Controversies in the Management of Central Nervous System Coccidioidomycosis.

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.

FDA Public Workshop Summary-Coccidioidomycosis (Valley Fever): Considerations for Development of Antifungal Drugs.

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.

Coccidioidomycosis and COVID-19 Infection. An Analysis from a Single Medical Center Within the Coccidioidal Endemic Area.

At a single medical center, we identified 60 cases of coccidioidomycosis that were coincident with COVID-19 infection. Among these, seven patients developed new or clinically progressive coccidioidomycosis. Receipt of dexamethasone for COVID-19 infection was the only significant risk factor for the progression or development of clinically active coccidioidomycosis in this cohort. All patients survived and none developed disseminated coccidioidomycosis.

Cavitary Coccidioidomycosis: Impact of azole antifungal therapy.

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.

Treatment for Early, Uncomplicated Coccidioidomycosis: What Is Success?

The care of primary pulmonary coccidioidomycosis remains challenging. Such infections produce a variety of signs, symptoms, and serologic responses that cause morbidity in patients and concern in treating clinicians for the possibility of extrapulmonary dissemination. Illness may be due to ongoing fungal growth that produces acute inflammatory responses, resulting in tissue damage and necrosis, and for this, administering an antifungal drug may be of benefit. In contrast, convalescence may be prolonged by other immunologic reactions to infection, even after fungal replication has been arrested, and in those situations, antifungal therapy is unlikely to yield clinical improvement. In this presentation, we discuss what findings are clinical indicators of fungal growth and what other sequelae are not. Understanding these differences provides a rational management strategy for deciding when to continue, discontinue, or reinstitute antifungal treatments.

Comparison of three anti-coccidioides antibody enzyme immunoassay kits for the diagnosis of coccidioidomycosis.

Coccidioidomycosis is a common cause of community-acquired pneumonia in endemic areas of the southwestern United States. Clinical presentations range from self-limited disease to severe, disseminated disease. As such, early and accurate diagnosis is essential to ensure appropriate treatment and monitoring. Currently available diagnostic testing has variable accuracy, particularly in certain patient populations, and new tests may offer improved accuracy for the diagnosis of coccidioidomycosis. Serum samples from patients with coccidioidomycosis and controls were tested for immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies using the MVista Coccidioides antibody detection EIA and two commonly used commercial enzyme immunoassay (EIA) kits: the IMMY Omega EIA and the Meridian Premier EIA. The sensitivity of the IgG antibody detection was 87.4% using the MVista test compared to 46.6% for IMMY and 70.9% for Meridian. The sensitivity for IgM antibody detection was 61.2% for the MVista test, 22.3% for IMMY and 29.1% for Meridian. For IgG antibody detection, specificity was 90% for the MVista EIA, 94.6% for IMMY, 96.4% for Meridian. For IgM antibody detection, specificity was 95.3% for the MVista test 98.2% for IMMY and 99.1% for Meridian. The MVista Coccidioides antibody EIA offers improved sensitivity, including among high-risk patient populations, for the detection of IgG and IgM antibodies in comparison to other currently available EIAs.

Tick-Borne Relapsing Fever in the White Mountains, Arizona, USA, 2013-2018.

Tick-borne relapsing fever (TBRF) is a bacterial infection transmitted by tick bites that occurs in several different parts of the world, including the western United States. We describe 6 cases of TBRF acquired in the White Mountains of Arizona, USA, and diagnosed during 2013-2018. All but 1 case-patient had recurrent fever, and some had marked laboratory abnormalities, including leukopenia, thrombocytopenia, hyperbilirubinemia, and elevated aminotransaminases. One patient had uveitis. Diagnosis was delayed in 5 of the cases; all case-patients responded to therapy with doxycycline. Two patients had Jarisch-Herxheimer reactions. The White Mountains of Arizona have not been previously considered a region of high incidence for TBRF. These 6 cases likely represent a larger number of cases that might have been undiagnosed. Clinicians should be aware of TBRF in patients who reside, recreate, or travel to this area and especially for those who sleep overnight in cabins there.

Coccidioidomycosis in selected immunosuppressed hosts.

After contracting coccidioidomycosis, persons with impaired cellular immunity are more likely than healthy persons to have severe infection, disseminated infection, and higher mortality rates. In this brief review, we summarize the clinical manifestations, diagnosis, treatment, and prevention of coccidioidomycosis in persons infected with human immunodeficiency virus (HIV), recipients of solid organ or hematopoietic stem cell transplants, and recipients of biologic response modifiers. Among individuals infected with HIV, a diagnosis of acquired immunodeficiency syndrome (AIDS) and a CD4 T-lymphocyte count <250 cells/µl were associated with more severe coccidioidomycosis, whereas less severe disease occurred among those with undetectable HIV-RNA and higher CD4 T-lymphocyte counts, indicating that controlled HIV viremia and improved cellular immune status are important in limiting disease. For transplant recipients whose immunosuppression typically peaks in the first 3 to 6 months and tapers thereafter, the greatest risk of acute coccidioidomycosis occurs 6 to 12 months after transplantation. Relapses of recent coccidioidomycosis may occur during ongoing immunosuppression when patients are not taking suppressive antifungal medication. Recipients of biologic agents, especially those that impair tumor necrosis factor α (TNF-α), may be at increased risk for poorly controlled coccidioidomycosis; however, the best way to prevent and treat such infections has yet to be defined.

Management of asymptomatic coccidioidomycosis in patients with rheumatic diseases.

Coccidioidomycosis is an endemic fungal infection common in the southwestern United States. Some rheumatology clinics periodically screen patients with coccidioidal serology, resulting in the identification of patients who are serologically positive but without clinical symptoms. The management of such patients is unclear. A retrospective study was conducted between 2007 and 2015 at two arthritis centers in Tucson, Arizona. The asymptomatic patients were identified who were receiving disease-modifying antirheumatic agents and had a positive coccidioidal serology. Serological testing including IgM and IgG was performed by enzyme immunoassay (EIA), immunodiffusion (IDTP and IDCF), or complement fixation. Out of 71 patients who were identified with positive coccidioidal serologies, 19 were asymptomatic. 18/19 patients continued antirheumatic therapy, 13 without interruption. 13/19 patients received no antifungal treatment, including 10 who remained on antirheumatic treatment. The other six were started on fluconazole, ranging from 8 to 73 months (median 30.5 months). After a median follow-up of 43 months, no patient developed clinically active coccidioidomycosis. Overall, 14 had only a positive EIA serological test. These results suggest that continued antirheumatic therapy is safe in asymptomatic patients with positive coccidioidal serological tests and that routine implementation of antifungal treatment may not always be warranted. The findings also raise concern regarding the utility of routine serological testing of asymptomatic patients residing in the coccidioidal endemic area, mainly using the EIA test.

An Analysis of Skin Test Responses to Spherulin-Based Coccidioidin (Spherusol®) Among a Group of Subjects with Various Forms of Active Coccidioidomycosis.

BACKGROUND: A reformulated skin test for coccidioidomycosis, Spherusol®, was recently approved for use in the USA. We hypothesized that it could be useful in predicting severity of illness and outcome in various types of coccidioidomycosis. METHODS: Subjects with non-meningeal coccidioidomycosis attending a clinic in the coccidioidal endemic region were skin tested with Spherusol® and clinical data were collected at the time of testing and at follow-up. RESULTS: Twenty-seven subjects were studied, eight of whom had extrathoracic dissemination. A total of 15 subjects had positive tests, including 11 of 19 subjects with non-disseminated pulmonary disease and four with extrathoracic disseminated coccidioidomycosis. Among those with non-disseminated pulmonary disease, age ≥ 65 years, female sex, and antifungal therapy were significantly associated with a negative test on univariate but not multivariate analysis. For 23 subjects, there was a trend for those not on antifungal therapy at the time of follow-up to have a positive test but no association with coccidioidal complement-fixation titer or overall outcome. CONCLUSIONS: Not all subjects with non-disseminated pulmonary coccidioidomycosis were found to be skin test positive and half of those with extrathoracic disseminated disease manifested dermal hypersensitivity. In this small study, the results of the skin test were not clinically predictive of disease severity or outcome.

Glucan-Chitin Particles Enhance Th17 Response and Improve Protective Efficacy of a Multivalent Antigen (rCpa1) against Pulmonary Coccidioides posadasii Infection.

Developing an effective and safe recombinant vaccine requires microbe-specific antigens combined with an adjuvant/delivery system to strengthen protective immunity. In this study, we designed and expressed a multivalent recombinant Coccidioides polypeptide antigen (rCpa1) that consists of three previously identified antigens (i.e., Ag2/Pra, Cs-Ag, and Pmp1) and five pathogen-derived peptides with high affinity for human major histocompatibility complex class II (MHC-II) molecules. The purified rCpa1 was encapsulated into four types of yeast cell wall particles containing ß-glucan, mannan, and chitin in various proportions or was mixed with an oligonucleotide (ODN) containing two methylated dinucleotide CpG motifs. This multivalent antigen encapsulated into glucan-chitin particles (GCP-rCpa1) showed significantly greater reduction of fungal burden for human HLA-DR4 transgenic mice than the other adjuvant-rCpa1 formulations tested. Among the adjuvants tested, both GCPs and ß-glucan particles (GPs) were capable of stimulating a mixed Th1 and Th17 response. Mice vaccinated with GCP-rCpa1 showed higher levels of interleukin 17 (IL-17) production in T-cell recall assays and earlier lung infiltration by activated Th1 and Th17 cells than GP-rCpa1-vaccinated mice. Both C57BL/6 and HLA-DR4 transgenic mice that were vaccinated with the GCP-rCpa1 vaccine showed higher survival rates than mice that received GCPs alone. Concurrently, the GCP-rCpa1 vaccine stimulated greater infiltration of the injection sites by macrophages, which engulf and process the vaccine for antigen presentation, than the GP-rCpa1 vaccine. This is the first attempt to systematically characterize the presentation of a multivalent coccidioidomycosis vaccine encapsulated with selected adjuvants that enhance the protective cellular immune response to infection.

Enhanced Antibody Detection and Diagnosis of Coccidioidomycosis with the MiraVista IgG and IgM Detection Enzyme Immunoassay.

Coccidioidomycosis is a common cause of community-acquired pneumonia in areas of the southwestern United States in which the disease is endemic. Clinical presentations range from self-limited disease to severe disseminated disease. Therefore, early and accurate diagnosis is essential to ensure appropriate treatment and monitoring. Currently available diagnostic tests have variable accuracy, particularly in certain patient populations, and new tests may offer improved accuracy for the diagnosis of coccidioidomycosis. Serum samples from 103 cases of coccidioidomycosis and 373 controls were tested for IgG and IgM antibodies using the MVista anti-Coccidioides antibody enzyme immunoassay. Serum specimens from 170 controls from areas in which the disease is endemic and 44 cases were tested by immunodiffusion at MiraVista Diagnostics. The sensitivity of the MVista antibody assay was 88.3%, and the specificity was 90%. The sensitivity was maintained in the presence of immunocompromising conditions or immunosuppressive therapies. The sensitivity of immunodiffusion was 60.2%, and the specificity was 98.8%. The sensitivity of complement fixation (62 cases) was 66.1%, but the specificity could not be determined. The MVista anti-Coccidioides antibody enzyme immunoassay offers improved sensitivity, compared with immunodiffusion and complement fixation, is not impaired in immunocompromised patients, and permits highly reproducible semiquantification.

Coccidioidomycosis among persons undergoing lung transplantation in the coccidioidal endemic region.

BACKGROUND: Coccidioidomycosis, an endemic fungal infection, is more likely to be symptomatic and severe among those receiving allogeneic transplants. While several case series have been published for various transplanted organs, none has described the incidence and outcomes in those receiving lung transplants within the coccidioidal endemic region. METHODS: Patients receiving a heart-lung, single-lung, or bilateral-lung transplantation at the University of Arizona between 1985 and 2009 were retrospectively reviewed. RESULTS: Coccidioidomycosis occurred post transplantation in 11 (5.8%) of 189 patients. All but one patient was diagnosed with pulmonary coccidioidomycosis and only one had a history of prior coccidioidomycosis. Two patients received transplants from donors found to have coccidioidomycosis at the time of transplantation and one death was directly attributed to coccidioidomycosis. The risk of developing active coccidioidomycosis was significantly higher if the patient did not receive some type of antifungal therapy post transplantation (P<.001). CONCLUSION: Within the coccidioidal endemic region, post-transplantation coccidioidomycosis was a definable risk among lung transplant recipients. Use of antifungals appeared to reduce this incidence of disease. Almost all cases resulted in pulmonary disease, suggesting that the lung is the primary site of infection.

Executive Summary: 2016 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Treatment of Coccidioidomycosis.

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. Infectious Diseases Society of America considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.Coccidioidomycosis, also known as San Joaquin Valley fever, is a systemic infection endemic to parts of the southwestern United States and elsewhere in the Western Hemisphere. Residence in and recent travel to these areas are critical elements for the accurate recognition of patients who develop this infection. In this practice guideline, we have organized our recommendations to address actionable questions concerning the entire spectrum of clinical syndromes. These can range from initial pulmonary infection, which eventually resolves whether or not antifungal therapy is administered, to a variety of pulmonary and extrapulmonary complications. Additional recommendations address management of coccidioidomycosis occurring for special at-risk populations. Finally, preemptive management strategies are outlined in certain at-risk populations and after unintentional laboratory exposure.

2016 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Treatment of Coccidioidomycosis.

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. Infectious Diseases Society of America considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.Coccidioidomycosis, also known as San Joaquin Valley fever, is a systemic infection endemic to parts of the southwestern United States and elsewhere in the Western Hemisphere. Residence in and recent travel to these areas are critical elements for the accurate recognition of patients who develop this infection. In this practice guideline, we have organized our recommendations to address actionable questions concerning the entire spectrum of clinical syndromes. These can range from initial pulmonary infection, which eventually resolves whether or not antifungal therapy is administered, to a variety of pulmonary and extrapulmonary complications. Additional recommendations address management of coccidioidomycosis occurring for special at-risk populations. Finally, preemptive management strategies are outlined in certain at-risk populations and after unintentional laboratory exposure.

The Return of Delayed-Type Hypersensitivity Skin Testing for Coccidioidomycosis.

A skin test that detects dermal hypersensitivity in persons with past infection with Coccidioides species is again available for clinical use. Nearly all of the clinical studies with similar materials were published prior to the 1990s, and as a result, many practicing physicians will be unfamiliar with how skin testing for coccidioidomycosis might be useful in patient management or as a research tool. We review clinical and epidemiological studies with past skin test antigens, the composition of past and current skin test preparations with particular attention to differences in the preservatives, and how the current preparation could be used today.

Recent advances in our understanding of the environmental, epidemiological, immunological, and clinical dimensions of coccidioidomycosis.

Coccidioidomycosis is the endemic mycosis caused by the fungal pathogens Coccidioides immitis and C. posadasii. This review is a summary of the recent advances that have been made in the understanding of this pathogen, including its mycology, genetics, and niche in the environment. Updates on the epidemiology of the organism emphasize that it is a continuing, significant problem in areas of endemicity. For a variety of reasons, the number of reported coccidioidal infections has increased dramatically over the past decade. While continual improvements in the fields of organ transplantation and management of autoimmune disorders and patients with HIV have led to dilemmas with concurrent infection with coccidioidomycosis, they have also led to advances in the understanding of the human immune response to infection. There have been some advances in therapeutics with the increased use of newer azoles. Lastly, there is an overview of the ongoing search for a preventative vaccine.

Positron emission tomography in the evaluation of pulmonary nodules among patients living in a coccidioidal endemic region.

BACKGROUND: Within a coccidioidal endemic region, pulmonary nodules due to coccidioidomycosis are common. Uptake of (18)fluorodeoxyglucose ((18)FDG) by positron emission tomography with computed axial tomography (PET/CT) has been used to assess whether pulmonary nodules are malignant but inflammatory lesions can be positive. The purpose of this study was to compare by PET/CT the (18)FDG uptake in pulmonary nodules likely due to coccidioidomycosis to that of nodules shown to be malignant among patients living in a coccidioidal endemic region. METHODS: We retrospectively reviewed patients who underwent a PET/CT at the Southern Arizona Veterans Affairs Health Care System between January 2008 and March 2012 who were subsequently found on biopsy to have pulmonary nodules that were coccidioidal or granulomatous or were due to malignancy. RESULTS: Among 245 diagnostic biopsies where the subject had a previous PET/CT, 15 (6.1 %) were either coccidioidal (n = 12) or granulomatous without an identified organism (n = 3). The median maximum standard unit of uptake (SUV(max)) on PET/CT of coccidioidal or granulomatous lesions was 2.0 compared to 9.8 for malignant lesions (P < 0.001). The maximum diameter of the coccidioidal or granulomatous nodules was 2.1 cm compared to 3.0 cm for the malignant lesions (P = 0.009). On multivariable analysis, an elevated SUV(max) was the only distinguishing feature between the malignant and the granulomatous lesions (OR 1.28, 95 % CI 1.05-1.55; P = 0.013). CONCLUSIONS: Coccidioidal pulmonary nodules take up significantly less (18)FDG than those due to malignancies, but there is considerable overlap between granulomatous and malignant lesions at lower SUV(max).

Immunological characterization of bronchoalveolar lavage fluid in patients with acute pulmonary coccidioidomycosis.

BACKGROUND: The specific cellular immunological characteristics of bronchoalveolar lavage (BAL) fluid in acute pulmonary coccidioidomycosis have not been defined. METHODS: BAL fluid from patients living in a coccidioidomycosis-endemic region of Arizona who were undergoing bronchoscopy because of pulmonary infiltrates was analyzed. Mononuclear cells from BAL fluid and peripheral blood mononuclear cells (PBMCs) were incubated with the coccidioidal antigen T27K in vitro, and cellular immunological assays were performed. RESULTS: Forty-six patients were studied. Twelve received a diagnosis of acute pulmonary coccidioidomycosis, 17 received other diagnoses, and 17 had no diagnosis established. There was an increased proportion of polyfunctional CD8(+) T cells after antigen stimulation from subjects with coccidioidomycosis as compared to those with another diagnosis (P = .025). In cells collected from BAL fluid and in PBMCs, the concentrations of interferon γ, tumor necrosis factor α, and interleukin 17 (IL-17) were all significantly increased in samples from those with acute pulmonary coccidioidomycosis, compared with the other 2 groups (for all, P<.05). CONCLUSIONS: When incubated in vitro with a coccidioidal antigen preparation, cells from both BAL fluid and peripheral blood obtained from patients with pulmonary coccidioidomycosis demonstrated specific cellular immune responses, including expression of IL-17.

Challenges to Implementing a Vaccine for Coccidioidomycosis.

A vaccine for coccidioidomycosis is likely to undergo trials in the near future. In this paper, we raise 4 questions that should be answered before its use and offer our solutions to these questions. These include defining the goals of vaccination, determining who should be vaccinated, how to measure vaccine immunity and protection, and how to address vaccine hesitancy and denial.