Cost-effectiveness of a potential vaccine for Coccidioides immitis. (Synopses).

Coccidioidomycosis, a systemic fungal infection, affects Americans living in the Southwest. We evaluated the cost-effectiveness of a potential vaccine against Coccidioides immitis. Using a decision model we developed, we estimate that among children, vaccination would save 1.9 quality-adjusted life days (QALD) and $33 per person. Among adults, screening followed by vaccination would save 0.5 QALD per person and cost $62,000 per quality adjusted life year gained over no vaccination. If the birth cohort in highly endemic counties of California and Arizona were immunized in 2001, 11 deaths would be averted and $3 million would be saved (in net present value) over the lifetime of these infants. Vaccination of adults to prevent disseminated coccidioidomycosis would provide a modest health benefit similar in magnitude to other vaccines but would increase net expenditures. Vaccination of children in highly endemic regions would provide a larger health benefit and would reduce total health care expenditures.

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Coccidioides immitis, an infectious fungus, grows in the arid soil of the Central Valley of California, southern Arizona, and parts of Nevada, New Mexico, Utah, and Texas, as well as northern Mexico and parts of Central and South America. Regions endemic for C. immitis are home to approximately 20% of the U.S. population; an estimated 5 million persons live in the areas of highest endemicity (Figure 1) (1-3). Humans are infected by inhaling dust containing C. immitis arthroconidia. Dust storms (4,5) and activities associated with heavy dust exposure such as agricultural labor (6), excavating archeologic ruins (7), and military combat training (8,9) increase infection rates, total infectious load, and the proportion of symptomatic cases. Infection rates, as reflected by positive skin tests, have decreased since the 1940s and 1950s from as high as 8% per month to approximately 2% to 3% per year in highly endemic regions. This decrease is likely the result of reduced dust exposure attributable to lifestyle changes and urbanization. However, population growth in endemic regions has been steady and is projected to increase.

[FIGURE 1 OMITTED]

Recent epidemics in California and Arizona highlight the continuing public health threat and costs of coccidioidomycosis (10,11) and have led to efforts to develop a vaccine. An economic analysis of the 7,130 cases from 1991 to 1993 in California's Kern County demonstrated a cost to that county of $56 million (12). Because the U.S. training post for desert warfare is located in the Mojave Desert, an area endemic for C. immitis, a vaccine is a military as well as a civilian priority. A killed whole spherule vaccine that showed promise in animal trials was not well tolerated in humans (13). Current efforts of the Valley Fever Vaccine Project, a consortium of researchers funded primarily by the California Healthcare Foundation and the California Department of Health Services, focus on a number of antigens successful in mice models that may form the basis of a subunit vaccine (G. Rutherford, pers. comm.).

Despite the potential clinical value of a vaccine, the only study of the cost-effectiveness of a vaccination program was an Institute of Medicine (IOM) analysis for the purposes of setting priorities in vaccine development (14). The IOM concluded that vaccine development would cost more than $100,000 per quality-adjusted life year (QALY) gained, but included vaccine development costs and used a very simplified model. If the vaccine would not be cost-effective, current development efforts might be in vain. We present the results of a detailed cost-effectiveness analysis of a potential vaccine against C. immitis.

Data and Methods

We used a decision model to evaluate the health and economic consequences of withholding the vaccine, screening and vaccinating only those susceptible to infection (screening/vaccination), or vaccinating all eligible persons. Taking a societal perspective, we calculated the incremental cost-effectiveness of these strategies (formula in Appendix I, online; URL: http://www.cdc.gov/ncid/eid/vol7no5/barnato_appendix1.htm), and we discounted both costs and benefits at an annual rate of 3%. We performed one-way sensitivity analyses on all the model variables, as well as a three-way sensitivity analysis of the most sensitive variables, and best-and worst-case scenarios.

We based the estimates for input variables on the literature whenever possible (Appendix II Table). Our base-case estimates represent our judgment about the best estimate from the literature and discussion with experts. The ranges for costs represent variation by 25% above and below the base-case estimate, except where otherwise specified. The ranges for sensitivity analyses on quality-of-life estimates represent the 25th and 75th percentiles of patients' assessments of quality of life (15), except where otherwise specified. The authors had complete scientific and editorial independence from the funding agencies.

Decision Model

We developed a Markov model (Figure 2) with Decision Maker software (version beta 0.99.11.14.0a, 2000, S. Pauker, et al., Boston, MA) (16,17) to track hypothetical cohorts of patients who either did not receive the C. immitis vaccine, received it, or received it only if their skin test was negative. Patients who received the vaccine were at risk for pain at the injection site, mild to moderate fever, and anaphylaxis without death. Vaccinated patients were at decreased risk for extrapulmonary dissemination after primary infection. Patients neither immune from previous infection nor successfully vaccinated were at risk for C. immitis infection and serious sequelae. All patients were at risk for dying from other causes (18). We followed cohorts until death, with a Markov cycle length of 1 month.

[FIGURE 2 OMITTED]

Patient Population

We used epidemiologic and demographic data from two California counties (Kern and Tulare) and eight Arizona counties (Cochise, Gila, Graham, Maricopa, Pima, Pinal, Santa Cruz, and Yavapai) as proxies for the population features of highly endemic regions (2,19; Internal Revenue Service, unpub, data). We used two cohorts representing the weighted average age and prior probability of naturally acquired immunity among children (ages [less than or equal to] 17) and adults (ages 18 to 65) in 10 highly disease-endemic counties. New residents with no natural immunity were added to these cohorts. Children had an average age of 8.85 years, and 14.5% were naturally immune; adults had an average age of 39.51 years, and 47.5% were naturally immune.

Clinical Manifestations

Smith's classic studies in military recruits stationed in disease-endemic regions during World War II established that 60% of infected persons have no symptoms and 40% have a flulike illness (20). Asymptomatic infection and symptomatic infection with recovery confer probable lifelong immunity with a positive delayed-type hypersensitivity skin-test reaction to coccidioidin or spherulin. However, a fraction of persons do not have simple self-limited disease and instead more serious illness develops, such as respiratory failure, chronic pneumonia, and extrapulmonary dissemination (20-23). We present more clinical detail in Appendix I, online, only (at URL:www.cdc.gov/eid/v7n5/barnato-appendix1.htm) and summarize probability estimates, costs, and utilities in the Appendix II Table.

Vaccine and Skin-Test Characteristics

Animal trials of the vaccine rely on intraperitoneal or intranasal challenge with large loads of C. immitis. The outcome measure is survival or death from disseminated disease. Because the mechanism of action of the putative vaccine is not known, we conservatively assumed that vaccination prevents extrapulmonary dissemination but not primary infection. We evaluated this assumption in a sensitivity analysis.

We assumed that all vaccinated persons comply with 3 doses in 1 year and all develop an antibody response. We assumed that the vaccine reduced the probability of dissemination by 75%, with lifelong duration, based on experience with hepatitis B vaccine, a widely used subunit vaccine. We examined the effects of compliance with each strategy and the effect of waning immunity.

Using data from hepatitis B vaccine as a proxy, we assumed that 25% of patients would experience mild side effects such as local arm pain, fever, and nausea and that 1 in 600,000 patients would experience nonfatal anaphylaxis requiring hospitalization (24).

For screening before vaccination, studies suggested a sensitivity of 70% and a specificity of 90% for the spherulin intradermal test (25-30).

Quality of Life

Our model included intermediate health states that may be associated with decrements in quality of life. To adjust for such decrements, we included quality adjustments in our model (Appendix II Table). Because there are no quality-of-life studies for coccidioidomycosis, we used proxy health state utilities in published studies or clinical judgment. All illness utilities were multiplied by age-specific "healthy" utilities to account for the age at which an illness was contracted. We assumed that primary pulmonary infection causes a substantial heath status decrement only in those who are sick enough to be diagnosed. Among those with primary pulmonary disease that goes undiagnosed, we assigned a health state utility equal to well for this illness episode, but accounted for lost time from work due to illness (see Costs, below). For the short-term vaccine side effects, we capture quality-of-life impact as a decrease in utility of onetenth of a quality-adjusted day. The base case and ranges for these quality-of-life adjustments reflect our judgment about the impact of these episodes on patients. We evaluated the effects of these utility assumptions in sensitivity analyses.

Costs

Direct Medical Costs

All costs are presented in 2000 U.S. dollars (Appendix II Table). For costs of inpatient care, we used cost-adjusted charges from the 1996 Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project (31). For outpatient services, we used the 2000 Medicare national physician fee schedule (32). For outpatient services not listed in the Medicare fee schedule, we used reimbursement received by Kern County service providers (R. Talbot, pers. comm.) We assumed that patients severely disabled by coccidioidal meningitis would require home support and used the average payment per Medicare home health beneficiary as a proxy for this cost (33).

Vaccine and Other Costs

In our base-case analysis, we assumed the cost of the vaccine was $180. We chose this value for the base case because it is the reimbursed fee for the three-shot hepatitis B series, an existing subunit vaccine. We examined a broad range of vaccine costs ($100 to $400) in sensitivity analyses.

For circumstances in which quality-of-life changes do not capture the inconvenience of illness or medical care, we included time costs, as noted in the online Appendix I.

Results

Prevention of Illness and Death

We calculated the number of cases of disseminated disease and deaths per 100,000 persons that would be prevented over the lifetime of each cohort if children and adults were immunized, assuming rates of vaccine coverage of 40%, 60%, 80%, and 100% (Table 1). For example, if 60% of children were vaccinated, 93 cases of dissemination, 64 cases of disability, and 7 deaths would be averted and $2 million saved per 100,000 population. If 60% of adults underwent screening followed by vaccination, 38 cases of dissemination, 24 cases of disability, and 2 deaths would be prevented at a cost of $5.4 million per 100,000 population.

Costs and Effectiveness

We calculated the effectiveness, costs, and cost-effectiveness of each strategy in each population, expressed in Table 2 as the per-person cost and health benefit. Among children, vaccination saved 1.9 quality-adjusted life days (QALD) and $33 per person. Among adults, screening followed by vaccination saved 0.5 QALD per person and cost $62,000 per QALY gained over no vaccination. For adults, the incremental gain from vaccinating all persons compared with screening followed by vaccination contributed an additional 0.05 QALD at a cost of $235,000 per QALY gained.

Sensitivity Analyses

We performed one-way sensitivity analyses over the ranges of all input variables listed in the table in Appendix II and on critical assumptions, such as the vaccine mechanism of action and target population. Among children, vaccination was no longer cost-saving at the lowest ranges of vaccine efficacy, infection rate, dissemination rate, long-term care cost for severe disability, and medical follow-up cost after nonmeningeal dissemination and chronic pulmonary disease; the vaccine also was not cost-saving in children when we used the highest ranges of vaccine cost, meningitis mortality, emigration, and discount rate among children. The counter-intuitive effect of meningitis deaths is due to the decrease in survivors subject to long-term care costs from post-meningitis disability. Among adults, sensitivity analyses that changed the cost-effectiveness ratio by [is greater than or equal to] $40,000 per QALY gained included infection rate, vaccine effectiveness, discount rate, vaccine cost, dissemination rate, emigration rate, and office visit time. Only the vaccine cost changed the preferred strategy among adults. Below $106 per 3 doses, vaccination was preferred over screening/vaccination, with a cost-effectiveness ratio of $30,000 per QALY gained.

Vaccine Duration

Our base-case analysis assumed lifetime immunity after vaccination, but vaccine protection may wane. If vaccine protection waned to zero in 15 years, vaccination saved 0.82 QALD per child and cost $47,300 per QALY gained, and screening/vacccination saved 0.28 QALD per adult and cost $165,500 per QALY gained.

Vaccine Mechanism of Action

If the vaccine prevented primary infection rather than dissemination alone, vaccination saved 2.26 QALD and $46 per vaccinated child over no vaccination. Screening/vaccination saved 0.66 QALD per adult, costing $46,500 per QALY saved.

Three-Way Sensitivity Analysis of Infection Rate, Vaccine Effectiveness, and Cost

Our base case assumed an infection rate of 2% per year, vaccine effectiveness of 75%, and a vaccine cost of $180. However, the vaccine may have some use in areas of lower endemicity. Also, because the vaccine does not yet exist, its cost and effectiveness are unknown. We present the effects of varying costs and effectiveness of the vaccine under two conditions: 0.5% infection rate per year and 2% per year (our base case of highly endemic regions) (Figure 3). In our base case for children, the $180 vaccine remains cost-saving down to an effectiveness of 65% and costs < $50,000 per QALY until vaccine effectiveness drops below 30%, confirming that the vaccine need not be highly effective to be cost-effective in younger populations. A $400 vaccine costs approximately $50,000 per QALY gained among children at 65% effectiveness. A $400 vaccine would be economically unfavorable for the screening/vaccination strategy in adults at an annual infection rate of 2%, even at 90% vaccine effectiveness. At an infection rate of 0.5% per year, as might be seen in southern California (34), all strategies except $180 vaccination at 90% effectiveness in children are economically unfavorable.

[FIGURE 3 OMITTED]

Discount Rate

Among children, vaccination saved 5.95 QALD and $563 over no vaccination when costs and benefits were not discounted. At a discount rate of 5%, vaccination was no longer cost-saving at $27,600 per QALY gained. For adults, changing the discount rate from 0% to 5% changed the cost-effectiveness ratio of screening/vaccination compared with no vaccination from $30,800 to $155,000 per QALY gained.

Dissemination Rate

Our base-case analysis used a dissemination rate of 0.38% based on the assumption that only blacks and Asians had higher rates of dissemination than whites. We evaluated a range of 0.25% to 0.55% to determine the effect of assuming all non-whites (including Hispanics) had rates of dissemination equal to that of whites (0.25%) or that of blacks (3.4%). Among children, vaccination saved 2.71 QALD and $143 per child vaccinated at an overall dissemination rate of 0.55%, and 1.22 QALD at a cost of $15,300 per QALY gained at the 0.25% dissemination rate. Among adults, varying the dissemination rate from 0.25% to 0.55% changed the cost-effectiveness ratio of screening/vaccination over no vaccination from $25,400 to $125,000 per QALY gained.

New Residents

If one considers new residents separately, vaccination saved 2.18 QALD and $75 per immigrant child vaccinated, and saved 1.13 QALD per immigrant adult vaccinated, costing $13,500 per QALY gained.

We present best- and worst-case scenarios in Appendix I (online).

Discussion

We evaluated the usefulness of a potential vaccine against C. immitis in highly disease-endemic regions. Vaccination was cost-saving among children. A screening/vaccination strategy cost $62,000 per QALY gained among adults. Although the increase in quality-adjusted life expectancy from an immunization program is modest for one individual patient, this aggregates to an important number of illnesses and deaths prevented (Table 1). Furthermore, the life expectancy gains are comparable with gains from other immunizations. Vaccination for coccidioidomycosis (universally among children and after screening in adults) saved 0.14 to 0.47 life days and 0.53 to 1.86 QALD per person over no vaccination. In comparison, vaccination against pneumococcal bacteremia among elderly people saves 1.2 QALD per person vaccinated (35); infant vaccinations against measles, mumps, rubella, and pertussis each save 2.7, 3, 0.3, and 3.3 life days, respectively (36). To further place benefits in perspective, if the birth cohort in highly endemic counties of California and Arizona were immunized in 2001, 11 deaths would be averted and $3 million would be saved (in net present value) over the lifetime of these children.

The only previous analysis of the cost-effectiveness of a vaccine against coccidioidomycosis drew different conclusions. An IOM report considered the costs and benefits of research and development into a vaccine for C. immitis and found that the immunization of infants in endemic regions and immigrants of any age would cost > $100,000 per QALY (14). Our analysis evaluated a different question: If a vaccine were currently available, would it be cost-effective to immunize people in highly endemic regions? Although the IOM report acknowledged that the committee used rough estimates and a simplified model, the primary reason that it reached a different conclusion was that the cost of vaccine development was included in the IOM model. Vaccine development costs will influence the sale price of the vaccine. Project directors of the Valley Fever Vaccine Project estimate that research and development through phase III clinical trials, supported largely by public and private philanthropic sources, will cost $28 million (G. Rutherford, pers. comm.). This figure is 10 times lower than that used by the IOM in its analysis. To recoup $28 million over 5 years by immunizing 60% of the 90,000 annual birth cohort in highly endemic regions of California and Arizona, the vaccine would have to be priced at $100 per vaccinated person. This is less than the $180 vaccine cost assumed in our base-case analysis.

Sensitivity analyses found that the vaccine would be cost-effective in children under assumptions of waning immunity and would be even more effective and cost-saving in children and cost-effective in adults if the vaccine prevented primary infection. In highly endemic regions, vaccination of children is cost-effective even at relatively low levels of vaccine effectiveness if the vaccine is priced at $180. A $180 vaccine had to be > 85% effective for screening/vaccination to cost [is less than or equal to] $50,000 per QALY in adults. Paradoxically, an even higher annual infection rate would make a screening/vaccination strategy less favorable in adults because most of them would have already acquired natural immunity by age 40. At an annual infection rate one-fourth of that seen in the Central Valley of California, such as might be seen in southern California, the only cost-effective strategy would be to immunize children with an inexpensive and highly efficacious vaccine. If dissemination rates are higher than our base case, as might be seen in the elderly and those with chronic diseases, screening/vacccination becomes cost-effective for adults.

The vaccine is much more effective in persons without naturally acquired immunity. A vaccination strategy that targeted new residents in highly endemic regions would exploit easily obtainable risk factor information. However, such a policy might be unacceptable to members of the population excluded by such a strategy. Finally, because vaccination is a preventive intervention that can take years before accruing a health benefit (in contrast to acute health-care interventions), our results were highly sensitive to discount rate.

Our model has limitations. The ecology of endemic regions has changed substantially with urbanization since Smith's study in the 1940s (20). Furthermore, his studies documenting infection and dissemination were conducted in the military, which may not be representative of general population exposures. Our base-case analysis used the demographics in highly endemic areas to estimate a composite dissemination rate for a multiracial population. We did not model race independently, nor did we model exposure risk. Workers with high levels of dust exposure may have higher rates of infection and more to gain from early immunization.

Our model assumed that all age groups without prior immunity were at equal risk for adverse health outcomes and had identical health-care costs. However, illness severity and costs may be higher among the elderly. Reported cases of coccidioidomycosis during Arizona's 1991 to 1995 epidemic occurred disproportionately among older adults (11). The study did not discern whether this was due to reporting differences, immune-suppressing coexisting conditions, a preponderance of new immigrants with higher risk for infection, or an independent age-related phenomenon. The death rate from primary pulmonary infection is as high as 26.8% among persons over 65 (37), much higher than our composite base-case estimate of 0.5%. The Kern County data on which we based our cost assumptions revealed that hospitalization, the greatest health-care expenditure associated with acute illness, was 4.2 times more likely among people > 50 years old. Thus, we may have underestimated the potential effectiveness and cost savings of the vaccine among older adults.

Finally, our analysis did not model the effects of an immunization program in immunocompromised patients. Persons with compromised cell-mediated immunity, including those with AIDS, malignancy, or therapeutic medical immunosuppression, have higher rates of serious illness. Many of these patients may have reactivation of previous infection; it is unclear whether vaccination would be useful in this clinical scenario. This is an area for future research as results from clinical trials become available.

An uncommon disease in a national context, coccidioidomycosis has substantial ramifications for several regions where epidemics have produced reported annual case rates as high as 15 per 100,000 and substantial economic impact. Diseases affecting < 200,000 persons annually (orphan diseases) require more incentives for research and development. Our findings may contribute to the policy decisions for vaccine development and distribution for C. immitis (39). Our analysis suggests that a vaccine against C. immitis would have substantial public health benefit. An update of this cost-effectiveness analysis can be performed when the results of human vaccine trials become available.

Appendix I. Clinical and Economic Background

Appendix I is online only; it contains the formula used to calculate the incremental cost-effectiveness of these strategies; URL: http://www.cdc.gov/ncid/eid/vol7/no5/barnato_appendix1.htm

Appendix II Table. Input variables, quality of data, and sources (a)

Input variable                            Base-case estimate (range)

Epidemiology (%)
  Vaccine effectiveness                           75 (20-90)
  Skin-test sensitivity                           70 (50-80)
  Skin-test specificity                           90 (70-97)
  Annual infection rate                           2 (0.25-3)
  Annual emigration among vaccinees out          0.5 (0-4.2)
  of highly endemic region
  Symptomatic primary pulmonary disease               40
  after infection
  Diagnosed symptomatic primary                   10 (5-15)
  pulmonary disease
  Death from primary pulmonary disease,           0.5 (0-26)
  given diagnosis
  Chronic pulmonary disease after                  5 (1-10)
  diagnosed primary infection
  Death from chronic pulmonary disease             5 (0-20)
  Dissemination after infection                0.38(0.25-0.55)
  Meningitis, given dissemination                 33 (23-44)
  Death from meningeal dissemination               7 (5-40)
  Moderate disability after meningeal             50 (40-60)
  dissemination
  Severe disability after meningeal               17 (10-30)
  dissemination
  Annual meningeal dissemination                   2 (0-5)
  relapse rate, on treatment
  Death from nonmeningeal dissemination            2 (0-10)
  Moderate disability after nonmeningeal          33 (20-50)
  dissemination
  Annual nonmeningeal dissemination
  relapse rate
    On treatment                                   2 (0-5)

    Off treatment                                 50 (35-65)
  Mild vaccine side effects                       25 (10-40)
  Vaccine anaphylaxis, x [10.sup.-4]            1.67 (0.1-10)

Direct medical costs ($)
  Three doses of vaccine                        180 (100-400)
  Skin test                                       12 (9-15)
  Home care, per month                       2,450 (1,840-3,060)
  Diagnosed pulmonary disease                2,090 (1,570-2,610)
  Incident meningeal dissemination           9,510 (7,130-11,890)
  Medication and follow-up afTer             1,510 (1,130-1,890)
  Coccidioides immitis meningitis, (f)
  per month
  Incident nonmeningeal dissemination        6,950 (5,210-8,690)
  Medication and follow-up for chronic          530 (290-790)
  pulmonary infection and nonmeningeal
  dissemination, (f) per month
  Inpatient vaccine anaphylaxis              2,180 (1,640-2,730)
  treatment

Time costs (h)
  Average wage ($ per hour)                       12 (9-15)
  Average clinic visit (hours)                   1.25 (0.5-2)
  Lost work due to undiagnosed primary             5 (0-10)
  pulmonary disease (days)
  For parents of sick children (days)              3 (0-5)

Utilities
  Well                                         0.94 to 0.70 (i)
  Diagnosed primary pulmonary infection        0.90 (0.85-0.95)
  Chronic pulmonary infection (proxy,          0.57 (0.29-0.84)
  pulmonary tuberculosis)
  Meningeal dissemination (proxy,              0.40 (0.21-0.52)
  paraplegia)
  Nonmeningeal dissemination (proxy,           0.59 (0.34-0.84)
  orthopedic impairment)
  Severe disability after meningitis           0.27 (0.10-0.38)
  (proxy, hemiplegia)
  Moderate disability after meningitis         0.72 (0.52-0.92)
  (proxy, sciatica)
  Moderate disability after nonmeningeal       0.69 (0.51-0.92)
  dissemination (proxy, arthritis)
  Chronic azole treatment (proxy,              0.98 (0.92-1.0)
  warfarin treatment)
  Dead                                                0
  Vaccine side effect quality-of-life            0.1 (0-0.2)
  decrement (days)

Other variables (%)
  Discount rate                                    3 (0-5)

Input variable                            Quality of evidence (b)

Epidemiology (%)
  Vaccine effectiveness                            I
  Skin-test sensitivity                          II-2
  Skin-test specificity                          II-2
  Annual infection rate                          II-3
  Annual emigration among vaccinees out        II-2, III
  of highly endemic region
  Symptomatic primary pulmonary disease          II-2
  after infection
  Diagnosed symptomatic primary                   III
  pulmonary disease
  Death from primary pulmonary disease,          II-2
  given diagnosis
  Chronic pulmonary disease after                 III
  diagnosed primary infection
  Death from chronic pulmonary disease            III
  Dissemination after infection                  II-2
  Meningitis, given dissemination                II-2
  Death from meningeal dissemination           II-2, III
  Moderate disability after meningeal             III
  dissemination
  Severe disability after meningeal               III
  dissemination
  Annual meningeal dissemination                I, II-2
  relapse rate, on treatment
  Death from nonmeningeal dissemination           III
  Moderate disability after nonmeningeal          III
  dissemination
  Annual nonmeningeal dissemination
  relapse rate
    On treatment                             I, II-2, III
    Off treatment                            I, II-2, III
  Mild vaccine side effects                      II-2
  Vaccine anaphylaxis, x [10.sup.-4]             II-2

Direct medical costs ($)
  Three doses of vaccine                          III
  Skin test                                       III
  Home care, per month                           II-2
  Diagnosed pulmonary disease                  II-2, III
  Incident meningeal dissemination               II-2
  Medication and follow-up afTer                 II-2
  Coccidioides immitis meningitis, (f)
  per month
  Incident nonmeningeal dissemination            II-2
  Medication and follow-up for chronic           II-2
  pulmonary infection and nonmeningeal
  dissemination? per month
  Inpatient vaccine anaphylaxis                  II-2
  treatment

Time costs (h)
  Average wage ($ per hour)                      II-2
  Average clinic visit (hours)                    III
  Lost work due to undiagnosed primary            III
  pulmonary disease (days)
  For parents of sick children (days)             III

Utilities
  Well                                           II-2
  Diagnosed primary pulmonary infection           III
  Chronic pulmonary infection (proxy,          II-2, III
  pulmonary tuberculosis)
  Meningeal dissemination (proxy,              II-2, III
  paraplegia)
  Nonmeningeal dissemination (proxy,           II-2, III
  orthopedic impairment)
  Severe disability after meningitis           II-2, III
  (proxy, hemiplegia)
  Moderate disability after meningitis         II-2, III
  (proxy, sciatica)
  Moderate disability after nonmeningeal       II-2, III
  dissemination (proxy, arthritis)
  Chronic azole treatment (proxy,              II-2, III
  warfarin treatment)
  Dead                                            III
  Vaccine side effect quality-of-life             III
  decrement (days)

Other variables (%)
  Discount rate                                   III

Input variable                                  Source

Epidemiology (%)
  Vaccine effectiveness                            2
  Skin-test sensitivity                           3-5
  Skin-test specificity                         4, 6, 7
  Annual infection rate                         5, 8-16
  Annual emigration among vaccinees out           (c)
  of highly endemic region
  Symptomatic primary pulmonary disease           18
  after infection
  Diagnosed symptomatic primary                   (d)
  pulmonary disease
  Death from primary pulmonary disease,          19-22
  given diagnosis
  Chronic pulmonary disease after                23-26
  diagnosed primary infection
  Death from chronic pulmonary disease          24 (e)
  Dissemination after infection                   17
  Meningitis, given dissemination               21, 26
  Death from meningeal dissemination           27 (d, e)
  Moderate disability after meningeal          27 (d, e)
  dissemination
  Severe disability after meningeal            27 (d, e)
  dissemination
  Annual meningeal dissemination                 28-30
  relapse rate, on treatment
  Death from nonmeningeal dissemination           (e)
  Moderate disability after nonmeningeal        (d, e)
  dissemination
  Annual nonmeningeal dissemination
  relapse rate
    On treatment                                  4 (c)
    Off treatment                               31-34 (c)
  Mild vaccine side effects                       35
  Vaccine anaphylaxis, x [10.sup.-4]              35

Direct medical costs ($)
  Three doses of vaccine                        36, 37
  Skin test                                       38
  Home care, per month                            39
  Diagnosed pulmonary disease                     40
  Incident meningeal dissemination                40
  Medication and follow-up after               41 (e, g)
  Coccidioides immitis meningitis, (f)
  per month
  Incident nonmeningeal dissemination             40
  Medication and follow-up for chronic         41 (e, g)
  pulmonary infection and nonmeningeal
  dissemination? per month
  Inpatient vaccine anaphylaxis                   40
  treatment

Time costs (h)
  Average wage ($ per hour)                       (d)
  Average clinic visit (hours)                  Assumed
  Lost work due to undiagnosed primary          Assumed
  pulmonary disease (days)
  For parents of sick children (days)           Assumed

Utilities
  Well                                            42
  Diagnosed primary pulmonary infection           (d)
  Chronic pulmonary infection (proxy,             42
  pulmonary tuberculosis)
  Meningeal dissemination (proxy,                 42
  paraplegia)
  Nonmeningeal dissemination (proxy,              42
  orthopedic impairment)
  Severe disability after meningitis              42
  (proxy, hemiplegia)
  Moderate disability after meningitis            42
  (proxy, sciatica)
  Moderate disability after nonmeningeal          42
  dissemination (proxy, arthritis)
  Chronic azole treatment (proxy,                 43
  warfarin treatment)
  Dead                                         Assumed
  Vaccine side effect quality-of-life          Assumed
  decrement (days)

Other variables (%)
  Discount rate                                    44

(a) The base-case estimate represents our best estimate for each
value. All costs are in 2000 U.S. dollars.

(b) The quality rating is derived from the U.S. Preventive Services
Task Force Guide to Clinical Preventive Services (1). Source of
evidence: I: at least one properly randomized controlled trial;
II-1: well-designed controlled trial without randomization; II-2:
well-designed cohort or case-control analytic studies; II-3: multiple
time series with or without intervention; III: opinions of respected
authorities; descriptive studies and case reports; or reports of
expert committees (1).

(c) Internal Revenue Service, unpub. data.

(d) John Galgiani, pers. comm.

(e) Hans Einstein, pers. comm.

(f) We assumed that meningitis patients were treated with 800 mg of
daily fluconazole, and chronic pulmonary and nonmeningeal
dissemination patients with either 400 mg fluconazole or 400 mg
ketoconazole daily (Royce Johnson, pers. comm., 1999). A 50:50
distribution of fluconazole and ketoconazole use represents our base
case; the upper end of the range assumes all nonmeningeal
dissemination patients receive fluconazole in follow-up, whereas the
lower end assumes they receive the less expensive ketoconazole.

(g) Ron Talbot, pers. comm.

(h) Based on a weighted adjusted gross income of $24,105 for
taxpayers in the 10 highly endemic counties (Internal Revenue Service,
unpub. data).

(i) Mean HALex scores for healthy persons, by age group (when men
and women had differing mean scores, we chose the higher of the
two scores): <5=0.94; 5-17=0.93; 18-24= 0.92; 25-34=0.91; 35-44=0.90;
45-54=0.87; 55-64=0.81; 65-74=0.78; >75=0.70 (43).

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(7.) Levine HB, Restrepon A, Eyck DR, Stevens DA. Spherulin and coccidioidin: cross-reactions in dermal sensitivity to histoplasmin and paracoccidioidin. Am J Epidemiol 1975;101:512-6.

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Table 1. Lifetime cases of dissemination, disability, and death
prevented and costs per 100,000 population if children are vaccinated
and adults are screened, then vaccinated

               Dissemination        Disability
                 prevented           prevented

Compliance   Children   Adults   Children   Adults

100%           154        63       106        39
80%            124        50        85        32
60%             93        38        64        24
40%             62        25        42        16

                  Deaths              Net cost
                prevented           ($ millions)

Compliance   Children   Adults   Children   Adults

100%            12        4       -3.3        9
80%             10        3       -2.6        7.2
60%              7        2       -2          5.4
40%              5        2       -1.3        3.6
Table 2. Health and economic outcomes of vaccination strategies (a)

                                           Incremental
                               Life            life
                            expectancy     expectancy (c)
   Age      Strategy (b)   (years; days)      (days)

[less       No vaccine     28; 160.15           --
than or
equal to]
   17        Screen/       28; 160.58          0.43
            vaccinate
            Vaccinate      28; 160.62          0.04

  18-65     No vaccine     21; 272.68           --
             Screen/       21; 272.82          0.14
            vaccinate
            Vaccinate      21; 272.84          0.02

                                           Incremental
                             Quality-        quality-
                           adjusted life   adjusted life
                            expectancy     expectancy (c)
   Age      Strategy (b)   (years; days)      (days)

[less       No vaccine     25; 172.98           --
than or
equal to]
   17        Screen/       25; 174.66          1.68
            vaccinate
            Vaccinate      25; 174.84          0.18

18-65       No vaccine     18; 60.12
             Screen/       18; 60.65           0.53
            vaccinate
            Vaccinate      18; 60.70           0.05

                                     Incremental
                            Cost      cost (d)      CE ratio
   Age      Strategy (b)     ($)         ($)       ($/QALY) (e)

[less       No vaccine      35,196       --            --
than or
equal to]
17           Screen/        35,187        -9           --
            vaccinate
            Vaccinate       35,163       -24        Dominates

18-65       No vaccine      47,477        --           --
             Screen/        47,568        90          62,000
            vaccinate
            Vaccinate       47,601        33         235,000

(a) Life expectancy and costs are discounted at 3% per year.

(b) Strategies are ranked by effectiveness, from the least to the
most effective, for each age group.

(c) All incremental values compare an alternative with the next most
effective strategy (e.g., cost [screen/vaccinate] - cost
[no vaccine] = incremental cost [screen/vaccinate over no vaccine]).

(d) Negative values reflect cost savings compared to the next most
effective strategy.

(e) Cost-effectiveness ratio: refer to online Appendix I for formula.
A strategy dominates if it is both more effective and less expensive
than all comparison strategies.

Screen/vaccinate = vaccination of susceptible persons identified
through a screening skin test; vaccinate = vaccination of all persons

Acknowledgments

The authors thank George Rutherford, John Galgiani, Royce Johnson, Hans Einstein, John Caldwell, and David Stevens for their expert advice; Janet Morrison and Kristen Jacobs for their library research assistance; and Todd Wagner for his cost- accounting assistance.

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(22.) Arsura E, Caldwell J, Johnson R, Einstein H, Welch G, Talbot R, et al. Coccidioidomycosis epidemic of 1991: epidemiologic features. In: Einstein HE, Catanzaro A, editors. 5th International Conference on Coccidioidomycosis. Stanford University, Aug 24-27, 1994. Bethesda (MD): National Foundation for Infectious Diseases; 1996. p. 98-107.

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(25.) Lebowitz MD, Johnson WM, Kaltenborn W. Coccidioidin skin test reactivity and cross-reactivity with histoplasmin in a Tucson population. In: Ajello L, editor. Coccidioidomycosis: current clinical and diagnostic status. Vol 1. Miami: Symposia Specialists; 1977. p. 45-61.

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(28.) Stevens DA, Levine HB, Deresinski SC, Ten Eyck DR, Restrepo MA. Epidemiological and clinical skin testing studies with spherulin. In: Ajello L, editor. Coccidioidomycosis: current clinical and diagnostic status. Vol 1. Miami: Symposia Specialists; 1977. p. 107-14.

(29.) Levine HB, Gonzalez-Ochoa A, Ten Eyck DR. Dermal sensitivity to Coccidioides immitis. A comparison of responses elicited in man by spherulin and coccidioidin. Am Rev Respir Dis 1973;107:379-86.

(30.) Levine HB, Restrepon A, Eyck DR, Stevens DA. Spherulin and coccidioidin: cross-reactions in dermal sensitivity to histoplasmin and paracoccidioidin. Am J Epidemiol 1975;101:512-6.

(31.) Healthcare Cost and Utilization Project: Nationwide Inpatient Sample. Rockville (MD): Agency for Healthcare Research and Quality; 1996.

(32.) Revised 2000 National physician fee schedule. Baltimore: Health Care Financing Administration; 2000.

(33.) Manton KG, Etallard E. Chapter 6: Program payment and utilization trends for Medicare beneficiaries with disabilities. In: Wiener JM, Clauser SB, Kenner DL, editors. Persons with disabilities. Washington: The Brookings Institution; 1995. p. 117-62.

(34.) Klotz AL, Biddle M. Coccidioidin skin test survey of San Fernando Valley State college students over a five year period. In: Ajello L, editor. The Second Symposium on Coccidioidomycosis. Phoenix (AZ): University of Arizona Press; 1965. p. 251-3.

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Amber E. Barnato, * Gillian D. Sanders, ([dagger]) and Douglas K. Owens ([dagger]) ([double dagger])

* University of Pittsburgh, Pittsburgh, Pennsylvania, USA; ([dagger]) Stanford University, Stanford, California, USA; and ([double dagger]) VA Palo Alto Health Care System, Palo Alto, California, USA

Dr. Owens was supported by a Career Development Award from the Department of Veterans Affairs Health Services Research and Development Service. Dr. Barnato was supported by a training grant from the Agency for Healthcare Research and Quality. This work was supported in part by a contract from the California State University Bakersfield Foundation.

Dr. Barnato was a fellow in health care research and policy in the Department of Medicine at Stanford University School of Medicine when she completed this work. She is currently assistant professor of medicine at the University of Pittsburgh School of Medicine. Her research interests include quantitative assessment of preventive interventions and policy tools for quality improvement and cost control in health care.

Address for correspondence: Amber E. Barnato, University of Pittsburgh School of Medicine, Division of General Internal Medicine, 933W-MUH, 200 Lothrop Street, Pittsburgh, PA 15213, USA; fax: [phone]; e-mail: [e-mail]