Endemic Fungi Presenting as Community-Acquired Pneumonia: A Review

2020 ◽  
Vol 41 (04) ◽  
pp. 522-537
Author(s):  
Marwan M. Azar ◽  
Joshua Malo ◽  
Chadi A. Hage
Keyword(s):  
Histoplasma Capsulatum ◽  
Fungal Infections ◽  
Treatment Strategies ◽  
Community Acquired Pneumonia ◽  
Land Utilization ◽  
Coccidioides Posadasii ◽  
Dimorphic Fungi ◽  
Pulmonary Histoplasmosis ◽  
Diagnostic Modalities ◽  
Endemic Fungi

AbstractIn endemic areas, dimorphic fungal infections due to Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides posadasii/immitis account for up to 30% of cases of community-acquired pneumonia. Because respiratory manifestations are often indistinguishable from common bacterial causes of pneumonia, the diagnosis of pulmonary histoplasmosis, blastomycosis, and coccidioidomycosis is often delayed and associated with antibiotics overuse. In addition to being highly endemic to certain regions of North America, dimorphic fungi have global significance due to established areas of endemicity in all six inhabited continents, an increasingly interconnected world of travelers and transported goods, and a changing epidemiology as a result of global heating and anthropomorphic land utilization. In this review, we discuss the epidemiology, pathogenesis, clinical presentation, diagnostic modalities, and treatment strategies for histoplasmosis, blastomycosis, and coccidioidomycosis.

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

2013 ◽  
Vol 1 (1) ◽  
pp. 18-22
Author(s):  
He Sun ◽  
Xin Su ◽  
Yi Shi
Keyword(s):  
Animal Models ◽  
Broad Spectrum ◽  
Fungal Infections ◽  
Current Status ◽  
Dimorphic Fungi ◽  
Antifungal Activities ◽  
Endemic Fungi ◽  
Yeasts And Molds

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.

scholarly journals Review of the Novel Investigational Antifungal Olorofim

2020 ◽  
Vol 6 (3) ◽  
pp. 122 ◽  
Author(s):  
Nathan P. Wiederhold
Keyword(s):  
Fungal Infections ◽  
Case Reports ◽  
Fusarium Species ◽  
Pharmacokinetic Profile ◽  
Outcome Data ◽  
Dimorphic Fungi ◽  
Key Enzyme ◽  
Endemic Fungi ◽  
Invasive Mold Infections

The incidence of invasive fungal infections caused by molds and endemic fungi is increasing. There is also concern regarding increased rates of reduced susceptibility or frank resistance among Aspergillus and Coccidioides species, while Scedosporium species, Lomentospora prolificans, and Fusarium species are inherently less susceptible or intrinsically resistant to clinically available antifungals. Olorofim (formerly F901318) is the first member of the orotomide class of antifungals to be evaluated clinically for the treatment of invasive mold infections. This agent inhibits dihydroorotate dehydrogenase, a key enzyme in the biosynthesis of pyrimidines. Olorofim has activity against many molds and thermally dimorphic fungi, including species that are resistant to azoles and amphotericin B, but lacks activity against yeasts and the Mucorales. It is currently being developed for both oral and intravenous administration. Although published clinical outcome data have been limited to case reports to date, the results against invasive and refractory infections are promising. This review describes the mechanism of action of olorofim, its in vitro spectrum of activity, and what is currently known about its pharmacokinetic profile and clinical efficacy.

scholarly journals Endemic and Other Dimorphic Mycoses in The Americas

2021 ◽  
Vol 7 (2) ◽  
pp. 151
Author(s):  
Shawn R. Lockhart ◽  
Mitsuru Toda ◽  
Kaitlin Benedict ◽  
Diego H. Caceres ◽  
Anastasia P. Litvintseva
Keyword(s):  
Histoplasma Capsulatum ◽  
Opportunistic Infections ◽  
Viral Disease ◽  
Dimorphic Fungi ◽  
Caribbean Islands ◽  
Resource Limited ◽  
Taxonomic Changes ◽  
The Caribbean ◽  
Endemic Fungi ◽  
Medical Burden

Endemic fungi are thermally dimorphic fungi that have a limited geographic range and can cause both primary disease and opportunistic infections. The Americas are home to more genera of endemic fungi than anywhere else on earth. These include Coccidioides, Histoplasma, Blastomyces, Paracoccidioides, and Sporothrix. Endemic fungi are found across the Americas and the Caribbean, from Blastomyces gilchristi, which extends into the northeast corners of North America, to Histoplasma capsulatum, which occurs all the way down in the southern regions of South America and into the Caribbean Islands. Symptoms of endemic fungal infection, when present, mimic those of many other diseases and are often diagnosed only after initial treatment for a bacterial or viral disease has failed. Endemic fungi place a significant medical burden on the populations they affect, especially in immunocompromised individuals and in resource-limited settings. This review summarizes the ecology, geographical range, epidemiology, and disease forms of the endemic fungi found in the Americas. An emphasis is placed on new and proposed taxonomic changes, including the assignment of new species names in Histoplasma, Blastomyces, and Paracoccidioides.

Current Concepts in the Epidemiology, Diagnosis, and Management of Histoplasmosis Syndromes

2020 ◽  
Vol 41 (01) ◽  
pp. 013-030 ◽  
Author(s):  
Marwan M. Azar ◽  
James L. Loyd ◽  
Ryan F. Relich ◽  
L. Joseph Wheat ◽  
Chadi A. Hage
Keyword(s):  
Amphotericin B ◽  
Histoplasma Capsulatum ◽  
Clinical Manifestations ◽  
Community Acquired Pneumonia ◽  
Current Evidence ◽  
Ohio River ◽  
Land Utilization ◽  
Diagnosis And Management ◽  
Disseminated Disease ◽  
River Valleys

AbstractHistoplasmosis is a global disease endemic to regions of all six inhabited continents. The areas of highest endemicity lie within the Mississippi and Ohio River Valleys of North America and parts of Central and South America. As a result of climate change and anthropogenic land utilization, the conditions suitable for Histoplasma capsulatum are changing, leading to a corresponding change in epidemiology. The clinical manifestations of histoplasmosis are protean, variably resembling other common conditions such as community-acquired pneumonia, tuberculosis, sarcoidosis, Crohn's disease, or malignancy. Making a successful diagnosis is contingent on a thorough understanding of epidemiology, common clinical presentations, and best testing practices for histoplasmosis. While most subclinical or self-limited diseases do not require treatment in immunocompetent patients, all immunocompromised patients and those with progressive disseminated disease or chronic pulmonary disease should be treated. Liposomal amphotericin B is the preferred agent for severe or disseminated disease, while itraconazole is adequate for milder cases and “step-down” therapy following response to amphotericin B. In this review, we discuss the current evidence-based approaches to the epidemiology, diagnosis, and management of histoplasmosis.

scholarly journals Applications of Invertebrate Animal Models to Dimorphic Fungal Infections

2018 ◽  
Vol 4 (4) ◽  
pp. 118 ◽  
Author(s):  
Junya L. Singulani ◽  
Liliana Scorzoni ◽  
Haroldo C. de Oliveira ◽  
Caroline M. Marcos ◽  
Patricia A. Assato ◽  
...  
Keyword(s):  
Animal Models ◽  
Histoplasma Capsulatum ◽  
Galleria Mellonella ◽  
Ethical Issues ◽  
Fungal Infections ◽  
Low Cost ◽  
Acanthamoeba Castellanii ◽  
Dimorphic Fungi ◽  
Invertebrate Animal ◽  
Different Strains

Dimorphic fungi can be found in the yeast form during infection and as hyphae in the environment and are responsible for a large number of infections worldwide. Invertebrate animals have been shown to be convenient models in the study of fungal infections. These models have the advantages of being low cost, have no ethical issues, and an ease of experimentation, time-efficiency, and the possibility of using a large number of animals per experiment compared to mammalian models. Invertebrate animal models such as Galleria mellonella, Caenorhabditis elegans, and Acanthamoeba castellanii have been used to study dimorphic fungal infections in the context of virulence, innate immune response, and the efficacy and toxicity of antifungal agents. In this review, we first summarize the features of these models. In this aspect, the growth temperature, genome sequence, availability of different strains, and body characteristics should be considered in the model choice. Finally, we discuss the contribution and advances of these models, with respect to dimorphic fungi Paracoccidioides spp., Histoplasma capsulatum, Blastomyces dermatitidis, Sporothrix spp., and Talaromyces marneffei (Penicillium marneffei).

scholarly journals Reintroduction of immunosuppressive medications in pediatric rheumatology patients with histoplasmosis: a case series

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Rachel A. Brown ◽  
Fatima Barbar-Smiley ◽  
Cagri Yildirim-Toruner ◽  
Monica I. Ardura ◽  
Stacy P. Ardoin ◽  
...  
Keyword(s):  
Rheumatic Disease ◽  
Lupus Erythematosus ◽  
Histoplasma Capsulatum ◽  
Case Series ◽  
Organ Damage ◽  
Necrosis Factor Alpha ◽  
Pulmonary Histoplasmosis ◽  
Immunosuppressive Medications ◽  
Biologic Dmard ◽  
Factor Alpha

Abstract Background Children with rheumatic diseases (cRD) receiving immunosuppressive medications (IM) are at a higher risk for acquiring potentially lethal pathogens, including Histoplasma capsulatum (histoplasmosis), a fungal infection that can lead to prolonged hospitalization, organ damage, and death. Withholding IM during serious infections is recommended yet poses risk of rheumatic disease flares. Conversely, reinitiating IM increases risk for infection recurrence. Tumor necrosis factor alpha inhibitor (TNFai) biologic therapy carries the highest risk for histoplasmosis infection after epidemiological exposure, so other IM are preferred during active histoplasmosis infection. There is limited guidance as to when and how IM can be reinitiated in cRD with histoplasmosis. This case series chronicles resumption of IM, including non-TNFai biologics, disease-modifying anti-rheumatic drugs (DMARDs), and corticosteroids, following histoplasmosis among cRD. Case presentation We examine clinical characteristics and outcomes of 9 patients with disseminated or pulmonary histoplasmosis and underlying rheumatic disease [juvenile idiopathic arthritis (JIA), childhood-onset systemic lupus erythematosus (cSLE), and mixed connective tissue disease (MCTD)] after reintroduction of IM. All DMARDs and biologics were halted at histoplasmosis diagnosis, except hydroxychloroquine (HCQ), and patients began antifungals. Following IM discontinuation, all patients required systemic or intra-articular steroids during histoplasmosis treatment, with 4/9 showing Cushingoid features. Four patients began new IM regimens [2 abatacept (ABA), 1 HCQ, and 1 methotrexate (MTX)] while still positive for histoplasmosis, with 3/4 (ABA, MTX, HCQ) later clearing their histoplasmosis and 1 (ABA) showing decreasing antigenemia. Collectively, 8/9 patients initiated or continued DMARDs and/or non-TNFai biologic use (5 ABA, 1 tocilizumab, 1 ustekinumab, 3 MTX, 4 HCQ, 1 leflunomide). No fatalities, exacerbations, or recurrences of histoplasmosis occurred during follow-up (median 33 months). Conclusions In our cohort of cRD, histoplasmosis course following reintroduction of non-TNFai IM was favorable, but additional studies are needed to evaluate optimal IM management during acute histoplasmosis and recovery. In this case series, non-TNFai biologic, DMARD, and steroid treatments did not appear to cause histoplasmosis recurrence. Adverse events from corticosteroid use were common. Further research is needed to implement guidelines for optimal use of non-TNFai (like ABA), DMARDs, and corticosteroids in cRD following histoplasmosis presentation.

scholarly journals Primary immune deficiencies with defects in neutrophil function

Hematology ◽  
2016 ◽  
Vol 2016 (1) ◽  
pp. 43-50 ◽  
Author(s):  
Mary C. Dinauer
Keyword(s):  
Fungal Infections ◽  
Leukocyte Adhesion ◽  
Genetic Disorders ◽  
Clinical Manifestations ◽  
Treatment Strategies ◽  
Adaptor Protein ◽  
Invasive Fungal Disease ◽  
Neutrophil Function ◽  
Microbial Pathogens ◽  
Immune Deficiencies

Abstract Immune deficiencies resulting from inherited defects in neutrophil function have revealed important features of the innate immune response. Although sharing an increased susceptibility to bacterial and fungal infections, these disorders each have distinctive features in their clinical manifestations and characteristic microbial pathogens. This review provides an update on several genetic disorders with impaired neutrophil function, their pathogenesis, and treatment strategies. These include chronic granulomatous disease, which results from inactivating mutations in the superoxide-generating nicotinamide dinucleotide phosphate oxidase. Superoxide-derived oxidants play an important role in the control of certain bacterial and fungal species, and also contribute to the regulation of inflammation. Also briefly summarized are updates on leukocyte adhesion deficiency, including the severe periodontal disease characteristic of this disorder, and a new immune deficiency associated with defects in caspase recruitment domain–containing protein 9, an adaptor protein that regulates signaling in neutrophils and other myeloid cells, leading to invasive fungal disease.

scholarly journals Challenges and opportunities to understanding genetics of fungal diseases: towards a functional genomics approach

2021 ◽  
Author(s):  
Mariolina Bruno ◽  
Vasiliki Matzaraki ◽  
Frank L van de Veerdonk ◽  
Vinod Kumar ◽  
Mihai G. Netea
Keyword(s):  
Infectious Diseases ◽  
Fungal Infections ◽  
Critical Role ◽  
Treatment Strategies ◽  
Risk Groups ◽  
Fungal Diseases ◽  
Human Pathogens ◽  
Challenges And Opportunities ◽  
Patients At Risk ◽  
Immune Related Genes

Infectious diseases are a leading cause of morbidity and mortality worldwide and human pathogens have long been recognized as one of the main sources of evolutionary pressure, resulting in a high variable genetic background in immune-related genes. The study of the genetic contribution to infectious diseases has undergone tremendous advances over the last decades. Here, focusing on genetic predisposition to fungal diseases, we provide an overview of the available approaches for studying human genetic susceptibility to infections, reviewing current methodological and practical limitations. We describe how the classical methods available, such as family-based studies and candidate-gene studies, have contributed to the discovery of crucial susceptibility factors for fungal infections. We will also discuss the contribution of novel unbiased approaches to the field, highlighting their success but also their limitations for the fungal immunology field. Finally, we show how a systems genomics approach can overcome those limitations and can lead to efficient prioritization and identification of genes and pathways with a critical role in susceptibility to fungal diseases. This knowledge will help stratify patients at risk groups and, subsequently, develop early appropriate prophylactic and treatment strategies.

scholarly journals Generation and Activity Evaluation of a Mouse-Human Immunoglobulin G1 Chimeric Antibody to Histoplasma capsulatum HSP60

2021 ◽  
Author(s):  
Ágata Nogueira D'Áurea Moura ◽  
Scott J. Garforth ◽  
Leandro Buffoni Roque da Silva ◽  
Darien Woodley ◽  
Filipe Vieira Barbalho ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Histoplasma Capsulatum ◽  
Physiological Stress ◽  
Human Monoclonal Antibody ◽  
Current Treatment ◽  
Chimeric Antibody ◽  
Human Antibody ◽  
Chimeric Mouse ◽  
Dimorphic Fungi

Heat shock proteins (Hsps) are highly conserved molecules that are constitutively expressed and upregulated in response to physiological stress conditions. These immunogenic chaperones can have essential functions in fungi, particularly in dimorphic pathogens. Histoplasma capsulatum and Paracoccidioides species are dimorphic fungi that are the causative agents of histoplasmosis and paracoccidioidomycosis, respectively, which are systemic mycoses with significant rates of morbidity and mortality. Current treatment consists of long-term antifungal agents, and there is an urgent need for new therapeutic approaches with higher efficacy, lower toxicity, better biodistribution and improved selectivity. We engineered an immunoglobulin G1 (IgG1) isotype chimeric mouse-human monoclonal antibody, titled ch-MAb 4E12, from the parental IgG2a MAb 4E12, a monoclonal antibody to H. capsulatum Hsp60 that is protective in experimental histoplasmosis and paracoccidioidomycosis models elicited by H. capsulatum var. capsulatum and Paracoccidioides lutzii, respectively. The ch-MAb 4E12 increased phagolysosomal fusion and enhanced the yeasts uptake by PMA differentiated human THP1 macrophage cells in vitro. At low concentrations, the chimeric antibody significantly reduced the pulmonary and splenic fungal burden compared to an irrelevant antibody or no treatment. These results are the first to show that a chimeric mouse-human antibody can modify infection caused by dimorphic fungi.

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