Histoplasma Capsulatum Research Articles

Histoplasmosis of the Head and Neck Region Mimicking Malignancy: A Clinic-Pathological Predicament.

Histoplasmosis is a systemic, deep mycotic infection caused by Histoplasma capsulatum. Disseminated histoplasmosis (DH) is synonymous with HIV seropositive immunocompromised individuals; however, isolated histoplasmosis involving the head and neck mucosal sites mimicking malignancy is a clinical predicament. The result, in a superficial biopsy with marked pseudoepitheliomatous hyperplasia (PEH), in a tertiary care cancer center where the number of squamous carcinomas far outnumber the infectious diseases, could be catastrophic. The archives of a tertiary care cancer hospital were searched (2010-2019) for cases of histoplasmosis involving the head and neck mucosal sites in HIV non-reactive patients. Six cases of isolated head and neck histoplasmosis were seen in biopsies from 4 men and 2 women, with an age range of 46-72 years. Three of these patients suffered from chronic illnesses. The most common site involved was the larynx (vocal cords) in three cases, two cases were involving lips, and one involving the tongue. The biopsies were reviewed in-house with a clinical diagnoses of malignancy in all and an outside biopsy diagnosis of "squamous cell carcinoma" in 2 cases. The important histological findings in the biopsy were PEH (3 cases), granulomas (2 cases), lymphoplasmacytic inflammation (all cases). Eosinophils were conspicuous by their absence. Intracellular histoplasma was seen in all cases, albeit to varying density, which was confirmed with GMS stain. A high index of suspicion, meticulous history taking by oncologists, and appropriate distinction of PEH from neoplastic squamous proliferation by pathologists in superficial biopsies and an apropos deeper wedge biopsy are essential to clinch the correct diagnosis.

Histoplasmosis in African children: clinical features, diagnosis and treatment.

Most of the reviews on histoplasmosis documented in literature have been in the adult population. Very few studies highlight the peculiarities associated with histoplasmosis in Africa especially in the pediatric population. This review addresses the above concerns with clinical summaries and diagnosis of some case reports of histoplasmosis in African children. We highlighted 44 case reports of histoplasmosis in African children (1950–2021) distributed across Western Africa (38.6%, n = 17), Eastern Africa (9.1%, n = 4), Southern Africa (9.1%, n = 4), and Central Africa (43.2%, n = 19). No case report was found from Northern Africa. The age range was 1–17 years, with a mean of 9.2. Of the 44 case reports, 8 cases (18.2%, 8/44) were caused by Histoplasma capsulatum var capsulatum, 33 cases (75%, 33/44) were caused by Histoplasma capsulatum var duboisii, and specie identification was not found in 3 cases. Only three (6.8%) cases were HIV positive; 56.8% (25/44) were disseminated histoplasmosis, pulmonary histoplasmosis accounted for just one case (2.3%, 1/44). Extrapulmonary presentation included skin lesions (ulcers, fistulas, nodules, patches, pigmentations, papules, and abscesses), bone lesions, osteoarthritis, and fractures. The commonest sites affected were skin (n = 29, 65.9%), bones (n = 20, 45.5%), and lymph nodes (n = 15, 34.1%). Histopathology was the commonest diagnostic method (n = 33, 75%). Amphotericin B was first-line therapy in 45.5% of the cases (n = 20) followed by ketoconazole (20.5%, n = 9); 27 cases (61.4%) had favorable outcomes, 8 cases (18.2%) had fatal outcomes, while in 9 cases, the outcome was not revealed. This review revealed several cases of histoplasmosis misdiagnosed as other conditions including tuberculosis (n = 3, 6.8%), pneumonia (n = 1, 2.3%), cancers (n = 4, 9.1%), nephritic syndrome (n = 1, 2.3%), leishmaniasis (n = 1, 2.3%), and hyperreactive malarial splenomegaly syndrome (n = 1, 2.3%). In addition, histoplasmosis was not considered in some case reports even when symptoms were suggestive. Diagnosis of histoplasmosis was made at autopsy with postmortem findings suggestive of histoplasmosis (n = 3, 6.8%). This report highlights the need for a paradigm shift on the part of pediatricians in Africa. They need to look beyond clinical conditions considered common in our environment for this age group and evaluate for other diseases including histoplasmosis.

Fever of Unknown Origin and Hypoxemic Respiratory Failure Secondary to Histoplasma Capsulatum Infection in Systemic Sclerosis Related Interstitial Lung Disease: A Case Report

Fever of Unknown Origin and Hypoxemic Respiratory Failure Secondary to Histoplasma Capsulatum Infection in Systemic Sclerosis Related Interstitial Lung Disease: A Case Report

English

Histoplasma capsulatum is a dimorphic fungus usually found in the few regions of West Bengal and Assam, the Gangetic Plains, western parts of India, and sporadically from southern and few northern Indian states.1 Humans are infected by inhalation of microconidia and mycelial fragments of H. capsulatum. 2 It commonly infects immunocompromised patients (HIV/AIDS, transplant patients and patients receiving immunosuppressive agents). In immunocompromised patients, it presents as nonspecific symptoms such as fever of unknown origin, weight loss, oral and aphthous ulcers, lymphadenopathy and hepatosplenomegaly.3 Here, we are reporting a case of disseminated histoplasmosis in an immunocompromised patient.

Primary Central Nervous System Infection by Histoplasma in an Immunocompetent Adult: A Case Report

Histoplasma capsulatum infection is endemic in many regions around the world, including Latin America [1]. However, cerebral presentation occurs in less than 25% of patients with disseminated histoplasmosis and even rarer as a stand-alone presentation. Three forms are described: meningeal, miliary granulomatous and parenchymal with formation of “histoplasmoma” [2]. Due to the rarity of the case and unusual clinical presentation and topography we describe the case below.

Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Histoplasmosis

Abstract Hemophagocytic lymphohistiocytosis is a syndrome of immune dysregulation that can lead to an overwhelming inflammatory state. In this case series, we describe 3 cases in which disseminated Histoplasma capsulatum infection caused hemophagocytic lymphohistiocytosis.

COVID-19 associated with disseminated histoplasmosis in a kidney transplant patient

We report a case of disseminated histoplasmosis and COVID-19 infection in a renal transplant recipient in Argentina. The patient exhibited respiratory symptoms, and a chest computed tomography scan (CT) showed multiple bilateral centrilobular opacities with a tree-in-bud pattern in both lobes. The patient was initially treated as having bacterial community-acquired pneumonia, and then tuberculosis. A month later, histoplasmosis was diagnosed, and Histoplasma capsulatum LAmB clade was isolated from sputum, skin and oral lesions. The patient was hospitalized and treatment was started with intravenous liposomal amphotericin B. During the course of the antifungal therapy the respiratory symptoms worsened, a new chest CT showed a unilateral lesion with a ground glass appearance and SARS-CoV-2 was detected in a new nasopharyngeal sample. In addition, plasma therapy was administered, and the immunosuppressive regimen was adjusted (everolimus was interrupted, mycophenolate mofetil reduced, and meprednisone increased). Finally, the patient's progress was favorable and was discharged after five days on oral itraconazole treatment for histoplasmosis.

Epidemiology of Epizootic Lymphangitis Among Carthorses in Ethiopia.

Epizootic lymphangitis caused by Histoplasma capsulatum variety farciminosum is a debilitating disease incurring considerable economic losses and affecting the welfare of carthorses. Understanding of its epidemiology is important for devising effective prevention and control measures. A cross-sectional study was conducted on 4,162 carthorses in 17 towns in Ethiopia between October 2018 and June 2019. Clinical and microscopic examinations, fungal culturing, and polymerase chain reaction were used to undertake this study. The overall prevalence of epizootic lymphangitis was 16.67% (95% CI: 15.55–17.84) in carthorses. Epizootic lymphangitis was detected in carthorses found in 16 of the 17 towns included in the study. The highest prevalence was recorded at Kombolcha Town (33.33; 95% CI: 27.54–39.52) whereas the lowest was recorded at Debre Birhan Town (0.00; 95% CI: 0.00–1.27). The results of univariable firth logistic regression analysis showed that the difference between the prevalence of Kombolcha and the prevalences of all the other towns except Holota and Shashemene were statistically significant. Statistically significantly lower prevalence was observed in other towns. Classification of the cases into different clinical forms showed that 87.18, 4.33, and 0.58% were cutaneous, ocular, and respiratory forms respectively, while the remaining 7.93% (55/694; 95% CI: 6.03–10.19) were classified as mixed form. In terms of the severity of the disease, 28.67, 60.52, and 0.81% were mild, moderate, and severe cases, respectively. The majority of the lesions (43.95%) were observed in the skin followed by forelimbs (14.55%) and neck region (14.27%). Higher mean annual temperature, lower annual rainfall, and higher humidity of the study towns were statistically significantly associated with an increased risk of epizootic lymphangitis. In conclusion this study revealed widespread occurrence of epizootic lymphangitis in carthorses yet a heterogeneous prevalence between towns. The veterinary and livestock authorities should take this into account while devising disease control.

A Histoplasma capsulatum Lipid Metabolic Map Identifies Antifungal Targets.

ABSTRACTLipids 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.

Immunoproteomic and Immunopeptidomic Analyses of Histoplasma capsulatum Reveal Promiscuous and Conserved Epitopes Among Fungi With Vaccine Potential.

As there are more than 6 million human deaths due to mycoses each year, there is an urgent need to develop fungal vaccines. Moreover, given the similarities among pathogenic fungi, it may be possible to create a multi-fungi vaccine. In this study, we combined immunoproteomic and immunopeptidomic methods, for which we have adapted a technique based on co-immunoprecipitation (Co-IP) that made it possible to map Histoplasma capsulatum epitopes for the first time in a natural context using murine dendritic cells (DCs) and macrophages (Mφ). Although polysaccharide epitopes exist, this research focused on mapping protein epitopes as these are more immunogenic. We used different algorithms to screen proteins and peptides identified by two-dimensional electrophoresis (2-D) and Co-IP. Seventeen proteins were revealed by 2-D gels, and 45 and 24 peptides from distinct proteins were presented by DCs and Mφ, respectively. We then determined which epitopes were restricted to MHC-I and II from humans and mice and showed high promiscuity, but lacked identity with human proteins. The 4 most promising peptides were synthesized, and the peptides with and without incorporation into glucan particles induced CD4+ and CD8+ T cell proliferation and produced a Th1 and Th17 response marked by the secretion of high levels of IFN-γ, IL-17 and IL-2. These epitopes were from heat shock protein 60, enolase, and the ATP-dependent molecular chaperone HSC82, and they each have a high degree of identity with proteins expressed by other medically important pathogenic fungi. Thus, the epitopes described in this study have the potential for use in the development of vaccines that could result in cross-protection among fungal species.

Answer to December 2021 Photo Quiz.

In the United States, Histoplasma capsulatum causes histoplasmosis east of the Mississippi River, historically in the Mississippi and Ohio River valleys. The mold grown on a fungal culture at the presenting hospital was sent to our reference laboratory for identification. Macroscopic and microscopic morphology strongly suggested Histoplasma capsulatum. The culture morphology was that of a white, cottony mold that grew slowly on an inhibitory mold agar plate, and the microscopic morphology demonstrated hyaline hyphae with microconidia and tuberculate, thick-walled macroconidia (1). Upon observation of the characteristic macroconidia for Histoplasma on the microscopic examination, an H. capsulatum-specific PCR was performed from the culture growth for confirmation of identification but the PCR result was negative. The PCR assay targets a 192-bp region of the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene of H. capsulatum (2). Given that the PCR result did not correlate with the microscopic morphology, Sanger nucleic acid sequencing was also performed utilizing the MicroSeq D2 large-subunit ribosomal DNA (rDNA) sequencing kit. Using NCBI GenBank database BLAST analysis, the sequence from the patient isolate was a perfect match for Histoplasma duboisii, while a Histoplasma capsulatum entry in the Mayo Clinic Fungal Database had a 1-bp mismatch (99.62% match). Since H. duboisii is an unusual isolate in our experience, the culture was sent to a second reference laboratory for confirmation of the identification. Sequencing of the α-tubulin 1 and the ADP-ribosylation factor genes and subsequent phylogenetic analyses gave high support (0.99 Bayesian posterior probabilities/84 to 95% similarity with bootstrap evaluation) to match to H. duboisii, further confirming the identification. The isolate was converted to the yeast form after serial passages at 35°C on brain heart infusion (BHI) agar. Figure 1B of the photo quiz shows the characteristic yeast form of H. duboisii , which is larger than the yeast form of H. capsulatum (2 to 5 μm).

Deletion of the Stress Response Gene DDR48 from Histoplasma capsulatum Increases Sensitivity to Oxidative Stress, Increases Susceptibility to Antifungals, and Decreases Fitness in Macrophages.

The stress response gene DDR48 has been characterized in Saccharomyces cerevisiae and Candida albicans to be involved in combating various cellular stressors, from oxidative agents to antifungal compounds. Surprisingly, the biological function of DDR48 has yet to be identified, though it is likely an important part of the stress response. To gain insight into its function, we characterized DDR48 in the dimorphic fungal pathogen Histoplasma capsulatum. Transcriptional analyses showed preferential expression of DDR48 in the mycelial phase. Induction of DDR48 in Histoplasma yeasts developed after treatment with various cellular stress compounds. We generated a ddr48∆ deletion mutant to further characterize DDR48 function. Loss of DDR48 alters the transcriptional profile of the oxidative stress response and membrane synthesis pathways. Treatment with ROS or antifungal compounds reduced survival of ddr48∆ yeasts compared to controls, consistent with an aberrant cellular stress response. In addition, we infected RAW 264.7 macrophages with DDR48-expressing and ddr48∆ yeasts and observed a 50% decrease in recovery of ddr48∆ yeasts compared to wild-type yeasts. Loss of DDR48 function results in numerous negative effects in Histoplasma yeasts, highlighting its role as a key player in the global sensing and response to cellular stress by fungi.

Presumed Ocular Histoplasmosis Syndrome: An Overview

Presumed ocular histoplasmosis syndrome (POHS) is an inflammatory condition that continues to be cause for debate. Although the evidence is not robust, it is thought to be associated with infection with the fungus Histoplasma capsulatum. Although H. capsulatum is endemic to specific regions within the United States (US), there have been reports of cases in India, United Kingdom and Mexico.

Primary Oral Histoplasmosis in Immunocompetent Host: Case Series with Review of Literature.

Histoplasmosis, a systemic mycosis caused by Histoplasma capsulatum manifests clinically in immunocompromised subjects as acute or chronic pulmonary infection or as a progressive disseminated disease. In oral region it clinically presents as multiple, granular and painful ulcers or verrucous growth. It is rare to find primary oral lesion of histoplasmosis in immunocompetent patient free from systemic disease. In presence of any unusual oral lesion possibility of Histoplasmosis should be considered and prompt diagnosis be attained with exclusion of false negative results as non-specific manifestation of disease may lead to gruesome misdiagnosis of lesion and inadequate treatment. In the present paper two cases of oral histoplasmosis in immunocompetent host have been discussed along with updated review of literature.

Restraint of Fumarate Accrual by HIF-1α Preserves miR-27a-Mediated Limitation of Interleukin 10 during Infection of Macrophages by Histoplasma capsulatum.

ABSTRACTHypoxia-inducible factor 1α (HIF-1α) regulates the immunometabolic phenotype of macrophages, including the orchestration of inflammatory and antimicrobial processes. Macrophages deficient in HIF-1α produce excessive quantities of the anti-inflammatory cytokine interleukin 10 (IL-10) during infection with the intracellular fungal pathogen Histoplasma capsulatum (R. A. Fecher, M. C. Horwath, D. Friedrich, J. Rupp, G. S. Deepe, J Immunol 197:565–579, 2016, https://doi.org/10.4049/jimmunol.1600342). Thus, the macrophage fails to become activated in response to proinflammatory cytokines and remains the intracellular niche of the pathogen. Here, we identify the tricarboxylic acid (TCA) cycle metabolite fumarate as the driver of IL-10 during macrophage infection with H. capsulatum in the absence of HIF-1α. Accumulation of fumarate reduced expression of a HIF-1α-dependent microRNA (miRNA), miR-27a, known to mediate decay of Il10 mRNA. Inhibition of fumarate accrual in vivo limited IL-10 and fungal growth. Our data demonstrate the critical role of HIF-1α in shaping appropriate TCA cycle activity in response to infection and highlight the consequences of a dysregulated immunometabolic response.

Detection of Cytokines and Collectins in Bronchoalveolar Fluid Samples of Patients Infected with Histoplasma capsulatum and Pneumocystis jirovecii.

Histoplasmosis and pneumocystosis co-infections have been reported mainly in immunocompromised humans and in wild animals. The immunological response to each fungal infection has been described primarily using animal models; however, the host response to concomitant infection is unknown. The present work aimed to evaluate the pulmonary immunological response of patients with pneumonia caused either by Histoplasma capsulatum, Pneumocystis jirovecii, or their co-infection. We analyzed the pulmonary collectin and cytokine patterns of 131 bronchoalveolar lavage samples, which included HIV and non-HIV patients infected with H. capsulatum, P. jirovecii, or both fungi, as well as healthy volunteers and HIV patients without the studied fungal infections. Our results showed an increased production of the surfactant protein-A (SP-A) in non-HIV patients with H. capsulatum infection, contrasting with HIV patients (p < 0.05). Significant differences in median values of SP-A, IL-1β, TNF-α, IFN-γ, IL-18, IL-17A, IL-33, IL-13, and CXCL8 were found among all the groups studied, suggesting that these cytokines play a role in the local inflammatory processes of histoplasmosis and pneumocystosis. Interestingly, non-HIV patients with co-infection and pneumocystosis alone showed lower levels of SP-A, IL-1β, TNF-α, IFN-γ, IL-18, IL-17A, and IL-23 than histoplasmosis patients, suggesting an immunomodulatory ability of P. jirovecii over H. capsulatum response.

Genomic Diversity Analysis Reveals a Strong Population Structure in Histoplasma capsulatum LAmA (Histoplasma suramericanum).

Histoplasmosis is a severe mycotic disease affecting thousands of immunocompetent and immunocompromised individuals with high incidence in Latin America, where the disease agents are Histoplasma capsulatum and Histoplasma suramericanum. In this work, we used whole-genome sequencing to infer the species diversity and the population structure of H. suramericanum in South America. We find evidence for strong population structure and little admixture within the species. Genome-level phylogenetic trees indicate the existence of at least three different discrete populations. We recovered the existence of a previously identified population, LAmB, and confirm that it is highly differentiated along the whole genome. We also find that H. suramericanum is composed of two populations, one in Northern South America, and another in the southern portion of the continent. Moreover, one of the lineages from the southern population is endemic to Rio de Janeiro and there was no association with clinical data and species isolated from patients with histoplasmosis. Our results point out the need to characterize the symptomatology of histoplasmosis caused by different species and lineages of Histoplasma spp.

HISTOPLASMOSIS IN NON-HIV IMMUNOCOMPROMISED PATIENT RESIDING IN A NON-ENDEMIC AREA IN BRAZIL

Introduction: Histoplasmosis is a fungal disease, caused by Histoplasma capsulatum. Goal: To report a case of an immunocompromised patient with diagnosis of histoplasmosis in a non-endemic region. Methodology: Case report. Case report: Patient carrier of rheumatoid arthritis, makes continuous use of methotrexate and has reported contact with large amount of bat guano. Result of cervical lymph node culture was positive for H. capsulatum. Discussion: The infection was presented related to drug-induced immunosuppression in a non-endemic area. Conclusion: In view of the location where the infection occurred, the geographic expansion of the disease and the importance of this report for the literature are clear.

Kinase Inhibitor Library Screening Identifies the Cancer Therapeutic Sorafenib and Structurally Similar Compounds as Strong Inhibitors of the Fungal Pathogen Histoplasma capsulatum.

Histoplasma capsulatum is a dimorphic fungal pathogen endemic to the midwestern and southern United States. It causes mycoses ranging from subclinical respiratory infections to severe systemic disease, and is of particular concern for immunocompromised patients in endemic areas. Clinical management of histoplasmosis relies on protracted regimens of antifungal drugs whose effectiveness can be limited by toxicity. In this study, we hypothesize that conserved biochemical signaling pathways in the eukaryotic domain can be leveraged to repurpose kinase inhibitors as antifungal compounds. We conducted a screen of two kinase inhibitor libraries to identify compounds inhibiting the growth of Histoplasma capsulatum in the pathogenic yeast form. Our approach identified seven compounds with an elongated hydrophobic polyaromatic structure, five of which share a molecular motif including a urea unit linking a halogenated benzene ring and a para-substituted polyaromatic group. The top hits include the cancer therapeutic Sorafenib, which inhibits growth of Histoplasma in vitro and in a macrophage infection model with low host cell cytotoxicity. Our results reveal the possibility of repurposing Sorafenib or derivatives thereof as therapy for histoplasmosis, and suggest that repurposing of libraries developed for human cellular targets may be a fruitful source of antifungal discovery.

Pulmonary histoplasmosis: A case report

Histoplasmosis is a systemic fungal infection caused by dimorphic fungus Histoplasma capsulatum. It is widely distributed throughout the world. In present study, the case of a 50-year-old male patient diagnosed as pulmonary histoplasmosis. Initially, the patient was suspected as a case of alcoholic hepatitis but subsequently the diagnosis of pulmonary histoplasmosis was confirmed by lung biopsy. The symptoms were dissuaded following amphotericin B and itraconazole treatment.