Diagnostic accuracy of a novel lateral flow assay for histoplasmosis.

Antigen testing is an important diagnostic tool for histoplasmosis but has limited availability globally. We evaluated the OIDx urine lateral flow antigen assay among 204 persons suspected to have histoplasmosis. Among patients with proven histoplasmosis, sensitivity was 33.3% (3/9, 95% CI 7.5-70.1%) and specificity 80.5% (157/195, 95% CI 74.3-85.8%). The MiraVista urine antigen test had better specificity (96.9%) and equal sensitivity. The OIDx test demonstrated 33.3% (3/9) positive agreement and 84.0% (163/194) negative agreement with the MiraVista test. These results should be considered in the context of our low HIV prevalence population with a mixture of pulmonary and disseminated disease.

We evaluated a new lateral flow antigen test for the diagnosis of histoplasmosis. Proven/probable cases were mostly pulmonary disease making antigen tests likely to be less sensitive in this population. The test had similar sensitivity to the established antigen test but was less specific.

Fulminant Disseminated Coccidioidomycosis With Histoplasma Antigen Cross-Reactivity.

A 79-year-old man with type II diabetes mellitus and recently diagnosed idiopathic thrombocytopenic purpura presented to the Emergency Department with progressive dyspnea over the course of two weeks. He was found to have diffuse miliary nodules, dense cavitary consolidation, and widespread cystic changes on chest imaging and died within 48 hours of admission to the hospital. His serum Coccidioides antibody and urine Histoplasma antigen were both positive. He later grew Coccidioides immitis from the blood, supporting the theory that Histoplasma positivity was likely the result of antigen test cross-reactivity. Coccidioidomycosis typically presents with mild, self-limited symptoms, but may also disseminate rapidly, causing fulminant, life-threatening disease. Prompt recognition of risk factors for fulminant coccidioidomycosis and understanding flaws in serologic testing are essential to the appropriate diagnosis and management of this disease.

Influence of Zinc on Histoplasma capsulatum Planktonic and Biofilm Cells.

Histoplasma capsulatum causes a fungal respiratory disease. Some studies suggest that the fungus requires zinc to consolidate the infection. This study aimed to investigate the influence of zinc and the metal chelator TPEN on the growth of Histoplasma in planktonic and biofilm forms. The results showed that zinc increased the metabolic activity, cell density, and cell viability of planktonic growth. Similarly, there was an increase in biofilm metabolic activity but no increase in biomass or extracellular matrix production. N'-N,N,N,N-tetrakis-2-pyridylmethylethane-1,2 diamine (TPEN) dramatically reduced the same parameters in the planktonic form and resulted in a decrease in metabolic activity, biomass, and extracellular matrix production for the biofilm form. Therefore, the unprecedented observations in this study highlight the importance of zinc ions for the growth, development, and proliferation of H. capsulatum cells and provide new insights into the role of metal ions for biofilm formation in the dimorphic fungus Histoplasma, which could be a potential therapeutic strategy.

Genotypic diversity, virulence, and molecular genetic tools in Histoplasma.

SUMMARYHistoplasmosis is arguably the most common fungal respiratory infection worldwide, with hundreds of thousands of new infections occurring annually in the United States alone. The infection can progress in the lung or disseminate to visceral organs and can be difficult to treat with antifungal drugs. Histoplasma, the causative agent of the disease, is a pathogenic fungus that causes life-threatening lung infections and is globally distributed. The fungus has the ability to germinate from conidia into either hyphal (mold) or yeast form, depending on the environmental temperature. This transition also regulates virulence. Histoplasma and histoplasmosis have been classified as being of emergent importance, and in 2022, the World Health Organization included Histoplasma as 1 of the 19 most concerning human fungal pathogens. In this review, we synthesize the current understanding of the ecological niche, evolutionary history, and virulence strategies of Histoplasma. We also describe general patterns of the symptomatology and epidemiology of histoplasmosis. We underscore areas where research is sorely needed and highlight research avenues that have been productive.

Endemic Fungal Infective Endocarditis Caused by Coccidioides, Blastomyces and Histoplasma Species in the United States.

We describe a recent case of Coccidioides bioprosthetic aortic valve infective endocarditis successfully managed at our institution. This led us to perform a literature review of endemic fungal infective endocarditis in the United States caused by Coccidioides, Blastomyces, and Histoplasma. Symptoms preceded infective endocarditis diagnosis by several months. Patients with Coccidioides and Blastomyces infective endocarditis were younger with fewer comorbid conditions. Valvular involvement was relatively uncommon in Blastomyces infective endocarditis (27%). Fungemia was noted in patients with infective endocarditis due to Histoplasma (30%) and Coccidioides (18%). Mortality rates for infective endocarditis were high (Histoplasma, 46%; Coccidioides, 58%; Blastomyces, 80%); infective endocarditis was commonly diagnosed post-mortem (Coccidioides, 58%; Blastomyces, 89%). Most surviving patients with infective endocarditis (Histoplasma, 79%; Coccidioides, 80%) underwent valve surgery along with prolonged antifungal therapy. The two surviving patients with Blastomyces infective endocarditis received antifungal therapy without surgery.

Phenotypic characterization of cryptic species in the fungal pathogen Histoplasma.

Histoplasmosis is an endemic mycosis that often presents as a respiratory infection in immunocompromised patients. Hundreds of thousands of new infections are reported annually around the world. The etiological agent of the disease, Histoplasma, is a dimorphic fungus commonly found in the soil where it grows as mycelia. Humans can become infected by Histoplasma through inhalation of its spores (conidia) or mycelial particles. The fungi transition into the yeast phase in the lungs at 37°C. Once in the lungs, yeast cells reside and proliferate inside alveolar macrophages. Genomic work has revealed that Histoplasma is composed of at least five cryptic phylogenetic species that differ genetically. Three of those lineages have received new names. Here, we evaluated multiple phenotypic characteristics (colony morphology, secreted proteolytic activity, yeast size, and growth rate) of strains from five of the phylogenetic species of Histoplasma to identify phenotypic traits that differentiate between these species: Histoplasma capsulatum sensu stricto, Histoplasma ohiense, Histoplasma mississippiense, Histoplasma suramericanum, and an African lineage. We report diagnostic traits for three species. The other two species can be identified by a combination of traits. Our results suggest that (i) there are significant phenotypic differences among the cryptic species of Histoplasma and (ii) those differences can be used to positively distinguish those species in a clinical setting and for further study of the evolution of this fungal pathogen.IMPORTANCEIdentifying species boundaries is a critical component of evolutionary biology. Genome sequencing and the use of molecular markers have advanced our understanding of the evolutionary history of fungal pathogens, including Histoplasma, and have allowed for the identification of new species. This is especially important in organisms where morphological characteristics have not been detected. In this study, we revised the taxonomic status of the four named species of the genus Histoplasma, H. capsulatum sensu stricto (ss), H. ohiense, H. mississippiense, and H. suramericanum, and propose the use of species-specific phenotypic traits to aid their identification when genome sequencing is not available. These results have implications not only for evolutionary study of Histoplasma but also for clinicians, as the Histoplasma species could determine the outcome of disease and treatment needed.

Histoplasmosis: An epidemiological and clinical update in China, review and a case report.

Histoplasmosis is a systemic mycosis caused by the dimorphic fungus in the genus Histoplasma. Histoplasmosis is overlooked in China. This study aims to provide an epidemiological and clinical update on histoplasmosis in China by literature review. We reviewed cases of histoplasmosis reported in recent 11 years and described a case of histoplasmosis-triggered hemophagocytic lymphohistiocytosis (HLH) in an immunocompetent patient. A total of 225 cases of histoplasmosis diagnosed in China between 2012 and 2022 were involved in this study, compared with 300 cases reviewed from 1990 to 2011, an increasing number of cases of histoplasmosis have been diagnosed in the last 11 years. The majority of cases of histoplasmosis were autochthonous cases, mainly from provinces Sichuan (56/225, 24.9%), Hunan (50/225, 22.2%), Guangdong (31/225, 13.8%), and Yunnan (24/225, 10.7%). Higher incidence (52.5%, 53/99) of histoplasmosis occurred in immunocompetent patients which is similar to those from the previous 21 years, and the prevalence of the disease did not vary highly over time. Of note, the number of histoplasmosis cases is increasing, and the geographic distribution is shifting southwards over time. Improved awareness is critically important for informing clinical practice in China.

Pulmonary Histoplasmosis Mimicking Lung Cancer.

Teaching point: Due to the mass-like appearance of pulmonary histoplasmosis in the lung, radiological misdiagnosis may occur. Fungal infections should be considered in the differential diagnosis, especially in immune-compromised patients.

Histoplasma capsulatum as a cause for prolonged pulmonary illness in an immunocompetent returning traveller from Bangladesh.

Fungal infections can be challenging to diagnose in returning travellers due to their non-specific clinical manifestations and changing epidemiology. We present a case of progressive disseminated histoplasmosis in a returning traveller from Bangladesh. The patient had a progressive and prolonged respiratory illness necessitating mechanical ventilatory support. The clue to potential fungal aetiology was provided by serum fungal markers - 1-3-ß-D-glucan and Aspergillus galactomannan. Diagnosis was eventually made using panfungal PCR on bronchioalveolar lavage fluid.

Histoplasma seropositivity and environmental risk factors for exposure in a general population in Upper River Region, The Gambia: A cross-sectional study.

Robust surveillance of Histoplasma species is warranted in endemic regions, including investigation of community-level transmission dynamics. This cross-sectional study explored anti-Histoplasma antibody seroprevalence and risk factors for exposure in a general population in Upper River Region (URR), The Gambia. Study participants were recruited (December 2022-March 2023) by random household sampling across 12 Enumeration Areas (EAs) of URR. A questionnaire and clinical examination were performed; exploring demographic, clinical and environmental risk factors for Histoplasma exposure. One venous blood sample per participant was subject to IMMY Latex Agglutination Histoplasma test to determine presence of a recent IgM response to Histoplasma. Seropositivity risk factors were explored by multi-level, multivariable logistic regression analysis. The study population (n = 298) aged 5-83 years, demonstrated a positively skewed age distribution and comprised 55.4% females. An apparent seroprevalence of 18.8% (n = 56/298, 95% CI 14.5-23.7%) was measured using the LAT. A multivariable model demonstrated increased odds of Histoplasma seropositivity amongst female participants (OR = 2.41 95% CI 1.14-5.10); and participants reporting involvement in animal manure management (OR = 4.21 95% CI 1.38-12.90), and management of domestic animals inside the compound at night during the dry season (OR = 10.72 95% CI 2.02-56.83). Increasing age (OR = 0.96 95% CI 0.93-0.98) was associated with decreased odds of seropositivity. Clustering at EA level was responsible for 17.2% of seropositivity variance. The study indicates frequent recent Histoplasma exposure and presents plausible demographic and environmental risk factors for seropositivity. Histoplasma spp. characterisation at this human-animal-environment interface is warranted, to determine public health implications of environmental reservoirs in The Gambia. The study was supported by Wellcome Trust (206,638/Z/17/Z to CES) and a University of Liverpool-funded PhD studentship (to TRC).

Hepatic insufficiency in two juvenile dogs with histoplasmosis.

A 9-month-old female intact toy poodle and a 1-year-old female intact Labrador retriever mix presented to separate teaching hospitals for chronic histories of malaise and clinicopathologic evidence of hepatic dysfunction. The signalment and clinical histories of these dogs prompted consideration of a congenital portosystemic shunt as a primary differential. However, microscopic evaluation of peritoneal effusion, pleural effusion, and peripheral blood samples from the dogs revealed round to ovoid yeast organisms morphologically most compatible with Histoplasma capsulatum. Additional testing confirmed histoplasmosis in each case. The poodle underwent a computed tomography (CT) study, which showed hepatomegaly with a spleno-gonadal shunt, pancreatic and gastric wall edema, and marked peritoneal effusion, findings compatible with portal hypertension and secondary acquired shunt formation. The dog was later humanely euthanized due to clinical deterioration, and on necropsy hepatic histoplasmosis was verified, with additional affected tissues comprising lungs and spleen. The Labrador Retriever mix responded clinically and clinicopathologically to antifungal therapy, though no abdominal imaging was performed to definitively exclude the possibility of a congenital portosystemic shunt. In retrospect, several features were more compatible with histoplasmosis than portosystemic shunt in these cases, including hyperbilirubinemia, effusion, and hepatomegaly. These findings serve as a reminder of the need to interpret serum biochemical findings in the context of the totality of the clinicopathologic data and imaging findings, as well as the diagnostic value of microscopy in the evaluation of hematologic and body cavity fluid samples.

Clinical Characteristics and Outcomes of Endemic Mycoses After Solid Organ Transplantation: A Comprehensive Review.

Background: Geographically endemic fungi can cause significant disease among solid organ transplant (SOT) recipients. We provide an update on the epidemiology, clinical presentation, and outcomes of 5 endemic mycoses in SOT recipients. Methods: Multiple databases were reviewed from inception through May 2023 using key words for endemic fungi (eg, coccidioidomycosis or Coccidioides, histoplasmosis or Histoplasma, etc). We included adult SOT recipients and publications in English or with English translation. Results: Among 16 cohort studies that reported on blastomycosis (n = 3), coccidioidomycosis (n = 5), histoplasmosis (n = 4), and various endemic mycoses (n = 4), the incidence rates varied, as follows: coccidioidomycosis, 1.2%-5.8%; blastomycosis, 0.14%-0.99%; and histoplasmosis, 0.4%-1.1%. There were 204 reports describing 268 unique cases of endemic mycoses, including 172 histoplasmosis, 31 blastomycosis, 34 coccidioidomycosis, 6 paracoccidioidomycosis, and 25 talaromycosis cases. The majority of patients were male (176 of 261 [67.4%]). Transplanted allografts were mostly kidney (192 of 268 [71.6%]), followed by liver (n = 39 [14.6%]), heart (n = 18 [6.7%]), lung (n = 13 [4.9%]), and combined kidney-liver and kidney-pancreas (n = 6 [2.7%]). In all 5 endemic mycoses, most patients presented with fever (162 of 232 [69.8%]) and disseminated disease (179 of 268 [66.8%]). Cytopenias were frequently reported for histoplasmosis (71 of 91 [78.0%]), coccidioidomycosis (8 of 11 [72.7%]) and talaromycosis (7 of 8 [87.5%]). Graft loss was reported in 12 of 136 patients (8.8%). Death from all-causes was reported in 71 of 267 (26.6%); half of the deaths (n = 34 [50%]) were related to the underlying mycoses. Conclusions: Endemic mycoses commonly present with fever, cytopenias and disseminated disease in SOT recipients. There is a relatively high all-cause mortality rate, including many deaths that were attributed to endemic mycoses.

Pulmonary histoplasmosis on the Chinese mainland: two case reports and literature review.

INTRODUCTION: Pulmonary histoplasmosis is a fungal disease that is endemic in North and Central America. It is relatively rare in China and commonly misdiagnosed as tuberculosis or cancer due to nonspecific clinical and radiographic manifestations. Rapid and accurate pathogen tests are critical for the diagnosis of pulmonary histoplasmosis. METHODOLOGY: We report two cases of pulmonary histoplasmosis. We collected all the relevant case reports on the Chinese mainland (from 1990 to 2022) to analyze features of this disease among Chinese patients. RESULTS: A total of 42 articles reporting 101 cases were identified, and the two cases reported in this article were also included for analysis. Sixty-three (61.2%) patients had respiratory symptoms and 35 (34.0%) patients were asymptomatic. The most common radiographic findings were pulmonary nodules or masses (81.6%). Twenty-two (21.4%) patients were misdiagnosed as tuberculosis, and 37 (35.9%) were misdiagnosed as lung tumors before pathological findings. Metagenomic next­generation sequencing (mNGS) testing provided a rapid diagnostic and therapeutic basis for three patients. CONCLUSIONS: Clinical features and imaging findings of pulmonary histoplasmosis are not specific. Relevant epidemiological history and timely pathogen detection are important for diagnosis. mNGS can shorten the time required for diagnosis and allow earlier initiation of targeted antibiotic therapy.

Epidemiological, clinical, diagnostic, and therapeutic features of histoplasmosis: A systematic review.

Histoplasmosis is a mycosis due to a dimorphic fungus Histoplasma capsulatum. This study aimed at providing an overview of histoplasmosis epidemiological, clinical, diagnostic, and therapeutic aspects from the last 30 years. This review was carried out using a systematic literature search on histoplasmosis from 1992 to 2021. We describe the clinical features, diagnostic methods and treatment. Empirical searches were conducted via the databases PubMed, Google Scholar and Science Direct. Between 1992 and 2021, 190 manuscripts were published and reported 212 cases of histoplasmosis. These publications included 115 and 97 cases of American and African histoplasmosis respectively. The number of publications increased over the last ten years with a maximum in 2020 (12.34 % of the cases reported). The disseminated forms of histoplasmosis were the most frequently reported cases as compared to the localized forms. This was the case with the American histoplasmosis (75.65 %) as well as with the African histoplasmosis (55.67 %). Itraconazole (31.17 %) and Amphotericin B (26.62 %) were the most used drugs in the management of these cases. American histoplasmosis is distributed worldwide whereas African histoplasmosis is mainly present in intertropical Africa. There is a critical need for setting up a global surveillance system, towards a better understanding of the disease.

Histoplasma capsulatum tenosynovitis: An unusual presentation in a kidney transplant recipient.

Histoplasmosis is an expected endemic mycosis in solid organ transplant recipients and occurs as a primary infection, reactivation, or, rarely, acquired from an infected allograft. Reactivation is favored by maintenance immunosuppression or anti-rejection therapy, which facilitates the appearance of disseminated forms as well as unusual presentations. We present the case of a 66-year-old woman with isolated tenosynovitis due to Histoplasma capsulatum 25 years after a kidney transplant.

Histoplasma antigens as novel players for the development of new enzyme immunoassays for the serodiagnosis of histoplasmosis: A comparative study of their analytical performance.

Definitive diagnosis of histoplasmosis relies on culture and/or cytology/histopathology; however, these procedures have limited sensitivity and cultures are time-consuming. Antibodies detection by immunodiffusion has low sensitivity in immunocompromised individuals and uses histoplasmin (HMN), a crude antigenic extract, as reagent. Novel protein antigen candidates have been recently identified and produced by DNA-recombinant techniques to obtain standardized and specific reagents for diagnosing histoplasmosis. To compare the analytical performance of novel enzyme-linked immunosorbent assays (ELISAs) for antibodies testing for diagnosing histoplasmosis using different Histoplasma capsulatum antigens as reagents. The H. capsulatum 100 kDa protein (Hcp100), the M antigen and its immunoreactive fragment F1 were produced by DNA-recombinant techniques. Galactomannan was purified from both the yeast and mycelial cell walls (yGM and mGM, respectively). The analytical performance of the ELISA tests for the serological detection of antibodies against these antigens was evaluated and compared with those obtained using HMN as reagent. Antibodies detection by the Hcp100 ELISA demonstrated 90.0% sensitivity and 92.0% specificity, versus 43.3% sensitivity and 95.0% specificity of the M ELISA, 33.3% sensitivity and 84.0% specificity of the F1 ELISA, 96.7% sensitivity and 94.0% specificity of the yGM ELISA, 83.3% sensitivity and 88.0% specificity of the mGM ELISA, and 70.0% sensitivity and 86.0% specificity for the HMN ELISA. In summary, Hcp100 is proposed as the most promising candidate for the serodiagnosis of histoplasmosis. The primary immunoreactive element in HMN proved to be GM rather than the M antigen. Nevertheless, a higher incidence of cross-reactions was noted with GM compared to M.

Hcp100 is a promising serodiagnostic candidate for histoplasmosis, boasting high sensitivity and specificity. Notably, GM, rather than M antigen, emerged as the primary immunoreactive element in HMN, despite a higher incidence of cross-reactions with GM compared to M.

Disseminated Histoplasmosis Infection Diagnosed by Metagenomic Next-Generation Sequencing: A Case Report.

Histoplasmosis is an endemic disease caused by Histoplasma capsulatum. This systemic disease can affect various organs beyond the lungs, such as the liver, spleen, adrenal gland, and lymph nodes. The clinical symptoms can range from asymptomatic to severe, life-threatening conditions, depending on the state of the patient's immune system. This report describes a 40-year-old male who presented with reports of weight loss, low back pain, and progressively worsening movement disorder of the bilateral lower extremities for months. Computed tomography (CT) examination showed multiple lytic lesions of vertebral bodies, bilateral ribs, and pelvic bone, histopathological examination and tumor-related serum markers exclude tumors. mNGS was employed to identify H. capsulatum var. capsulatum as the etiological agent of the lesions in the bone biopsy. Through phylogenetic tree analysis, Histoplasma capsulatum var. Capsulatum (Hcc) was the main responsible pathogen, rarely reported in bone lesions. The patient underwent spinal surgery and was successfully treated with liposomal amphotericin B and itraconazole. Based on the diagnosis and treatment of this case, we discuss the epidemiologic status, clinical presentations, diagnostic criteria, and treatment guidelines of histoplasmosis to provide additional information about this disease. mNGS is utilized in this case, and it appears to be a reliable method for early and accurate diagnosis of this disease.

Haemophagocytic lymphohistiocytosis secondary to disseminated histoplasmosis in an immunocompetent patient.

Haemophagocytic lymphohistiocytosis secondary to Histoplasma infection is rare and almost always occurs in immunocompromised hosts. We report a 32-year-old immunocompetent man presenting with a nonspecific febrile illness found to have disseminated histoplasmosis and associated haemophagocytic lymphohistiocytosis. The diagnosis was confirmed on histopathological examination and PCR of liver and bone marrow biopsies. He was successfully treated with steroids, intravenous immunoglobulin and itraconazole.