. comm., 1999). Because case series in published articles include only patients with diagnosed coccidioidomycosis, we built the probability of diagnosis proximally into the disease model. A proportion of cases progress to respiratory compromise requiring hospitalization; 42.5% of the hospitalizations for coccidioidomycosis in Arizona during 1995 were due to primary pulmonary infection and 11.4% to chronic pulmonary infection (10). The overall death rate from serious pulmonary disease is 0.5% (11). Using Kern County utilization data, we assume that 27% of diagnosed primary pulmonary cases are hospitalized and that each case has an average of 6 physician visits (12). Disseminated InfectionA small fraction of infections disseminate. We calculated the overall dissemination rate in highly disease-endemic areas by using black and white dissemination rates observed among the military (8) and 1999 U.S. census data for population by race in the 10 counties used in our analysis (2). Higher rates of dissemination occur among blacks, Filipinos, and Native Americans (8,13-25). It is unclear whether race is a biologic risk factor via human lymphocyte antigen haplotypes (26) or a confounding variable for those in high-risk occupations and poorer housing conditions that may increase exposure to C. immitis (24,27; Rosenstein N, unpub. data). Even a seemingly uniform exposure, such as occurred in a dust storm carrying arthroconidia from the Central Valley into urban Sacramento in 1979 (17,28), may not be uniform if different groups have different housing quality (e.g., air-conditioning versus open windows and fans). We assumed that whites and Hispanics had a rate of 0.25% (the rate among whites in Smith's studies [18]) and that blacks, Native Americans, and Asians had a rate of 3.4% (the rate among blacks in Smith's studies), for an overall rate of 0.38%. In our model, we took advantage of the Kern County finding that 4.7% of all diagnosed cases of primary pulmonary disease disseminated (29). Folding this number back into the overall dissemination rate of 0.38%, we calculated that nondiagnosed primary pulmonary infection and asymptomatic cases disseminated at a rate of 0.20%. We did not model the increased risk of dissemination that may accompany pregnancy (27,30-36). A utilization study from Kern County found that 84% of all disseminated cases were hospitalized and that each patient had an average of 35 visits in the course of one year (12). We assumed that all meningitis patients were hospitalized, leaving 4/14 non-meningeal dissemination cases to be managed without hospitalization. Further, we assumed that most physician visits took place during the incident month and that follow-up care involved one visit per month. Costs for treating incident disseminated disease, which may include the use of amphotericin B, are contained in the cost of hospitalization for incident disease. We assumed all meningitis patients were treated chronically with 800 mg of fluconazole and that nonmeningeal dissemination patients were treated with either 400 mg of fluconazole or 400 mg of ketoconazole. DisabilitySome patients with disseminated coccidioidomycosis become disabled, causing a lower quality of life and higher costs for long-term care. No studies were published on this topic. Experts assert that half of patients who survive C. immitis meningitis suffer moderate disability, such as chronic cluster headaches, poor concentration, low back pain, and residual focal neurologic defects; and that one sixth of patients suffer disability severe enough to require skilled nursing or home-care support (e.g., major neurologic deficits and coma). One third of patients who survive nonmeningeal dissemination have an orthopedic disability (John Galgiani, pers. comm., 2000). CostsInpatient costs used discharge diagnoses of primary pulmonary coccidioidomycosis (ICD-9 114.0, Diagnosis-Related Group [DRG] 80), coccidioidal meningitis (ICD-9 114.2, DRG 20), disseminated coccidioidomycosis (ICD-9 114.3, DRG 423), and anaphylaxis (ICD-9 999.4, DRG 447) (37). Outpatient costs from the National Medicare Fee Schedule included intermediate established outpatient office visit (Current Procedural Terminology [CPT] code 99212 and coccidoidomycosis skin testing (CPT code 86490). Other costs obtained from the Kern County Public Health Department included the C. immitis laboratory tests: enzyme immunoassay (EIA) immunoglobulin (Ig) M (CPT code 83171), complement fixation (CPT code 86171), and immunodiffusion (CPT code 86331) and hepatitis B immunization (CPT code 90746). By calculating the weighted average adjusted gross income for the 10 California and Arizona counties in our model from IRS tax return data (IRS, unpub. data), we obtained a figure of $12/hour as the value of a person's time. For a person with undiagnosed primary pulmonary illness, we assumed 5 days of lost time from work for a working adult (<65 years old) and 3 days of lost time from work for the parent of a sick child (children, on average, have less severe primary illness). We assumed that the first vaccination in a vaccination strategy would be delivered during a visit scheduled for another purpose, adding 15 minutes to the visit. The two successive vaccinations would require clinic visits with 1-hour travel and waiting time and 15 minutes vaccination time. For a screen and vaccinate strategy, the screening visit and the successive reading plus vaccination (if indicated) would take 1 hour 15 minutes, as would each of two successive vaccination visits. Results: Best- and Worst-Case ScenariosWe examined scenarios in which the input variables were most and least favorable to vaccination. Under a best-case scenario, in which the vaccine prevents infection, childhood vaccination saved $608 and 112 quality-adjusted life days (QALD) per person, and a screen and vaccinate strategy saved $55 and 16 QALD per adult over no vaccination. A worst-case scenario, in which the vaccine is ineffective, caustic, costly, and applied to a population in a lightly disease-endemic region, the vaccine does more harm than good in all ages. The probability of either scenario, however, is essentially zero. References
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