Search

Introduction: The present study investigated the impact of immune recovery and the duration of antifungal adherence in the consolidation phase of disseminated histoplasmosis (DH) in acquired immune deficiency syndrome (AIDS) patients living in a hyperendemic area in northeastern Brazil., Material and Methods: Sixty-nine patients with DH/AIDS, admitted to the São José Hospital between 2010 and 2015, who continued histoplasmosis consolidation therapy at the outpatient clinic were studied. The follow-up duration was at least 24 months., Results: Sixty-eight patients used itraconazole 200-400 mg/day or amphotericin B deoxycholate weekly during the consolidation phase, and six patients relapsed during follow-up. The overall median duration of consolidation antifungal use was 250 days [IQR 101 - 372]. Antifungal withdrawal by medical decision occurred in 41 patients (70.7 %) after a median of 293 days [IQR 128 - 372] of use; 16 patients discontinued by their own decision, with a median of 106 days [IQR 37 - 244] of therapy; three patients had no information available, and nine continued on AF therapy. The median CD4+ T-cell count in the group without relapse was 248 cells/µL [IQR 115-355] within 6 months after admission; conversely, in the relapse group, the median cell count remained below 100 cells/µL. Irregular adherence to highly active antiretroviral therapy (HAART) was the leading risk factor associated with relapse and death (p< 0.01)., Discussion: The regular use of HAART, combined with immune recovery, proved to be highly effective in preventing relapses in DH/AIDS patients, suggesting that long-term antifungal therapy may not be necessary., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 SFMM. Published by Elsevier Masson SAS. All rights reserved.)

The clearance of the pathogenic fungus, Histoplasma capsulatum, requires cooperation between innate and adaptive immunity. Since this organism is inhaled, lung macrophages and dendritic cells (DCs) are the first lines of defense. Moreover, DCs act as APCs to drive the education of type 1 Th cells to produce IFNγ, which contributes to the final elimination of H. capsulatum. In this study, we explored the importance of Notch signaling in host defenses using a mouse model of pulmonary histoplasmosis. We found up-regulation of Notch ligands (NLs) and Notch receptors (NRs) on phagocytes and IFNγ + CD4 + T cells upon infection in lungs and lymph nodes. To ascertain the influence of Notch on the course of infection, we used a gamma-secretase inhibitor (GSI), LY-411,575, which inhibits NR downstream signaling. This compound impaired fungal clearance when given at the time of infection or 7 days after infection. However, GSI did not impact fungal clearance in mice with preexisting immunity. The dampened host defenses were associated with reduced differentiation and maturation of monocyte-derived DCs and elevatmonocyte-derived macrophage and alveolar macrophage polarization to M2. Our study reveals the critical nature of Notch signaling in maintaining control of this infectious agent., (© 2022 The Authors. Journal of Leukocyte Biology published by Wiley Periodicals LLC on behalf of Society for Leukocyte Biology.)

Histoplasma antigen detection in urine is a rapid diagnostic method for disseminated histoplasmosis, although cross-reactivity has been reported in specimens from patients with other thermally dimorphic fungal infections. We tested urine specimens, from persons with suspected invasive fungal infections, using a commercial monoclonal antibody Histoplasma enzyme immunoassay (EIA) at a South African national mycology reference laboratory from August 2014 through December 2018. Corresponding fungal culture and histopathology results were obtained from an electronic laboratory information system. In some cases, cultured fungal isolates were sent with the urine specimen for species-level identification by phenotypic and molecular methods. Cross-reactivity was confirmed using culture filtrates of several fungal pathogens. Of 212 referred cases, 41 (19%) were excluded since they had no recorded clinical history (n = 1), alternative diagnoses were confirmed (n = 2), or no fungal culture or histopathology results (n = 38). Eighty-seven of 212 (41%) had laboratory evidence of an invasive fungal disease, while 84 (40%) did not. Of the 87 cases, 37 (43%) were culture-confirmed mycoses: emergomycosis (n = 18), histoplasmosis (n = 8), sporotrichosis (n = 6), cryptococcosis (n = 2), talaromycosis (n = 1), and other fungi isolated (n = 2). The sensitivity and specificity of the EIA were calculated for two groups: culture-confirmed (n = 37) and histology-confirmed invasive fungal disease (n = 50). The sensitivity and specificity of the EIA for diagnosis of histoplasmosis compared to culture were 88% (7/8, 95%CI 47-100%) and 72% (21/29, 95%CI 53-87%), respectively, and for diagnosis of emergomycosis/histoplasmosis compared to histology was 83% (29/35, 95%CI 66-93%) and 93% (14/15, 95%CI 68-100%), respectively. Cross-reactions occurred in urine specimens of patients with Emergomyces africanus infection and in culture filtrates of E. africanus, T. marneffei and Blastomyces species. A commercial Histoplasma EIA had satisfactory accuracy for diagnosis of culture-confirmed histoplasmosis, but cross-reacted in urine specimens from patients with invasive disease caused by the closely-related pathogen, E. africanus and in culture filtrates of E. africanus and other related fungi., Lay Summary: Emergomyces africanus and Histoplasma capsulatum are fungi that cause a multi-system disease among HIV-seropositive persons with a low CD4 cell count. Handling live cultures of these fungi to confirm a diagnosis requires specialized laboratory equipment and infrastructure which is infrequently accessible in low-resource settings. The features of the two diseases (i.e., disseminated histoplasmosis and emergomycosis) may be indistinguishable when infected tissue is prepared, stained, and examined under a microscope. Enzyme immunoassays (EIA) have been developed as rapid diagnostic tools for the detection of a cell wall component of H. capsulatum in urine specimens, although cross-reactions have been reported in specimens from patients with other fungal infections. We evaluated the accuracy of a commercial Histoplasma EIA to diagnose histoplasmosis and to assess cross-reactions in urine specimens from persons with emergomycosis and in cultures of E. africanus and related fungi. We report a sensitivity and specificity of 88% (95%CI 47-100%) and 72% (95%CI 53-87%) for diagnosis of histoplasmosis compared to culture and 83% (95%CI 66-93%) and 93% (95%CI 68-100%) for diagnosis of either histoplasmosis/emergomycosis compared to a diagnosis made by microscopic examination of infected tissue. The assay cross-reacted in urine specimens from patients with emergomycosis and in culture filtrates of related fungi. Although the EIA cross-reacted with other related fungi, this test can decrease the time to diagnosis and facilitate early treatment of emergomycosis and histoplasmosis in South Africa., (© The Author(s) 2020. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Histoplasma capsulatum is the causative agent of histoplasmosis, a systemic disease responsible for most reported causes of morbidity and mortality among immunosuppressed individuals. Peptidogalactomannan (pGM) was purified from the yeast cell wall of H. capsulatum isolated from bats, and its structure and involvement in modulating the host immune response were evaluated. Gas chromatography, methylation analysis, and two-dimensional nuclear magnetic resonance (2D-NMR) were used for the structural characterization of pGM. Methylation and 2D-NMR data revealed that pGM comprises a main chain containing α-D-Manp (1 → 6) residues substituted at O-2 by α-D-Manp (1 → 2)-linked side chains, non-reducing end units of α-D-Galf, or β-D-Galp linked (1→ 6) to α-D-Manp side chains. The involvement of H. capsulatum pGM in antigenic reactivity and in interactions with macrophages was demonstrated by ELISA and phagocytosis assay, respectively. The importance of the carbohydrate and protein moieties of pGM in sera reactivity was evaluated. Periodate oxidation abolished much pGM antigenic reactivity, suggesting that the sugar moiety is the most immunogenic part of pGM. Reactivity slightly decreased in pGM treated with proteinase K, suggesting that the peptide moiety plays a minor role in pGM antigenicity. In vitro experiments suggested that pGM is involved in the phagocytosis of H. capsulatum yeast and induction of IL-10 and IFN-γ secretion by peritoneal macrophages from C57BL/6 mice. These findings demonstrated the role of pGM in the H. capsulatum-host interaction.

Although fibrotic disorders are frequently assumed to be linked to T H2 cells, quantitative tissue interrogation studies have rarely been performed to establish this link and certainly many fibrotic diseases do not fall within the type 2/allergic disease spectrum. We have previously linked two human autoimmune fibrotic diseases, IgG4-related disease and systemic sclerosis, to the clonal expansion and lesional accumulation of CD4 + CTLs. In both these diseases T H2 cell accumulation was found to be sparse. Fibrosing mediastinitis linked to Histoplasma capsulatum infection histologically resembles IgG4-related disease in terms of the inflammatory infiltrate and fibrosis, and it provides an example of a fibrotic disease of infectious origin in which the potentially profibrotic T cells may be induced and reactivated by fungal Ags. We show in this study that, in this human disease, CD4 + CTLs accumulate in the blood, are clonally expanded, infiltrate into disease lesions, and can be reactivated in vitro by H. capsulatum Ags. T H2 cells are relatively sparse at lesional sites. These studies support a general role for CD4 + CTLs in inflammatory fibrosis and suggest that fibrosing mediastinitis is an Ag-driven disease that may provide important mechanistic insights into the pathogenesis of idiopathic fibrotic diseases., (Copyright © 2021 by The American Association of Immunologists, Inc.)

Competing Interests: The authors declare no conflicts of interest.

Neutrophils are leukocytes that are capable of eliminating both intra- and extracellular pathogens by mechanisms such as phagocytosis, degranulation, and release of neutrophil extracellular traps (NETs). Histoplasma capsulatum var. capsulatum (H. capsulatum) is a dimorphic fungus with a global distribution that causes histoplasmosis, a disease that is endemic in different geographic areas and is spreading worldwide. The release of NETs has been described as an important host defense mechanism against different fungi; however, there are no reports demonstrating that this process is implicated in neutrophil response to H. capsulatum infection. Therefore, the aim of this work is to investigate whether isolated human neutrophils release NETs in response to H. capsulatum and the potential mechanisms involved, as well as delineate the NETs antifungal activity. Using both confocal fluorescence and scanning electron microscopy techniques, we determined that NETs are released in vitro in response to H. capsulatum via an oxidative mechanism that is downstream of activation of the Syk and Src kinase pathways and is also dependent on CD18. NETs released in response to H. capsulatum yeasts involve the loss of neutrophil viability and are associated with elastase and citrullinated histones, however also can occur in a PAD4 histone citrullination independent pathway. This NETs also presented fungicidal activity against H. capsulatum yeasts. Our findings may contribute to the understanding of how neutrophils recognize and respond as immune effector cells to H. capsulatum, which may lead to better knowledge of histoplasmosis pathophysiology and treatment., (© 2020 John Wiley & Sons Ltd.)

Histoplasma capsulatum is the agent of histoplasmosis, one of the most frequent mycoses in the world. The infection initiates with fungal spore inhalation, transformation into yeasts in the lungs and establishment of a granulomatous disease, which is characterized by a Th1 response. The production of Th1 signature cytokines, such as IFN-γ, is crucial for yeast clearance from the lungs, and to prevent dissemination. Recently, it was demonstrated that IL-17, a Th17 signature cytokine, is also important for fungal control, particularly in the absence of Th1 response. IL-22 is another cytokine with multiple functions on host response and disease progression. However, little is known about the role of IL-22 during histoplasmosis. In this study, we demonstrated that absence of IL-22 affected the clearance of yeasts from the lungs and increased the spreading to the spleen. In addition, IL-22 deficient mice ( Il22 -/- ) succumbed to infection, which correlated with reductions in the numbers of CD4 + IFN-γ + T cells, reduced IFN-γ levels, and diminished nitric oxide synthase type 2 (NOS2) expression in the lungs. Importantly, treatment with rIFN-γ mitigated the susceptibility of Il22 -/- mice to H. capsulatum infection. These data indicate that IL-22 is crucial for IFN-γ/NO production and resistance to experimental histoplasmosis.

Histoplasmosis is an infection caused by the dimorphic fungus Histoplasma capsulatum. While the lungs are the most common site of infection, disseminated disease affecting multiple organs can occur, particularly in immunocompromised patients. Gastrointestinal histoplasmosis is usually diagnosed in the context of disseminated disease and can present in any part of the digestive system, the ileum being the most frequently affected. We report the case of a 60-year-old female patient who underwent liver transplant for alcoholic liver cirrhosis. The patient had a 10 mm polypoid lesion in the sigmoid colon diagnosed in a screening colonoscopy performed 8 months prior to the transplant, but biopsy was not done for fear of bleeding due to extensive anorectal varices. There were no other lesions in the rest of the colon at that time. Four months after the transplant, the patient was asymptomatic and was submitted to a control colonoscopy, which showed 8 polypoid lesions in different parts of the colon, all of which were biopsied. Histologic results showed extensive infiltration of the colonic mucosa by Histoplasma capsulatum. Imaging and laboratorial screening for other sites of infection was negative, and the patient was treated with itraconazole for 12 months. A marked reduction in the dose of tacrolimus was necessary to maintain therapeutic levels during itraconazole treatment. Asymptomatic isolated colonic histoplasmosis is an uncommon manifestation of infection by Histoplasma capsulatum, with no previous reports in the literature of this condition affecting liver transplant recipients. This manuscript is compliant with the Helsinki Congress and the Istanbul Declaration., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Histoplasma capsulatum is the most common endemic mycosis in the United States and frequently presents as an opportunistic infection in immunocompromised hosts. Though liver involvement is common in disseminated histoplasmosis, primary gastrointestinal histoplasmosis of the liver in absence of lung involvement is rare. Similarly, cholestatic granulomatous hepatitis in liver histoplasmosis is rarely seen., Case Presentation: We present a rare case of primary gastrointestinal histoplasmosis manifesting with acute granulomatous hepatitis and cholestasis in a 48-year-old female with psoriatic arthritis, receiving methotrexate and infliximab. The epidemiology, risk factors, clinical presentation, diagnosis, and treatment of histoplasmosis is discussed. Furthermore, we review the published cases of biopsy-proven disseminated histoplasmosis with cholestatic jaundice to highlight histoplasmosis involvement in the liver., Conclusion: Histoplasmosis should be considered in immunosuppressed patients with fever, chills, abdominal pain and cholestasis with progressive jaundice, particularly in subjects without evidence of biliary obstruction. Future studies are needed to accurately assess the risk of this fungal infection, specifically in patients on immunomodulatory therapy for autoimmune disease.

Background: Pneumonia caused by opportunistic fungi is a serious complication in immunocompromised patients. Hypercalcemia has been described in renal transplantation associated with Pneumocystis jirovecii (PJP) or Histoplasma capsulatum (HCP) pneumonia., Methods: We describe 5 patients who underwent kidney transplant between 2014 and 2019 and developed hypercalcemia before the diagnosis of pulmonary fungal infection: 4 patients with PJP and 1 with HCP. We assessed calcium metabolism and kidney function by total and ionized calcium, phosphorus, intact parathormone (iPTH), 25-OH vitamin D, 1,25(OH)2 vitamin D, and serum creatinine levels., Results: Mean albumin-corrected calcium and ionized calcium were 12.56 mg/dL (range, 10.8-13.8 mg/dL) and 1.57 mmol/L (range, 1.43-1.69 mmol/L). Patients were normocalcemic, at 10.12 mg/dL (range, 9.6-10.5 mg/dL), before diagnosis and resolved hypercalcemia after antifungal treatment, at 8.86 mg/dL (range, 8.0-9.5 mg/dL). All patients had low or normal iPTH values, at 29.1 pg/mL (range, <3-44 pg/mL), with higher PTH levels 3 months before diagnosis and after treatment, at 147.3 pg/mL (range, 28.1-479 pg/mL) and 117.5 pg/mL (range, 18.2-245 pg/mL), respectively. The mean value for 25-OH vitamin D was 30.8 ng/mL (range, 14.6-62.8 ng/mL). This supports a PTH-independent mechanism, and we postulated an extrarenal production of 1,25(OH)2 vitamin D., Conclusion: In kidney transplant patients, hypercalcemia independent of PTH and refractory to treatment should alert for the possibility of opportunistic fungal pneumonia., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Progressive disseminated histoplasmosis (PDH) is an important cause of mortality in persons living with HIV (PLHIV), especially in countries where patients have limited access to antiretroviral therapies and diagnostic testing., Objective: A lateral flow assay (LFA) to detect Histoplasma capsulatum antigen in serum developed by MiraVista ® was evaluated., Methods: We tested 75 serum samples: 24 from PLHIV and culture-proven PDH and 51 from PLHIV with other fungal and bacterial infections as well as people without HIV. LFA devices were read manually (read by eye) and by an automated reader., Results: When the LFA was read manually, sensitivity was 96% and specificity was 90%. When an automated reader was used, sensitivity was 92% and specificity was 94%. The Kappa index comparing manual and automated reader was 0.90. Cross-reactions were observed principally in samples from patients with proven diagnosis of paracoccidioidomycosis., Conclusions: The MiraVista ® Diagnostics Histoplasma antigen LFA had high analytical performance and good agreement between manual and automated reader. This LFA allows Histoplasma antigen testing with minimal laboratory equipment and infrastructure requirements., (© 2019 Blackwell Verlag GmbH.)

Temperature serves as a fundamental signal in biological systems. In some microbial pathogens of humans, mammalian body temperature triggers establishment and maintenance of a developmental program that allows the microbe to survive and thrive in the host. Histoplasma capsulatum is one of a group of fungal pathogens called thermally dimorphic fungi, all of which respond to mammalian body temperature by converting from an environmental mold form that inhabits the soil into a parasitic form that causes disease in the host. It has been known for decades that temperature is a key signal that is sufficient to trigger the switch from the soil to host form (and vice versa) in the laboratory. Recent molecular studies have identified a number of key regulators that are required to specify each of the developmental forms in response to temperature. Here we review the regulatory circuits that govern temperature-dependent dimorphism in Histoplasma., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Histoplasmosis is one of the invasive fungal infections and presents with symptoms mainly in the lungs. Disseminated histoplasmosis (DH) is rare and its lesions in the gastrointestinal tract are even uncommon. The concomitant involvement of the upper and lower gastrointestinal tract has never been described in the immunocompetent individuals., Case Presentation: A 44-year-old immunocompetent Chinese man presented with fever, hepatosplenomegaly, fungal esophagitis and protuberant lesions with central depression and erosion along the mucous membrane of the colon. The patient was diagnosed as disseminated histoplasmosis by gastrointestinal endoscopy., Conclusions: Histoplasmosis should be taken caution in patients with fever and hepatosplenomegaly. Actions should be taken to avoid its disseminated infection associated high mortality.

Background: Data on pediatric histoplasmosis have been limited to those from outbreak and case reports. We sought to evaluate the contemporary clinical manifestations, laboratory findings, and outcomes in children with histoplasmosis living in an area of endemicity., Methods: This study was a single-center retrospective review of proven and probable cases of histoplasmosis in children aged 0 to 18 years between April 2008 and April 2014. Case ascertainment was ensured by us using International Classification of Diseases, Ninth Revision codes cross-referenced with laboratory, microbiology, and histopathology tests that detected Histoplasma capsulatum. Demographics, diagnostics, clinical management, and outcomes were evaluated., Results: Seventy-three children with histoplasmosis (41 males; median age, 13 years [range, 3-18 years]) were diagnosed with proven (n = 17 [23%]) or probable (n = 56 [77%]) histoplasmosis, which manifested as pulmonary (n = 52 [71%]) or disseminated (n = 21 [29%]) disease. Symptoms at presentation were nonspecific; the examination of 21 (29%) patients revealed abnormal physical findings. Detection of H capsulatum by serologic methods occurred in 93% (63 of 68) of the patients tested. Histoplasma antigen in blood or urine was detected in 42% (20 of 48) and 28% (15 of 53) of the patients tested, respectively. The 16 (22%) patients who were immunocompromised had significantly higher rates of disseminated disease (56% vs 21%, respectively; P = .01), antigenuria (62% vs 18%, respectively; P = .004), and antigenemia (69% vs 31%, respectively; P = .02) and longer durations of antigenuria (403 vs 120 days, respectively; P = .003) and antigenemia (451 vs 149 days, respectively; P < .0001) than did the immunocompetent children., Conclusions: Pediatric histoplasmosis manifests most frequently as pulmonary disease. The highest diagnostic yield was achieved when multiple diagnostic modalities were used. Presentation with disseminated disease and evidence of antigenemia, antigenuria, and delayed antigen clearance were more likely to be seen in immunocompromised children., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Urine antigen testing is a rapid sensitive method for detecting active infection with the endemic fungi Histoplasma capsulatum and Blastomyces dermatitidis . Herein, we compared the performance of the MiraVista Diagnostics (MVista) Histoplasma urine antigen assay with the Niche Diagnostics (ND) Histoplasma urine antigen assay for the detection of histoplasmosis and blastomycosis., Methods: Two hundred fifty urine samples from 234 patients previously tested by the MVista Histoplasma urine antigen assay as part of routine care were tested by the ND Histoplasma and Blastomyces urine antigen assays. The electronic medical records of all patients whose samples were tested were retrospectively reviewed to identify patients with a clinical diagnosis of and/or treatment for histoplasmosis or blastomycosis, and the diagnostic workup undertaken to support these diagnoses., Results: The MVista and ND Histoplasma urine antigen assays were highly concordant, showing 99% overall agreement (90.5% positive agreement and 99.6% negative agreement). Three specimens collected after antifungal therapy returned discrepant results, with the MVista assay positive in 2 of these and the ND assay positive in 1; in each case, the antigen concentration was near the lower quantification limit. Both Histoplasma assays were positive in all patients with culture-proven blastomycosis (n = 3)., Conclusions: The MVista and ND Histoplasma urine antigen assays performed similarly in identifying histoplasmosis cases encountered in routine clinical practice, with discrepancies affecting posttreatment specimens. Given the paucity of Blastomyces -positive samples, further studies are needed to better compare the utility of the MVista and ND Histoplasma urine antigen assays in diagnosing blastomycosis., (© 2019 American Association for Clinical Chemistry.)

Introduction: Histoplasmosis can present in a myriad of clinical manifestations, which often makes its diagnosis difficult and occasionally, deceptive., Case Report: We describe a case of a 33 years old gentleman who was clinically diagnosed as acute appendicitis at initial presentation in view of a one-week history of fever, right lower quadrant abdominal pain- and guarding at right iliac fossa. He had thrombocytopenia and lymphopenia on presentation. Mesenteric lymphadenitis and small bowel lesion were found intraoperatively, which was respectively biopsied and resected. Histopathological result confirms disseminated histoplasmosis. Retroviral screen was positive. He was treated with amphotericin B for one week, subsequently switched to oral itraconazole, followed by initiation of highly active antiretroviral therapy (HAART)., Discussion: This case illustrates the various nature of histoplasmosis presentation. A high index of suspicion is needed to clinch the diagnosis and subsequently institute prompt treatment as disseminated disease can be fatal if left untreated in an immunosuppressed host.

Histoplasmosis is the most common endemic mycosis in the Americas. Currently, there is no laboratory test capable to detect subclinical or latent infections by Histoplasma capsulatum (Hc), which might develop as severe infections in immunocompromised individuals. For the first time to our knowledge, we explore the suitability of an interferon gamma release assay (IGRA) to detect latent Hc infection in asymptomatic individuals. A cohort of 126 volunteers was enrolled in the study, 13 of which underwent a Hc infection in the past, and 93 of them showing risk factors for this infection. The remaining 20 participants did not refer any risk factors of Hc infection, but eight of them showed evidences of infection with Mycobacterium tuberculosis. All participants were recruited in Medellin, Colombia, between January 2014 and December 2017. Whole blood samples were cultured with four different Hc crude antigens and phytohemaglutinin as positive control. The interferon (IFN)-γ released by T lymphocytes upon antigen stimulation was quantified by ELISA. A defined cutoff value of 20 pg/ml for the IFN-γ concentration allowed us to distinguish between the group with documented past infections and the group of noninfected individuals with high sensitivity (70-92%) and specificity (85-95%), for the four tested antigens. Positive 82-95% and negative 77-92% predictive values were also very high, comparable to those reported for commercially available IGRAs. The new test constitutes a promising screening method to detect individuals with latent Hc infection, even decades after the primary infection, as evidenced in this study., (© The Author(s) 2018. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

A wide differential diagnosis must be entertained in patients with unusual oral and pharyngeal ulcerations. A mucosal biopsy is essential. We retrospectively reviewed 10 cases from the Infectious Diseases Division at Mayo Clinic Rochester (MN, USA), in which the diagnosis proved to be Histoplasma capsulatum infection. Between 1995 and 2016, 10 patients were diagnosed with oropharyngeal histoplasmosis. Common presenting symptoms included weight loss, weakness and oropharyngeal pain with ulcerations. Despite specialty evaluation at other facilities, diagnostic delay occurred in six patients due to lack of biopsy or fungal staining. Yeast forms consistent with H. capsulatum were identified in the biopsy specimens of all our patients. Treatment included intravenous amphotericin B and prolonged courses of azoles. Oral histoplasmosis occurred in both immunocompetent and immunosuppressed patients, and was a manifestation of disseminated infection. Severe pain involving all areas of the mouth was typical. Diagnostic delay may be avoided by early biopsy using fungal stains., (© 2019 British Association of Dermatologists.)

The fungal pathogen Histoplasma capsulatum causes a spectrum of disease, ranging from local pulmonary infection to disseminated disease. The organism seeks residence in macrophages, which are permissive for its survival. Hypoxia-inducible factor 1α (HIF-1α), a principal regulator of innate immunity to pathogens, is necessary for macrophage-mediated immunity to H. capsulatum in mice. In the present study, we analyzed the effect of HIF-1α in human macrophages infected with this fungus. HIF-1α stabilization was detected in peripheral blood monocyte-derived macrophages at 2 to 24 h after infection with viable yeast cells. Further, host mitochondrial respiration and glycolysis were enhanced. In contrast, heat-killed yeasts induced early, but not later, stabilization of HIF-1α. Since the absence of HIF-1α is detrimental to host control of infection, we asked if large amounts of HIF-1α protein, exceeding those induced by H. capsulatum , altered macrophage responses to this pathogen. Exposure of infected macrophages to an HIF-1α stabilizer significantly reduced recovery of H. capsulatum from macrophages and produced a decrement in mitochondrial respiration and glycolysis compared to those of controls. We observed recruitment of the autophagy-related protein LC3-II to the phagosome, whereas enhancing HIF-1α reduced phagosomal decoration. This finding suggested that H. capsulatum exploited an autophagic process to survive. In support of this assertion, inhibition of autophagy activated macrophages to limit intracellular growth of H. capsulatum Thus, enhancement of HIF-1α creates a hostile environment for yeast cells in human macrophages by interrupting the ability of the pathogen to provoke host cell autophagy., (Copyright © 2019 Friedrich et al.)

The dimorphic fungal pathogen Histoplasma capsulatum takes advantage of the innate immune system, utilizing host macrophages as a proliferative niche while largely avoiding stimulation of signaling host receptors. As a result, innate immune cells are unable to control H. capsulatum on their own. Not all host phagocytes respond to H. capsulatum in the same way, with neutrophils and dendritic cells playing important roles in impeding fungal growth and initiating a protective T H 1 response, respectively. Dendritic cells prime T-cell differentiation after internalization of yeasts via VLA-5 receptors and subsequent degradation of the yeasts. Dendritic cell-expressed TLR7 and TLR9 promote a type I interferon response for T H 1 polarization. In contrast to dendritic cells, macrophages provide a hospitable intracellular environment. H. capsulatum yeasts enter macrophages via binding to phagocytic receptors. Simultaneously, α-glucan masks immunostimulatory cell wall β-glucans and a secreted endoglucanase removes exposed β-glucans to minimize recognition of yeasts by Dectin-1. This review highlights how phagocytes interact with H. capsulatum yeasts and the mechanisms H. capsulatum uses to limit the innate immune response., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Granulomas caused by infectious lung diseases present as indeterminate pulmonary nodules (IPNs) on radiography. Newly available serum enzyme immunoassay (EIA) for histoplasmosis has not been studied for the evaluation of IPNs. We investigated serum biomarkers of histoplasmosis antibodies as an indication of benign disease in IPNs from a highly endemic region., Methods: A total of 152 serum samples from patients presenting with pulmonary nodules ≤30 mm in maximum diameter were analyzed for histoplasmosis antibodies by immunodiffusion and EIA IgG and IgM tests. Serology and FDG-PET/CT scan diagnostic test characteristics were estimated and compared., Results: Cancer prevalence was 55% ( n = 83). Thirty-nine (26%) individuals were positive for IgG histoplasmosis antibodies. Twelve samples were IgM antibody positive. Immunodiffusion serology was similar to IgM antibody results with 13 positive tests. Diagnostic likelihood ratios for benign disease were 0.62, 0.33, and 0.28 for FDG-PET/CT, IgG, and IgM antibodies, respectively. When both IgG and IgM were positive ( n = 8), no nodules were cancerous and six were FDG-PET/CT avid., Conclusions: A positive EIA test for both IgM and IgG strongly suggested histoplasmosis etiology and benign granuloma for 12% of benign nodules arising from a highly endemic region. Presence of either IgG or IgM histoplasma antibodies was associated with benign disease. The EIA test was more sensitive in assessing histoplasma exposure than immunodiffusion serology., Impact: A new CLIA-certified histoplasmosis antibody EIA test measures histoplasmosis exposure, offers a possible alternative clinical diagnosis for benign IPNs, and may improve IPN evaluation while avoiding harmful invasive biopsies., (©2018 American Association for Cancer Research.)

Histoplasmosis, caused by the dimorphic environmental fungus Histoplasma capsulatum, is a major mycosis on the global stage. Acquisition of the fungus by mammalian hosts can be clinically silent or it can lead to life-threatening systemic disease, which can occur in immunologically intact or deficient hosts, albeit severe disease is more likely in the setting of compromised cellular immunity. H. capsulatum yeast cells are highly adapted to the mammalian host as they can effectively survive within intracellular niches in select phagocytic cells. Understanding the biological response by both the host and H. capsulatum will facilitate improved approaches to prevent and/or modify disease. This review presents our current understanding of the major pathogenic mechanisms involved in histoplasmosis.

Background: Histoplasmosis is a fungal infection highly endemic in the American continent. The disease can be severe in immunocompromised subjects. In immunocompetent subjects the clinical manifestations are variable. Aim of this work was to review the cases of acute histoplasmosis in immunocompetent travelers reported in literature., Methods: A systematic review of literature was conducted. Electronic search was performed in Pubmed and LILACS. Two reviewers independently extracted data on demographic, clinical and radiological features, and treatment. Cases were classified according to Wheat's definitions., Results: Seventy-one studies were included in the analysis, comprising a total of 814 patients. Twenty-one patients diagnosed at the Centre of Tropical Diseases, Negrar (VR), Italy were also included. The most common travel destination was Central America (168 people, 29.8%); the most common way of exposure to histoplasma was the exploration of caves and/or contact with bat guano (349 people, 60.9%). The multivariate logistic regression model showed association between the development of disseminated histoplasmosis (DH) and activities that involved the exploration of caves and/or the contact with bats' guano (adjusted OR: 34.20 95% CI: 5.29 to 220.93) or other outdoor activities (adjusted OR: 4.61 95% CI: 1.09 to 19.56). No significant difference in the attack rate between countries of destination was observed (p-value: 0.8906, Kruskal-Wallis test)., Conclusions: Histoplasmosis often causes no or mild symptoms in immunocompetent individuals, although a severe syndrome may occur. The infection can mimic other diseases, and the epidemiological risk of exposure is an important clue to raise the index of suspicion.

LC3-associated phagocytosis (LAP) is an emerging non-canonical autophagy process that bridges signaling from pattern-recognition receptors (PRRs) to autophagic machinery. LAP formation results in incorporation of lipidated LC3 into phagosomal membrane (termed LAPosome). Increasing evidence reveals that LAP functions as an innate defense mechanism against fungal pathogens. However, the molecular mechanism involved and the consequence of LAP in regulating anti-fungal immune response remain largely unexplored. Here we show that Histoplasma capsulatum is taken into LAPosome upon phagocytosis by macrophages. Interaction of H. capsulatum with Dectin-1 activates Syk and triggers subsequent NADPH oxidase-mediated reactive oxygen species (ROS) response that is involved in LAP induction. Inhibiting LAP induction by silencing LC3α/β or treatment with ROS inhibitor impairs the activation of MAPKs-AP-1 pathway, thereby reduces macrophage proinflammatory cytokine response to H. capsulatum . Additionally, we unravel the importance of NLRX1 in fungus-induced LAP. NLRX1 facilitates LAP by interacting with TUFM which associates with autophagic proteins ATG5-ATG12 for LAPosome formation. Macrophages from Nlrx1 -/- mice or TUFM-silenced cells exhibit reduced LAP induction and LAP-mediated MAPKs-AP-1 activation for cytokine response to H. capsulatum . Furthermore, inhibiting ROS production in Nlrx1 -/- macrophages almost completely abolishes H. capsulatum -induced LC3 conversion, indicating that both Dectin-1/Syk/ROS-dependent pathway and NLRX1-TUFM complex-dependent pathway collaboratively contribute to LAP induction. Our findings reveal new pathways underlying LAP induction by H. capsulatum for macrophage cytokine response.

Allergens such as house dust mites (HDM) and papain induce strong Th2 responses, including elevated IL-4, IL-5, and IL-13 and marked eosinophilia in the airways. Histoplasma capsulatum is a dimorphic fungal pathogen that induces a strong Th1 response marked by IFN-γ and TNF-α production, leading to rapid clearance in nonimmunocompromised hosts. Th1 responses are generally dominant and overwhelm the Th2 response when stimuli for both are present, although there are instances when Th2 stimuli downregulate a Th1 response. We determined if the Th2 response to allergens prevents the host from mounting a Th1 response to H. capsulatum in vivo. C57BL/6 mice exposed to HDM or papain and infected with H. capsulatum exhibited a dominant Th2 response early, characterized by enhanced eosinophilia and elevated Th2 cytokines in lungs. These mice manifested exacerbated fungal burdens, suggesting that animals skewed toward a Th2 response by an allergen are less able to clear the H. capsulatum infection despite an intact Th1 response. In contrast, secondary infection is not exacerbated by allergen exposure, indicating that the memory response may suppress the Th2 response to HDM and quickly clear the infection. In conclusion, an in vivo skewing toward Th2 by allergens exacerbates fungal infection, even though there is a concurrent and unimpaired Th1 response to H. capsulatum., (Copyright © 2018 by The American Association of Immunologists, Inc.)

Histoplasmosis of the head and neck is rarely seen in immunocompetent patients. We report 2 new cases of histoplasmosis of the head and neck in immunocompetent patients, one an 80-year-old man and the other a 57-year-old man. The older man presented with oral cavity histoplasmosis; his symptoms included pain, dysphagia, and ulcerative lesions. The younger man had laryngeal histoplasmosis, which resulted in hoarseness and dyspnea. We discuss the methods of diagnosis and the classic findings in histoplasmosis, including the microscopic appearance of caseating granulomas, the results of periodic acid-Schiff staining and Gomori staining, and antibody detection of histoplasmosis. We also review the treatment options with antifungals, including amphotericin B and the oral conazole drugs. With an accurate diagnosis and proper treatment, both of our patients recovered well and their symptoms resolved. Because their symptoms overlapped with those of other, more common disease processes, an accurate diagnosis of these patients was essential to treating their infection.

Infection with the dimorphic fungus, Histoplasma capsulatum, occurs world-wide, but North and South America are regions of high endemicity. Interventions to mitigate exposure and consequent disease are limited to remediating a habitat harboring the fungus. The development of a vaccine to prevent infection or lessen its severity is an important advance in disease prevention. Accordingly, we prepared an alkaline extract from the yeast phase of Histoplasma and encased it in glucan particles that act as an adjuvant and delivery vehicle. Immunization of C57BL/6 mice with this encapsulated extract decreased the number of CFUs in lungs and spleens at days 7 and 14 following intranasal infection. Moreover, this vaccine conferred protection against a lethal challenge with the fungus. Cytokine assessment in lungs at a time when the CFUs were similar between controls and vaccinated groups revealed increased quantities of interferon-γ and interleukin-17 in vaccine recipients. This finding was supported by increased generation of both Th1 and Th17 cells in lungs and draining lymph nodes of vaccinated mice compared to controls. Neutralization of interferon-γ or interleukin-17 blunted the effectiveness of vaccination. To identify the proteins comprising this extract, liquid chromatography tandem mass spectrometry was performed. Thus, an H. capsulatum alkaline extract packaged in glucan particles confers protection in an interferon-γ and interleukin-17-dependent manner. Discovery of a single protein or a few proteins in this admixture that mediate protective immunity would represent significant progress in efforts to prevent histoplasmosis., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Diverse pathogenic fungi secrete extracellular vesicles (EV) that contain macromolecules, including virulence factors that can modulate the host immune response. We recently demonstrated that the binding of monoclonal antibodies (mAb) modulates how Histoplasma capsulatum load and releases its extracellular vesicles (EV). In the present paper, we addressed a concentration-dependent impact on the fungus' EV loading and release with different mAb, as well as the pathophysiological role of these EV during the host-pathogen interaction. We found that the mAbs differentially regulate EV content in concentration-dependent and independent manners. Enzymatic assays demonstrated that laccase activity in EV from H. capsulatum opsonized with 6B7 was reduced, but urease activity was not altered. The uptake of H. capsulatum by macrophages pre-treated with EV, presented an antibody concentration-dependent phenotype. The intracellular killing of yeast cells was potently inhibited in macrophages pre-treated with EV from 7B6 (non-protective) mAb-opsonized H. capsulatum and this inhibition was associated with a decrease in the reactive-oxygen species generated by these macrophages. In summary, our findings show that opsonization quantitatively and qualitatively modifies H. capsulatum EV load and secretion leading to distinct effects on the host's immune effector mechanisms, supporting the hypothesis that EV sorting and secretion are dynamic mechanisms for a fine-tuned response by fungal cells.

Tumor necrosis factor (TNF) antagonists are popular therapies for inflammatory diseases. These agents enhance the numbers and function of regulatory T cells (Tregs), which are important in controlling inflammatory diseases. However, elevated Treg levels increase susceptibility to infections, including histoplasmosis. We determined the mechanism by which Tregs expand in TNF-neutralized mice infected with Histoplasma capsulatum Lung CD11c + CD11b + dendritic cells (DCs), but not alveolar macrophages, from H. capsulatum -infected mice treated with anti-TNF induced a higher percentage of Tregs than control DCs in vitro CD11b + CD103 + DCs, understood to be unique to the intestines, were augmented in lungs with anti-TNF treatment. In the absence of this subset, DCs from anti-TNF-treated mice failed to amplify Tregs in vitro CD11b + CD103 + DCs from TNF-neutralized mice displayed higher retinaldehyde dehydrogenase 2 (RALDH2) gene expression, and CD11b + CD103 + RALDH + DCs exhibited greater enzyme activity. To determine if CD11b + CD103 + DCs migrated from gut to lung, fluorescent beads were delivered to the gut via oral gavage, and the lungs were assessed for bead-containing DCs. Anti-TNF induced migration of CD11b + CD103 + DCs from the gut to the lung that enhanced the generation of Tregs in H. capsulatum -infected mice. Therefore, TNF neutralization promotes susceptibility to pulmonary H. capsulatum infection by promoting a gut/lung migration of DCs that enhances Tregs., (Copyright © 2018 American Society for Microbiology.)

Objectives: Disseminated histoplasmosis is an AIDS-defining illness. Histoplasmosis is commonly misdiagnosed as tuberculosis. Nigeria has the second highest number of people living with HIV/AIDS in Africa. The present study was carried out to investigate the prevalence of skin sensitivity amongst Nigerians to histoplasmin., Design: A cross-sectional study was conducted in six centres across five geopolitical zones of Nigeria., Methods: We recruited both healthy non-HIV and HIV-positive adults with CD4 count ≥ 350 cells/mm3 regardless of their ART status from March to May 2017. Skin tests were performed intradermally; induration ≥5 mm were considered to be histoplasmin positive., Results: 750 participants were recruited from Lagos (n = 52), Yola (n = 156), Ilorin (n = 125), Calabar (n = 120), Ibadan (n = 202) and Benin (n = 95). 467 (62.3%) were HIV negative, 247 (32.9%) were HIV positive and 36 (4.8%) did not know their HIV status. A total of 32/735 (4.4%) participants had a positive skin test. Study centre (p<0.001), education (p = 0.002) and age (p = 0.005) appeared to be significantly associated with positive skin reactivity at the 0.5% significance level, while sex (p = 0.031) and occupation (p = 0.031) would have been significant at the 5% significance level. Males had a higher rate of reactivity than females (p = 0.031, 7% vs 3%). The highest positive rates were recorded from Benin City (13/86 (15%)) and Calabar (7/120 (6%)) and no positives were recorded in Lagos (p<0.001). HIV status was not statistically significant (p = 0.70)., Conclusion: Histoplasmosis diagnostics should be included in the Nigerian HIV guidelines. Epidemiological vigilance of progressive disseminated histoplasmosis should be considered by local health authorities.

Histoplasmosis is a systemic mycosis caused by the dimorphous fungus Histoplasma capsulatum (H. capsulatum). The fungus enters the body through the respiratory tract in the form of microconidia, which are transformed into intracellular yeast-like structures in the lungs before disseminating hematogenously. Primary infection is usually asymptomatic and self-resolving. Some patients develop severe disease with acute or chronic respiratory involvement. Immunosuppressed patients, mainly those with altered cellular immunity, may have disseminated disease with variable mucocutaneous involvement characterized by papules, nodules, gummas, or ulcers with a granulomatous base. We report the case of 3 HIV-negative patients infected by H capsulatum in whom diagnosis based on the skin lesions proved essential for early initiation of treatment., (Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Mud runs are an increasingly popular recreational fitness activity across the United States, combining a running race through an obstacle course with submersion in mud. Recent reports estimate 4 million people have participated in these types of events over the last 5 years. We describe an atypical case of myocarditis and multiorgan failure from disseminated histoplasmosis in a previously healthy pediatric patient, likely acquired during participation in a mud run. Although cases of histoplasmosis-associated endocarditis and pericarditis have been reported in the literature, cases of histoplasmosis myocarditis are rare., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Fungal infections are usually seen in elderly or immuno-compromised individuals particularly with human immunodeficiency virus infection. In immuno-competent individuals, they seldom present with overt clinical symptoms. In such cases diagnosis is made by combination of tests along with direct microscopic visualization of the organism. We present a case of immuno-competent individual who presented with unexplained fever and found to have Histoplasma capsulatum infection on bone marrow examination., (© 2017 Wiley Periodicals, Inc.)

Case Presentation: We analysed a 38-year-old woman with disseminated histoplasmosis for primary immunodeficiency. Her blood showed no IFN-γ response while her peripheral blood mononuclear cells (PBMCs) did. We identified IFN-γ autoantibodies of the IgG class in her serum., Conclusion: IFN-γ autoantibodies leading to infections were so far mainly detected in people from Asian descent, where it was found to be associated with certain HLA types. This may be the first patient of African descent, and without the typical HLA types that predispose to this problem, that produces IFN-γ autoantibodies.

Voriconazole is an antifungal agent that is commonly used in immunocompromised patients who develop fungal infections. We report a case of severe recurrent hyperkalemia that developed after starting voriconazole for the treatment of histoplasmosis in a kidney transplant patient who was maintained on tacrolimus-based immunosuppression. Hyperkalemia developed despite reducing the tacrolimus dose to maintain levels in a low therapeutic range. Although interactions between azoles and calcineurin inhibitors are widely recognized, this is the 1st report describing new-onset hyperkalemia following initiation of voriconazole in a kidney transplant patient receiving tacrolimus., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Disseminated cutaneous histoplasmosis (DCH) is one of the manifestations of systemic histoplasmosis infection in HIV-positive patients. Interaction between host immune status and histoplasmosis infection is still poorly understood. It is thought that immune status, represented by CD4 counts, may be correlated with clinical and histopathological findings., Objective: To correlate the CD4 counts with the different clinical and histopathological findings in cutaneous histoplasmosis., Methods: This was a serial case report of seven HAART-treated HIV positive patients with disseminated histoplasmosis observed within the period of January 2004 through December 2014 from the Dermatology and Venereology Department, Cipto Mangunkusumo Hospital, Jakarta, Indonesia. The patients came with different complaints and clinical findings. CD4 counts were recorded prior to lesion biopsy., Results: The CD4 counts were independent from clinical morphology and distribution of lesions. Lower CD4 counts were associated with the presence of intraepidermal yeast-like cells, whereas there is the ability of forming granulomas at higher CD4 counts., Conclusion: CD4 count correlates to histopathological findings of cutaneous histoplasmosis., (© 2017 The International Society of Dermatology.)

Inflammasome is an intracellular protein complex that serves as cytosolic pattern recognition receptor (PRR) to engage with pathogens and to process cytokines of the interleukin-1 (IL-1) family into bioactive molecules. It has been established that interleukin-1β (IL-1β) is important to host defense against Histoplasma capsulatum infection. However, the detailed mechanism of how H. capsulatum induces inflammasome activation leading to IL-1β production has not been studied. Here, we showed in dendritic cells (DCs) that H. capsulatum triggers caspase-1 activation and IL-1β production through NLRP3 inflammasome. By reciprocal blocking of Dectin-1 or Dectin-2 in single receptor-deficient DCs and cells from Clec4n-/-, Clec7a-/-, and Clec7a-/-Clec4n-/- mice, we discovered that while Dectin-2 operates as a primary receptor, Dectin-1 serves as a secondary one for NLRP3 inflammasome. In addition, both receptors trigger Syk-JNK signal pathway to activate signal 1 (pro-IL-1β synthesis) and signal 2 (activation of caspase-1). Results of pulmonary infection with H. capsulatum showed that CD103+ DCs are one of the major producers of IL-1β and Dectin-2 and Dectin-1 double deficiency abolishes their IL-1β response to the fungus. While K+ efflux and cathepsin B (but not ROS) function as signal 2, viable but not heat-killed H. capsulatum triggers profound lysosomal rupture leading to cathepsin B release. Interestingly, cathepsin B release is regulated by ERK/JNK downstream of Dectin-2 and Dectin-1. Our study demonstrates for the first time the unique roles of Dectin-2 and Dectin-1 in triggering Syk-JNK to activate signal 1 and 2 for H. capsulatum-induced NLRP3 inflammasome activation.