Histoplasmosis: A systematic review to inform the World Health Organization of a fungal priority pathogens list.

Histoplasmosis, a significant mycosis primarily prevalent in Africa, North and South America, with emerging reports globally, poses notable health challenges, particularly in immunocompromised individuals such as people living with HIV/AIDS and organ transplant recipients. This systematic review, aimed at informing the World Health Organization's Fungal Priority Pathogens List, critically examines literature from 2011 to 2021 using PubMed and Web of Science, focusing on the incidence, mortality, morbidity, antifungal resistance, preventability, and distribution of Histoplasma. We also found a high prevalence (22%-44%) in people living with HIV, with mortality rates ranging from 21% to 53%. Despite limited data, the prevalence of histoplasmosis seems stable, with lower estimates in Europe. Complications such as central nervous system disease, pulmonary issues, and lymphoedema due to granuloma or sclerosis are noted, though their burden remains uncertain. Antifungal susceptibility varies, particularly against fluconazole (MIC: ≥32 mg/l) and caspofungin (MICs: 4-32 mg/l), while resistance to amphotericin B (MIC: 0.125-0.16 mg/l), itraconazole (MICs: 0.004-0.125 mg/l), and voriconazole (MICs: 0.004-0.125 mg/l) remains low. This review identifies critical knowledge gaps, underlining the need for robust, globally representative surveillance systems to better understand and combat this fungal threat.

Histoplasmosis in domestic cats: new minimally invasive diagnostic techniques.

OBJECTIVES: The aim of the present study was to evaluate minimally invasive diagnostic techniques, such as the semi-quantitative indirect IgG antibody enzyme immunoassay (EIA) using blood serum and the urinary lateral flow assay (LFA), for the detection of Histoplasma capsulatum in cats with histoplasmosis. METHODS: Eight client-owned domestic cats diagnosed with histoplasmosis were selected based on cytological, histopathological, mycological, molecular or antigenic techniques. The blood serum of these animals was tested in a semi-quantitative indirect IgG antibody EIA for the detection of H capsulatum. Urine samples were tested for H capsulatum antigen using LFA. RESULTS: Five cats were seropositive on IgG EIA (5/8, with diagnostic sensitivity equal to 62.5%; 95% confidence interval [CI] 24.5-91.5) and five cats were positive on H capsulatum antigen LFA (5/7, with diagnostic sensitivity equal to 71.4%; 95% CI 29.0-96.3). The combined diagnostic sensitivity when interpreted in parallel was 87.5% (7/8, 95% CI 47.3-99.7). The specificity for the anti-Histoplasma IgG EIA was 100% (95% CI 71.5-100) and for the H capsulatum antigen LFA it was also 100% (95% CI 71.5-100). CONCLUSIONS AND RELEVANCE: The semi-quantitative indirect IgG antibody EIA for the detection of H capsulatum in blood serum and the urinary LFA for the detection of the same agent emerge as new minimally invasive diagnostic techniques that can assist in the approach to disseminated and pulmonary feline histoplasmosis, especially when both techniques are considered together.

Rare Case of Disseminated Histoplasmosis Mitral Valve Endocarditis in Florida.

BACKGROUND Histoplasma capsulatum is prevalent in the mid-eastern United States and is an environmental fungus that causes human infection by the inhalation of its spores. It is commonly associated with areas containing large amounts of bird excrement and can survive for years in the soil. Only 1% of infected individuals develop disseminated histoplasmosis or Histoplasma endocarditis. CASE REPORT A 61-year-old man with atrial fibrillation had 8 months of fatigue, low-grade fevers, night sweats, and unexplained weight loss presented to the Emergency Department. He worked and lived in Central Florida and although he raised cattle, he denied exposure to birds or bats with regularity. A transesophageal echocardiogram confirmed a sessile echo density on the atrial surface of the mitral valve. His microbial Karius cell-free DNA test from his blood sample was positive for Histoplasma capsulatum, and he was immediately given intravenous liposomal amphotericin for 2 weeks. A tissue valve was used to successfully replace his mitral valve along with a coronary artery bypass and a maze procedure for his persistent atrial fibrillation and atrial flutter. The diagnosis of mitral valve endocarditis from disseminated histoplasmosis was confirmed by pathological analysis, and he was sent home on long-term itraconazole maintenance treatment. CONCLUSIONS Surgical intervention in combination with anti-fungal medication can be a lifesaving intervention for disseminated histoplasmosis. A thorough history is particularly important when evaluating a patient with an unknown infectious source, especially assessing for risk factors, including exposure to environmental factors, workplace, and animals.

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.

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.

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.

Case Report: Primary Cutaneous Histoplasmosis in an Immunocompetent Patient After Cosmetic Injection of Platelet-Rich Plasma Treated with Trimethoprim-Sulfamethoxazole.

BACKGROUND Histoplasmosis is typically associated with immunocompromised individuals, but cases in immunocompetent patients are rare. Primary cutaneous histoplasmosis (PCH) is a challenging diagnosis due to its clinical polymorphism and can mimic other infectious and non-infectious diseases. Previous cases of PCH have been reported in immunocompetent patients with underlying medical conditions or trauma history. So far there have been no reports of PCH after platelet-rich plasma (PRP) application due to inadequate hygiene measures in an immunocompetent host. CASE REPORT This case report presents a rare occurrence of PCH following a cosmetic procedure (PRP injection) in an immunocompetent patient. The patient developed nodule-like lesions at the application sites, which progressed to ulceration with purulent discharge. Initially, atypical mycobacterial infection was suspected, and empirical antibiotic therapy was initiated. Complementary tests were performed, ruling out immunosuppression and systemic pathogens. The patient showed complete resolution of the lesions after one month of atypical treatment with trimethoprim-sulfamethoxazole (TMP/SMX). Pathological examination confirmed the diagnosis of PCH with intracytoplasmic inclusions of Histoplasma sp. CONCLUSIONS This case highlights the importance of considering histoplasmosis as a diagnostic possibility, especially in hyperendemic areas like Venezuela. Direct inoculation of Histoplasma sp. after aesthetic procedures without proper hygiene measures can lead to pathological lesions, even in immunocompetent individuals. TMP/SMX can be considered as an alternative treatment option in the absence of the first-line medication. Further exploration of this treatment approach may benefit patients with similar clinical conditions or when ideal treatment options are unavailable.

Molecular detection of Histoplasma capsulatum in organ samples from bats randomly captured in urban areas of Araraquara, São Paulo state, Brazil.

The mycosis histoplasmosis is also considered a zoonosis that affects humans and other mammalian species worldwide. Among the wild mammals predisposed to be infected with the etiologic agent of histoplasmosis, bats are relevant because they are reservoir of Histoplasma species, and they play a fundamental role in maintaining and spreading fungal propagules in the environments since the infective mycelial phase of Histoplasma grows in their accumulated guano. In this study, we detected the fungal presence in organ samples of bats randomly captured in urban areas of Araraquara City, São Paulo, Brazil. Fungal detection was performed using a nested polymerase chain reaction to amplify a molecular marker (Hcp100) unique to H. capsulatum, which revealed the pathogen presence in organ samples from 15 out of 37 captured bats, indicating 40.5% of infection. Out of 22 Hcp100-amplicons generated, 41% corresponded to lung and trachea samples and 59% to spleen, liver, and kidney samples. Data from these last three organs suggest that bats develop disseminated infections. Considering that infected bats create environments with a high risk of infection, it is important to register the percentage of infected bats living in urban areas to avoid risks of infection to humans, domestic animals, and wildlife.

Survival Against the Odds-Hemophagocytic Lymphohistiocytosis Amidst the Shadows of Disseminated Histoplasmosis: A Case Report and Literature Review.

Hemophagocytic lymphohistiocytosis (HLH) secondary to Histoplasma capsulatum is rare, impacting <1% globally, with a mortality rate of up to 31%. Herein, we present a rare case of HLH secondary to H capsulatum, affecting a 57-year-old female with rheumatoid arthritis. Extensive investigations were unrevealing and despite broad-spectrum antibiotics, her condition worsened, leading to respiratory failure requiring extracorporeal membrane oxygenation (ECMO) support, shock requiring multiple vasopressors, and acute kidney injury (AKI) requiring hemodialysis. Diagnosis confirmed disseminated histoplasmosis (DHP), prompting Amphotericin B and methylprednisolone treatment, resulting in significant improvement and discharge with posaconazole therapy. Secondary HLH, primarily arising from severe infections like DHP, is discussed. Limited research exists on this condition in human immunodeficiency virus (HIV)-seronegative individuals. Diagnosis involves HLH-2004 and HScore criteria. Managing histoplasmosis-associated HLH remains challenging due to multiorgan failure risks and treatment complexities and needs further research.

Presentación atípica de histoplasmosis diseminada / Atypical presentation of disseminated histoplasmosis

La histoplasmosis es una micosis sistémica producida por una variedad de hongo dimorfo perteneciente al complejo Histoplasma capsulatum. Es una enfermedad prevalente en nuestro medio y sobre todo en pacientes viviendo con HIV con recuento de <200 linfocitos CD4/ml y con cargas virales mayores a 100.000 copias/ml. La presentación de la forma diseminada raramente suele afectar al aparato reproductor; siendo la forma más frecuente pulmonar

A Case Report of Pulmonary Vein Stenosis Within the Labyrinth of Fibrosing Mediastinitis.

This case centers on a 76-year-old male experiencing exertional dyspnea and hemoptysis, with a medical history marked by recurrent pulmonary embolism and chronic obstructive pulmonary disease (COPD). Notably, he resides in a histoplasmosis-endemic area. A computed tomography (CT) pulmonary embolism scan revealed notable findings, including an enlarged right lower pulmonary artery, vascular congestion, atelectasis, and a mass exerting pressure on the right lower pulmonary vein. Biopsy results identified the mass as fibrosing mediastinitis, likely attributed to histoplasmosis. A transthoracic echocardiogram indicated right ventricular dilatation, impaired function, and a right ventricular systolic pressure of 63 mm Hg. During right heart catheterization, the patient displayed disparate pulmonary artery wedge pressures (PAWPs) between the right and left sides. This discrepancy was linked to a blunted back wave from the left atrium to the catheter, induced by pulmonary vein compression. Although an infrequent phenomenon, the recorded asymmetry in PAWPs played a crucial role in guiding accurate patient management. The absence of subsequent evaluation of PAWP on the left side could have altered the treatment plan, potentially delaying appropriate patient care. This case emphasizes the necessity of thorough exploration with right heart catheterization when clinical symptoms warrant, highlighting the importance of standardized practices in such procedures.

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.

Implementation of a rapid diagnostic assay package for cryptococcosis, histoplasmosis and tuberculosis in people living with HIV in Paraguay.

BACKGROUND: Opportunistic infections (OIs) are common causes of mortality among people living with HIV (PLHIV). We determined prevalence and 30-day mortality due to histoplasmosis, cryptococcosis, and TB in PLHIV with advanced HIV disease (AHD). METHODS: PLHIV 18 years and older, with a CD4 + T-cell count of less than 350 cells/mm3 newly diagnosed with HIV infection or re-engaged in care after being without ART for more than 90 days (Group A). The second group included symptomatic PLHIV regardless of ART status or CD4 + T-cell count (Group B); all followed for 30 days. Detection of Histoplasma Ag (HisAg) in urine was done by enzyme immunoassay (EIA), Cryptococcus antigen (CrAg) was detected in serum and cerebrospinal fluid (CSF) specimens by lateral flow assay (LFA), and lipoarabinomannan (LAM) detection in urine was by LFA (TB LAM) and in sputum by GeneXpert for diagnosis of Mycobacterium infections. RESULTS: From August 2021 to June 2022, 491 PLHIV were enrolled; 482 (98%) had a CD4 + T-cell result, and 381 patients (79%) were classified with AHD according to CD4 + T-cell count (< 200 CD4/mm3). Frequency of an OI was 38% (n = 145/381). Antigen test positivity rate was 16% (72/467) for TB-LAM, 9% (43/464) for HisAg, and 11% (51/484) for CrAg. Twenty-one of 34 (62%) patients receiving CSF CrAg tests were positive, confirming meningitis. Significant differences in 30-day mortality were observed in patients with an OI (16%) vs. no OI (7%) (p = 0.002). Mortality was highest in patients with histoplasmosis (25%), co-infection (22%), cryptococcosis (18% overall; 19% for cryptococcal meningitis), and TB (10%). CONCLUSIONS: TB and fungal OIs, including co-infection, were common in PLHIV in Paraguay and had high associated mortality. Laboratories and health facilities need access to CD4 + T-cell testing and rapid diagnostic assays.

Tracing histoplasmosis genomic epidemiology and species occurrence across the USA.

ABSTRACTHistoplasmosis is an endemic mycosis in North America frequently reported along the Ohio and Mississippi River Valleys, although autochthonous cases occur in non-endemic areas. In the United States, the disease is provoked by two genetically distinct clades of Histoplasma capsulatum sensu lato, Histoplasma mississippiense (Nam1) and H. ohiense (Nam2). To bridge the molecular epidemiological gap, we genotyped 93 Histoplasma isolates (62 novel genomes) including clinical, environmental, and veterinarian samples from a broader geographical range by whole-genome sequencing, followed by evolutionary and species niche modelling analyses. We show that histoplasmosis is caused by two major lineages, H. ohiense and H. mississippiense; with sporadic cases caused by H. suramericanum in California and Texas. While H. ohiense is prevalent in eastern states, H. mississipiense was found to be prevalent in the central and western portions of the United States, but also geographically overlapping in some areas suggesting that these species might co-occur. Species Niche Modelling revealed that H. ohiense thrives in places with warmer and drier conditions, while H. mississippiense is endemic to areas with cooler temperatures and more precipitation. In addition, we predicted multiple areas of secondary contact zones where the two species co-occur, potentially facilitating gene exchange and hybridization. This study provides the most comprehensive understanding of the genomic epidemiology of histoplasmosis in the USA and lays a blueprint for the study of invasive fungal diseases.

Insights, experiences, and perspectives on the rapid diagnosis of tuberculosis, histoplasmosis, and cryptococcosis in people with advanced HIV disease in Porto Alegre

People living with HIV (PLHIV) with severe advanced disease are at high risk of developing opportunistic infections and may face barriers related to diagnosis and treatment. The objective of this study was to describe insights, experiences and perspectives around the feasibility of implementing a package for the rapid diagnosis of frequent opportunistic infections among patients with advanced HIV, in order to support the development and implementation of HIV care policies. The study was carried out between June 30 and October 30, 2023, comprising two focus groups with health professionals involved in the rapid diagnosis intervention (n=10); four in-depth interviews with health managers dedicated to HIV care policies; and 12 interviews with patients with advanced HIV. The intervention in question was considered relevant for allowing a more timely diagnosis of diseases that are difficult to investigate. Patient compliance was generally collaborative, especially in research hospitals, but more vulnerable patients may require expanded psychosocial support. Among the barriers, delays in results, communication challenges between professionals and patients were highlighted, as well as the lack of alignment in the flow of exam request, collection, results and communication for patients and the extended team. At the management level, the importance of integrating the intervention into the line of care for patients with HIV was highlighted. It is relevant to investigate the issue of social determinants of HIV/AIDS mortality in the future to provide valuable insights into improving prevention and treatment strategies.

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.

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.