Coccidioidal Meningitis

To the Editor: We read with interest the experience by Mathisen et al3 on meningitis due to Coccidioides immitis. The authors compared their cohort (termed "2008") with a geographically identical historical cohort from 1980, to evaluate the clinical presentation and management of coccidioidal meningitis in 2 different eras of antifungal therapy. A critical point raised by the authors is that human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) emerged as an important underlying condition in a significant proportion of affected patients (10/30, 33.3%). However, a necessary question complementary to this observation remains: "What accounts for the disseminated disease in the other patients?" While exposure to Coccidioides species is prevalent in endemic areas, symptomatic disease occurs in only one-third of exposed individuals, typically presenting as a localized pulmonary process. Disseminated disease, including coccidioidal meningitis, is estimated to occur in <5% of symptomatic individuals and <1% of all infections.2 Epidemiologic studies have established that individuals of Filipino, African-American, or Hispanic ancestry; women in their third trimester of pregnancy; patients with advanced HIV/AIDS; and transplant recipients undergoing immunosuppression are at increased risk for severe and/or disseminated disease.1 However, the biological bases for this susceptibility have remained undefined. In the cohort of Mathisen et al,3 of the 20 patients without HIV, 14 were African-American or Hispanic (1 was Asian), and 2 of the white patients were peripartum. Sub-group analysis by ethnicity reveals the mean ages of presentation were 38.9 (Hispanic), 45.75 (African-American), and 53.2 (white) years. The discrepancy in age of disease onset is compatible with racial differences in disease susceptibility, since ethnic vulnerability has not been previously accounted for by differences in fungal exposure.1 Further support for the race-associated severity is the observation that 100% of the African-American patients died of fungal disease, compared with only about 10% (Hispanic) to 20% (white). The identification of pregnancy, advanced HIV, and transplant-related immunosuppression as risk factors critically implicates cell-mediated immunity in the control of Coccidioides. The ethnic association, supported in this study, insinuates that there are also significant genetic determinants to this susceptibility. We have recently identified mutations in the interleukin (IL)-12/interferon (IFN)-γ axis in adults with refractory/relapsing disseminated coccidioidomycosis.4,5 In this immunologic construct, when Coccidioides encounters monocytes/macrophages, IL-12 is released, stimulating its cognate receptors on T- and NK-cells. These lymphocytes elaborate IFN-γ, which acts on its receptors on the activated monocytes/macrophages, triggering the release of chemokines and pro-inflammatory mediators (for example, tumor necrosis factor) and stimulating intracellular pathways that concertedly function to augment fungal killing. Likewise, other genetic immunodeficiencies that converge on this axis (for example, CD40-ligand deficiency) have been complicated by disseminated coccidioidomycosis. The defects identified to date in the IFN-γ receptor and the IL-12 receptor-complex have been circumvented only when adjunctive IFN-γ was added to antifungal therapy. These exceptional cases clearly demonstrate that mutations interrupting this pathway do confer susceptibility to disseminated Coccidioides in humans; they also allude to the strong possibility that functional polymorphisms in the genetic constituents of this axis may account, in part, for the observed ethnic susceptibility. Thus, while HIV/AIDS has emerged in the 2008 cohort as a significant underlying predisposition to coccidioidal meningitis, the majority of patients with this condition do not, in fact, have HIV. Pursuit of other immunodeficiencies should be undertaken in these patients. Donald C. Vinh, MD Division of Infectious Diseases Division of Clinical Immunology Department of Medicine Department of Medical Microbiology McGill University Health Centre Montreal, Quebec, Canada donald.vinh)mcgill.ca

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