Genetic and Other Determinants for the Severity of Coccidioidomycosis: A Clinician’s Perspective

Abstract

The endemic fungal infection, coccidioidomycosis, occurs after inhalation of one or very few Coccidioides spp. spores. Infections produce diverse clinical manifestations, ranging from insignificant to extremely destructive, even fatal. Approaches to understanding this range of consequences have traditionally categorized patients into a small number of groups (asymptomatic, uncomplicated self-limited, fibro-cavitary, and extra-thoracic disseminated) and then looked for immunologic differences among them. Recently, variants within genes of innate pathways have been found to account, in part, for infections that result in disseminated disease. This discovery raises the very attractive theory that, in patients without severe immunosuppression, much of the disease spectrum can be accounted for by various combinations of such deleterious variants in innate pathways. In this review, we summarize what is known about genetic determinants that are responsible for the severity of coccidioidal infections and how complex innate genetic differences among different people might account for the spectrum of disease observed clinically.

Coccidioidomycosis in Oklahoma: A retrospective case series

“…Genetic polymorphisms in the innate and adaptive immune system, blood type and sex hormones in addition to social vulnerabilities such as concentration of these populations in deprived areas with high disease incidence coupled with limited access to healthcare and outdoor occupations associated with increased exposure might play a role. 13,16,17 A recent report obtained from data provided by the National Notifiable Diseases Surveillance System (NNDSS)…”

A Clinicopathological Categorization System for Clinical Research in Coccidioidomycosis

“…All have extensive experience in clinical or translational research in CM [ 6 , 11 , 12 , 16 ]. We initiated this process with a round table discussion based on established general categorizations of clinical CM [ 4 , 11 , 17 ]. A written and graphic summary of a proposed schema was prepared and circulated among participants for a subsequent virtual meeting.…”

“…Individuals in this group (category 2) will have had a clinical diagnosis of pulmonary CM (eg, fatigue, cough, chest pain, sputum production, and/or fever [ 4 , 8 , 10 ]) with proved or probable Coccidioides infection by ≥1 microbiological, serological, or histopathological method (see footnote to Table 2 ). Consequently, uncomplicated disease refers to cases in which pulmonary symptoms last for ≤6 months with no evidence of cavitation or fibrocavitary disease in a subsequent chest radiograph.…”

“…As summarized by Galgiani and colleagues [ 4 ], coccidioidal infections exhibit a wide range in the severity of clinical outcomes that may be placed into 4 general categories ( Table 1 ). Delayed-type hypersensitivity testing studies conducted in the mid-20th century in California demonstrated that the majority of coccidioidal infections (approximately 60%) are inapparent or unrecognized.…”

“…Furthermore, in an estimated 0.5% of cases, extrapulmonary dissemination of disease occurs. While any organ system can become involved, musculoskeletal, central nervous system (CNS) infections and granulomatous skin lesions are the most common manifestations of disseminated disease [ 4 , 6 , 8 ]. Meningitis is a dreaded complication; CNS cerebrospinal fluid shunting is needed in approximately half of cases, and death nearly always occurs in the absence of treatment with antifungal agents [ 4 , 11 , 12 ].…”