By Stan Deresinski, MD, FACP, FIDSA

Dr. Deresinski is Clinical Professor of Medicine, Stanford University; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center.

In the fifth and sixth decades of the 20th century, Charles Smith reported the results of skin testing with coccidioidin, a culture filtrate of the mycelial phase of Coccidioides. This preparation became widely used in the detection of delayed hypersensitivity (DH) to this regionally acquired fungus, but became unavailable in the United States after 1997. In the meantime, beginning in the 1960s, a spherule-derived reagent was evaluated and, after coccidioidin became unavailable, was commercialized as Spherulin®.1 Studies indicated that Spherulin® had modestly greater sensitivity compared to coccidioidin in the detection of DH to Coccidioides, and modestly improved specificity as evidenced, e.g., by less cross-reactivity in patients with histoplasmosis. In 2000, however, this product suffered the same commercial fate as coccidioidin so that, once again, no skin test reagent for detection of DH to Coccidioides was commercially available.

This has since been rectified by the availability of Spherusol®, which contains spherulin but has phenol added as a preservative together with a reduction in the concentration of thimerosal to 1:1,000,000 by volume. The FDA states that "Spherusol® is a skin test antigen indicated for the detection of delayed-type hypersensitivity to Coccidioides immitis in individuals with a history of pulmonary coccidioidomycosis. Spherusol is approved for use in individuals 18-64 years of age."2

In the absence of prior knowledge of a recent negative test result, DH skin testing is not useful in the diagnosis of acute coccidioidomycosis, and a negative test does not rule out infection, especially in patients with disseminated and/or progressive disease. In circumstances in which individuals are at continued high risk of infection, such as some microbiology personnel, surveillance skin testing or testing after exposures may prove useful. It also may provide information regarding the patient’s cellular immune status as reflected by delayed hypersensitivity and has been used in this way in the serial monitoring of patients with severe coccidioidomycosis who may be initially anergic but subsequently, with effective antifungal therapy, regain reactivity. Furthermore, the presence of absence of DH to coccidioidal antigens in infected patients has prognostic significance.

An oddity of this history of skin testing is the fact that one of the places chosen to examine the specificity of spherulin was Spokane, Washington chosen because it was believed to be an area non-endemic for coccidioidomycosis and where it, in fact, performed well, with a specificity of 98.2%. Recently, however, Coccidioides immitis was recovered from soil in south central Washington state during an investigation following the occurrence of 3 cases of coccidioidomycosis in that area that appeared to have been autochthonously acquired.3 The lesson: Do not assume non-endemicity of Coccidioides or other "endemic" fungi.


  1. Johnson R, Kernerman SM, Sawtelle BG, et al. A reformulated spherule-derived coccidioidin (Spherusol) to detect delayed-type hypersensitivity in coccidioidomycosis. Mycopathologia 2012;174:353-358.
  2. Spherusol. Highlights of prescribing information. Spherusol-full-prescribing.pdf.
  3. Marsden-Haug N, Hill H, Litvintseva AP, et al; Centers for Disease Control and Prevention (CDC). Coccidioides immitis identified in soil outside of its known range — Washington, 2013. MMWR Morb Mortal Wkly Rep 2014;63:450.