Coccidioidomycosis

All work with Coccidioides organism requires a biosafety-level 3 containment, primarily because infectious particles are easily produced and aerosolized (Stevens et al. 2009). The organism was previously designated as a select agent but was removed in 2012 (Oct 5 2012 Federal Register; Dixon 2001).

In Arizona and California, an increase in coccidioidomycosis (CM) has been reported since 1995 (Thompson et al. 2015; Twarog and Thompson 2015). Because CM severity is so variable, not all infections are diagnosed and reported, and the overall infection rate is closer to 200,000 per year in the USA (Nguyen et al. 2013; Galgiani 2007). Mild CM in humans presents with general symptoms, such as coughing, fever, and malaise. Indeed, many community-acquired pneumonias caused by Coccidioides in endemic regions are misdiagnosed as viral or bacterial pneumonia (Valdivia et al. 2006). Normally, acute disease is self-limiting and antifungal therapy is not necessary. However, some of these patients can experience symptoms for many months, and medical intervention may be recommended (Chen et al. 2011; Sunenshine et al. 2007). Although severe disease manifests in less than 5% of cases, it can result in life-threatening disease, which may require surgery, antifungal drug therapy, and hospitalization (Sondermeyer et al.

Variable exposures could also play a role in differential severity of CM. Infectious dosages of 50 arthroconidia of a highly virulent strain have an LD₅₀ of 17 days in a murine model of CM (Sorensen et al. 1999; Kirkland and Fierer 1983). The infectious dose of arthroconidia administered to cattle determined the level of infection (Reed 1960). Dogs infected with between 10⁶ and 10⁴ conidia died or had severe disease; whereas infection with 10³ conidia resulted in mild CM (Hugenholtz et al. 1958). Similarly, monkeys exposed to 10⁴ conidia had 80% fatality, and infection with 50 conidia produced nonfatal infection (Converse et al. 1962b).

In addition to infectious dose, phenotypic variation among isolates of Coccidioides may play a role in CM disease progression. Strain morphology varies from floccus non-pigmented to flat glabrous pigmented colonies, which suggests that the strains may produce different secondary metabolites (Baker et al. 1943). In one classic study, arthroconidia production was assessed in 47 strains (Friedman et al. 1953). The majority had typical 3-5 μm barrel-shaped arthroconidia; however, the number of conidia produced was highly variable. Growth media type affected this phenotype: some strains grown on glucose yeast extract produced conidia, but not on Sabouraud's agar, and vice versa. Three strains produced no conidia on either media. This variation in conidial production could result in variable host exposure.

Variation in virulence has been described (Friedman and Smith 1957; Berman et al. 1956; Friedman et al. 1955; Huppert et al. 1967). Three human clinical strains' LD₅₀ values ranged from 17 to 90 days after infection with 100 arthroconidia (Friedman et al. 1955). The same group further assessed 27 clinical isolates with average LD₅₀ from 17 to 41 days; however, 10 strains did not reach an LD₅₀ after 90 days (Berman et al. 1956). Upon necropsy, mice showed infection for four of the nonfatal strains, but the mice did not exhibit outward signs of illness. Interestingly, one of the four strains was obtained from a fatal human infection. This strain was reassessed and showed similar virulence results. Additionally, the strain did not produce typical 3 x 5 micron arthroconidia and produced fewer conidia than other “normal” strains (Friedman and Smith 1957).

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