Coccidioides immitis and posadasii are closely related fungal species that cause coccidioidomycosis. These dimorphic organisms cause disease in immunocompetent as well as immunocompromised individuals and as much as 40% of the population is infected in the endemic area. Although most infections resolve spontaneously, the infection can be prolonged and, in some instances, fatal. Coccidioides has been studied for more than 100 years and many aspects of the organism and the disease it causes have been investigated. There are over 500 manuscripts concerning Coccidioides (excluding clinical articles) referenced in PubMed over the past 50 years, so there is a large body of evidence to review. We reviewed the most accurate and informative basic research studies of these fungi including some seminal older studies as well as an extensive review of current research. This is an attempt to gather the most important basic research studies about this fungus into one publication. To focus this review, we will discuss the mycology of the organism exclusively rather than the studies of the host response or clinical studies. We hope that this review will be a useful resource to those interested in Coccidioides and coccidioidomycosis.

BACKGROUND: Disseminated coccidioidomycosis (DCM) is an often fatal and otherwise intractable condition requiring lifelong antifungal treatment. We have previously shown that a deranged polarization of CD4 ⁺ T cells toward a Th2 phenotype can exist in the context of DCM. Here, we studied a large population to determine the frequency of abnormal Th2 skewing of CD4 ⁺ T cells in patients with coccidioidomycosis and to identify underlying genetic mechanisms supporting this phenotype. METHODS: We collected PBMCs from 204 patients with coccidioidomycosis, including 96 patients with disseminated disease. We measured immune phenotypes and cytokine production by CD4 ⁺ T cells from patients and healthy controls, and comparisons between groups were made based on disease severity and demographics. Whole-genome sequencing was conducted on 180 individuals who also had cytokine profiling. RESULTS: We found that approximately 25% of patients with DCM had a CD4 ⁺ T cell compartment that was abnormally skewed toward a Th2 phenotype, and Th2 skewing was highly correlated with male sex. Coculture of T cells with the IL-4R/IL-13R–blocking antibody dupilumab reduced Th2 skewing. Sequencing revealed rare variants in genes involved in the IL-12/IFN-γ axis in several Th2-skewed patients, and we validated one such variant in IFNGR1 as hypomorphic. CONCLUSION: Patients with DCM, especially males, should be screened for Th2 skewing of CD4 ⁺ T cells. Patients with Th2 skewing should be additionally screened for genetic defects in the IL-12/IFN-γ axis. Our findings give a mechanistic rationale for blockade of IL-4R in Th2-skewed patients with refractory coccidioidomycosis. FUNDING: National Institute of Allergy and Infectious Diseases/NIH grants R21 AI149654 and U19 AI166059 and University of California Office of the President grant VFR-19-633386.

Coccidioides spp are thermally dimorphic fungi found in geographically defined areas of the Western Hemisphere. The primary portal of entry is respiratory, with a symptomatic pneumonic disease as the most common presentation. Subsequent pulmonary complications as well as extrapulmonary metastatic infection may occur, either of which may be the presenting disease manifestation. Cavitary lung disease may be found incidentally or when investigating symptoms such as cough or hemoptysis. This study aims to explore the spectrum of coccidioidal cavities and the evaluation and management in a cohort of patients seen at Kern Medical over the last 12 years.

Coccidioides species are thermally dimorphic fungi found in geographically defined areas of the Western Hemisphere. The primary portal of entry is respiratory, with symptomatic pneumonic diseases as the most common presentation. Subsequent pulmonary complications as well as extrapulmonary metastatic infection may occur, either of which may be the presenting disease manifestation. Cavitary lung disease may be found incidentally or when investigating symptoms such as cough or hemoptysis. This study aims to explore the spectrum of coccidioidal cavities and the evaluation and management in a cohort of patients seen at Kern Medical over the last 12 years.

BACKGROUNDCoccidioidomycosis ranges from self-limiting uncomplicated Valley fever (UVF) in most cases to life-threatening disseminated coccidioidomycosis (DCM) in rare individuals. A few patterns of immunologic deficits allowing for dissemination have been identified, although the specific defects in most individuals with DCM remain undefined. We hypothesized that chronic antigen exposure in DCM engenders a state of T cell exhaustion.METHODSFrom a cohort of over 300 individuals with confirmed diagnoses of coccidioidomycosis, circulating T cell phenotypes were characterized via flow cytometry and Coccidioides-specific T cell responses were measured by activation-induced marker (AIM) assay.RESULTSMale sex was significantly associated with disseminated disease (OR 2.5, 95% CI 1.5-4.0). A majority (52%) of individuals showed Coccidioides-specific T cell responses in our AIM assay. We noted a significant difference in patients sampled in the first year of diagnosis, where only 8% of patients with DCM had T cell responses during this time, as compared with 44% of individuals with UVF (P = 0.04). Among DCM patients with detectable AIM responses, CD4+ T cells demonstrated an exhausted phenotype with elevated PD-1 expression compared with UVF individuals. In vitro PD-1 blockade augmented IFN-γ production in most tested individuals with DCM.CONCLUSIONThese findings suggest that dissemination may occur in some individuals during a period of impaired antigen-specific T cell activity. Importantly, these responses can be augmented in vitro by PD-1-blocking antibodies, supporting further study of immune checkpoint therapy as an adjunct to antifungal treatment in disseminated coccidioidomycosis.FUNDINGNational Institute of Allergy and Infectious Diseases grants U19 AI166059 and R21 AI149654 and University of California Office of the President grant VFR-19-633386.

Coccidioidomycosis (CM) is an endemic disease in the western United States, northern Mexico, and Central and South America. The severity of coccidioidal infection is highly variable, with potential factors including comorbidities and the patient’s innate and adaptive immune response. Based on data from a predominantly healthy and mainly Caucasian male survey conducted nearly a century ago, approximately 60% of infections are asymptomatic, with an estimated 40% of people experiencing some respiratory symptoms; with 10% of those diagnosed with CM. Disseminated disease occurs in approximately 1% of cases and can involve the meninges and, potentially, any place in the body. It is not yet fully understood why some people experience severe disease while many people do not; it is understood that the immune response has a major role. Immunomodulators, including dupilumab and interferon-gamma (IFN-γ), have shown promise in treating patients with disseminated infection. This article summarizes the latest genetic and immunologic evidence demonstrating immune dysfunction. Immunomodulators and potential therapeutic strategies based on the above are reviewed.