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Mycoses Sep 2021The endemic mycoses are a diverse group of environmental fungi that share several characteristics. Pitfalls in the recognition and management of endemic fungal... (Review)
Review
The endemic mycoses are a diverse group of environmental fungi that share several characteristics. Pitfalls in the recognition and management of endemic fungal infections are common. A general understanding of common presenting manifestations and their lingering effects is of paramount importance to the treating physician. We review the unmet needs of recently published guidelines and outline future areas of research.
Topics: Endemic Diseases; Humans; Mycoses
PubMed: 34036653
DOI: 10.1111/myc.13326 -
Journal of Fungi (Basel, Switzerland) Dec 2019Histoplasmosis is an emerging fungal disease, with global distribution. The disseminated form of the disease is a more severe infection, generally associated with AIDS.... (Review)
Review
Histoplasmosis is an emerging fungal disease, with global distribution. The disseminated form of the disease is a more severe infection, generally associated with AIDS. Classic diagnostic methods for histoplasmosis consist of microscopy, culture, and histopathology. More recently, the importance of antigen detection has dominated the literature on histoplasmosis diagnosis, but the relevance of molecular assays has not been as much studied. Here we describe the results of a systematic literature review focusing on studies that mainly compared immunological techniques ( urine antigen detection) with molecular tests for the diagnosis of histoplasmosis. In addition to the review of comparative studies using such diagnostic techniques, the literature on polymerase chain reaction (PCR) tests in patients with disseminated histoplasmosis is also summarized. Two studies reported the comparison between immunological and molecular methods applied simultaneously for the diagnosis of disseminated histoplasmosis. PCR demonstrates a satisfactory performance assisting in the detection of spp. DNA in clinical samples.
PubMed: 31861302
DOI: 10.3390/jof6010001 -
Journal of Fungi (Basel, Switzerland) Jun 2021Human histoplasmosis is a mycosis caused by two distinct varieties of a dimorphic fungus: var. and var. . In Europe, it is usually imported by migrants and... (Review)
Review
Human histoplasmosis is a mycosis caused by two distinct varieties of a dimorphic fungus: var. and var. . In Europe, it is usually imported by migrants and travellers, although there have been some autochthonous cases, especially in Italy; however, most European physicians are unfamiliar with its clinical and pathological picture, particularly among immunocompromised patients without HIV infection. This systematic review of all the cases of histoplasmosis reported in Europe and Israel between 2005 and 2020 identified 728 cases diagnosed in 17 European countries and Israel described in 133 articles. The vast majority were imported (mainly from Central and South America), but there were also seven autochthonous cases (six in Europe and one in Israel). The patients were prevalently males (60.4%), and their ages ranged from 2 to 86 years. The time between leaving an endemic region and the diagnosis of histoplasmosis varied from a few weeks to more than 40 years. Progressive disseminated histoplasmosis was the most frequent clinical picture among people living with HIV infection (89.5%) or a different immunocompromising condition (57.1%), but it was also recorded in 6.2% of immunocompetent patients. Twenty-eight cases were caused by . Immunocompromised patients without HIV infection had the worst outcomes, with a mortality rate of 32%.
PubMed: 34198597
DOI: 10.3390/jof7060481 -
MBio Dec 2021Lipids play a fundamental role in fungal cell biology, being essential cell membrane components and major targets of antifungal drugs. A deeper knowledge of lipid...
Lipids play a fundamental role in fungal cell biology, being essential cell membrane components and major targets of antifungal drugs. A deeper knowledge of lipid metabolism is key for developing new drugs and a better understanding of fungal pathogenesis. Here, we built a comprehensive map of the Histoplasma capsulatum lipid metabolic pathway by incorporating proteomic and lipidomic analyses. We performed genetic complementation and overexpression of H. capsulatum genes in Saccharomyces cerevisiae to validate reactions identified in the map and to determine enzymes responsible for catalyzing orphan reactions. The map led to the identification of both the fatty acid desaturation and the sphingolipid biosynthesis pathways as targets for drug development. We found that the sphingolipid biosynthesis inhibitor myriocin, the fatty acid desaturase inhibitor thiocarlide, and the fatty acid analog 10-thiastearic acid inhibit H. capsulatum growth in nanomolar to low-micromolar concentrations. These compounds also reduced the intracellular infection in an alveolar macrophage cell line. Overall, this lipid metabolic map revealed pathways that can be targeted for drug development. It is estimated that 150 people die per hour due to the insufficient therapeutic treatments to combat fungal infections. A major hurdle to developing antifungal therapies is the scarce knowledge on the fungal metabolic pathways and mechanisms of virulence. In this context, fungal lipid metabolism is an excellent candidate for developing drugs due to its essential roles in cellular scaffolds, energy storage, and signaling transductors. Here, we provide a detailed map of Histoplasma capsulatum lipid metabolism. The map revealed points of this fungus lipid metabolism that can be targeted for developing antifungal drugs.
Topics: Fatty Acids; Fungal Proteins; Histoplasma; Histoplasmosis; Humans; Lipid Metabolism; Lipidomics; Proteomics; Sphingolipids
PubMed: 34809453
DOI: 10.1128/mBio.02972-21 -
Clinical Infectious Diseases : An... Aug 2021Histoplasmosis caused by Histoplasma capsulatum var. duboisii (Hcd) is a rare, but probably underestimated, endemic infection described in intertropical Africa.... (Review)
Review
BACKGROUND
Histoplasmosis caused by Histoplasma capsulatum var. duboisii (Hcd) is a rare, but probably underestimated, endemic infection described in intertropical Africa. Therefore, the epidemiology of the infection remains unclear, and there is no consensus on therapeutic management.
METHODS
Using a comprehensive search on different Internet databases, we collected case reports of Hcd infection published from 1993 to 2019. Epidemiological and clinical charts and therapeutic strategies were analyzed.
RESULTS
We found 94 well-documented cases of Hcd infection, and 30.1% of the patients were under 18 years old. Symptoms occurred in some patients several decades after leaving the endemic area. Cutaneous/subcutaneous lesions, bone infections, and lymphadenopathies, both isolated and combined, were the most frequent presentations. The human immunodeficiency virus (HIV) coinfection rate was at 20.8%, with fever, lymphadenopathies, and an absence of bone infection being the differentiating elements from patients living without HIV. The rate of disseminated forms (60.6% in our review) significantly increased as compared to studies published before 1993, but without correlation with HIV infection. The global mortality rate was at 23.4% by the end of follow-up. The outcome was not correlated with the antifungal drug prescribed, nor with HIV serologic status, but was correlated with the initiation of an antifungal therapy.
CONCLUSIONS
Hcd histoplasmosis is a severe fungal infection for which the precise mode of acquisition remains to be determined. There is a need for affordable and more specific diagnostic tools. Itraconazole and amphotericin B are the best therapeutic alternatives and should be available in all low-income countries of the endemic area.
Topics: Adolescent; Africa; HIV Infections; Histoplasma; Histoplasmosis; Humans; Itraconazole
PubMed: 32887981
DOI: 10.1093/cid/ciaa1304 -
Emerging Infectious Diseases Mar 2022We evaluated disseminated histoplasmosis (DH) in HIV patients over 10 years in southern Brazil. The incidence was 12 cases/1,000 hospitalizations (2010-2019); the...
We evaluated disseminated histoplasmosis (DH) in HIV patients over 10 years in southern Brazil. The incidence was 12 cases/1,000 hospitalizations (2010-2019); the mortality rate was 35%. Tuberculosis frequently obscured the diagnosis of DH. We emphasize the need in our region to suspect and investigate DH using more sensitive methods.
Topics: AIDS-Related Opportunistic Infections; Brazil; HIV Infections; Histoplasma; Histoplasmosis; Humans
PubMed: 35202533
DOI: 10.3201/eid2803.212150 -
MBio Apr 2022Intracellular pathogens residing within macrophage phagosomes are challenged with recognizing the phagosomal environment and appropriately responding to changing host...
Intracellular pathogens residing within macrophage phagosomes are challenged with recognizing the phagosomal environment and appropriately responding to changing host defense strategies imposed in this organelle. One such phagocyte defense is the restriction of available copper as a form of nutritional immunity during the adaptive immune response to fungal pathogens. The intracellular fungal pathogen Histoplasma capsulatum adapts to this decreased copper through upregulation of the Ctr3 copper transporter. In this study, we show that recognizes the characteristic low-copper phagosomal environment of activated macrophages through the copper-dependent transcriptional regulator Mac1. Multiple -acting regulatory sequences in the promoter control upregulation of transcription under low-copper conditions, and the loss of Mac1 function prevents induction of Ctr3 under low-copper conditions. During adaptive immunity, this loss of copper sensing by Mac1 attenuates virulence more severely than loss of Ctr3 alone, indicating that Mac1 controls the expression of additional mechanisms important for pathogenesis. Transcriptional profiling of yeasts identified a small regulon of Mac1-dependent genes, with the most strongly regulated genes encoding proteins linked to copper, iron, and zinc homeostasis and defenses against reactive oxygen (iron-requiring catalase [CatB] and superoxide dismutase [Sod4]). Accordingly, the loss of Mac1 function increased sensitivity to copper and iron restriction and blocked low-copper-induced expression of extracellular catalase activity. Thus, Mac1-mediated sensing of low-copper signals to yeasts their residence within the activated macrophage phagosome, and in response, yeasts produce factors, including non-copper-dependent factors, to combat the enhanced defenses of activated macrophages. Histoplasma capsulatum is a fungal pathogen that survives and grows within host macrophages. For successful infection, must sense and adapt to a dynamic intracellular environment over the course of an infection. We demonstrate that the copper-dependent transcription factor, Mac1, enables sensing of low copper that characterizes the phagosome environment of activated macrophages. Histoplasma recognition of this state leads not only to upregulation of copper acquisition mechanisms but also to other non-copper-related pathogenesis strategies, including scavenging of other metals and detoxification of reactive oxygen produced by host cells. The limited set of genes regulated by Mac1 compared to those of other fungal pathogens suggests a response that has been tailored specifically for 's life inside the phagosome. Thus, low levels of phagosomal copper serve as a signal to , enabling responses to the enhanced antimicrobial defenses resulting from immune activation of macrophages.
Topics: Adaptive Immunity; Catalase; Copper; Histoplasma; Iron; Oxygen; Phagosomes
PubMed: 35404120
DOI: 10.1128/mbio.03773-21 -
Journal of Fungi (Basel, Switzerland) Dec 2019Histoplasmosis is a common but neglected AIDS-defining condition in endemic areas for . At the advanced stage of HIV infection, the broad spectrum of clinical features... (Review)
Review
Histoplasmosis is a common but neglected AIDS-defining condition in endemic areas for . At the advanced stage of HIV infection, the broad spectrum of clinical features may mimic other frequent opportunistic infections such as tuberculosis and makes it difficult for clinicians to diagnose histoplasmosis in a timely manner. Diagnosis of histoplasmosis is difficult and relies on a high index of clinical suspicion along with access to medical mycology facilities with the capacity to implement conventional diagnostic methods (direct examination and culture) in a biosafety level 3 laboratory as well as indirect diagnostic methods (molecular biology, antibody, and antigen detection tools in tissue and body fluids). Time to initiation of effective antifungals has an impact on the patient's prognosis. The initiation of empirical antifungal treatment should be considered in endemic areas for and HIV. Here, we report on 30 years of experience in managing HIV-associated histoplasmosis based on a synthesis of clinical findings in French Guiana with considerations regarding the difficulties in determining its differential diagnosis with other opportunistic infections.
PubMed: 31847076
DOI: 10.3390/jof5040115 -
Journal of Fungi (Basel, Switzerland) Jul 2023Histoplasmosis is caused by and, although endemic in large parts of the world, is often underrecognized in many locations. In addition to underrecognition, inadequate... (Review)
Review
Histoplasmosis is caused by and, although endemic in large parts of the world, is often underrecognized in many locations. In addition to underrecognition, inadequate availability of diagnostic tests is a major contributor to poor outcomes in disseminated disease in people with HIV. For those with advanced HIV and disseminated disease, antibody testing is less useful. Culture and histopathology can be useful in this situation, but each has limitations, including variable sensitivity by site and, in the case of culture, the need for a biosafety level three laboratory and a long period of growth. Antigen testing has proven useful for disseminated histoplasmosis due to the excellent sensitivity of urine. Yet, turnaround is slower than ideal due to use in a limited number of centers. The development of lateral flow assays has the potential to make for true rapid point-of-care assays for histoplasmosis, but in order to meet that promise, the tests must be widely available and affordable.
PubMed: 37623564
DOI: 10.3390/jof9080793 -
Journal of Clinical Microbiology Oct 2022Establishing diagnosis of latent and active histoplasmosis is challenging. Interferon gamma-release assays (IGRAs) may provide evidence of latent and active infection....
Establishing diagnosis of latent and active histoplasmosis is challenging. Interferon gamma-release assays (IGRAs) may provide evidence of latent and active infection. An enzyme-linked immunospot (ELISpot) assay was developed using yeast cell lysate (YCL) antigen prepared from a representative North American Histoplasma capsulatum strain. Assay parameters were optimized by measuring responses in healthy volunteers with and without infection. Assay performance as an aid for diagnosing histoplasmosis was assessed in a prospective cohort of 88 people with suspected or confirmed infection, and 44 healthy controls enrolled in two centers in North America (2013 to 2018). Antigen specificity of IFN-γ release was demonstrated using ELISpot and enzyme-linked immunosorbent assay (ELISA). Antigen-evoked, single-cell mRNA expression by memory T cells was shown using flow cytometry. The area under the receiver operating characteristic curve (AUC) was estimated at 0.89 (95% confidence interval [CI]: 78.5% to 99.9%). At optimal cutoff, sensitivity was 77.2% (95% CI: 54.6% to 92.2%) and specificity was 100% (95% CI: 89.7% to 100%). Sixteen of 44 healthy volunteers (36.4%) from a region of hyperendemicity had positive responses, suggesting detection of previously unrecognized (latent) infection. The ELISpot assay is sensitive and specific as an aid to diagnose H. capsulatum infection and disease, supporting proof of concept and further development.
Topics: Humans; Interferon-gamma Release Tests; Histoplasmosis; Interferon-gamma; Prospective Studies; Enzyme-Linked Immunospot Assay; Antigens, Fungal; Enzyme-Linked Immunosorbent Assay; RNA, Messenger; Sensitivity and Specificity
PubMed: 36190260
DOI: 10.1128/jcm.01128-22