Coccidioidomycosis—A Fungal Disease of the Americas

Coccidioidomycosis was first recognized as a serious disease over 100 years ago, but the disease remains an enigma and often goes undiagnosed, even in endemic areas

symptoms is established by serodiagnosis in conjunction with patient history. In previous decades, a coccidioidal skin test antigen was a useful adjunct in the diagnosis, but it became unavailable in the 1980s [13]. The incidence of primary pulmonary disease outside the United States is not established; most reports are limited to disseminated or unusual cases [14]. Diagnosis in Latin America is usually based on microbiologic fi ndings, as serology is not always available [14].

Clinical Features
In their pioneering epidemiologic studies, Smith and colleagues found that about 60% of exposures to the fungus result in asymptomatic infection [15]. In the 40% of patients who have symptomatic disease, there are protean manifestations. These range from a primary, or benign, pulmonary infection (commonly known as "Valley Fever") to a progressive pulmonary or extrapulmonary disease involving the skin, bones and/or joints, the central nervous system, and other organ systems. Fortunately, most patients with primary disease recover spontaneously and retain lifelong immunity to exogenous reinfection. Chronic and disseminated disease is estimated to occur in up to 5% of infected individuals, with comparatively more cases occurring in older individuals and in males [12]. The most dangerous form of the disease is meningeal infection, which occurs in about 0.15%-0.75% of extrapulmonary coccidioidomycosis cases and requires treatment for life [16].
In regions where tuberculosis rates are high, the two diseases may occur together. Tuberculosis and coccidioidomycosis share common epidemiological, clinical, radiographic, and even histopathological features, making a correct diagnosis extremely diffi cult in cases where both diseases coexist. In areas where both diseases are endemic, the pertinent studies for diagnosing both conditions should be performed in every patient with compatible clinical features. The diagnosis of one of them does not exclude the possible existence of the other [17].

Treatment
Historically, patients with the primary respiratory form of the disease were not treated because the vast majority recovered on their own. Instead, such patients were given supportive care and were monitored, often with radiographs, until the disease resolved. In recent years, however, an increasing number of physicians are prescribing azole antifungals in  cases of primary disease, both because drugs like fl uconazole have a good safety record, and because there is a perception that treatment may prevent progression to more serious forms of the disease. This latter presumption, however, is not supported by controlled trial data.
All cases of chronic or disseminated disease call for antifungal therapy, but the choice of drugs, route, and duration of therapy is highly dependent on the form of the disease, the severity and site(s) of infection, and the immune status of the patient. Galgiani and colleagues have published clinical practice guidelines on the choice of drug and duration of therapy for a given form of the disease [18].
There are only two classes of antifungal therapy routinely used for treatment of coccidioidomycosis. The fi rst class is the polyenes, with amphotericin B desoxycholate and the newer lipid formulations used for the more serious forms of disease. The second class is the azoles, with ketoconazole, fl uconazole, itraconazole, and the newer analogue voriconazole as available options. Voriconazole, in particular, is being used more and more often in life-threatening mycoses, and was found to be better than amphotericin B in the primary therapy of invasive aspergillosis [19]. According to available reports, treatment in Latin America usually consists of one of the azoles (fl uconazole or itraconazole) and/or amphotericin B desoxycholate; lipid formulations are too costly to be accessible [20].
Treatment of the more serious or aggressive forms of the disease is typically of long duration and often results in less than complete resolution of disease; relapse is common [21]. Unfortunately, information on the treatment of coccidioidomycosis is limited, due to the small numbers of controlled trials performed for what is perceived to be a niche market. Clearly, newer, more powerful drugs are needed.
In addition to drugs, surgery is sometimes indicated to remove focalized infections, such as pulmonary cavities, or to debride osseous forms of the disease [22].

Immunology and the Basis for a Vaccine
Acquired resistance to coccidioidomycosis strongly correlates with the development of a delayed-type hypersensitivity skin test response to coccidioidal antigens [23] and the production of T-helper-1 (Th1)-associated cytokines to coccidioidal antigens, such as interferon-gamma (IFN-γ) and Interleukin-2 (IL-2) [24]. Humoral immunity plays no known role in overcoming infection.
Although all humans are equally susceptible to initial infection, there is evidence of genetic predisposition to dissemination, independent of socioeconomic or environmental factors, particularly among African-Americans and Filipinos [25]. Pregnancy is also a risk factor.
In cases of marked immunosuppression, either in advanced AIDS or other forms of depressed cellular immunity, the management of coccidioidomycosis is particularly challenging and requires aggressive treatment [26].
As previously mentioned, recovery from disease confers lifelong immunity to reinfection, and is a rationale for the development and implementation of a vaccine for the prevention of symptomatic or serious forms of the disease. The combination of increasing incidence of disease, a growing population in the endemic area, and the lack of a highly effective drug treatment justifi es efforts to prevent (rather than treat) this disease. To that end, a university-based consortium, the Valley Fever Vaccine Project (www.valleyfever.com), has identifi ed and cloned immunogenic proteins that have proven effective in the prevention of deaths and fungal burdens in mouse models of coccidioidomycosis. This suggests that a vaccine for use in humans could be created [27]. A candidate vaccine comprised of a fusion protein based on two antigens has been selected and is currently in pharmaceutical development under the sponsorship of this project, with the goal of evaluating the safety and immunogenicity in humans.

Conclusion
Although the vast majority of infected individuals emerge from coccidioidomycosis without complications, an unlucky minority are faced with a debilitating disease that lacks adequate drug options for rapid and completely effective treatment. In the absence of newer therapeutics, discoveries that lead to immunologic intervention [28] or prevention by vaccines may ultimately bring a measure of relief.

Box 1. Glossary
Mycelial phase-The growth form in the soil, composed of fi lamentous hyphae and reproductive spores called arthroconidia.
Arthroconidia-Reproductive spores, highly resistant to dessication, which are the infectious particles inhaled by man and animals.
Spherules-The parasitic phase of this dimorphic fungus; spherules are round cells of 30-100 µM or more that reproduce the progeny endospores.
Endospores-The progeny units of the parasitic phase, derived from spherules.