RARE DISEASE
Histoplasmosis
Histoplasmosis
Histoplasmosis
Synonyms: Darling disease
Synonyms: Darling disease
Synonyms: Darling disease
Drug discovery
1
drug
With orphan designation
Overview
Histoplasmosis is a fungal infection caused by Histoplasma capsulatum, endemic to the Ohio-Mississippi River Valleys, Central/South America, Africa, and Asia. Transmission occurs via inhalation of spores from soil contaminated with bird/bat droppings. Clinical presentations range from asymptomatic or self-limited pneumonia to severe disseminated disease, particularly in immunocompromised individuals. Diagnosis combines antigen testing, histopathology, and imaging [1][5][6].
Therapies
Categories: rare infectious diseases
Research Papers
1,122 drug discovery papers about Histoplasmosis, with 14 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,122 drug discovery papers about Histoplasmosis, with 14 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-11 | Outcomes After Antifungal Discontinuation in Immunocompromised Patients Treated for Histoplasmosis
Abstract Background Histoplasmosis is an important opportunistic infection. Current guidelines recommend prolonged antifungal therapy, typically 12 months of therapy. However, antifungal therapy is occasionally discontinued earlier in clinical practice due to medication intolerance, drug interactions, or adherence challenges. Data describing outcomes after antifungal discontinuation in immunocompromised patients remain limited. Methods We conducted a retrospective cohort study of immunocompromised adults treated for histoplasmosis within a large healthcare system between 2005 and 2025. Patients who discontinued antifungal therapy and had clinical follow-up were included. Patients were categorized according to treatment duration (<12 months vs ≥12 months). The primary outcome was a composite of histoplasmosis-related adverse events after antifungal discontinuation, including relapse, hospitalization attributed to histoplasmosis, or histoplasmosis-related death. Secondary outcomes included all-cause adverse events. Cox proportional hazards models with inverse probability of treatment weighting (IPTW). Results 106 patient met inclusion criteria and 75% presented with disseminated disease. Histoplasmosis-related adverse events were uncommon. Relapse occurred in 7/106 (6.6%), including 3/28 (11%) treated for <12 months and 4/78 (5.1%) treated for ≥12 months. No deaths were attributed to histoplasmosis. Shorter treatment duration was not associated with a higher hazard of histoplasmosis-related outcomes (HR 2.34, 95% CI 0.52–10.62). Lower antigen burden at diagnosis was associated with reduced risk of adverse outcomes. Conclusions Relapse after antifungal discontinuation was uncommon. Baseline disease burden, reflected by antigen levels and timing of diagnosis, appeared to influence post-treatment outcomes. These findings suggest further investigation is warranted into individualized antifungal treatment duration based on disease severity and fungal burden.
2026-09-01 | Orbital Histoplasmosis (Darling’s disease) in a Young Male from Yangon, Myanmar
"This case report discusses a rare instance of orbital histoplasmosis in a 25-year-old man, a painter who resided at Shwe Pyi Thar township, Yangon, Myanmar, an endemic area for histoplasmosis. The report highlights the clinical presentation, diagnostic imaging, histopathological findings, and treatment approach, contributing to the understanding of this rare manifestation. Histoplasmosis is a systemic fungal infection caused by Histoplasma capsulatum, typically found in endemic regions such as the river valleys of the Americas. The first reported case of orbital histoplasmosis was in the United States in 2016. However, cases have also been reported in parts of Southeast Asia, including Myanmar. Histoplasmosis, primarily a pulmonary disease, occasionally manifests in atypical forms such as orbital involvement, especially in immunocompromised individuals or endemic regions. This report highlights a case with extensive orbital and sinus involvement, emphasizing the diagnostic and therapeutic challenges. Aware
2026-08-31 | Bilateral granulomatous uveitis mimicking tuberculosis: an atypical ocular presentation of biopsy-proven disseminated histoplasmosis.
Ocular histoplasmosis typically presents as presumed ocular histoplasmosis syndrome, characterised by chorioretinal scars and peripapillary atrophy without intraocular inflammation. Active inflammatory presentations are exceedingly rare and may closely mimic tuberculosis in endemic regions, posing significant diagnostic challenges.We report a middle-aged immunocompetent male farmer who presented with acute bilateral visual loss, redness and floaters. Examination revealed bilateral granulomatous anterior uveitis with dense vitritis with mutton-fat keratic precipitates, dense vitritis and 4+ anterior chamber reaction. Systemic evaluation identified a laryngeal mass; histopathological examination confirmed disseminated Histoplasma capsulatum infection. QuantiFERON-TB Gold and HIV serology were negative. Itraconazole was initiated before systemic corticosteroids, with marked clinical improvement and visual recovery from 6/60 to 6/18 bilaterally within 1 week.This case underscores the importance of systemic evaluation, tissue diagnosis and appropriate antifungal cover preceding corticosteroid use in presumed histoplasma-associated granulomatous uveitis in endemic settings.
2026-08-07 | Novel antifungal agents for treating endemic mycoses: hope on the horizon?
Current treatments for endemic mycoses are limited by toxicity, drug-drug interactions, the need for therapeutic drug monitoring, and suboptimal penetration to sequestered sites. At the same time, several new antifungal strategies and agents are nearing clinical availability and may change practice. Current literature highlights limitations of standard therapy for histoplasmosis, coccidioidomycosis, blastomycosis, paracoccidioidomycosis, talaromycosis, sporotrichosis, and emergomycosis, which often rely on amphotericin B-based induction regimens followed by triazole antifungals. Emerging studies are evaluating single high-dose liposomal amphotericin B, shorter treatment durations for histoplasmosis, and flucytosine combined with amphotericin B-based induction for talaromycosis. Novel antifungals such as olorofim, fosmanogepix, and turletricin are especially promising, and treatment strategies guided by patient phenotypes and immune endotypes are also beginning to emerge. Growing evidence suggests therapy for endemic mycoses may change substantially in the near future. New drugs and alternative treatment approaches have the potential to improve safety, tolerability, oral availability, drug-drug interaction profiles, and treatment duration, with important implications for both clinical care and future research.
2026-08-06 | Bilateral adrenal histoplasmosis incidentally detected on 18F-FDG PET/CT in an immunocompetent man with primary adrenal insufficiency: A case report.
Adrenal histoplasmosis is an uncommon manifestation of Histoplasma capsulatum infection and may closely mimic malignancy or granulomatous diseases on imaging. We describe an immunocompetent 51 year old man with 5 months of constitutional symptoms who underwent 18F-FDG PET/CT for evaluation of occult disease. The scan revealed intensely FDG avid bilateral adrenal masses with necrotic components, with no other abnormal sites. Biochemical testing confirmed primary adrenal insufficiency. CT guided adrenal biopsy, targeted to the most FDG-avid viable component, demonstrated necrotizing granulomatous inflammation with intracellular yeast forms consistent with Histoplasma capsulatum. Antifungal therapy with itraconazole plus glucocorticoid replacement led to clinical improvement and interval regression of adrenal lesions on follow-up. This case highlights the value of 18F-FDG PET/CT for detecting unsuspected adrenal histoplasmosis, localizing optimal biopsy targets, and facilitating timely treatment even in immunocompetent patients presenting with nonspecific symptoms.
vaccines
2025-11-17 | Fungal vaccines: so needed, so feasible, and yet so far off.
Invasive fungal infections carry high morbidity and mortality, but there are no fungal vaccines. In this issue of the JCI, Okaa et al. report that endonuclease 2 (Eng2), an antigen shared by the Blastomyces, Histoplasma, and Coccidioides species of fungi, elicits protective immunity in mice against blastomycosis, histoplasmosis, and coccidioidomycosis. These results establish a common antigen that can elicit protection against multiple mycoses, encouraging the development of a pan-fungal vaccine. The road to fungal vaccines is made difficult by the need for effectiveness in immunocompromised individuals, the sporadic nature of fungal disease, and the economics of vaccine development. Despite these hurdles, there is optimism that such vaccines can be developed and perhaps find usefulness as adjuncts to antifungal therapy.
2024-01-22 | Design of a Multi-Epitope Vaccine against Histoplasma capsulatum through Immunoinformatics Approaches.
Histoplasmosis is a widespread systemic disease caused by Histoplasma capsulatum, prevalent in the Americas. Despite its significant morbidity and mortality rates, no vaccines are currently available. Previously, five vaccine targets and specific epitopes for H. capsulatum were identified. Immunoinformatics has emerged as a novel approach for determining the main immunogenic components of antigens through in silico methods. Therefore, we predicted the main helper and cytotoxic T lymphocytes and B-cell epitopes for these targets to create a potential multi-epitope vaccine known as HistoVAC-TSFM. A total of 38 epitopes were found: 23 common to CTL and B-cell responses, 11 linked to HTL and B cells, and 4 previously validated epitopes associated with the B subunit of cholera toxin, a potent adjuvant. In silico evaluations confirmed the stability, non-toxicity, non-allergenicity, and non-homology of these vaccines with the host. Notably, the vaccine exhibited the potential to trigger both innate and adaptive immune responses, likely involving the TLR4 pathway, as supported by 3D modeling and molecular docking. The designed HistoVAC-TSFM appears promising against Histoplasma, with the ability to induce important cytokines, such as IFN-γ, TNF-α, IL17, and IL6. Future studies could be carried out to test the vaccine's efficacy in in vivo models.
2019-03-26 | Immunization Strategies for the Control of Histoplasmosis
Histoplasmosis is an infection caused by the dimorphic fungus Histoplasma capsulatum. Histoplasmosis is typically self-limited and presents asymptomatically in most people. Nevertheless, histoplasmosis can cause severe pulmonary disease and death. Histoplasmosis is increasingly found worldwide; however, it is best documented in the endemic region of the Mississippi river valley system in the Eastern part of the United States (US). Epidemiological studies from the US detailing the morbidity, mortality, and cost associated with histoplasmosis underscore the need to develop a vaccine.This review will detail some of the major developments in potential vaccines against histoplasmosis, with particular emphasis on those that could be used to immunize immunocompromised hosts. Additionally, this review will highlight some non-traditional vaccine-like ideas for the prevention of diverse mycoses.Historically, immunization strategies against histoplasmosis have largely focused on identifying immunogenic proteins that confer protection in animal models. More recently, novel active, therapeutic, and immunomodulatory strategies have been explored as potential alternatives for those with various immune-deficiencies.The studies summarized in this review demonstrate that more research is needed to clarify the immunobiology, clinical role and efficacy of each candidate vaccine in the ever-expanding potential armamentarium against histoplasmosis.
2018-05-01 | Vaccination with an alkaline extract of Histoplasma capsulatum packaged in glucan particles confers protective immunity in mice
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.
2017-09-14 | Heat Shock Proteins in Histoplasma and Paracoccidioides
ABSTRACT Heat shock proteins (Hsps) are highly conserved biomolecules that are constitutively expressed and generally upregulated in response to various stress conditions (biotic and abiotic). Hsps have diverse functions, categorizations, and classifications. Their adaptive expression in fungi indicates their significance in these diverse species, particularly in dimorphic pathogens. Histoplasma capsulatum and Paracoccidioides species are dimorphic fungi that are the causative agents of histoplasmosis and paracoccidioidomycosis, respectively. This minireview focuses on the pathobiology of Hsps, with particular emphasis on their roles in the morphogenesis and virulence of Histoplasma and Paracoccidioides and the potential roles of active and passive immunization against Hsps in protection against infection with these fungi.
antibodies
2026-08-07 | Histoplasmosis in children: emerging insights and evolving guidelines.
This review provides an update on the epidemiology, risk factors, clinical presentation, diagnosis, and management recommendations incorporating recommendations from recent publications including the Infectious Disease Society of America guidelines for the management of pulmonary and disseminated histoplasmosis. Updates to the epidemiology of histoplasmosis indicate a broader geographic range than historically defined. Updated guidelines do not recommend routine treatment for asymptomatic, mild and moderate pulmonary histoplasmosis although itraconazole can be offered for immunocompromised children or for prolonged or worsening symptoms. Liposomal amphotericin B is recommended as initial treatment for severe histoplasmosis syndromes (severe pulmonary and disseminated histoplasmosis). Fibrosing mediastinitis, a late complication of histoplasmosis is treated with stenting of vessels and bronchi. Recent studies demonstrate that rituximab (anti-CD20 monoclonal antibody) may stop progression or lead to regression of progressive fibrosis. Histoplasmosis has manifold manifestations, many of which are self-limited and do not require treatment. Severe histoplasmosis and its complications should be treated with liposomal amphotericin B followed by itraconazole. Clinical trials are needed to assess the efficacy of rituximab for the treatment of fibrosing mediastinitis.
2026-03-25 | Beyond the Usual Suspects: Gastrointestinal Histoplasmosis as a Marker of Undiagnosed Common Variable Immunodeficiency.
A 28-year-old woman presented with chronic diarrhea, weight loss, and recurrent gastrointestinal infections. Intestinal biopsies unexpectedly revealed Histoplasma capsulatum, prompting immunologic evaluation that demonstrated severe hypogammaglobulinemia and reduced B-cell counts, consistent with common variable immunodeficiency. She improved with intravenous immunoglobulin and antifungal therapy. This case highlights gastrointestinal histoplasmosis as a potential early marker of undiagnosed common variable immunodeficiency and underscores the importance of considering primary immunodeficiency in adults with persistent gastrointestinal symptoms.
2024-08-06 | A Retrospective Evaluation of the Treatment Effects of Rituximab in Patients with Progressive and Symptomatic Fibrosing Mediastinitis.
Rationale: Fibrosing mediastinitis (FM) is an uncommon fibroinflammatory condition without established or effective medical therapies. Infiltrating B lymphocytes are commonly present, and progressive fibrosis compromises mediastinal structures, including blood vessels and airways, resulting in significant morbidity and mortality. Objective: To evaluate the benefits and side effects of rituximab in patients with progressive and symptomatic FM. Methods: We treated 22 patients (median age, 35 yr; range, 15-68 yr; 45% female) with metabolically active, progressive FM with rituximab on an off-label basis. Additionally, patients were administered pneumocystis and antifungal prophylaxis when immunosuppressed with rituximab. Modeling of longitudinal treatment response based on changes in relative lesion volume from baseline was performed retrospectively using functional data analysis, and time-to-event modeling was performed to estimate treatment response rates based on a >30% reduction in pretreatment volume. The primary endpoints were lack of disease progression and change in mediastinal lesion volume on computed tomography (evaluated retrospectively). Results: No patient experienced disease progression after rituximab therapy. Median clinical follow-up was 42 months (range, 7-94 mo) and imaging follow-up 21 months (range, 7-62 mo). A total of 82% of patients had confirmed histoplasmosis-associated FM. After rituximab treatment, a 49.6% (95% confidence interval, 17.5-64.4%) mean estimated decrease in pretreatment lesion volume was observed at 24 months. The estimated objective treatment response rate was 47.9% (95% confidence interval, 26.7-70.3%). Conclusions: This observational study suggests that rituximab is a well tolerated and potentially effective therapy in a cohort of patients with symptomatic and progressive FM.
2024-05-27 | Presumed Ocular Histoplasmosis Syndrome with Choroidal Neovascularization: Case Report
Presumed Ocular Histoplasmosis Syndrome (PHOS) is a clinical condition characterized by chronic inflammation of the choroid and retina, often accompanied by the growth of abnormal blood vessels in the macula known as choroidal neovascularization (CNV). While PHOS is typically seen in regions where Histoplasma capsulatum is endemic, there have been reported cases in non-endemic areas. This case report presents the details of a 32-year-old Moroccan patient with PHOS and macular CNV, highlighting the diagnostic, therapeutic, and practical considerations involved in their treatment. The patient, who had no significant medical history, came to us with a six-month history of central vision loss, intermittent metamorphopsia, and central scotomas in the left eye. Despite having no exposure to environmental risk factors or travel to areas where histoplasmosis is prevalent, our clinical examination revealed choroidal and retinal lesions consistent with histospots and active CNV. Further tests such as fluorescein angiography and optical coherence tomography (OCT) confirmed the presence of CNV, revealing a subretinal fibrovascular membrane and serohemorrhagic detachment. Based on these findings, we diagnosed the patient with PHOS and CNV. We proceeded with treatment using intravitreal ranibizumab, a monoclonal antibody that targets vascular endothelial growth factor (VEGF). Monthly injections resulted in the stabilization of the patient's condition, both clinically and anatomically. The CNV regressed, the serohemorrhagic detachment resolved, and there was a significant improvement in the patient's visual acuity. The discussion in this report highlights the fact that while PHOS is typically associated with Histoplasma capsulatum infection, the occurrence of cases in non-endemic areas raises questions about its etiology and diagnosis. In this particular instance, the patient's exposure to the fungus or potential infection by other fungal species complicates the process ..........
2024-01-25 | PULMONARY HISTOPLASMOSIS IN A PATIENT WITH CROHN’S DISEASE ON ANTI-TNF INHIBITOR THERAPY
Abstract INTRODUCTION Infliximab, an anti-tumor necrosis factor (TNF) alpha inhibitor, is a commonly used biologic therapy for patients with inflammatory bowel disease (IBD). However, the increased risk of serious infections, including both new and re-activated infections, is a major concern while patients are on this therapy. Often the presence or development of such serious infections necessitates stopping treatment with anti-TNF inhibitors. We describe a case of a patient who developed Histoplasmosis while on infliximab but was later restarted on the same therapy due to risk of severe Crohn’s disease while maintaining him on ongoing Histoplasmosis treatment. CASE DESCRIPTION We describe the case of a 34-year-old male with a past medical history of Crohn’s disease on infliximab, hypertension, depression, and nephrolithiasis who presented to the hospital with dyspnea on exertion, cough, malaise, and night sweats, and was found to have multifocal pulmonary infiltrates on imaging, concerning for atypical pneumonia. He underwent a bronchoscopy and BAL, with pathology reports showing small oval shaped yeast within necrotic granulomas suspicious for Histoplasmosis. He was taken off infliximab and started on liposomal amphotericin for Histoplasma treatment initially, subsequently transitioned to itraconazole for total of 12 months. He was discharged home but was subsequently re-admitted to the hospital with a Crohn’s flare after being taken off infliximab. He was treated with steroids and started on vedolizumab for more gut-selectivity after a multidisciplinary risk/benefit discussion. However, patient was subsequently re-admitted with diarrhea and hematochezia, due to a Crohn’s disease flare while still on steroid taper and having received 2 doses of vedolizumab. He was transitioned to IV steroids and had a colonoscopy which showed large ulcers and mucosal inflammatory changes with a Simple endoscopic score for Crohn’s disease of 18. After a multidisciplinary discussion, he was restarted on infliximab. He was slowly tapered off steroids as his symptoms improved. Repeat colonoscopy after restarting infliximab showed improved but ongoing mucosal inflammatory changes with a Simple endoscopic score for Crohn’s disease of 7. DISCUSSION While anti-TNF inhibitor biologics are commonly used for patients with IBD, opportunistic and fungal infections remain a significant concern while on immunosuppressing biologic therapies, which necessitates stopping the anti-TNF inhibitor. Previously, a study has shown that it is safe to restart anti-TNF therapy after treatment for Histoplasmosis is completed for a 12-month duration. Our case shows that in patients such as ours with severe Crohn’s disease flares while off infliximab, treatment with anti-TNF inhibitors can be resumed after having a multidisciplinary risk/benefit discussion. Figure 1 Colonoscopy findings showing large ulcers and significant mucosal inflammatory changes after patient started on vedolizumab and admitted for Crohn’s Disease flare. Figure 2 Colonoscopy findings showing ongoing mucosal inflammation but improved from prior after restarting treatment with infliximab.
proteins
2025-10-25 | Expansion of secreted cystine knot proteins reveals virulence factors in the human fungal pathogen Histoplasma.
Identifying fungal secreted factors that influence host infection remains a key challenge in microbial pathogenesis. While secreted effectors, particularly small cysteine-rich proteins, are well characterized in plant fungal pathogens, their counterparts in mammalian pathogens are understudied. We apply criteria from plant fungal effectors to the mammalian fungal pathogen Histoplasma, yielding a set of putative effectors highly enriched for knottins, proteins that adopt a distinctive cystine knot fold. Using an algorithm, we further identify 25 putative knottins in the Histoplasma genome, revealing a significant expansion of knottin genes. Knottin domains are found in diverse molecules but play an unknown role in virulence. Functional studies of individual Histoplasma knottins demonstrate their critical roles in intracellular survival and host cell lysis during macrophage infection as well as virulence in vivo. These findings highlight the importance of knottins in fungal pathogenesis and suggest their broader relevance for discovering conserved mechanisms of host manipulation.
2025-04-01 | Disseminated histoplasmosis induced hemophagocytic lymphohistiocytosis in an immunocompromised patient
• Disseminated histoplasmosis induced HLH is a severe disorder. • Immunotherapy may worsen the underlying infection in secondary HLH. • Evidence for the use of etoposide in adults with HLH is scarce. • This is a first case of the use of anakinra in histoplasmosis induced HLH. • HLH treatment should be tailored to the condition of the patient. The search for the trigger of hemophagocytic lymphohistiocytosis (HLH) and its management can be challenging in immunocompromised patients. In HLH triggered by infection, immunosuppressive therapy is desired to suppress hyperinflammation, but may worsen the underlying infection. To review available literature on the management and prognosis of immunocompromised patients with disseminated histoplasmosis induced HLH. We describe a case and review all previously reported cases of disseminated histoplasmosis induced HLH on PubMed until June 2023. The literature review yielded 30 cases. Antifungal therapy was administered in all except one patient. In 18 cases, HLH was treated with immunosuppressive therapy. The most common immunosuppressive regimens were corticosteroid monotherapy and corticosteroids combined with etoposide. This case report is the first to describe the use of anakinra. The overall mortality rate was 23.3 % (n = 7). Disseminated histoplasmosis induced HLH is a severe disorder, requiring prompt recognition and immediate intervention. Currently, no specific treatment protocol exists for this disorder. Treatment should be tailored to the patient’s condition, symptoms and individual characteristics. Careful consideration regarding immunosuppressive therapy for HLH is needed to prevent worsening of the infection. Additionally, anticipating the progression of the disease is necessary to ensure timely and appropriate interventions.
2024-06-06 | Successful management of haemophagocytic lymphohistiocytosis in an adolescent with newly diagnosed HIV/AIDS and histoplasmosis.
Haemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening hyperinflammatory syndrome characterised by persistent fevers, cytopenia, hepatosplenomegaly and systemic inflammation. Secondary HLH can be triggered by various aetiologies including infections, malignancies and autoimmune conditions. We highlight the complexity of HLH diagnosis and management by describing a case of an adolescent Salvadoran immigrant with HLH, newly diagnosed HIV, Streptococcal bacteraemia and disseminated histoplasmosis. The patient presented with neurological and ocular findings along with persistent fevers and cytopenia. He was diagnosed with HLH and treated with anakinra in addition to receiving treatment for HIV, Streptococcal bacteraemia and histoplasmosis. The patient's HLH resolved without corticosteroids or chemotherapy, which are considered the mainstays for HLH treatment. This case underscores the need for the evaluation and management of multiple infections and individualised management in patients presenting with HLH to achieve favourable outcomes.
2021-06-07 | Reintroduction of immunosuppressive medications in pediatric rheumatology patients with histoplasmosis: a case series
Abstract Background Children with rheumatic diseases (cRD) receiving immunosuppressive medications (IM) are at a higher risk for acquiring potentially lethal pathogens, including Histoplasma capsulatum (histoplasmosis), a fungal infection that can lead to prolonged hospitalization, organ damage, and death. Withholding IM during serious infections is recommended yet poses risk of rheumatic disease flares. Conversely, reinitiating IM increases risk for infection recurrence. Tumor necrosis factor alpha inhibitor (TNFai) biologic therapy carries the highest risk for histoplasmosis infection after epidemiological exposure, so other IM are preferred during active histoplasmosis infection. There is limited guidance as to when and how IM can be reinitiated in cRD with histoplasmosis. This case series chronicles resumption of IM, including non-TNFai biologics, disease-modifying anti-rheumatic drugs (DMARDs), and corticosteroids, following histoplasmosis among cRD. Case presentation We examine clinical characteristics and outcomes of 9 patients with disseminated or pulmonary histoplasmosis and underlying rheumatic disease [juvenile idiopathic arthritis (JIA), childhood-onset systemic lupus erythematosus (cSLE), and mixed connective tissue disease (MCTD)] after reintroduction of IM. All DMARDs and biologics were halted at histoplasmosis diagnosis, except hydroxychloroquine (HCQ), and patients began antifungals. Following IM discontinuation, all patients required systemic or intra-articular steroids during histoplasmosis treatment, with 4/9 showing Cushingoid features. Four patients began new IM regimens [2 abatacept (ABA), 1 HCQ, and 1 methotrexate (MTX)] while still positive for histoplasmosis, with 3/4 (ABA, MTX, HCQ) later clearing their histoplasmosis and 1 (ABA) showing decreasing antigenemia. Collectively, 8/9 patients initiated or continued DMARDs and/or non-TNFai biologic use (5 ABA, 1 tocilizumab, 1 ustekinumab, 3 MTX, 4 HCQ, 1 leflunomide). No fatalities, exacerbations, or recurrences of histoplasmosis occurred during follow-up (median 33 months). Conclusions In our cohort of cRD, histoplasmosis course following reintroduction of non-TNFai IM was favorable, but additional studies are needed to evaluate optimal IM management during acute histoplasmosis and recovery. In this case series, non-TNFai biologic, DMARD, and steroid treatments did not appear to cause histoplasmosis recurrence. Adverse events from corticosteroid use were common. Further research is needed to implement guidelines for optimal use of non-TNFai (like ABA), DMARDs, and corticosteroids in cRD following histoplasmosis presentation.
2020-06-05 | IL-22 Promotes IFN-γ-Mediated Immunity against Histoplasma capsulatum Infection
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.
other
2026-01-06 | Rapid gain and loss of a chromosome drives key morphology and virulence phenotypes in the fungal pathogen Histoplasma.
Heritable phenotypic switches are fundamental to the ability of cells to respond to specific conditions. Such switches are key to the success of environmental pathogens, which encounter disparate conditions as they transition between the environment and host. We determine that the copy number of chromosome seven in the thermally dimorphic fungus Histoplasma dramatically affects the rate of transition. Though Histoplasma is haploid, a second copy of this chromosome is present in natural isolates of multiple Histoplasma species and is gained and lost at a high rate. Cells carrying two copies of this chromosome exhibit aspects of the environmental transcriptome even under host-like conditions and have a competitive advantage in the transition to the environmental form. Conversely, these cells are considerably less virulent than euploid cells and have a competitive disadvantage in the mouse model of infection. Chromosome seven contains a previously unstudied transcription factor that, when expressed at higher copy number in euploid Histoplasma, is sufficient to promote some of the key phenotypes of aneuploidy. We hypothesize that rapid gain and loss of this chromosome benefits Histoplasma by increasing phenotypic variation, thus helping populations of cells survive abrupt transitions between environment and host.
2025-05-16 | Left Recurrent Laryngeal Nerve Vocal Fold Paralysis in Pediatric Patient Secondary to Mediastinal Histoplasmosis Infection.
Histoplasma capsulatum is a dimorphic soil-based fungus endemic to the Ohio and Mississippi River valleys and southeastern United States. An extremely rare presentation is the involvement of the mediastinum leading to vocal fold paralysis, with only 2 reported cases in the literature. This report presents the youngest patient to whom this pathology has been described and the third overall patient. In this case report, we present a 15-year-old boy with vocal fold paralysis secondary to left recurrent laryngeal nerve paralysis in the setting of confirmed histoplasmosis infection. On further workup, he was noted to have mediastinum lymphadenopathy on computed tomography (CT) chest. Pathology of the biopsy indicated granulomatous inflammation without the evidence of malignancy, prompting fungal serology testing resulting in a positive histoplasma antibody result. The patient received appropriate treatment, yet the dysphonia persisted. On flexible laryngoscopy, he was noted to have left vocal fold paralysis. After 2 years of ongoing paralysis, the decision was made to proceed with recurrent laryngeal nerve innervation for long-term benefits. After nerve innervation and fat laryngoplasty, the patient has had significant improvement in dysphonia and voice parameters.
2021-06-01 | Histoplasma capsulatum-induced extracellular DNA trap release in human neutrophils.
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.
2018-05-21 | Helper T‐cell responses and pulmonary fungal infections
Summary The mucosal surface of the respiratory tract encounters microbes, such as fungal particles, with every inhaled breath. When pathogenic fungi breach the physical barrier and innate immune system within the lung to establish an infection, adaptive immunity is engaged, often in the form of helper CD4 T‐cell responses. Type 1 responses, characterized by interferon‐ γ production from CD4 cells, promote clearance of Histoplasma capsulatum and Cryptococcus neoformans infection. Likewise, interleukin‐17A (IL‐17A) production from Th17 cells promotes immunity to Blastomyces dermatitidis and Coccidioides species infection by recruiting neutrophils. In contrast the development of T helper type 2 responses, characterized by IL‐5 production from T cells and eosinophil influx into the lungs, drives allergic bronchopulmonary aspergillosis and poor outcomes during C. neoformans infection. Experimental vaccines against several endemic mycoses, including Histoplasma capsulatum , Coccidioides , Cryptococcus and Blastomyces dermatitidis , induce protective T‐cell responses and foreshadow the development of vaccines against pulmonary fungal infections for use in humans. Additionally, recent work using antifungal T cells as immunotherapy to protect immune‐compromised patients from opportunist fungal infections also shows great promise. This review covers the role of T‐cell responses in driving protection and pathology in response to pulmonary fungal infections, and highlights promising therapeutic applications of antifungal T cells.
2010-05-03 | Antigen-presenting dendritic cells rescue CD4-depleted CCR2-/- mice from lethal Histoplasma capsulatum infection.
Excessive production of interleukin-4 impairs clearance of the fungal pathogen Histoplasma capsulatum in mice lacking the chemokine receptor CCR2. An increase in the interleukin-4 level is associated with decreased recruitment of dendritic cells to lungs; therefore, we investigated the possibility that these cells influence interleukin-4 production. Adoptive transfer of wild-type or CCR2(-/-) bone marrow-derived dendritic cells loaded with heat-killed yeast cells to infected CCR2(-/-) mice suppressed interleukin-4 transcription. Surprisingly, transfer of cells did not reduce the fungal burden despite the fact that it limited interleukin-4 transcription. Yeast cell-loaded bone marrow-derived dendritic cell-mediated regulation of interleukin-4 transcription was dependent on major histocompatibility complex II antigen presentation to CD4(+) T cells. We previously showed that CD4(+) T cells were a source of interleukin-4 in infected CCR2(-/-) mice, but their contribution to the TH2 phenotype was unclear. Here we demonstrated that these cells were functionally important since elimination of them prior to infection, but not elimination of them at the time of infection, reduced the interleukin-4 level in infected CCR2(-/-) mice. However, the fungal burden was reduced only in CD4-depleted CCR2(-/-) mice that received yeast cell-loaded bone marrow-derived dendritic cells. Taken together, the data indicate that generation of excess interleukin-4 in lungs of H. capsulatum-infected CCR2(-/-) mice is at least partially a consequence of decreased recruitment of dendritic cells capable of antigen presentation. Furthermore, CD4(+) T cells had a deleterious impact on immunity in infected CCR2(-/-) mice.
small molecules
2026-09-11 | Outcomes After Antifungal Discontinuation in Immunocompromised Patients Treated for Histoplasmosis
Abstract Background Histoplasmosis is an important opportunistic infection. Current guidelines recommend prolonged antifungal therapy, typically 12 months of therapy. However, antifungal therapy is occasionally discontinued earlier in clinical practice due to medication intolerance, drug interactions, or adherence challenges. Data describing outcomes after antifungal discontinuation in immunocompromised patients remain limited. Methods We conducted a retrospective cohort study of immunocompromised adults treated for histoplasmosis within a large healthcare system between 2005 and 2025. Patients who discontinued antifungal therapy and had clinical follow-up were included. Patients were categorized according to treatment duration (<12 months vs ≥12 months). The primary outcome was a composite of histoplasmosis-related adverse events after antifungal discontinuation, including relapse, hospitalization attributed to histoplasmosis, or histoplasmosis-related death. Secondary outcomes included all-cause adverse events. Cox proportional hazards models with inverse probability of treatment weighting (IPTW). Results 106 patient met inclusion criteria and 75% presented with disseminated disease. Histoplasmosis-related adverse events were uncommon. Relapse occurred in 7/106 (6.6%), including 3/28 (11%) treated for <12 months and 4/78 (5.1%) treated for ≥12 months. No deaths were attributed to histoplasmosis. Shorter treatment duration was not associated with a higher hazard of histoplasmosis-related outcomes (HR 2.34, 95% CI 0.52–10.62). Lower antigen burden at diagnosis was associated with reduced risk of adverse outcomes. Conclusions Relapse after antifungal discontinuation was uncommon. Baseline disease burden, reflected by antigen levels and timing of diagnosis, appeared to influence post-treatment outcomes. These findings suggest further investigation is warranted into individualized antifungal treatment duration based on disease severity and fungal burden.
2026-09-01 | Orbital Histoplasmosis (Darling’s disease) in a Young Male from Yangon, Myanmar
"This case report discusses a rare instance of orbital histoplasmosis in a 25-year-old man, a painter who resided at Shwe Pyi Thar township, Yangon, Myanmar, an endemic area for histoplasmosis. The report highlights the clinical presentation, diagnostic imaging, histopathological findings, and treatment approach, contributing to the understanding of this rare manifestation. Histoplasmosis is a systemic fungal infection caused by Histoplasma capsulatum, typically found in endemic regions such as the river valleys of the Americas. The first reported case of orbital histoplasmosis was in the United States in 2016. However, cases have also been reported in parts of Southeast Asia, including Myanmar. Histoplasmosis, primarily a pulmonary disease, occasionally manifests in atypical forms such as orbital involvement, especially in immunocompromised individuals or endemic regions. This report highlights a case with extensive orbital and sinus involvement, emphasizing the diagnostic and therapeutic challenges. Aware
2026-08-31 | Bilateral granulomatous uveitis mimicking tuberculosis: an atypical ocular presentation of biopsy-proven disseminated histoplasmosis.
Ocular histoplasmosis typically presents as presumed ocular histoplasmosis syndrome, characterised by chorioretinal scars and peripapillary atrophy without intraocular inflammation. Active inflammatory presentations are exceedingly rare and may closely mimic tuberculosis in endemic regions, posing significant diagnostic challenges.We report a middle-aged immunocompetent male farmer who presented with acute bilateral visual loss, redness and floaters. Examination revealed bilateral granulomatous anterior uveitis with dense vitritis with mutton-fat keratic precipitates, dense vitritis and 4+ anterior chamber reaction. Systemic evaluation identified a laryngeal mass; histopathological examination confirmed disseminated Histoplasma capsulatum infection. QuantiFERON-TB Gold and HIV serology were negative. Itraconazole was initiated before systemic corticosteroids, with marked clinical improvement and visual recovery from 6/60 to 6/18 bilaterally within 1 week.This case underscores the importance of systemic evaluation, tissue diagnosis and appropriate antifungal cover preceding corticosteroid use in presumed histoplasma-associated granulomatous uveitis in endemic settings.
2026-08-07 | Novel antifungal agents for treating endemic mycoses: hope on the horizon?
Current treatments for endemic mycoses are limited by toxicity, drug-drug interactions, the need for therapeutic drug monitoring, and suboptimal penetration to sequestered sites. At the same time, several new antifungal strategies and agents are nearing clinical availability and may change practice. Current literature highlights limitations of standard therapy for histoplasmosis, coccidioidomycosis, blastomycosis, paracoccidioidomycosis, talaromycosis, sporotrichosis, and emergomycosis, which often rely on amphotericin B-based induction regimens followed by triazole antifungals. Emerging studies are evaluating single high-dose liposomal amphotericin B, shorter treatment durations for histoplasmosis, and flucytosine combined with amphotericin B-based induction for talaromycosis. Novel antifungals such as olorofim, fosmanogepix, and turletricin are especially promising, and treatment strategies guided by patient phenotypes and immune endotypes are also beginning to emerge. Growing evidence suggests therapy for endemic mycoses may change substantially in the near future. New drugs and alternative treatment approaches have the potential to improve safety, tolerability, oral availability, drug-drug interaction profiles, and treatment duration, with important implications for both clinical care and future research.
2026-08-06 | Bilateral adrenal histoplasmosis incidentally detected on 18F-FDG PET/CT in an immunocompetent man with primary adrenal insufficiency: A case report.
Adrenal histoplasmosis is an uncommon manifestation of Histoplasma capsulatum infection and may closely mimic malignancy or granulomatous diseases on imaging. We describe an immunocompetent 51 year old man with 5 months of constitutional symptoms who underwent 18F-FDG PET/CT for evaluation of occult disease. The scan revealed intensely FDG avid bilateral adrenal masses with necrotic components, with no other abnormal sites. Biochemical testing confirmed primary adrenal insufficiency. CT guided adrenal biopsy, targeted to the most FDG-avid viable component, demonstrated necrotizing granulomatous inflammation with intracellular yeast forms consistent with Histoplasma capsulatum. Antifungal therapy with itraconazole plus glucocorticoid replacement led to clinical improvement and interval regression of adrenal lesions on follow-up. This case highlights the value of 18F-FDG PET/CT for detecting unsuspected adrenal histoplasmosis, localizing optimal biopsy targets, and facilitating timely treatment even in immunocompetent patients presenting with nonspecific symptoms.
vaccines
2025-11-17 | Fungal vaccines: so needed, so feasible, and yet so far off.
Invasive fungal infections carry high morbidity and mortality, but there are no fungal vaccines. In this issue of the JCI, Okaa et al. report that endonuclease 2 (Eng2), an antigen shared by the Blastomyces, Histoplasma, and Coccidioides species of fungi, elicits protective immunity in mice against blastomycosis, histoplasmosis, and coccidioidomycosis. These results establish a common antigen that can elicit protection against multiple mycoses, encouraging the development of a pan-fungal vaccine. The road to fungal vaccines is made difficult by the need for effectiveness in immunocompromised individuals, the sporadic nature of fungal disease, and the economics of vaccine development. Despite these hurdles, there is optimism that such vaccines can be developed and perhaps find usefulness as adjuncts to antifungal therapy.
2024-01-22 | Design of a Multi-Epitope Vaccine against Histoplasma capsulatum through Immunoinformatics Approaches.
Histoplasmosis is a widespread systemic disease caused by Histoplasma capsulatum, prevalent in the Americas. Despite its significant morbidity and mortality rates, no vaccines are currently available. Previously, five vaccine targets and specific epitopes for H. capsulatum were identified. Immunoinformatics has emerged as a novel approach for determining the main immunogenic components of antigens through in silico methods. Therefore, we predicted the main helper and cytotoxic T lymphocytes and B-cell epitopes for these targets to create a potential multi-epitope vaccine known as HistoVAC-TSFM. A total of 38 epitopes were found: 23 common to CTL and B-cell responses, 11 linked to HTL and B cells, and 4 previously validated epitopes associated with the B subunit of cholera toxin, a potent adjuvant. In silico evaluations confirmed the stability, non-toxicity, non-allergenicity, and non-homology of these vaccines with the host. Notably, the vaccine exhibited the potential to trigger both innate and adaptive immune responses, likely involving the TLR4 pathway, as supported by 3D modeling and molecular docking. The designed HistoVAC-TSFM appears promising against Histoplasma, with the ability to induce important cytokines, such as IFN-γ, TNF-α, IL17, and IL6. Future studies could be carried out to test the vaccine's efficacy in in vivo models.
2019-03-26 | Immunization Strategies for the Control of Histoplasmosis
Histoplasmosis is an infection caused by the dimorphic fungus Histoplasma capsulatum. Histoplasmosis is typically self-limited and presents asymptomatically in most people. Nevertheless, histoplasmosis can cause severe pulmonary disease and death. Histoplasmosis is increasingly found worldwide; however, it is best documented in the endemic region of the Mississippi river valley system in the Eastern part of the United States (US). Epidemiological studies from the US detailing the morbidity, mortality, and cost associated with histoplasmosis underscore the need to develop a vaccine.This review will detail some of the major developments in potential vaccines against histoplasmosis, with particular emphasis on those that could be used to immunize immunocompromised hosts. Additionally, this review will highlight some non-traditional vaccine-like ideas for the prevention of diverse mycoses.Historically, immunization strategies against histoplasmosis have largely focused on identifying immunogenic proteins that confer protection in animal models. More recently, novel active, therapeutic, and immunomodulatory strategies have been explored as potential alternatives for those with various immune-deficiencies.The studies summarized in this review demonstrate that more research is needed to clarify the immunobiology, clinical role and efficacy of each candidate vaccine in the ever-expanding potential armamentarium against histoplasmosis.
2018-05-01 | Vaccination with an alkaline extract of Histoplasma capsulatum packaged in glucan particles confers protective immunity in mice
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.
2017-09-14 | Heat Shock Proteins in Histoplasma and Paracoccidioides
ABSTRACT Heat shock proteins (Hsps) are highly conserved biomolecules that are constitutively expressed and generally upregulated in response to various stress conditions (biotic and abiotic). Hsps have diverse functions, categorizations, and classifications. Their adaptive expression in fungi indicates their significance in these diverse species, particularly in dimorphic pathogens. Histoplasma capsulatum and Paracoccidioides species are dimorphic fungi that are the causative agents of histoplasmosis and paracoccidioidomycosis, respectively. This minireview focuses on the pathobiology of Hsps, with particular emphasis on their roles in the morphogenesis and virulence of Histoplasma and Paracoccidioides and the potential roles of active and passive immunization against Hsps in protection against infection with these fungi.
antibodies
2026-08-07 | Histoplasmosis in children: emerging insights and evolving guidelines.
This review provides an update on the epidemiology, risk factors, clinical presentation, diagnosis, and management recommendations incorporating recommendations from recent publications including the Infectious Disease Society of America guidelines for the management of pulmonary and disseminated histoplasmosis. Updates to the epidemiology of histoplasmosis indicate a broader geographic range than historically defined. Updated guidelines do not recommend routine treatment for asymptomatic, mild and moderate pulmonary histoplasmosis although itraconazole can be offered for immunocompromised children or for prolonged or worsening symptoms. Liposomal amphotericin B is recommended as initial treatment for severe histoplasmosis syndromes (severe pulmonary and disseminated histoplasmosis). Fibrosing mediastinitis, a late complication of histoplasmosis is treated with stenting of vessels and bronchi. Recent studies demonstrate that rituximab (anti-CD20 monoclonal antibody) may stop progression or lead to regression of progressive fibrosis. Histoplasmosis has manifold manifestations, many of which are self-limited and do not require treatment. Severe histoplasmosis and its complications should be treated with liposomal amphotericin B followed by itraconazole. Clinical trials are needed to assess the efficacy of rituximab for the treatment of fibrosing mediastinitis.
2026-03-25 | Beyond the Usual Suspects: Gastrointestinal Histoplasmosis as a Marker of Undiagnosed Common Variable Immunodeficiency.
A 28-year-old woman presented with chronic diarrhea, weight loss, and recurrent gastrointestinal infections. Intestinal biopsies unexpectedly revealed Histoplasma capsulatum, prompting immunologic evaluation that demonstrated severe hypogammaglobulinemia and reduced B-cell counts, consistent with common variable immunodeficiency. She improved with intravenous immunoglobulin and antifungal therapy. This case highlights gastrointestinal histoplasmosis as a potential early marker of undiagnosed common variable immunodeficiency and underscores the importance of considering primary immunodeficiency in adults with persistent gastrointestinal symptoms.
2024-08-06 | A Retrospective Evaluation of the Treatment Effects of Rituximab in Patients with Progressive and Symptomatic Fibrosing Mediastinitis.
Rationale: Fibrosing mediastinitis (FM) is an uncommon fibroinflammatory condition without established or effective medical therapies. Infiltrating B lymphocytes are commonly present, and progressive fibrosis compromises mediastinal structures, including blood vessels and airways, resulting in significant morbidity and mortality. Objective: To evaluate the benefits and side effects of rituximab in patients with progressive and symptomatic FM. Methods: We treated 22 patients (median age, 35 yr; range, 15-68 yr; 45% female) with metabolically active, progressive FM with rituximab on an off-label basis. Additionally, patients were administered pneumocystis and antifungal prophylaxis when immunosuppressed with rituximab. Modeling of longitudinal treatment response based on changes in relative lesion volume from baseline was performed retrospectively using functional data analysis, and time-to-event modeling was performed to estimate treatment response rates based on a >30% reduction in pretreatment volume. The primary endpoints were lack of disease progression and change in mediastinal lesion volume on computed tomography (evaluated retrospectively). Results: No patient experienced disease progression after rituximab therapy. Median clinical follow-up was 42 months (range, 7-94 mo) and imaging follow-up 21 months (range, 7-62 mo). A total of 82% of patients had confirmed histoplasmosis-associated FM. After rituximab treatment, a 49.6% (95% confidence interval, 17.5-64.4%) mean estimated decrease in pretreatment lesion volume was observed at 24 months. The estimated objective treatment response rate was 47.9% (95% confidence interval, 26.7-70.3%). Conclusions: This observational study suggests that rituximab is a well tolerated and potentially effective therapy in a cohort of patients with symptomatic and progressive FM.
2024-05-27 | Presumed Ocular Histoplasmosis Syndrome with Choroidal Neovascularization: Case Report
Presumed Ocular Histoplasmosis Syndrome (PHOS) is a clinical condition characterized by chronic inflammation of the choroid and retina, often accompanied by the growth of abnormal blood vessels in the macula known as choroidal neovascularization (CNV). While PHOS is typically seen in regions where Histoplasma capsulatum is endemic, there have been reported cases in non-endemic areas. This case report presents the details of a 32-year-old Moroccan patient with PHOS and macular CNV, highlighting the diagnostic, therapeutic, and practical considerations involved in their treatment. The patient, who had no significant medical history, came to us with a six-month history of central vision loss, intermittent metamorphopsia, and central scotomas in the left eye. Despite having no exposure to environmental risk factors or travel to areas where histoplasmosis is prevalent, our clinical examination revealed choroidal and retinal lesions consistent with histospots and active CNV. Further tests such as fluorescein angiography and optical coherence tomography (OCT) confirmed the presence of CNV, revealing a subretinal fibrovascular membrane and serohemorrhagic detachment. Based on these findings, we diagnosed the patient with PHOS and CNV. We proceeded with treatment using intravitreal ranibizumab, a monoclonal antibody that targets vascular endothelial growth factor (VEGF). Monthly injections resulted in the stabilization of the patient's condition, both clinically and anatomically. The CNV regressed, the serohemorrhagic detachment resolved, and there was a significant improvement in the patient's visual acuity. The discussion in this report highlights the fact that while PHOS is typically associated with Histoplasma capsulatum infection, the occurrence of cases in non-endemic areas raises questions about its etiology and diagnosis. In this particular instance, the patient's exposure to the fungus or potential infection by other fungal species complicates the process ..........
2024-01-25 | PULMONARY HISTOPLASMOSIS IN A PATIENT WITH CROHN’S DISEASE ON ANTI-TNF INHIBITOR THERAPY
Abstract INTRODUCTION Infliximab, an anti-tumor necrosis factor (TNF) alpha inhibitor, is a commonly used biologic therapy for patients with inflammatory bowel disease (IBD). However, the increased risk of serious infections, including both new and re-activated infections, is a major concern while patients are on this therapy. Often the presence or development of such serious infections necessitates stopping treatment with anti-TNF inhibitors. We describe a case of a patient who developed Histoplasmosis while on infliximab but was later restarted on the same therapy due to risk of severe Crohn’s disease while maintaining him on ongoing Histoplasmosis treatment. CASE DESCRIPTION We describe the case of a 34-year-old male with a past medical history of Crohn’s disease on infliximab, hypertension, depression, and nephrolithiasis who presented to the hospital with dyspnea on exertion, cough, malaise, and night sweats, and was found to have multifocal pulmonary infiltrates on imaging, concerning for atypical pneumonia. He underwent a bronchoscopy and BAL, with pathology reports showing small oval shaped yeast within necrotic granulomas suspicious for Histoplasmosis. He was taken off infliximab and started on liposomal amphotericin for Histoplasma treatment initially, subsequently transitioned to itraconazole for total of 12 months. He was discharged home but was subsequently re-admitted to the hospital with a Crohn’s flare after being taken off infliximab. He was treated with steroids and started on vedolizumab for more gut-selectivity after a multidisciplinary risk/benefit discussion. However, patient was subsequently re-admitted with diarrhea and hematochezia, due to a Crohn’s disease flare while still on steroid taper and having received 2 doses of vedolizumab. He was transitioned to IV steroids and had a colonoscopy which showed large ulcers and mucosal inflammatory changes with a Simple endoscopic score for Crohn’s disease of 18. After a multidisciplinary discussion, he was restarted on infliximab. He was slowly tapered off steroids as his symptoms improved. Repeat colonoscopy after restarting infliximab showed improved but ongoing mucosal inflammatory changes with a Simple endoscopic score for Crohn’s disease of 7. DISCUSSION While anti-TNF inhibitor biologics are commonly used for patients with IBD, opportunistic and fungal infections remain a significant concern while on immunosuppressing biologic therapies, which necessitates stopping the anti-TNF inhibitor. Previously, a study has shown that it is safe to restart anti-TNF therapy after treatment for Histoplasmosis is completed for a 12-month duration. Our case shows that in patients such as ours with severe Crohn’s disease flares while off infliximab, treatment with anti-TNF inhibitors can be resumed after having a multidisciplinary risk/benefit discussion. Figure 1 Colonoscopy findings showing large ulcers and significant mucosal inflammatory changes after patient started on vedolizumab and admitted for Crohn’s Disease flare. Figure 2 Colonoscopy findings showing ongoing mucosal inflammation but improved from prior after restarting treatment with infliximab.
proteins
2025-10-25 | Expansion of secreted cystine knot proteins reveals virulence factors in the human fungal pathogen Histoplasma.
Identifying fungal secreted factors that influence host infection remains a key challenge in microbial pathogenesis. While secreted effectors, particularly small cysteine-rich proteins, are well characterized in plant fungal pathogens, their counterparts in mammalian pathogens are understudied. We apply criteria from plant fungal effectors to the mammalian fungal pathogen Histoplasma, yielding a set of putative effectors highly enriched for knottins, proteins that adopt a distinctive cystine knot fold. Using an algorithm, we further identify 25 putative knottins in the Histoplasma genome, revealing a significant expansion of knottin genes. Knottin domains are found in diverse molecules but play an unknown role in virulence. Functional studies of individual Histoplasma knottins demonstrate their critical roles in intracellular survival and host cell lysis during macrophage infection as well as virulence in vivo. These findings highlight the importance of knottins in fungal pathogenesis and suggest their broader relevance for discovering conserved mechanisms of host manipulation.
2025-04-01 | Disseminated histoplasmosis induced hemophagocytic lymphohistiocytosis in an immunocompromised patient
• Disseminated histoplasmosis induced HLH is a severe disorder. • Immunotherapy may worsen the underlying infection in secondary HLH. • Evidence for the use of etoposide in adults with HLH is scarce. • This is a first case of the use of anakinra in histoplasmosis induced HLH. • HLH treatment should be tailored to the condition of the patient. The search for the trigger of hemophagocytic lymphohistiocytosis (HLH) and its management can be challenging in immunocompromised patients. In HLH triggered by infection, immunosuppressive therapy is desired to suppress hyperinflammation, but may worsen the underlying infection. To review available literature on the management and prognosis of immunocompromised patients with disseminated histoplasmosis induced HLH. We describe a case and review all previously reported cases of disseminated histoplasmosis induced HLH on PubMed until June 2023. The literature review yielded 30 cases. Antifungal therapy was administered in all except one patient. In 18 cases, HLH was treated with immunosuppressive therapy. The most common immunosuppressive regimens were corticosteroid monotherapy and corticosteroids combined with etoposide. This case report is the first to describe the use of anakinra. The overall mortality rate was 23.3 % (n = 7). Disseminated histoplasmosis induced HLH is a severe disorder, requiring prompt recognition and immediate intervention. Currently, no specific treatment protocol exists for this disorder. Treatment should be tailored to the patient’s condition, symptoms and individual characteristics. Careful consideration regarding immunosuppressive therapy for HLH is needed to prevent worsening of the infection. Additionally, anticipating the progression of the disease is necessary to ensure timely and appropriate interventions.
2024-06-06 | Successful management of haemophagocytic lymphohistiocytosis in an adolescent with newly diagnosed HIV/AIDS and histoplasmosis.
Haemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening hyperinflammatory syndrome characterised by persistent fevers, cytopenia, hepatosplenomegaly and systemic inflammation. Secondary HLH can be triggered by various aetiologies including infections, malignancies and autoimmune conditions. We highlight the complexity of HLH diagnosis and management by describing a case of an adolescent Salvadoran immigrant with HLH, newly diagnosed HIV, Streptococcal bacteraemia and disseminated histoplasmosis. The patient presented with neurological and ocular findings along with persistent fevers and cytopenia. He was diagnosed with HLH and treated with anakinra in addition to receiving treatment for HIV, Streptococcal bacteraemia and histoplasmosis. The patient's HLH resolved without corticosteroids or chemotherapy, which are considered the mainstays for HLH treatment. This case underscores the need for the evaluation and management of multiple infections and individualised management in patients presenting with HLH to achieve favourable outcomes.
2021-06-07 | Reintroduction of immunosuppressive medications in pediatric rheumatology patients with histoplasmosis: a case series
Abstract Background Children with rheumatic diseases (cRD) receiving immunosuppressive medications (IM) are at a higher risk for acquiring potentially lethal pathogens, including Histoplasma capsulatum (histoplasmosis), a fungal infection that can lead to prolonged hospitalization, organ damage, and death. Withholding IM during serious infections is recommended yet poses risk of rheumatic disease flares. Conversely, reinitiating IM increases risk for infection recurrence. Tumor necrosis factor alpha inhibitor (TNFai) biologic therapy carries the highest risk for histoplasmosis infection after epidemiological exposure, so other IM are preferred during active histoplasmosis infection. There is limited guidance as to when and how IM can be reinitiated in cRD with histoplasmosis. This case series chronicles resumption of IM, including non-TNFai biologics, disease-modifying anti-rheumatic drugs (DMARDs), and corticosteroids, following histoplasmosis among cRD. Case presentation We examine clinical characteristics and outcomes of 9 patients with disseminated or pulmonary histoplasmosis and underlying rheumatic disease [juvenile idiopathic arthritis (JIA), childhood-onset systemic lupus erythematosus (cSLE), and mixed connective tissue disease (MCTD)] after reintroduction of IM. All DMARDs and biologics were halted at histoplasmosis diagnosis, except hydroxychloroquine (HCQ), and patients began antifungals. Following IM discontinuation, all patients required systemic or intra-articular steroids during histoplasmosis treatment, with 4/9 showing Cushingoid features. Four patients began new IM regimens [2 abatacept (ABA), 1 HCQ, and 1 methotrexate (MTX)] while still positive for histoplasmosis, with 3/4 (ABA, MTX, HCQ) later clearing their histoplasmosis and 1 (ABA) showing decreasing antigenemia. Collectively, 8/9 patients initiated or continued DMARDs and/or non-TNFai biologic use (5 ABA, 1 tocilizumab, 1 ustekinumab, 3 MTX, 4 HCQ, 1 leflunomide). No fatalities, exacerbations, or recurrences of histoplasmosis occurred during follow-up (median 33 months). Conclusions In our cohort of cRD, histoplasmosis course following reintroduction of non-TNFai IM was favorable, but additional studies are needed to evaluate optimal IM management during acute histoplasmosis and recovery. In this case series, non-TNFai biologic, DMARD, and steroid treatments did not appear to cause histoplasmosis recurrence. Adverse events from corticosteroid use were common. Further research is needed to implement guidelines for optimal use of non-TNFai (like ABA), DMARDs, and corticosteroids in cRD following histoplasmosis presentation.
2020-06-05 | IL-22 Promotes IFN-γ-Mediated Immunity against Histoplasma capsulatum Infection
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.
other
2026-01-06 | Rapid gain and loss of a chromosome drives key morphology and virulence phenotypes in the fungal pathogen Histoplasma.
Heritable phenotypic switches are fundamental to the ability of cells to respond to specific conditions. Such switches are key to the success of environmental pathogens, which encounter disparate conditions as they transition between the environment and host. We determine that the copy number of chromosome seven in the thermally dimorphic fungus Histoplasma dramatically affects the rate of transition. Though Histoplasma is haploid, a second copy of this chromosome is present in natural isolates of multiple Histoplasma species and is gained and lost at a high rate. Cells carrying two copies of this chromosome exhibit aspects of the environmental transcriptome even under host-like conditions and have a competitive advantage in the transition to the environmental form. Conversely, these cells are considerably less virulent than euploid cells and have a competitive disadvantage in the mouse model of infection. Chromosome seven contains a previously unstudied transcription factor that, when expressed at higher copy number in euploid Histoplasma, is sufficient to promote some of the key phenotypes of aneuploidy. We hypothesize that rapid gain and loss of this chromosome benefits Histoplasma by increasing phenotypic variation, thus helping populations of cells survive abrupt transitions between environment and host.
2025-05-16 | Left Recurrent Laryngeal Nerve Vocal Fold Paralysis in Pediatric Patient Secondary to Mediastinal Histoplasmosis Infection.
Histoplasma capsulatum is a dimorphic soil-based fungus endemic to the Ohio and Mississippi River valleys and southeastern United States. An extremely rare presentation is the involvement of the mediastinum leading to vocal fold paralysis, with only 2 reported cases in the literature. This report presents the youngest patient to whom this pathology has been described and the third overall patient. In this case report, we present a 15-year-old boy with vocal fold paralysis secondary to left recurrent laryngeal nerve paralysis in the setting of confirmed histoplasmosis infection. On further workup, he was noted to have mediastinum lymphadenopathy on computed tomography (CT) chest. Pathology of the biopsy indicated granulomatous inflammation without the evidence of malignancy, prompting fungal serology testing resulting in a positive histoplasma antibody result. The patient received appropriate treatment, yet the dysphonia persisted. On flexible laryngoscopy, he was noted to have left vocal fold paralysis. After 2 years of ongoing paralysis, the decision was made to proceed with recurrent laryngeal nerve innervation for long-term benefits. After nerve innervation and fat laryngoplasty, the patient has had significant improvement in dysphonia and voice parameters.
2021-06-01 | Histoplasma capsulatum-induced extracellular DNA trap release in human neutrophils.
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.
2018-05-21 | Helper T‐cell responses and pulmonary fungal infections
Summary The mucosal surface of the respiratory tract encounters microbes, such as fungal particles, with every inhaled breath. When pathogenic fungi breach the physical barrier and innate immune system within the lung to establish an infection, adaptive immunity is engaged, often in the form of helper CD4 T‐cell responses. Type 1 responses, characterized by interferon‐ γ production from CD4 cells, promote clearance of Histoplasma capsulatum and Cryptococcus neoformans infection. Likewise, interleukin‐17A (IL‐17A) production from Th17 cells promotes immunity to Blastomyces dermatitidis and Coccidioides species infection by recruiting neutrophils. In contrast the development of T helper type 2 responses, characterized by IL‐5 production from T cells and eosinophil influx into the lungs, drives allergic bronchopulmonary aspergillosis and poor outcomes during C. neoformans infection. Experimental vaccines against several endemic mycoses, including Histoplasma capsulatum , Coccidioides , Cryptococcus and Blastomyces dermatitidis , induce protective T‐cell responses and foreshadow the development of vaccines against pulmonary fungal infections for use in humans. Additionally, recent work using antifungal T cells as immunotherapy to protect immune‐compromised patients from opportunist fungal infections also shows great promise. This review covers the role of T‐cell responses in driving protection and pathology in response to pulmonary fungal infections, and highlights promising therapeutic applications of antifungal T cells.
2010-05-03 | Antigen-presenting dendritic cells rescue CD4-depleted CCR2-/- mice from lethal Histoplasma capsulatum infection.
Excessive production of interleukin-4 impairs clearance of the fungal pathogen Histoplasma capsulatum in mice lacking the chemokine receptor CCR2. An increase in the interleukin-4 level is associated with decreased recruitment of dendritic cells to lungs; therefore, we investigated the possibility that these cells influence interleukin-4 production. Adoptive transfer of wild-type or CCR2(-/-) bone marrow-derived dendritic cells loaded with heat-killed yeast cells to infected CCR2(-/-) mice suppressed interleukin-4 transcription. Surprisingly, transfer of cells did not reduce the fungal burden despite the fact that it limited interleukin-4 transcription. Yeast cell-loaded bone marrow-derived dendritic cell-mediated regulation of interleukin-4 transcription was dependent on major histocompatibility complex II antigen presentation to CD4(+) T cells. We previously showed that CD4(+) T cells were a source of interleukin-4 in infected CCR2(-/-) mice, but their contribution to the TH2 phenotype was unclear. Here we demonstrated that these cells were functionally important since elimination of them prior to infection, but not elimination of them at the time of infection, reduced the interleukin-4 level in infected CCR2(-/-) mice. However, the fungal burden was reduced only in CD4-depleted CCR2(-/-) mice that received yeast cell-loaded bone marrow-derived dendritic cells. Taken together, the data indicate that generation of excess interleukin-4 in lungs of H. capsulatum-infected CCR2(-/-) mice is at least partially a consequence of decreased recruitment of dendritic cells capable of antigen presentation. Furthermore, CD4(+) T cells had a deleterious impact on immunity in infected CCR2(-/-) mice.
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Drug Discovery Landscape
1 orphan drug designation for Histoplasmosis.
1 orphan drug designation for Histoplasmosis.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Liposomal amphotericin B | small molecules | FDA | Fujisawa USA, Inc. |
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