History

 The first patient recognized with what is now known as coccidioidomycosis was an Argentinian soldier in 1893. The first North American patient was recognized by a San Francisco surgeon in the following year. First thought to be a protozoan infection, its true fungal nature was determined in 1900. Initially, this infection was considered rare and fatal. However, by 1935, it had been linked to the common illness known as San Joaquin Valley Fever and by the 1950's its existence within southern Arizona was well appreciated. No effective therapies became available for any form of coccidioidomycosis until the late 1950's when intravenous amphotericin B was first introduced. In the 1970's, azole antifungal therapies were first used which led to the current availability of several active compounds of this class including: ketoconazole, fluconazole, and itraconazole.

Mycology

The fungus that causes Valley Fever is Coccidioides immitis (Figure 1). In the soil it survives as a mycelial organism, growing from just beneath the surface to a depth of a few feet.

During rainy periods, mycelia proliferate and grow closer to the surface. When the rains cease and the ground becomes drier, the mycelia stop growing. Along their length, alternating cells lose their internal contents and their walls become extremely brittle. The remaining individual barrel-shaped cells (known as arthroconidia) are easily disrupted. The size of an arthroconidium (approximately 3-5 m) is small enough to become suspended in air and inhaled into a terminal bronchiole. Once in the lungs, an arthroconidium transforms into a spherical shape and enlarges. Inside the growing spherule, the cell wall invaginates to repeatedly transect the space, dividing into many scores of subcompartments, each containing viable cells, termed endospores. Eventually the mature spherule, that can grow to as much as 75 m in diameter, ruptures its outer wall and releases the endospore progeny. In tissue the spherule may continue to propagate and produce infection. If specimens containing spherules are cultured in a laboratory, growth reverts to the mycelial form.

Epidemiology

 The endemic regions of C. immitis roughly correspond to the "lower Sonoran life zone," which are areas of low rain fall, high summer temperatures, and moderate winter temperatures.

Regions that fit that description are found in the southern deserts of Arizona, the central valley and southern portions of California, southern Nevada, southern Utah southern New Mexico, western Texas, and northern and Pacific coastal areas of Mexico (Figure 2). Some areas have been identified in Central and South America as well.

Within endemic regions, however, the distribution in the soil is not uniform so that disruption of certain areas is more likely than others to result in aerosolizing arthroconidia. Infection occurs after inhaling arthroconidia that have developed in the soil, therefore, virtually all infections are associated with exposure to one of these endemic regions.

Very rarely, dirt which contains arthroconidia carried from the endemic region has been the source of infection elsewhere. Infection resulting from respiratory exposure to an infected patient has never been reported. Peak infection rates occur during the driest periods of the year. In southern Arizona this is the early summer and late fall whereas in central California it is a single season lasting throughout the summer.

Spectrum of disease

The majority of patients may not seek medical attention because the illness is very mild or asymptomatic. Of persons that do suffer clinical illness, the symptoms are primarily respiratory and overlap substantially with many other causes of pulmonary infection. Approximately 5 - 10% of infections result in pulmonary sequelae and less than 1% result in spread of infection outside of the lungs to cause lesions in the skin, bones, joints, meninges, or virtually any other organ or tissue in the body. These complications produce a great deal of chronic morbidity and a greater concern is the impact of infection in its nonlethal morbidity form.

Current therapies

Many infections require no treatment, but patients who need treatment often have problems that are difficult to control. Amphotericin B is only effective if administered parenterally and usually is associated with significant side-effects and toxicities. Initially, despite these drawbacks, in the most rapidly progressive infections, amphotericin B remains the preferred treatment. For many patients with chronic infections, there is growing reliance on orally administered azole antifungals such as ketoconazole, fluconazole, or itraconazole. Typically, treatment is administered for many months to years. When therapy is discontinued after the apparent successful control of disease, a relapse of infection occurs in approximately one-third of patients. Thus, some patients may need lifelong therapy for control. Patients with deficiencies in cellular immunity or those with coccidioidal meningitis are most likely to need prolonged therapy.