Coccidioidomycosis is associated with a broad spectrum of illness severity, ranging from asymptomatic or self-limited pulmonary infection to life-threatening manifestations of disseminated disease. Serologic studies before the widespread availability of antifungals established current understanding of serologic kinetics and dynamics.
Disseminated coccidioidomycosis (DCM) is caused by Coccidioides, pathogenic fungi endemic to the Southwestern United States and Mexico. Illness occurs in approximately 30% of those infected, <1% of whom develop disseminated disease. To address why some individuals allow dissemination, we enrolled DCM patients and performed whole-exome sequencing. In an exploratory set of 67 DCM patients, two had haploinsufficient STAT3 mutations, while defects in b-glucan sensing and response were seen in 34/67 (50.7%) cases. Damaging CLEC7A (n=14) and PLCG2 (n=11) variants were associated with impaired production of b-glucan-stimulated TNF-a from peripheral blood mononuclear cells compared to healthy controls (P<0.005). Using ancestry-matched controls, damaging CLEC7A and PLCG2 variants were over-represented in DCM (P=0.0206, P=0.015, respectively) including CLEC7A Y238* (P=0.0105) and PLCG2 R268W (P=0.0025). A validation cohort of 111 DCM patients confirmed PLCG2 R268W (P=0.0276), CLEC7A I223S (P=0.044), and CLEC7A Y238* (P=0.0656). Stimulation with a DECTIN-1 agonist induced DUOX1/DUOXA1-derived H2O2 in transfected cells. Heterozygous DUOX1 or DUOXA1 variants which impaired H2O2 production were overrepresented in discovery and validation cohorts. Patients with DCM have impaired b-glucan sensing or response affecting TNF-a and H2O2 production. Impaired Coccidioides recognition and decreased cellular response are associated with disseminated coccidioidomycosis.
The use of voriconazole, a trifluorinated antifungal, has been associated with the development of fluoride excess and periostitis/ exostoses. We evaluated a cohort of patients on long-term triazole therapy and found that other fluorinated triazoles (fluconazole and posaconazole) conferred no risk for the development of hyperfluorosis and its complications in our cohort. Atotal of 3 to 5% of patients with coccidioidomycosis have disseminated disease or chronic pulmonary infection requiring long-term suppressive antifungal therapy with a triazole. Concerns regarding the potential toxicity of long-term triazole therapy have been raised, and recent observations have presented compelling evidence for the causal role of long-term voriconazole, a trifluorinated antifungal, as a risk factor for the development of fluoride excess and subsequent painful periostitis and exostoses in posttransplant patients (1, 2, 5). However, the safety and potential toxicity of fluconazole and posaconazole (difluorinated triazoles) have not been assessed, nor has hyperfluorosis been reported for nontransplant patients. We have subsequently sought to determine if fluoride excess is common and if clinical sequalae consistent with hyperfluorosis are present in our cohort of chronic coccidioidomycosis patients receiving long-term antifungal therapy. This is a cohort study designed to test whether patients receiving long-term antifungal therapy (Ͼ6 months' duration) with different triazoles were at risk for hyperfluoremia and/or the clinical development of periostitis or exostoses. This study was approved by the Institutional Review Board of the University of California-Davis.Patients referred to the University of California-Davis Medical Center for chronic pulmonary, disseminated, or meningeal coccidioidomycosis as defined by existing European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria (3) who were also receiving a fluorinated triazole (fluconazole, posaconazole, or voriconazole) for greater than 6 months were included. All patient samples were collected over a 60-day enrollment period. Patients taking long-term itraconazole (a nonfluorinated triazole) were included as a control group.All patients were assessed for clinical symptoms suggestive of coccidioidal osteomyelitis or arthritis and periostitis or exostoses, and radiographic studies were obtained if suggestive symptoms were present. Demographic and laboratory data were abstracted from patient medical records, and serum fluoride levels were determined using an Accumet pH/ion meter equipped with a fluoride-specific electrode. Serum samples were buffered with TISAB prior to analysis.Analysis of variance (ANOVA) between groups with Tukey's posttest analysis was used to compare demographic characteristics, clinical factors, and laboratory values between groups. Then using the residuals from each model, Q-Q plots and ShapiroWilk's testing was performed to assess normality of the residuals.For variables found to depart significantly from normali...
The serum (1¡3)--D-glucan assay has emerged as an important diagnostic test for invasive fungal disease. The utility of this assay in coccidioidomycosis has not been previously studied. Using a cutoff value of >80 pg/ml, we found the sensitivity (43.9%), specificity (91.1%), positive predictive value (81.8%), and negative predictive value (64.1%) to be similar to those of the assay in diagnosing other invasive mycoses.T he incidence of invasive fungal disease (IFDs) has increased in recent years, primarily due to the expanding immunosuppressed population (8,15). IFDs are associated with significant morbidity and mortality and are often not readily diagnosed, leading to delays in treatment. Blood cultures are frequently unhelpful in the diagnosis of IFDs and histopathologic diagnosis is not always feasible in those at highest risk. For these reasons, interest in noninvasive diagnostic testing has increased. Among the newer diagnostic techniques is the assay measuring serum levels of (1¡3)--D-glucan (BG), which is derived from fungal cell walls. This assay has exhibited a high specificity and positive predictive value (PPV) in studies evaluating its use in the diagnosis of invasive candidiasis and aspergillosis (9,(11)(12)(13)17); however, its utility in the diagnosis of coccidioidomycosis has not been previously examined. We evaluated the performance characteristics of BG testing in a diverse cohort of patients with coccidioidomycosis.(This work was presented, in part, at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL.)Subjects evaluated for serologic evidence of coccidioidomycosis by the University of California Davis Coccidioidomycosis Serology Laboratory were included in this analysis. Patient samples and medical information arrived from requesting physicians across California and Arizona. Samples were included if sufficient clinical information was available for chart abstraction between September and December of 2010 and subsequently deidentified. Patients with hematologic malignancy, receiving dialysis, receiving current care within an intensive care unit, or receiving medications known to cause false-positive BG values were excluded, as these conditions were more likely to cause false-positive BG testing or placed the patient at significantly higher risk for an alternative IFD (10).All samples were tested for coccidioidal antibodies by both immunodiffusion and complement fixation at the University of California-Davis Coccidioidomycosis Serology Laboratory using previously described methods (14). BG testing was performed in a blinded fashion by Beacon Diagnostics Laboratory using the Fungitell (Associates of Cape Cod) assay (13). All serum aliquots were kept frozen (Ϫ80°C) and shipped in bulk for testing. This study was approved by the UC-Davis Medical Center Institutional Review Board.Two hundred twenty-eight patients met the criteria for inclusion in this study. Of these, 40 patients were excluded because of underlying diagnoses as outlined above. The remaining 18...
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