epiglucan and Coccidioidomycosis

Topics: Antibodies, Fungal; beta-Glucans; Biomarkers; Coccidioides; Coccidioidomycosis; Humans; Immunodiffusion; Immunologic Tests; Paracoccidioides; Paracoccidioidomycosis; Proteoglycans; Reference Values

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, less than 1% of whom develop disseminated disease. To address why some individuals allow dissemination, we enrolled patients with DCM and performed whole-exome sequencing. In an exploratory set of 67 patients with DCM, 2 had haploinsufficient STAT3 mutations, and defects in β-glucan sensing and response were seen in 34 of 67 cases. Damaging CLEC7A and PLCG2 variants were associated with impaired production of β-glucan-stimulated TNF-α from PBMCs compared with healthy controls. Using ancestry-matched controls, damaging CLEC7A and PLCG2 variants were overrepresented in DCM, including CLEC7A Y238* and PLCG2 R268W. A validation cohort of 111 patients with DCM confirmed the PLCG2 R268W, CLEC7A I223S, and CLEC7A Y238* variants. Stimulation with a DECTIN-1 agonist induced DUOX1/DUOXA1-derived hydrogen peroxide [H2O2] in transfected cells. Heterozygous DUOX1 or DUOXA1 variants that impaired H2O2 production were overrepresented in discovery and validation cohorts. Patients with DCM have impaired β-glucan sensing or response affecting TNF-α and H2O2 production. Impaired Coccidioides recognition and decreased cellular response are associated with disseminated coccidioidomycosis.

Topics: beta-Glucans; Coccidioides; Coccidioidomycosis; Humans; Hydrogen Peroxide; Tumor Necrosis Factor-alpha

Diagnosing coccidioidal meningitis (CM) can be problematic owing to its infrequency and/or a delay in the positivity of a cerebrospinal fluid (CSF) culture or CSF antibody, particularly if the primary coccidioidal infection is unrecognized. We tested 37 CSF specimens, 26 from patients with confirmed CM and 11 from patients with suspected microbial meningitis without fungal diagnosis, for (1,3)-beta-glucan (BG). BG in CM CSF specimens ranged from 18 to 3,300 pg/ml and in controls ranged from <3.9 to 103 pg/ml. Diagnostic performance was determined using a 31-pg/ml cutoff (the bottom of the serum range according to the directions for the commercial kit, although further serial dilutions of the standard indicated linearity to 3.9). Sensitivity was 96%, specificity was 82%, positive and negative predictive values were 93% and 90%, and the area under the receiver operating characteristic curve was 0.937. Fifteen of 15 samples of >103 pg/ml were CM. The one false-negative specimen was from a patient with a pseudosyrinx, without inflammatory evidence of meningitis activity. Serial samples from some patients were positive at ≤8 years, indicating no loss of positivity with chronicity. Samples stored frozen since 2000 included those with 2 of the 3 highest values, indicating that fresh samples not required. A previous study indicated serum sensitivities of 53% in acute, 50% in resolved, and 83% in disseminated and meningeal coccidioidomycosis. Three studies of other fungal meningitides ranged from 86 to 1,524 pg/ml CSF, with 37 controls of <4 to 115 pg/ml CSF. CSF BG analysis had good diagnostic performance in CM. CSF BG testing can be useful in CM, and a commercial kit is available. It will be of interest to correlate this with course, treatment, outcome, inflammation, and antigen. The only mycoses with common central nervous system (CNS) involvement are cryptococcal and coccidioidal, so CSF BG screening can be useful in meningitis diagnosis.

Topics: Adult; beta-Glucans; Cerebrospinal Fluid; Coccidioidomycosis; False Negative Reactions; Humans; Meningitis, Fungal; Predictive Value of Tests; Proteoglycans; ROC Curve; Sensitivity and Specificity

Fungal antigen testing in immunosuppressed patients has emerged as a powerful diagnostic tool. Some assays are relatively nonspecific, and misinterpretation can have severe clinical consequences. Additionally, when new assays become commercially available it is important to evaluate the potential for cross reactivity. We recently observed several immunosuppressed patients with positive (1→3)-β-D-glucan (BG) who were eventually diagnosed with coccidioidomycosis in the endemic area of Tucson, Arizona. Although the BG assay is known to detect glucans of many fungal pathogens, reports of cross-reactivity with Coccidioides remain sparsely reported. To test the cross-reactivity of fungal antigens in detection assays, serum samples from patients with coccidioidomycosis testing positive for Coccidioides antigen were evaluated for BG. Of 12 samples positive for Coccidioides antigen (≥0.07 ng/ml), 11 (92%) were positive by BG (>80 pg/ml), and of 11 positive for Aspergillus galactomannan, 10 (91%) were positive by BG (>80 pg/ml). We conclude that the BG assay is nonspecific, detecting glucans from many fungal pathogens, including Coccidioides. In the endemic area, a positive BG warrants further specific testing.

Topics: Arizona; Aspergillosis; beta-Glucans; Coccidioides; Coccidioidomycosis; Cross Reactions; False Positive Reactions; Humans; Immunocompromised Host; Proteoglycans; Sensitivity and Specificity

The serum (1→3)-β-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.

Topics: beta-Glucans; Coccidioidomycosis; Humans; Predictive Value of Tests; Proteoglycans; Sensitivity and Specificity; Serum

A 54-year-old man was admitted to our hospital to be operated on for inguinal hernia, but complained of dry cough and cervical lymph nodes swelling after traveling to California in the United States. The chest X-ray films taken on admission showed consolidations in both lungs. The laboratory data revealed an increase in white blood cell counts with eosinophilia, and elevated ESR, IgE and beta-D-glucan. The biopsied lung specimen by VATS showed epithelioid granulomas consisting of giant cells and eosinophils. In addition, spherulitic forms filled with endopores were detected in the specimen. A diagnosis of primary pulmonary coccidioidomycosis was made. Eosinophilia and elevated in IgE and beta-D-glucan were closely related to the severity of the disease gravity after the treatment with fluconazole.

Topics: Antifungal Agents; beta-Glucans; Biomarkers; California; Coccidioidomycosis; Eosinophils; Fluconazole; Humans; Immunoglobulin E; Leukocyte Count; Lung Diseases, Fungal; Male; Middle Aged; Radiography, Thoracic; Severity of Illness Index; Thoracic Surgery, Video-Assisted; Travel