Blair, Janis E.

Introduction: Coccidioidal meningitis (CM) is the most lethal form of disseminated coccidioidomycosis. Current guidelines recommend fluconazole as initial therapy but there has been a paucity of data regarding failure of fluconazole and optimal fluconazole dosage in the treatment of CM. We conducted this study to understand risk factors for fluconazole failure. Methods: We conducted a single-center retrospective chart review of patients diagnosed with coccidioidal meningitis between 1 January 1988 and 15 May 2021. Relevant demographic and clinical variables were collected, along with outcomes including treatment failure and death at any point. Univariate tests were conducted using the chi-squared goodness of fit test and analysis of variance. Results: Among 71 patients who began treatment for CM with fluconazole, 22 (31%) developed worsening meningitis at a median time of 206 days. Longer time from symptom onset to diagnosis of CM was a risk factor for fluconazole failure. Although the absolute failure rate of fluconazole starting dose of 400 mg daily was higher than that of 800 mg daily, the differences did not achieve statistical significance (p = 0.39). Conclusion: Fluconazole failure is not uncommon in the treatment of CM. A dose of 800 mg daily was not superior to a dose of 400 mg daily. All patients on fluconazole for CM require close monitoring.

The COVID-19 pandemic has disrupted medical care worldwide and caused delays in care for many illnesses and procedures unrelated to COVID-19; however, less clear is how it may have affected diagnosis of conditions that present with similar symptoms, such as primary pulmonary coccidioidomycosis (PPC). We conducted an observational cohort study of patients diagnosed with PPC between March 1 and December 1 in 2 years: 2019 (before COVID-19) and in 2020 (after COVID-19) to compare the time from symptom onset to PPC diagnosis. Relevant demographic and clinical variables were collected, and statistical analyses were performed with the χ 2 test, Wilcoxon rank sum test, and Cox proportional hazards regression analysis. During 2019, 83 patients were diagnosed with PPC. During 2020, 113 patients were diagnosed with PPC. For both groups, the median time from symptom onset to diagnosis of PPC was 14 days (P = .13). No significant differences in time to diagnosis existed between the 2 years for location of diagnosis (outpatient clinic, emergency department, or in hospital), for computed tomographic imaging performed before diagnosis, or for number of COVID-19 tests received before PPC diagnosis. In addition, there were no differences in the 2 years between the total number of clinical visits before diagnosis. However, patients in the post-COVID-19 group who had fever were diagnosed with PPC earlier than those without fever (hazard ratio, 1.77; 95% confidence interval, 1.15–2.73; P = .01). Contrary to what we expected, no significant delay in diagnosis of PPC occurred during the COVID-19 pandemic.

Abstract Central nervous system infection with Coccidioides spp. is fatal if untreated and complications occur even when therapy is directed by experienced clinicians. We convened a panel of clinicians experienced in the management of coccidioidal meningitis to summarize current controversies and provide consensus for the management of this difficult infection.

Abstract Background Despite the endemic nature of Coccidioides sp. to the American Southwest, the incidence Coccidioides sp. infective endocarditis (CIE) is rare. Following successful treatment of a patient with CIE at our institution, we reviewed the literature to identify trends in disease presentation, patient characteristics, and outcomes. Methods We reviewed all cases of CIE reported since 1938. Details including patient demographics, underlying immunodeficiency, time to diagnosis, treatment, and outcome were collected for analysis of diagnostic challenges and survival. Results Including ours, we identified 11 published cases of CIE. The majority (7) occurred in men. 5 patients were of either African American or Hispanic descent. Of the 10 patients with reported ages, the median age was 35.5 years (range 3 weeks – 61 years). 5 patients had a previous diagnosis of coccidioidomycosis and only 3 had an immunocompromising condition. These comprised pregnancy, heart transplant, and juvenile inflammatory arthritis. Three cases had multi-valvular involvement, but the majority affected the mitral (5) and the aortic (4) valves. Only 2 of the 11 cases involved a prosthetic valve. Of the 8 cases with reported blood cultures, only 2 were positive. Ten of the 11 cases had extra-cardiac disease. Complement fixation (CF) titers were heterogenous with a median of 1:32 and a range of 1:1 to 1:2048. There was no obvious correlation between a patient’s CF titer and their survival. Average time to diagnosis was 3.5 months (range 2.5 – 36 months). Diagnosis was made post-mortem in 4 of the 11 cases. 6 patients (54%) did not survive. Notably, 2 of the fatal cases preceded the discovery of amphotericin B (1969) and 4 occurred prior to the discovery of fluconazole (1990). Of the five patients that survived, four required surgical intervention in addition to azole therapy. Conclusion CIE is a diagnostic and therapeutic challenge. The diagnosis itself is rare, culture incubation times are long, and the symptoms are often non-specific thus delaying definitive therapy. The introduction of azole therapy appears to have had significant impact on rates of survival. Despite this, successful management of CIE still requires concurrent surgical intervention with aggressive, indefinite anti-fungal therapy. Disclosures All Authors: No reported disclosures

Abstract Coccidioidomycosis is a fungal disease endemic to the southwestern United States, Mexico, and Central and South America. Prevalence rates are increasing steadily, and new endemic areas of Coccidioides are emerging. Standard treatment is often administered for months to decades, and intolerance to medications and treatment failures are common. No new treatments for coccidioidomycosis have been approved in the United States in nearly 40 years. On 5 August 2020, the US Food and Drug Administration convened experts in coccidioidomycosis from academia, industry, patient groups, and other government agencies to discuss the disease landscape and strategies to facilitate product development for treatment of coccidioidomycosis. This article summarizes the key topics concerning drug development for coccidioidomycosis presented by speakers and panelists during the workshop, such as unmet need, trial designs, endpoints, incentives, research and development support, and collaborations to facilitate antifungal drug development.

Abstract Background Coccidioidomycosis is often diagnosed with a collection of tests that measure a patient’s ability to mount an immune response to the fungus (antibody-based diagnostics) utilizing fungal protein preparations. Here we present an antigen-based assay that detects and quantifies coccidioidal chitinase-1 (CTS1) in diagnostic antigen preparations with potential for use in human serum. Methods An inhibition-based enzyme-linked immunoassay (ELISA) was developed that utilizes a monoclonal antibody specific for coccidioidal CTS1. CTS1 was quantified in commercial antigen preparations using recombinant CTS1 as a standard. Sera from 192 individuals from an endemic area were tested which included 78 patients (40.6%) with proven or probable coccidioidomycosis. Results The quantity of CTS1 in diagnostic commercial antigen preparations from different suppliers varied. Temporal constraints of availability of different lots of commercial antigens does not allow for immediate comparison of lot-to-lot variability. Assay results from patient serum samples correlated with low- and high-titer serology from patients with a coccidioidomycosis diagnosis. Further analysis suggested that patient derived anti-CTS1 antibodies may overlap with the mouse monoclonal antibody used in the assay. This unexpected overlap in CTS1 binding suggests the assay can detect antigen, antibody, or both, which contributes to its high level of clinical sensitivity of 89.74% and specificity of 94.90%. Conclusions The CTS1 inhibition ELISA described in this report is a promising tool to aid in quality control of antigens used in the diagnosis of coccidioidomycosis. Further optimization is needed to harness its utility as a diagnostic tool to aid in diagnosis and disease monitoring of coccidioidomycosis.

Abstract Most patients with coronavirus disease 2019 (COVID-19) have mild to moderate illness not requiring hospitalization. However, no study has detailed the evolution of symptoms in the first month of illness. At our institution, we conducted remote (telephone and video) visits for all adult outpatients diagnosed with COVID-19 within 24 h of a positive nasopharyngeal polymerase chain test for SARS-CoV-2. We repeated regular video visits at 7, 14, and 28 days after the positive test, retrospectively reviewed the prospective data collected in the remote visits, and constructed a week by week profile of clinical illness, through week 4 of illness. We reviewed the courses of 458 symptomatic patients diagnosed between March 12, 2020, and June 22, 2020, and characterized their weekly courses. Common initial symptoms included fever, headache, cough, and chest pain, which frequently persisted through week 3 or longer. Upper respiratory or gastrointestinal symptoms were much shorter lived, present primarily in week 1. Anosmia/ageusia peaked in weeks 2 to 3. Emergency department visits were frequent, with 128 visits in the 423 patients who were not hospitalized and 48 visits among the 35 outpatients (7.6%) who were eventually hospitalized (2 subsequently died). By the fourth week, 28.9% said their illness had completely resolved. After the 4-week follow up, 20 (4.7%) of the 423 nonhospitalized patients had further medical evaluation and management for subacute or chronic COVID-19 symptoms. Mild to moderate outpatient COVID-19 is a prolonged illness, with evolving symptoms commonly lasting into the fourth week of illness.

Coccidioides is an endemic fungus of the Southwest United States that causes the disease coccidioidomycosis. Immunocompromised persons are at increased risk for severe infection and dissemination. One such population is allogeneic bone marrow transplant (allo-HCT) recipients, but accounts of coccidioidal infection in these patients have rarely been documented. We present two cases of Coccidioides in allo-HCT recipients with good outcomes: one patient who developed pulmonary coccidioidomycosis in the late post-engraftment phase and another with known controlled disseminated infection at the time of transplant. A review of the literature identified 19 allo-HCT recipients with coccidioidomycosis. Due to the limited published literature, no guidelines have yet been established regarding optimal prophylaxis and treatment of Coccidioides infection in allo-HCT recipients. Candidates for transplantation should undergo a rigorous pre-transplant assessment to identify evidence of prior or active coccidioidomycosis. In our experience, patients who visit or live in Coccidioides-endemic areas should receive primary prophylaxis for at least the first 100 days post-transplant, and duration should be extended as long as the patient remains on immunosuppression. Those with prior infection should receive secondary prophylaxis while immunosuppressed. Patients with active infection should have treatment and stabilization of infection and continue anti-fungal treatment through immunosuppression.

Abstract Approximately 5 to 15% of patients with pulmonary coccidioidomycosis subsequently develop pulmonary cavities. These cavities may resolve spontaneously over a number of years; however, some cavities never close, and a small proportion causes complications such as hemorrhage, pneumothorax or empyema. The impact of azole antifungal treatment on coccidioidal cavities has not been studied. Because azoles are a common treatment for symptomatic pulmonary coccidioidomycosis, we aimed to assess the impact of azole therapy on cavity closure. From January 1, 2004, through December 31, 2014, we retrospectively identified 313 patients with cavitary coccidioidomycosis and excluded 42 who had the cavity removed surgically, leaving 271 data sets available for study. Of the 271 patients, 221 (81.5%) received azole therapy during 5-year follow-up; 50 patients did not receive antifungal treatment. Among the 271 patients, cavities closed in 38 (14.0%). Statistical modeling showed that cavities were more likely to close in patients in the treated group than in the nontreated group (hazard ratio, 2.14 [95% CI: 1.45–5.66]). Cavities were less likely to close in active smokers than nonsmokers (11/41 [26.8%] vs 97/182 [53.3%]; P = 0.002) or in persons with than without diabetes (27/74 [36.5%] vs 81/149 [54.4%]; P = 0.01).We did not find an association between cavity size and closure. Our findings provide rationale for further study of treatment protocols in this subset of patients with coccidioidomycosis. Lay Summary Coccidioidomycosis, known as valley fever, is a fungal infection that infrequently causes cavities to form in the lungs, which potentially results in long-term lung symptoms. We learned that cavities closed more often in persons who received antifungal drugs, but most cavities never closed completely.