Coccidioidomycosis.

Coccidioidomycosis, caused by the dimorphic pathogenic fungi Coccidioides immitis and Coccidioides posadassi, is endemic to the southwestern United states and Central and South America. The incidence of coccidioidomycosis continues to increase. Coccidioidomycosis is typically a self-limiting influenza-like respiratory illness; however, it can lead to disseminated disease outside of the lungs. Not all nondisseminated cases require therapy, but antifungal therapy is typically beneficial requiring treatment ranging from months to lifelong. Clinical factors related to treatment decisions include severity of symptoms, radiography, coccidioidomycosis serologic results, and concurrent medical problems including immunosuppression. This review summarizes the epidemiology, clinical manifestations, and treatment options.

Coccidioidomycosis in patients with various inflammatory disorders treated with tumor necrosis factor α inhibitors.

Coccidioides fungi are found primarily in the southwestern United States and are the cause of coccidioidomycosis. Tumor necrosis factor α inhibitors (TNFIs) are therapies for autoimmune and inflammatory conditions; their association with coccidioidomycosis is not well characterized. We aimed to determine the prevalence and characteristics of coccidioidomycosis among TNFI recipients with different inflammatory disorders at a tertiary care center. We retrospectively reviewed the electronic health records of patients at our institution from April 4, 2010 to December 17, 2017, who received TNFIs (infliximab, etanercept, adalimumab, certolizumab pegol, or golimumab) and had positive culture, pathologic, and/or serologic results for coccidioidomycosis. Among 1770 patients identified who received TNFIs, 49 (2.8%) had proven or probable coccidioidomycosis. Of these 49, 28 (57%) were men, 47 (96%) were White, and 42 (86%) had pulmonary coccidioidomycosis. The most common TNFIs used were adalimumab, infliximab, and etanercept. Coccidioidomycosis was identified in 25 of 794 patients with rheumatologic disorders (3.1%), 18 of 783 patients with inflammatory bowel disease (IBD) (2.3%), and six of 193 patients with dermatologic disorders (3.1%) (P = .34). There was no difference in coccidioidal infections among recipients of any particular TNFI agents. A minority of patients (7/49, 14%) had an extrapulmonary infection, and the majority of these (6/7) had IBD. Our study shows a low prevalence of coccidioidomycosis in TNFI recipients, even within the Coccidioides-endemic area. Persons with IBD were disproportionately represented among those with extrapulmonary coccidioidomycosis. Treatment with azoles was effective. LAY SUMMARY: Among 1770 patients who received tumor necrosis factor α inhibitors, 49 (2.8%) had newly acquired coccidioidomycosis over a 7-year period. Dissemination occurred in 14.3%, but disproportionately among those with underlying inflammatory bowel disease. All patients recovered with medical management.

Pulmonary Coccidioidomycosis Mimicking Aspergillosis Fungus Ball.

The genus Coccidioides is composed of C. immitis and C. posadasii. Both can cause coccidioidomycosis and are geographically restricted to certain areas of endemicity. The histopathologic features in pulmonary coccidioidomycosis include necrotizing granulomatous inflammation and the presence of spherules, which is considered to be a key diagnostic finding. Cavitary lung disease containing a fungal ball with branching septate hyphae is an unusual funding in pulmonary coccidioidomycosis but is typical for aspergillosis. We present a case of 42 year old man who underwent wedge resection of the lung for a persistent cavitary lesion. The microscopic examination shows a fungal ball composed of acute-angle branching septate hyphae, consistent with a diagnosis of aspergillosis. However, cultures and molecular testing by DNA sequencing of the 28S ribosomal DNA gene confirmed the identification of C. posadasii. This finding highlights the importance of exposure history and organism identification by either conventional cultivation or molecular testing in rendering an accurate diagnosis.

A case report of Coccidioides posadasii meningoencephalitis in an immunocompetent host.

BACKGROUND: Coccidioides spp. are dimorphic fungi endemic to Central America, regions of South America and southwestern USA. Two species cause most human disease: Coccidioides immitis (primarily California isolates) and Coccidioides posadasii. Coccidioidomycosis is typically acquired through inhalation of soil or dust containing spores. Coccidioidal meningitis (CM), most common in the immunocompromised host, can also affect immunocompetent hosts. CASE PRESENTATION: We report a case of C. posadasii meningoencephalitis in a previously healthy 42-year-old Caucasian male who returned to Canada after spending time working in New Mexico. He presented with a 3-week history of headache, malaise and low-grade fevers. He developed progressive confusion and decreasing level of consciousness following hospitalization. Evidence of hydrocephalus and leptomeningeal enhancement was demonstrated on magnetic resonance imaging (MRI) of his brain. Serologic and PCR testing of the patient's CSF confirmed Coccidioides posadasii. Despite appropriate antifungal therapy he continues to have significant short-term memory deficits and has not returned to his full baseline functional status. CONCLUSIONS: Travel to endemic regions can result in disease secondary to Coccidioides spp. and requires physicians in non-endemic areas to have a high index of suspicion. Effective therapeutic options have reduced the mortality rate of CM, however, it is still associated with significant morbidity and requires life-long therapy.

The mysterious desert dwellers: Coccidioides immitis and Coccidioides posadasii, causative fungal agents of coccidioidomycosis.

The genus Coccidioides consists of two species: C. immitis and C. posadasii. Prior to 2000, all disease was thought to be caused by a single species, C. immitis. The organism grows in arid to semiarid alkaline soils throughout western North America and into Central and South America. Regions in the United States, with highest prevalence of disease, include California, Arizona, and Texas. The Mexican states of Baja California, Coahuila, Sonora, and Neuvo Leon currently have the highest skin test positive results. Central America contains isolated endemic areas in Guatemala and Honduras. South America has isolated regions of high endemicity including areas of Colombia, Venezuela, Argentina, Paraguay, and Brazil. Although approximately 15,000 cases per year are reported in the United States, actual disease burden is estimated to be in the hundreds of thousands, as only California and Arizona have dedicated public health outreach, and report and track disease reliably. In this review, we survey genomics, epidemiology, ecology, and summarize aspects of disease, diagnosis, prevention, and treatment.

APX001 and Other Gwt1 Inhibitor Prodrugs Are Effective in Experimental Coccidioides immitis Pneumonia.

Coccidioidomycosis is a systemic fungal infection caused by the inhalation of the arthroconidia of either of two closely related dimorphic fungi, Coccidioides immitis and C. posadasii, that are endemic in the southwestern United States and other areas in the Western Hemisphere. Chronic cavitary pulmonary infections and extrapulmonary sites of infection are very difficult to treat and often require lifelong azole therapy. APX001A is the first in a new class of broad-spectrum antifungal agents that inhibit Gwt1, an enzyme which is required for cell wall localization of glycosylphosphatidylinositol (GPI)-anchored mannoproteins in fungi. APX001A and several analogs were highly active against clinical isolates of Coccidioides, inhibiting hyphal growth at low nanogram/ml concentrations. APX001 is the N-phosphonooxymethyl prodrug of APX001A, currently in clinical trials for the treatment of invasive fungal infections. Mice were treated orally once daily with 26 mg/kg/day of APX001 and the prodrug analog APX2097, 2 h after administration of the pan-cytochrome P450 inhibitor 1-aminobenzotriazole, which was used to enhance drug half-life and exposures to more closely mimic human pharmacokinetics of APX001A. Five days of treatment reduced lung colony counts by nearly 3 logs and prevented dissemination, similar to the efficacy of fluconazole dosed orally at 25 mg/kg twice daily. In a survival experiment, both APX001- and APX2097-treated mice survived significantly longer than control and fluconazole-treated mice. APX001 and other members of this new class of antifungal agents may offer great promise as effective therapies for coccidioidomycosis.

Coccidioides immitis and posadasii; A review of their biology, genomics, pathogenesis, and host immunity.

Coccidioides immitis and C. posadasii are two highly pathogenic dimorphic fungal species that are endemic in the arid areas of the new world, including the region from west Texas to southern and central California in the USA that cause coccidioidomycosis (also known as Valley Fever). In highly endemic regions such as southern Arizona, up to 50% of long term residents have been infected. New information about fungal population genetics, ecology, epidemiology, and host-pathogen interactions is becoming available. However, our understanding of some aspects of coccidioidomycosis is still incomplete, including the extent of genetic variability of the fungus, the genes involved in virulence, and how the changes in gene expression during the organism's dimorphic life cycle are related to the transformation from a free-living mold to a parasitic spherule. Unfortunately, efforts to develop an effective subunit vaccine have not yet been productive, although two potential live fungus vaccines have been developed.

Viable spores of Coccidioides posadasii Δcps1 are required for vaccination and provide long lasting immunity.

Coccidioidomycosis is a systemic fungal infection for which a vaccine has been sought for over fifty years. The avirulent Coccidioides posadasii strain, Δcps1, which is missing a 6 kb gene, showed significant protection in mice. These studies explore conditions of protection in mice and elucidate the immune response. Mice were vaccinated with different doses and viability states of Δcps1 spores, challenged with virulent C. posadasii, and sacrificed at various endpoints, dependent on experimental objectives. Tissues from vaccinated mice were harvested for in vitro elucidation of immune response. Vaccination with viable Δcps1 spores was required for protection from lethal challenge. Viable spore vaccination produced durable immunity, lasting at least 6 months, and prolonged survival (≥6 months). The C. posadasii vaccine strain also protected mice against C. immitis (survival ≥ 6 months). Cytokines from infected lungs of vaccinated mice in the first four days after Cp challenge showed significant increases of IFN-γ, as did stimulated CD4+ spleen cells from vaccinated mice. Transfer of CD4+ cells, but not CD8+ or B cells, reduced fungal burdens following challenge. IFN-γ from CD4+ cells in vaccinated mice indicates a Th1 response, which is critical for host control of coccidioidomycosis.

Pathology of coccidioidomycosis in llamas and alpacas.

Coccidioidomycosis is a fungal disease caused by either Coccidioides immitis or Coccidioides posadasii. Anecdotal evidence suggests that camelids are particularly susceptible to this disease and that a relatively large percentage of pneumonias in these animals are caused by Coccidioides spp. In a search of 21 y (1992-2013) of records from the California Animal Health and Food Safety Laboratory, we found 79 cases of coccidioidomycosis diagnosed in camelids; 66 (84%) had pneumonia and 13 (16%) had lesions only in organs other than the lungs. The organs most frequently affected were lung (84%) and liver (78%). Coccidioides spp. were the cause of pneumonia in 66 of 362 (18%) camelid cases during the study period. The lesions in affected organs were multifocal-to-coalescing pyogranulomas, which in most cases were visible grossly. Ten of the 12 formalin-fixed, paraffin-embedded lung samples tested by a universal Coccidioides spp. PCR assay were positive (4 C. immitis, 2 C. posadasii); the species could not be determined in 4 of the 10 cases positive by PCR. Coccidioidomycosis is an important cause of pneumonia in camelids in California, and can be caused by either C. immitis or C. posadasii.

Detection of Coccidioides posadasii from xerophytic environments in Venezuela reveals risk of naturally acquired coccidioidomycosis infections.

A wide range of mammals are susceptible to infection by the fungal species Coccidioides immitis and C. posadasii. In humans, 60% of infections are asymptomatic; however, certain patients may develop a severe and deep systemic mycosis called coccidioidomycosis. Genetic analysis suggests that the majority of clinical isolates recovered from South America are C. posadasii; however, little is known about the prevalence, species distribution, and ecological factors that favor the occurrence of this pathogen in those areas. By using a combined quantitative polymerase chain reaction (qPCR)-based approach and mycobiome amplicon sequencing, we provide evidence that at least two genotypes of C. posadasii are found in the xerophytic environment in Venezuela. We detected a 3806-fold range in the amount of Coccidioides DNA when comparing among the sampled locations, which indicates that human exposure risk is variable, and is one critical factor for disease manifestation. We identified fungal communities that are correlated with a higher prevalence of C. posadasii, suggesting that a combination of specific microbes and a xeric microenvironment may favor the growth of Coccidioides in certain locations. Moreover, we discuss the use of a combinatorial approach, using both qPCR and deep-sequencing methods to assess and monitor fungal pathogen burden at outbreak sources.

The Novel Fungal Cyp51 Inhibitor VT-1598 Is Efficacious in Experimental Models of Central Nervous System Coccidioidomycosis Caused by Coccidioides posadasii and Coccidioides immitis.

Coccidioidal meningitis can cause significant morbidity, and lifelong antifungal therapy is often required. VT-1598 is a fungus-specific Cyp51 inhibitor that has potent in vitro activity against Coccidioides species. We evaluated the in vivo efficacy of VT-1598 in murine models of central nervous system coccidioidomycosis caused by C. posadasii and C. immitis Infection was introduced via intracranial inoculation, and therapy began 48 h postinoculation. Oral treatments consisted of vehicle control, VT-1598, and positive controls of fluconazole in the C. immitis study and VT-1161 in the C. posadasii study. Treatment continued for 7 and 14 days in the fungal-burden and survival studies, respectively. Fungal burden was assessed in brain tissue collected 24 to 48 h posttreatment in the fungal-burden studies, on the days the mice succumbed to infection, or at prespecified endpoints in the survival studies. VT-1598 plasma concentrations were also measured in the C. posadasii study. VT-1598 resulted in significant improvements in survival in mice infected with either species. In addition, the fungal burden was significantly reduced in the fungal-burden studies. Plasma concentrations 48 h after dosing stopped remained above the VT-1598 MIC against the C. posadasii isolate, although levels were undetectable in the survival study after a 4-week washout. Whereas fungal burden remained suppressed after a 2-week washout in the C. immitis model, a higher fungal burden was observed in the survival arm of the C. posadasii model. This in vivo efficacy supports human studies to establish the utility of VT-1598 for the treatment of coccidioidomycosis.

Coccidioidomycosis Transmission Through Organ Transplantation: A Report of the OPTN Ad Hoc Disease Transmission Advisory Committee.

Donor-derived coccidioidomycosis has caused unexpected morbidity and mortality in transplant recipients. All proven or probable reports of donor-derived coccidioidomycosis to the Disease Transmission Advisory Committee between 2005 and August 2012 were reviewed. Six reports of proven or probable coccidioidomycosis were discovered. In four of six, the infection was first detected at autopsy in the recipient. In two cases it was first identified in the donor. Twenty-one recipients received organs from these six donors. Transmission occurred in 43% at a median of 30 days posttransplant with a mortality rate of 28.5%. Eleven recipients received preemptive antifungals, seven did not receive treatment, and treatment information was not reported for three recipients. Five of seven who did not receive prophylaxis/treatment died and all 11 who received early therapy survived. Six deaths occurred 14 to 55 days after transplant, with a median of 21 days. For exposed recipients, donor-derived coccidioidomycosis is a significant cause of morbidity and mortality. Evidence of infection in one recipient should prompt immediate evaluation for treatment of all other recipients from the same donor as preemptive treatment was effective. Further studies are needed to decide whether all donors from endemic areas should have routine serologic screening.

Emerging Fungal Infections in the Pacific Northwest: The Unrecognized Burden and Geographic Range of Cryptococcus gattii and Coccidioides immitis.

Both Cryptococcus gattii and Coccidioides can cause debilitating diseases if not identified early. It is imperative that clinicians recognize these diseases and begin treatment quickly when necessary. In order to have these two mycoses in their differential diagnosis, clinicians, microbiologists, and public health officials must be aware of the expanding geographic boundary in the case of Coccidioides immitis and the new emergence in the case of C. gattii. Accordingly, there is now mandatory reporting for cases of C. gattii and C. immitis in both Washington and Oregon, and the Centers for Disease Control and Prevention keeps a repository of available isolates. Through the One Health initiative, clinicians, veterinarians, and public health officials are collaborating to better understand the emergence and expanding geographic range of these extremely important fungal diseases.

Coccidioidomycosis among Workers Constructing Solar Power Farms, California, USA, 2011-2014.

Coccidioidomycosis is associated with soil-disruptive work in Coccidioides-endemic areas of the southwestern United States. Among 3,572 workers constructing 2 solar power-generating facilities in San Luis Obispo County, California, USA, we identified 44 patients with symptom onset during October 2011-April 2014 (attack rate 1.2 cases/100 workers). Of these 44 patients, 20 resided in California outside San Luis Obispo County and 10 resided in another state; 9 were hospitalized (median 3 days), 34 missed work (median 22 days), and 2 had disseminated disease. Of the 25 patients who frequently performed soil-disruptive work, 6 reported frequent use of respiratory protection. As solar farm construction in Coccidioides-endemic areas increases, additional workers will probably be exposed and infected unless awareness is emphasized and effective exposure reduction measures implemented, including limiting dust generation and providing respiratory protection. Medical providers, including those in non-Coccidioides-endemic areas, should suspect coccidioidomycosis in workers with compatible illness and report cases to their local health department.

Cerebrospinal fluid Coccidioides antigen testing in the diagnosis and management of central nervous system coccidioidomycosis.

The goal of this study was to report on the potential utility of cerebrospinal fluid (CSF) Coccidioides antigen testing in the diagnosis and management of Coccidioides meningitis. We retrospectively reviewed medical records of seven patients with Coccidioides meningitis who had Coccidioides antigen tests performed on CSF. In two severely immunocompromised patients, CSF Coccidioides antigen testing was helpful in the diagnosis when other testing modalities were negative. Coccidioides antigen testing was also useful in the management of patients who had progression of disease due to non-adherence, development of resistance, failure of therapy and the presence of vasculitis. Changing antigen levels helped identify disease complications in three patients that led to alterations in therapy or management. On the basis of our review of these seven patients with Coccidioides meningitis, we concluded that the Coccidioides antigen test contributed to the diagnosis and management of patients with Coccidioides meningitis.

Coccidioidomicosis diseminada y embarazo. Reporte de un caso / Disseminated coccidioidomycosis in pregnancy. A case report

La coccidioidomicosis es una infección fúngica causada por la inhalación del Coccidioides immitis oCoccidioides posadasii. Ha sido descrita durante el embarazo como devastadora y se estima que las embarazadas con infecciones sintomáticas tienen un aumento del 10% de riesgo de diseminación extrapulmonar y, si esta ocurre, un 90% de mortalidad. Se presenta el caso de una paciente embarazada de 39 semanas con dolor torácico y tos seca. La radiografía de tórax demostró opacificación de ambos campos pulmonares y neumomediastino. El diagnóstico definitivo se confirmó en la necropsia por la presencia de Coccidioides immitis en el tejido pulmonar y nódulos mediastinales

Coccidioidomycosis is a fungal infection caused by inhalation of Coccidioides immitis or Coccidioides posadasii. Infection by this fungus during pregnancy can be devastating and it is estimated that pregnant women with symptomatic infections have a 10% increase in the risk of extra-pulmonary dissemination, which carries a 90% risk of mortality. We describe the case of a woman at 39 weeks of pregnancy with chest pain and dry cough. Chest X-ray showed opacity of both lungs and pneumomediastinum. Definitive diagnosis was confirmed at autopsy due to the presence ofCoccidioides immitis in lung tissue and mediastinal nodules

Coccidioides parenchymal cerebral abscess in the setting of lymphoma.

Coccidioides immitis is a dimorphic fungus endemic to southwestern United States of America. When symptomatic, infection usually results in a subacute respiratory infection. Disseminated coccidioidomycosis occurs in less than 1% of all cases. We report a patient with follicular lymphoma and recent travel to Arizona, who underwent resection of a cerebral Coccidioides abscess. Serology testing was negative. This case highlights the importance of clinical suspicion in patients with neurologic symptoms and travel to an endemic location.

Call for a California coccidioidomycosis consortium to face the top ten challenges posed by a recalcitrant regional disease.

Coccidioidomycosis ('Valley Fever'), caused by the inhalation of the fungus Coccidioides, remains a recalcitrant health problem in large parts of California. The incidence and severity of the disease continues to rise in many parts of the state. In this manuscript, we highlight unanswered questions about the disease. Specifically, the extent of disease burden, genetic determinants of host susceptibility, diagnostic and treatment guidelines, natural reservoirs of the pathogens, antifungal drug resistance, and fungal determinants of mild or severe disease are all areas awaiting in depth investigations. We also recommend establishment of a California Coccidioidomycosis Registry to improve clinical care and translational research.

Thermally Dimorphic Human Fungal Pathogens--Polyphyletic Pathogens with a Convergent Pathogenicity Trait.

Fungi are adept at changing their cell shape and developmental program in response to signals in their surroundings. Here we focus on a group of evolutionarily related fungal pathogens of humans known as the thermally dimorphic fungi. These organisms grow in a hyphal form in the environment but shift their morphology drastically within a mammalian host. Temperature is one of the main host signals that initiates their conversion to the "host" form and is sufficient in the laboratory to trigger establishment of this host-adapted developmental program. Here we discuss the major human pathogens in this group, which are Blastomyces dermatiditis, Coccidioides immitis/posadasii, Histoplasma capsulatum, Paracoccidioides brasiliensis/lutzii, Sporothrix schenckii, and Talaromyces marneffei (formerly known as Penicillium marneffei). The majority of these organisms are primary pathogens, with the ability to cause disease in healthy humans who encounter them in endemic areas.