Endemic Fungi Research Articles

Clinical Characteristics and Outcomes in Hospitalized Patients with Proven and Probable Coccidioidomycosis at the National Institute of Respiratory Diseases in Mexico City

Background Coccidioides spp. an endemic dimorphic fungi is present in the north and south of Mexico. The Ministry of Health report in Mexico between 1988 and 1994 0.5 to 1.3 cases per 100,000 habitants. The clinical picture ranges from asymptomatic to disseminated disease. They should be classified according to the EORTC/MSG criteria in proven and probable disease, in Mexico there is no study about clinical characteristics and outcomes in hospitalized patients according to this classification.ObjectiveEvaluate the clinical characteristics and outcomes in hospitalized patients with proven and probable coccidioidomycosis according to EORTC/MSG criteria.Methods The National Institute of Respiratory Diseases in Mexico City is the national referral center for complicated pulmonary infectious diseases. This retrospective cohort from 2010 to 2016 included proven and probable Coccidioidomycosis hospitalized patients classified according to EORTC/MSG 2008 criteria. We collected data about clinical characteristics on admission and outcomes.ResultsFifty-seven patients were evaluated, 26 proven and 31 probable, mean age was 43 years. The proven group was associated with DM2 OR 2.8 (IC95% 1.1–7, P = 0.014) and hemoptysis OR 3.2 (IC95% 1.1–9, P = 0.013), the probable group with dyspnea OR 3.5 (IC 95% 1.08–11, P = 0.024), high respiratory rate 27.2 ± 13 vs. 22 ± 3.3 (P = 0.05), and low O2 saturation 83.97% ± 11.1 vs. 91.8% ± 4.31 (P < 0.001). In the proven group, multiple cavities in CT scan were more frequent. The probable had association with severe ARDS (P 0.011), use of invasive mechanical ventilation (P 0.025), and increase in mortality 14% vs. 1.8% OR 1.2 (IC95% 1.03–1.6 P = 0.025) with lower survival in Kaplan–Meier (P < 0.02). In the proven group, there was more disseminated disease (P <0.001), HIV was associated with lower survival (P <0.001) and they received more days of antifungal treatment 109.5 ± 127 vs. 59.8 ± 93 days. Amphotericin B was the most prescribed in both groups.Conclusion At present, we do not use the EORTC/MSG criteria due to lack of tests in our country, in this study the probable group referred usually from community centers had worse outcome and clinical characteristics, that is why we cannot underestimate this group of patients. We need to have better diagnostic tests in order to identify promptly these patients and avoid a late disease presentation.Disclosures All authors: No reported disclosures.

Alder and the Golden Fleece: high diversity of Frankia and ectomycorrhizal fungi revealed from Alnus glutinosa subsp. barbata roots close to a Tertiary and glacial refugium

BackgroundRecent climatic history has strongly impacted plant populations, but little is known about its effect on microbes. Alders, which host few and specific symbionts, have high genetic diversity in glacial refugia. Here, we tested the prediction that communities of root symbionts survived in refugia with their host populations. We expected to detect endemic symbionts and a higher species richness in refugia as compared to recolonized areas.MethodsWe sampled ectomycorrhizal (EM) root tips and the nitrogen-fixing actinomycete Frankia communities in eight sites colonized by Alnus glutinosa subsp. barbata close to the Caucasus in Georgia. Three sites were located in the Colchis, one major Eurasian climatic refugia for Arcto-Tertiary flora and alders, and five sites were located in the recolonized zone. Endemic symbionts and plant ITS variants were detected by comparing sequences to published data from Europe and another Tertiary refugium, the Hyrcanian forest. Species richness and community structure were compared between sites from refugia and recolonized areas for each symbionts.ResultsFor both symbionts, most MOTUs present in Georgia had been found previously elsewhere in Europe. Three endemic Frankia strains were detected in the Colchis vs two in the recolonized zone, and the five endemic EM fungi were detected only in the recolonized zone. Frankia species richness was higher in the Colchis while the contrary was observed for EM fungi. Moreover, the genetic diversity of one alder specialist Alnicola xanthophylla was particularly high in the recolonized zone. The EM communities occurring in the Colchis and the Hyrcanian forests shared closely related endemic species.DiscussionThe Colchis did not have the highest alpha diversity and more endemic species, suggesting that our hypothesis based on alder biogeography may not apply to alder’s symbionts. Our study in the Caucasus brings new clues to understand symbioses biogeography and their survival in Tertiary and ice-age refugia, and reveals that isolated host populations could be of interest for symbiont diversity conservation.

Coccidioidomycosis A Cause of Sarcoidosis.

BackgroundSarcoidosis is a granulomatous disease of unknown etiology and coccidioidomycosis is a granulomatous fungal infection endemic to the southwestern United States. Clinical observations on patients with sarcoidosis and coccidioidomycosis simultaneously led to the hypothesis that sarcoidosis can be caused by the fungus Coccidioides.MethodsTwo patients with sarcoidosis and coccidioidomycosis were studied, one prospectively (ie, a patient with sarcoidosis was predicted to develop coccidioidomycosis) and the other retrospectively (ie, a patient with coccidioidomycosis develops sarcoidosis). In addition, a literature review found 5 patients with these 2 diseases, and they were analyzed to establish an archived relationship between the 2 entities. In addition, polymerase chain reaction (PCR) testing for Coccidioides deoxyribonucleic acid (DNA) was performed on tissue from 15 Arizona patients diagnosed with sarcoidosis.ResultsPatient 1 was diagnosed with sarcoid in Arizona and followed prospectively. There was no evidence for coccidioidomycosis at diagnosis. This patient was observed for 8 years before he was documented to have disseminated coccidioidomycosis. Patient 2 was retrospectively studied. He was diagnosed with disseminated coccidioidomycosis, but after 3 years, while on antifungal therapy, he developed respiratory failure. A lung biopsy was consistent with sarcoidosis with no evidence of Coccidioides; cultures, histopathology, and serology were all negative. Paradoxically, PCR testing for Coccidioides DNA on tissue taken at the time of the sarcoidosis diagnosis were all negative, including Patient 2 who had proven coccidioidomycosis.ConclusionsThe 2 study patients and 5 case reports from the literature support the hypothesis that Coccidioides can cause sarcoidosis in Arizona. There are similar reports in the literature that Histoplasma can be associated with sarcoidosis. Based on these observations, we propose that sarcoidosis can be caused by endemic fungi in different areas of the United States, coccidioidomycosis in the Southwest and histoplasmosis in the Midwest.

Cellular and Molecular Defects Underlying Invasive Fungal Infections—Revelations from Endemic Mycoses

The global burden of fungal diseases has been increasing, as a result of the expanding number of susceptible individuals including people living with human immunodeficiency virus (HIV), hematopoietic stem cell or organ transplant recipients, patients with malignancies or immunological conditions receiving immunosuppressive treatment, premature neonates, and the elderly. Opportunistic fungal pathogens such as Aspergillus, Candida, Cryptococcus, Rhizopus, and Pneumocystis jiroveci are distributed worldwide and constitute the majority of invasive fungal infections (IFIs). Dimorphic fungi such as Histoplasma capsulatum, Coccidioides spp., Paracoccidioides spp., Blastomyces dermatiditis, Sporothrix schenckii, Talaromyces (Penicillium) marneffei, and Emmonsia spp. are geographically restricted to their respective habitats and cause endemic mycoses. Disseminated histoplasmosis, coccidioidomycosis, and T. marneffei infection are recognized as acquired immunodeficiency syndrome (AIDS)-defining conditions, while the rest also cause high rate of morbidities and mortalities in patients with HIV infection and other immunocompromised conditions. In the past decade, a growing number of monogenic immunodeficiency disorders causing increased susceptibility to fungal infections have been discovered. In particular, defects of the IL-12/IFN-γ pathway and T-helper 17-mediated response are associated with increased susceptibility to endemic mycoses. In this review, we put together the various forms of endemic mycoses on the map and take a journey around the world to examine how cellular and molecular defects of the immune system predispose to invasive endemic fungal infections, including primary immunodeficiencies, individuals with autoantibodies against interferon-γ, and those receiving biologic response modifiers. Though rare, these conditions provide importance insights to host defense mechanisms against endemic fungi, which can only be appreciated in unique climatic and geographical regions.

Antifungal Resistance, Metabolic Routes as Drug Targets, and New Antifungal Agents: An Overview about Endemic Dimorphic Fungi.

Diseases caused by fungi can occur in healthy people, but immunocompromised patients are the major risk group for invasive fungal infections. Cases of fungal resistance and the difficulty of treatment make fungal infections a public health problem. This review explores mechanisms used by fungi to promote fungal resistance, such as the mutation or overexpression of drug targets, efflux and degradation systems, and pleiotropic drug responses. Alternative novel drug targets have been investigated; these include metabolic routes used by fungi during infection, such as trehalose and amino acid metabolism and mitochondrial proteins. An overview of new antifungal agents, including nanostructured antifungals, as well as of repositioning approaches is discussed. Studies focusing on the development of vaccines against antifungal diseases have increased in recent years, as these strategies can be applied in combination with antifungal therapy to prevent posttreatment sequelae. Studies focused on the development of a pan-fungal vaccine and antifungal drugs can improve the treatment of immunocompromised patients and reduce treatment costs.

Disseminated Histoplasmosis in Patients Receiving Tumor Necrosis Factor-α Inhibitors

Abstract Since their introduction in the late 1990s, tumor necrosis factor (TNF)-α inhibitors have proven effective in the treatment of several inflammatory disorders, and their use has become increasingly common. Tumor necrosis factor-α blockade is nonetheless associated with an increase in the risk of infection by intracellular, granuloma-forming pathogens, such as Histoplasma capsulatum. We performed a query of our medical records for all cases of disseminated histoplasmosis in patients receiving TNF-α inhibitors between the years 1999 and 2014 at University Hospitals Case Medical Center in Cleveland, Ohio, an area of moderate histoplasmosis endemicity. A total of 357 cases of disseminated histoplasmosis were identified, 8 (2.2%) of whom were receiving TNF-α inhibitor therapy at the time of diagnosis. Five patients were receiving infliximab, and 3 were receiving adalimumab. All patients had generalized, nonspecific presenting symptoms, and all but one had a complete response to antifungal treatment and the cessation of the inciting TNF-α inhibitor. Five of the patients eventually resumed TNF-α inhibitor therapy a year after their initial diagnosis with disseminated histoplasmosis. The only patient who succumbed to the infection had a delayed diagnosis. The increasing use of TNF-α inhibitors should come with an increased awareness of its association with opportunistic infections including disseminated histoplasmosis and by other endemic fungi. This case series highlights the importance of early diagnosis of such infections to achieve a favorable outcome. Further research will need to focus on determining the best long-term treatment strategies in managing these patients after the resolution of the acute infection.

CD103+ Conventional Dendritic Cells Are Critical for TLR7/9-Dependent Host Defense against Histoplasma capsulatum, an Endemic Fungal Pathogen of Humans.

Innate immune cells shape the host response to microbial pathogens. Here we elucidate critical differences in the molecular response of macrophages vs. dendritic cells (DCs) to Histoplasma capsulatum, an intracellular fungal pathogen of humans. It has long been known that macrophages are permissive for Histoplasma growth and succumb to infection, whereas DCs restrict fungal growth and survive infection. We used murine macrophages and DCs to identify host pathways that influence fungal proliferation and host-cell viability. Transcriptional profiling experiments revealed that DCs produced a strong Type I interferon (IFN-I) response to infection with Histoplasma yeasts. Toll-like receptors 7 and 9 (TLR7/9), which recognize nucleic acids, were required for IFN-I production and restriction of fungal growth in DCs, but mutation of TLR7/9 had no effect on the outcome of macrophage infection. Moreover, TLR7/9 were essential for the ability of infected DCs to elicit production of the critical cytokine IFNγ from primed CD4+ T cells in vitro, indicating the role of this pathway in T cell activation. In a mouse model of infection, TLR7/9 were required for optimal production of IFN-I and IFNγ, host survival, and restriction of cerebral fungal burden. These data demonstrate the critical role of this pathway in eliciting an appropriate adaptive immune response in the host. Finally, although other fungal pathogens have been shown to elicit IFN-I in mouse models, the specific host cell responsible for producing IFN-I has not been elucidated. We found that CD103+ conventional DCs were the major producer of IFN-I in the lungs of wild-type mice infected with Histoplasma. Mice deficient in this DC subtype displayed reduced IFN-I production in vivo. These data reveal a previously unknown role for CD103+ conventional DCs and uncover the pivotal function of these cells in modulating the host immune response to endemic fungi.

Marine fungi isolated from Chilean fjord sediments can degrade oxytetracycline.

Salmon farming is the main economic activity in the fjords area of Southern Chile. This activity requires the use of antibiotics, such as oxytetracycline, for the control and prevention of diseases, which have a negative impact on the environment. We analyzed the abilities of endemic marine fungi to biodegrade oxytetracycline, an antibiotic used extensively in fish farming. We isolated marine fungi strains from sediment samples obtained from an area of fish farming activity. The five isolated strains showed an activity on oxytetracycline and were identified as Trichoderma harzianum, Trichoderma deliquescens, Penicillium crustosum, Rhodotorula mucilaginosa, and Talaromyces atroroseus by a scanning electron microscopy and characterized by molecular techniques. Results showed significant degradation in the concentration of oxytetracycline at the first 2days of treatment for all strains analyzed. At 21days of treatment, the concentration of oxytetracycline was decreased 92% by T. harzianum, 85% by T. deliquescens, 83% by P. crustosum, 73% by R. mucilaginosa, and 72% by T. atroroseus, all of which were significantly higher than the controls. Given these results, we propose that fungal strains isolated from marine sediments may be useful tools for biodegradation of antibiotics, such as oxytetracycline, in the salmon industry.

Filamentous Fungi.

Filamentous mycoses are often associated with significant morbidity and mortality. Prompt diagnosis and aggressive treatment are essential for good clinical outcomes in immunocompromised patients. The host immune response plays an essential role in determining the course of exposure to potential fungal pathogens. Depending on the effectiveness of immune response and the burden of organism exposure, fungi can either be cleared or infection can occur and progress to a potentially fatal invasive disease. Nonspecific cellular immunity (i.e., neutrophils, natural killer [NK] cells, and macrophages) combined with T-cell responses are the main immunologic mechanisms of protection. The most common potential mold pathogens include certain hyaline hyphomycetes, endemic fungi, the Mucorales, and some dematiaceous fungi. Laboratory diagnostics aimed at detecting and differentiating these organisms are crucial to helping clinicians make informed decisions about treatment. The purpose of this chapter is to provide an overview of the medically important fungal pathogens, as well as to discuss the patient characteristics, antifungal-therapy considerations, and laboratory tests used in current clinical practice for the immunocompromised host.

Masking the Pathogen: Evolutionary Strategies of Fungi and Their Bacterial Counterparts.

Pathogens reduce immune recognition of their cell surfaces using a variety of inert structural polysaccharides. For example, capsular polysaccharides play critical roles in microbial survival strategies. Capsules are widely distributed among bacterial species, but relatively rare in eukaryotic microorganisms, where they have evolved considerable complexity in structure and regulation and are exemplified by that of the HIV/AIDS-related fungus Cryptococcus neoformans. Endemic fungi that affect normal hosts such as Histoplasma capsulatum and Blastomyces dermatitidis have also evolved protective polysaccharide coverings in the form of immunologically inert α-(1,3)-glucan polysaccharides to protect their more immunogenic β-(1,3)-glucan-containing cell walls. In this review we provide a comparative update on bacterial and fungal capsular structures and immunogenic properties as well as the polysaccharide masking strategies of endemic fungal pathogens.

Fungal Infections of the Central Nervous System.

This article summarizes current knowledge on the epidemiology, clinical presentations, diagnosis, and management of selected fungal infections of the central nervous system (CNS). Key syndromes, differential diagnoses, and therapeutic interventions according to host immune status and exposure are reviewed. Advancements in imaging of the brain and spinal cord, and molecular DNA and antigen-based laboratory diagnostics afford improved sensitivity for CNS mycoses. Newer therapeutic strategies may improve outcomes if provided early and host immunosuppression is abrogated. Adjunctive corticosteroid use for disabling neuroinflammation and cerebral edema in the setting of microbiological control may be considered. In addition, nonspecific presentations and absence of fevers in patients without human immunodeficiency virus suggest that screening for Cryptococcus meningitis be performed in all patients with subcortical dementias using a simple CSF or serum antigen test. CNS fungal infections comprise a wide spectrum of clinical syndromes, including abscesses, meningitis/meningoencephalitis, focal masses, stroke/vasculitides, immune reconstitution inflammatory syndrome (IRIS), and spinal pathologies such as arachnoiditis. The main etiologies include Aspergillus, Cryptococcus, Candida, Mucorales, dematiaceous molds, and dimorphic endemic fungi, with the route of acquisition being respiratory or traumatic inoculation with subsequent spread hematogenously or contiguously. Proper management focuses on early effective antifungal therapy and surgery for large or compressive mass lesions. While adjunctive recombinant cytokine or growth factor use has been supported in certain hosts with refractory infections, IRIS-like reactions may occur, suggesting alternative approaches such as high-dose pulse corticosteroids followed by taper.

A Review on Emerging Fungal Infections and Their Significance

The incidence of fungal infections is increasing at an alarming rate, presenting an enormous pressure and challenge to healthcare professionals for their diagnosis and treatment. Emerging fungal infections is also cause of significant morbidity and mortality. This emergence is directly related to the growing population of immune-compromised individuals. Patient with condition such as Granulocytopenia, advanced HIV infection, bone marrow and solid organ transplantation, cancer, diabetes mellitus, severe burn and trauma and severe malnutrition are among many others predisposing factor for low immunity. Demographics changes, Microbial adaptation and Technological advances are few factors which promote these emergences. Infection may be caused by various types of fungi such as yeast and mould including hyaline as well as dematiaceous mould. Populations which are not exposed to endemic fungi and are healthy may also are at risk by dimorphic fungi. Increase in surveillance, availability of rapid noninvasive diagnostic test, monitoring of development of resistance to antifungal agents, research on pathogenesis, prevention, and control of fungal infection are few steps we may put together to cope up with these emerging health problems.

65-Year-Old Woman With Intermittent Fevers, Lower Extremity Paresthesia, Weight Loss, and Malaise

65-Year-Old Woman With Intermittent Fevers, Lower Extremity Paresthesia, Weight Loss, and Malaise

Spatial epidemiology of blastomycosis hospitalizations: detecting clusters and identifying environmental risk factors.

Blastomycosis is a disease caused by endemic fungi that ranges from severe pulmonary or disseminated to mild or asymptomatic. Environmental factors associated with it are not well described throughout the endemic area. We used the intramural State Inpatient Database from the Agency for Healthcare Research and Quality and ArcMap GIS to identify geographic high-risk clusters of blastomycosis hospitalizations in 13 states in the US endemic regions (AR, IA, IL, IN, KY, LA, MI, MN, MO, MS, OH, TN, and WI). We then used logistic regression to identify risk factors associated with these high-risk clusters. We describe six clusters of counties in which there was an elevated incidence of blastomycosis hospitalizations. We identified maximum mean annual temperature, percentage of persons aged ≥65 years, and mercury and copper soil content as being associated with high-risk clusters. Specifically, the odds of a county being part of a high-risk cluster was associated with increasing percentage of population over age 65, decreasing maximum temperature, increasing mercury, and decreasing copper soil content. Healthcare providers should be aware of these high-risk areas so that blastomycosis can be included, as appropriate, in a differential diagnosis for patients currently or previously residing in these areas.

Antifungal clinical trials and guidelines: what we know and do not know.

For over the last three decades, extensive testing of antifungal compounds in clinical trials has been essential to the development of treatment guidelines for the most common invasive fungal infections, including cryptococcosis, candidiasis, aspergillosis, and the endemic fungi. These guidelines have greatly helped guide clinicians in the management of these complicated diseases. The data on which most of these guidelines are based are among the most widely recognized and cited clinical trials comparing antimicrobial agents. Unfortunately, there are many unanswered questions with respect to the diagnosis and treatment of these emerging disorders. Regarding treatment, there is a need for more clinically effective and less toxic agents. The current armamentarium of antifungal agents represents important progress over gold standard agents such as amphotericin B, but there is much progress to be made. With respect to diagnostics, mycology has generally lagged behind other disciplines in microbiology, as there are very few rapid, sensitive, specific, and point-of-care diagnostics. The ability to implement therapies for at-risk patients based on positive early diagnostic signals would greatly enhance the ability to intervene with appropriate antifungal therapy in a more targeted and specific manner. This article will review some of the major advances, as well as significant challenges that remain in the management of invasive mycoses.

Diversity Patterns, Ecology and Biological Activities of Fungal Communities Associated with the Endemic Macroalgae Across the Antarctic Peninsula

We surveyed diversity patterns and engaged in bioprospecting for bioactive compounds of fungi associated with the endemic macroalgae, Monostroma hariotii and Pyropia endiviifolia, in Antarctica. A total of 239 fungal isolates were obtained, which were identified to represent 48 taxa and 18 genera using molecular methods. The fungal communities consisted of endemic, indigenous and cold-adapted cosmopolitan taxa, which displayed high diversity and richness, but low dominance indices. The extracts of endemic and cold-adapted fungi displayed biological activities and may represent sources of promising prototype molecules to develop drugs. Our results suggest that macroalgae along the marine Antarctic Peninsula provide additional niches where fungal taxa can survive and coexist with their host in the extreme conditions. We hypothesise that the dynamics of richness and dominance among endemic, indigenous and cold-adapted cosmopolitan fungal taxa might be used to understand and model the influence of climate change on the maritime Antarctic mycota.

Rapid Progression of Pulmonary Blastomycosis in an Untreated Patient of Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is associated with a state of immunosuppression characterized by hypogammaglobulinemia as well as B and T lymphocyte dysfunction. Though opportunistic infections are common in CLL patients, particularly after treatment, reports of infections by endemic dimorphic fungi are very few. Here we report a case of pulmonary blastomycosis in a CLL patient who initially presented with an indolent pulmonary mass lesion. The pulmonary lesions progressed rapidly over a two-week period. The diagnosis was established by transbronchial lung biopsy. He was treated with Amphotericin B lipid complex followed by oral itraconazole and recovered uneventfully. This case illustrates the importance of a timely diagnosis and treatment. The presentation of blastomycosis in immunocompromised patients, diagnosis, and treatment are discussed.

Current status of in vitro and in vivo antifungal activities of posaconazole

Abstract Posaconazole (POS) is a new triazole drug with broad-spectrum in vitro activity against most yeasts and molds such as Candida, Cryptococcus neoformans, Aspergillus, Fusarium and Zygomycetes, as well as certain species of dimorphic fungi and endemic fungi. In immunocompetent or immunocompromised animal models with invasive fungal infections, POS has demonstrated highly effective, broad-spectrum antifungal activities. In vitro and in vivo antifungal activities of POS were superior to those of other azoles against Candida glabrata, Candida krusei, Aspergillus terrus, Fusarium and Zygomycetes. In vivo susceptibility studies have shown promising efficacy of POS against life-threatening fungal infections in animal models with different immune status and infection sites.

Efficacy of Nikkomycin Z for respiratory coccidioidomycosis in naturally infected dogs

Nikkomycin Z (NikZ) is a chitin synthase inhibitor with antifungal efficacy against Coccidioides spp. and other endemic fungi. Dogs suffer a rate and range of natural coccidioidomycosis similar to humans and were considered an excellent model for initially testing NikZ against naturally acquired disease. Twelve dogs with coccidioidal pneumonia that had been present for an average of three months were treated with 250 mg (5-15 kg) or 500 mg (> 15-30 kg) twice daily for 60 days. Nine dogs completed the course of treatment and seven dogs had improvement in disease based on radiographs, clinicopathological parameters, physical examination findings, and subjective assessment by owners; three dogs had resolution or near resolution of disease. Based on this small study, NikZ shows efficacy to treat naturally acquired coccidioidomycosis and merits further development for trials in humans.

Endemic Fungal Infections in Solid Organ Transplantation

Endemic Fungal Infections in Solid Organ Transplantation