Measurement of Cellular Immunity in Human Coccidioidomycosis

Measurement of cellular immune response in human coccidioidomycosis, a disease of the Western Hemisphere caused by the soil-dwelling fungus Coccidioides, began more than 75 years ago. Numerous studies have shown that measurement of coccidioidal cellular immunity is a useful epidemiologic and clinical tool. The first widely used coccidioidal skin-test reagent, coccidioidin, was derived from a filtrate of cultured mycelia of Coccidioides by Smith and colleagues in the 1940's. It remained the standard until the 1970's, when spherulin, obtained from the spherule form of the fungus, was found to be more sensitive. Both reagents are specific indicators of coccidioidal cellular immunity. Since then, other coccidioidal antigens have been identified and in vitro tests of cellular immunity have been shown to yield comparable results to skin testing. In vitro assays have also begun to open a window on the specific immunologic events of coccidioidal cellular immunity. Persistent expression of coccidioidal cellular immune response appears to augur an improved clinical outcome. Despite this, a study of a coccidioidal vaccine failed to demonstrate efficacy. Current and future studies are focused on modulating the coccidioidal immune response in vitro and in vivo and on developing an improved vaccine.     

Coccidioidomycosis of the male reproductive tract

Coccidioides immitis infection of the male reproductive tract is a rare entity that can evade diagnosis and pose a dilemma in management. Initially, patients are often evaluated for malignancy or other infections such as tuberculosis. In the past, surgery was the only management option for C. immitis infection of the male reproductive tract, but azole therapy now provides an adjunct or an alternative. We describe two patients who received azole therapy for C. immitis infection of the male reproductive tract. One received fluconazole for prostatic disease, while one received surgery followed by itraconazole for testicular disease. After 12 months of therapy, both remain asymptomatic and have decreased antibody titers against C. immitis.Disclaimer: The Views expressed herein are those of the authors do not reflect the official policy or position of the Department of the Air Force, Department of the Army, Department of Defence, or the U.S. Government.     

Serologic testing for symptomatic coccidioidomycosis in immunocompetent and immunosuppressed hosts

Serologic studies are an important diagnostic tool in the clinical evaluation and follow-up of persons with coccidioidomycosis. Numerous types of serologic tests are available, including immunodiffusion, enzyme immunoassay, and complement fixation. We conducted a retrospective review of the results of 1,797 serologic tests spanning 12 months from the onset of coccidioidomycosis in 298 immunocompetent and 62 immunosuppressed persons with symptomatic infection. Using the onset of symptoms as a reference point, we plotted the positive or negative serologic results over time for both groups. Compared with the immunocompetent group, immunosuppressed persons had lower rates of seropositivity for every type of test during the first year after onset of symptoms for coccidioidomycosis, although many results did not achieve statistical significance. Combining the results of these tests increased the sensitivity of the serologic evaluation in immunocompromised patients. Immunosuppressed persons have the ability to mount a serologic response to coccidioidomycosis, but in some circumstances, multiple methods may be required to improve detection.     

Murine models of blastomycosis,coccidioidomycosis, and histoplasmosis

Animal models have contributed much to the knowledge of fungal infections and their corresponding therapeutic treatments. This is true for animal models of the primary fungal pathogens, Blastomyces dermatitidis, Coccidioides immitis, and Histoplasma capsulatum. This review gives a brief background of human diseases associated with these organisms and describes the development, details, and utility of murine models of blastomycosis, as well as coccidioidomycosis and histoplasmosis. This revised version was published online in June 2006 with corrections to the Cover Date.     

Proteogenomic Re‐Annotation of Coccidioides posadasii Strain Silveira

The aims of this study are to provide protein‐based evidence upon which to reannotate the genome of Coccidiodes posadasii, one of two closely related species of Coccidioides, a dimorphic fungal pathogen that causes coccidioidomycosis, also called Valley fever. Proteins present in lysates and filtrates of in vitro grown mycelia and parasitic phase spherules from C. posadasii strain Silveira are analyzed using a GeLC‐MS/MS method. Acquired spectra are processed with a proteogenomics workflow comprising a Silveira proteome database, a six‐frame translation of the Silveira genome and an ab initio gene prediction tool prior to validation against published ESTs. This study provides evidence for 837 genes expressed at the protein level, of which 169 proteins (20.2%) are putative proteins and 103 (12.3%) are not annotated in the Silveira genome. Additionally, 275 novel peptides are derived from intragenic regions of the genome and 13 from intergenic regions, resulting in 172 gene refinements. Additionally, we are the first group to report translationally active retrotransposon elements in a Coccidioides spp. Our study reveals that the currently annotated genome of C. posadasii str. Silveira needs refinement, which is likely to be the case for many nonmodel organisms.     

Evidence of Hypertrophic Pulmonary Osteoarthropathy in a Chimpanzee,Pan troglodytes

Dissection of a chimpanzee has revealed the association of an intrathoracic disease (probably coccidioidomycosis) with periosteal lesions that are restricted almost entirely to the appendicular skeleton and are distributed with bilateral symmetry. These pathological conditions are compatible with a diagnosis of hypertrophic pulmonary osteoarthropathy.     

Environmental vVariability and coccidioidomycosis (valley fever)

Coccidioidomycosis (valley fever) is a disease endemic to arid regions in the western hemisphere, and is caused by the soil-dwellingfungus Coccidioides immitis (C. immitis). In this paper, we provide an overview of the current state of knowledge regarding valley fever and C. immitis as related to climatic conditions and habitat requirements. Previous research shows there is a relationship between temperature and precipitation, and outbreaks of coccidioidomycosis. Incidence of the disease varies seasonally as well as annually due to changing climatic conditions. However, the specific environmental conditions that may produce an outbreak of coccidioidomycosis are not well understood in space and time. Previous studies have attempted characterize C. immitis' habitat. Temperature, moisture, salinity, and pH of the soil have all been considered separately in the geographic distribution of the fungus. Medical and proactive intervention are served best, however, by an integrative strategy that folds climate and surface variables into spatially-explicit models. We conclude with recommendations for future research directions.     

An Archived Lot of Coccidioidin Induces Specific Coccidioidal Delayed-type Hypersensitivity and Correlates with in vitro Assays of Coccidioidal Cellular Immune Response

No test for assessing cellular immune response in coccidioidomycosis is currently available in the United States. In the present study, we tested 49 healthy subjects living in the coccidioidal endemic region with a 1:55.8 dilution of a single lot of coccidioidin archived since the 1970s. In this group, 23 evaluable subjects demonstrated ≥5 mm of induration at 24, 48 or 72 h, with a mean±SEM maximum induration of 18.4±4.0 mm. The induration results among 14 subjects reactive at 24 h were compared to those from 179 individuals in an historical cohort studied in the 1980s using a reference lot of coccidioidin. Results were within 5% and not significantly different (P=0.924). The maximum induration response of all evaluable subjects correlated significantly with the results of in vitro tests of coccidioidal cellular immunity using supernatant interferon-gamma concentration and CD69 expression on T cells (Spearman rank correlation coefficients 0.69 and 0.68, respectively; P<0.01 for both). These data suggest that archived coccidioidin retains its potency and specificity and that in vitro test of coccidioidal immunity may have utility in the measurement of coccidioidal cellular immunity.     

Investigation of an outbreak of endemic coccidioidomycosis in Brazil's Northeastern State of Piauí with a review of the occurrence and distribution of Coccidioides immitis in three other Brazilian states

An outbreak of coccidioidomycosis is described that involved three individuals and eight of their dogs, who had engaged in a successful hunt for nine-banded armadillos (Dasypus novemcinctus) in the environs of Oeiras, a community in Brazil's north eastern state of Piauí.Diagnosis was based on clinical, serological and cultural findings. Four of 24 soil samples collected in and around the burrow of an armadillo yielded cultures of Coccidioides immitis, thus establishing the endemicity of that mould in the state of Piauí. A literature review revealed that C. immitis, aside from that state, is endemic in three other Brazilian states — Bahia, Ceará and Maranhão. These four contiguous states have semi-arid regions where climatic conditions and their flora are similar to those that exist in C. immitis's endemic regions in North, Central and South America.This revised version was published online in October 2005 with corrections to the Cover Date.     

Molecular markers reveal differentiation among isolates of Coccidioides immitis from California, Arizona and Texas

Coccidioides immitis causes coccidioidomycosis, a fungal disease of both immunocompromised and otherwise healthy people; it is capable of causing large epidemics and the disease is often refractory to chemotherapy. To quantify the magnitude of population differentiation and estimate levels of gene flow in C. immitis , multilocus genotypes were scored for 20–25 clinical isolates from each of Bakersfield (California), Tucson (Arizona), and San Antonio (Texas). The molecular markers used were PCR products with polymorphic restriction endonuclease sites, found and characterized in a previous study of the Tucson population. The data show very highly significant differences in allele frequencies between all three populations, and suggest very low levels of migration between populations. One isolate in the San Antonio sample was an outlier, showing the California-specific allele at all four of the loci distinguishing the two populations, and subsequent inquiries indicated that the infection had indeed been acquired in California. Thus, genetic information can be used to infer the geographical origin of a fungal infection.