Molecular identification of Histoplasma capsulatum in patients with disseminated histoplasmosis and acquired immunodeficiency syndrome.

Histoplasmosis is caused by the fungus Histoplasma capsulatum and is often fatal for individuals with acquired immunodeficiency syndrome (AIDS). Delayed diagnosis is a major factor in worsening coinfection, as it can be mistaken for other diseases. Thus, rapid identification of Histoplasma in immunocompromised patients is essential. Molecular techniques, particularly polymerase chain reaction (PCR), were used in this study to identify H. capsulatum in patients coinfected with histoplasmosis and AIDS. Blood samples from 14 individuals with AIDS and disseminated histoplasmosis were collected and analyzed. The PCR method successfully amplified the fungal region in whole blood samples, while PCR-RFLP analysis confirmed a consistent profile in the samples. Genetic sequencing further confirmed the fungal species. Compared to clinical tests such as fungal culture and urinary antigen detection, molecular analysis proved faster, more sensitive, and cost-effective. These molecular markers can potentially be incorporated into routine diagnostics in the future. Further studies are needed to expand and enhance this diagnostic approach, particularly in patients with nonprogressive clinical forms of histoplasmosis.

Haemophagocytic lymphohistiocytosis secondary to disseminated histoplasmosis in a patient with leprosy.

Multidrug therapy has significantly reduced the global burden of Hansen's disease; however, complications from long-term treatment persist. A male resident of southern Kentucky, in his 30s and of Micronesian descent, presented with worsening abdominal pain associated with anorexia, fatigue, functional decline and occasional haemoptysis. He was compliant with multidrug therapy for leprosy. Laboratory investigations revealed pancytopenia. He was initially treated under a sepsis protocol and later switched to high-dose steroids due to a suspected immune reaction from missed corticosteroid doses. Despite aggressive treatment for refractory pancytopenia, the patient's condition deteriorated, and he passed away from cardiac arrest. Posthumous bone marrow biopsy revealed haemophagocytic lymphohistiocytosis secondary to disseminated histoplasmosis with bone marrow infiltration. This case highlights the importance of proactive fungal screening in immunocompromised leprosy patients, particularly in endemic regions, as early detection and timely intervention can prevent severe complications.

Associations between Minority Health Social Vulnerability Index Scores, Rurality, and Histoplasmosis Incidence, 8 US States.

To explore associations between histoplasmosis and race and ethnicity, socioeconomic status, and rurality, we conducted an in-depth analysis of social determinants of health and histoplasmosis in 8 US states. Using the Minority Health Social Vulnerability Index (MH SVI), we analyzed county-level histoplasmosis incidence (cases/100,000 population) from the 8 states by applying generalized linear mixed hurdle models. We found that histoplasmosis incidence was higher in counties with limited healthcare infrastructure and access as measured by the MH SVI and in more rural counties. Other social determinants of health measured by the MH SVI tool either were not significantly or were inconsistently associated with histoplasmosis incidence. Increased awareness of histoplasmosis, more accessible diagnostic tests, and investment in rural health services could address histoplasmosis-related health disparities.

Disseminated Histoplasma captulatum infection in a patient with HIV.

Histoplasmosis capsulatum is a dimorphic fungus, recognised for its endemic presence in multiple global regions. It may cause severe opportunistic disseminated infection in immunocompromised individuals. This is a case report of a 33-year-old man from Thailand who was admitted at a Danish hospital with fever, weight loss, cough, nosebleeds, and newly diagnosed HIV. The clinical condition rapidly deteriorated with lung and kidney failure. The patient was diagnosed with H. capsulatum fungaemia first detected on blood smear. He was treated with intravenous amphotericin B followed by oral itraconazole as well as antiretroviral therapy.

Central Nervous System Histoplasmosis After Acute COVID-19 in An Adolescent.

Central nervous system histoplasmosis is a serious complication of a common endemic mycosis, but it is rare in immunocompetent hosts. SARS-CoV-2 has introduced significant challenges into the healthcare setting with overlapping clinical presentations that may delay the diagnosis of alternative conditions. Additionally, it may lead to immune dysregulation and increase the risk for secondary infections, including invasive fungal diseases. Limited reports have described disseminated histoplasmosis in adults associated with COVID-19, but none have described central nervous system infection or complications in pediatric patients. We report a case of disseminated histoplasmosis involving the central nervous system in a previously healthy 13-year-old male with SARS-CoV-2 infection. An extensive immunological evaluation did not identify an underlying immunodeficiency. We highlight the potential of COVID-19 immune dys-regulation to contribute to the development or progression of invasive fungal disease. [Pediatr Ann. 2024;53(8):e305-e309.].

Haemophagocytic lymphohistiocytosis (HLH) secondary to disseminated histoplasmosis infection in a patient with HIV.

A male in his 30s who was recently diagnosed with HIV arrived at the emergency department exhibiting an altered mental state and acute respiratory distress. Initial laboratory tests revealed a high anion gap metabolic acidosis, elevated liver enzyme levels and bicytopenia. A CT scan identified a miliary pattern. Bronchoscopy with bronchoalveolar lavage displayed epithelial and inflammatory cells. However, subsequent tests ruled out the presence of fungi, Pneumocystis organisms, malignancies, granulomas and viral inclusions. Broad-spectrum antibiotics with emphasis on Mycobacterium tuberculosis and antifungal treatments were administered. The regimen was adjusted after a positive urine test for the Histoplasma antigen.The patient later manifested signs and symptoms, including increased ferritin level, fever, splenomegaly, diminished natural killer cell function and heightened interleukin-2 receptor levels, confirming haemophagocytic lymphohistiocytosis. Given the patient's gravely decompensated state, the treatment incorporated dexamethasone, and the patient's vasopressor-resistant septic shock was addressed with methylene blue.

Disseminated Histoplasmosis Presenting as Pyrexia of Unknown Origin in a Rheumatoid Arthritis Patient.

We present a case of a 56-year-old female with rheumatoid arthritis (RA) who has been on methotrexate for 9 years and has been complaining of high-grade fever for the past 1 month with no localizing signs and symptoms. She was thoroughly evaluated before being labeled as pyrexia of unknown origin. Histoplasmosis was suspected after bone marrow aspiration smear examination. The presence of histoplasma antigen in the urine confirmed our diagnosis. Fever responded after 2 weeks of liposomal amphotericin B and patient discharged in stable condition on tablet itraconazole.

The impact of immune recovery and treatment duration on disseminated histoplasmosis consolidation therapy in AIDS patients.

INTRODUCTION: The present study investigated the impact of immune recovery and the duration of antifungal adherence in the consolidation phase of disseminated histoplasmosis (DH) in acquired immune deficiency syndrome (AIDS) patients living in a hyperendemic area in northeastern Brazil. MATERIAL AND METHODS: Sixty-nine patients with DH/AIDS, admitted to the São José Hospital between 2010 and 2015, who continued histoplasmosis consolidation therapy at the outpatient clinic were studied. The follow-up duration was at least 24 months. RESULTS: Sixty-eight patients used itraconazole 200-400 mg/day or amphotericin B deoxycholate weekly during the consolidation phase, and six patients relapsed during follow-up. The overall median duration of consolidation antifungal use was 250 days [IQR 101 - 372]. Antifungal withdrawal by medical decision occurred in 41 patients (70.7 %) after a median of 293 days [IQR 128 - 372] of use; 16 patients discontinued by their own decision, with a median of 106 days [IQR 37 - 244] of therapy; three patients had no information available, and nine continued on AF therapy. The median CD4+ T-cell count in the group without relapse was 248 cells/µL [IQR 115-355] within 6 months after admission; conversely, in the relapse group, the median cell count remained below 100 cells/µL. Irregular adherence to highly active antiretroviral therapy (HAART) was the leading risk factor associated with relapse and death (p< 0.01). DISCUSSION: The regular use of HAART, combined with immune recovery, proved to be highly effective in preventing relapses in DH/AIDS patients, suggesting that long-term antifungal therapy may not be necessary.

Molecular characterisation of Histoplasma capsulatum sensu lato from Ethiopian horses reveals two distinct phylogenetic clades.

Epizootic lymphangitis (EL) is a highly prevalent and contagious infectious disease affecting horses in many parts of Ethiopia caused by Histoplasma capsulatum sensu lato ('var. farciminosum'). In this study, 12 suspected isolates of H. capsulatum sensu lato or yeasts unidentified by conventional biochemical tests isolated from Ethiopian horses with EL were characterised by internal transcribed spacer sequencing. Six of the 12 isolates were identified to be members of H. capsulatum sensu lato and the other six were Pichia kudriavzevii (synonym: Candida krusei) (n = 3), Trichosporon asahii (n = 1), Geotrichum silvicola (n = 1) and Moesziomyces aphidis (n = 1), respectively. The six H. capsulatum sensu lato isolates were further characterised by multilocus sequence analysis. Four distinct gene loci (arf [462 bases], H-anti [410 bases], ole1 [338 bases] and tub1 [272 bases]) of these six isolates as well as those of two H. capsulatum sensu lato ('var. farciminosum') reference strains (ATCC 58332 and ATCC 28798) were polymerase chain reaction (PCR)-amplified and sequenced. Phylogenetic analyses of their concatenated nucleotide sequences showed that three of the isolates and the reference strain ATCC 58332 were identical and belonged to the Eurasia clade within Latin American (LAm) A (H. suramericanum), and those of the other three isolates and the reference strain ATCC 28798 were identical and belonged to the Africa clade. At least two distinct phylogenetic clades of H. capsulatum sensu lato were circulating in Ethiopian horses with EL. Advanced molecular technologies and bioinformatics tools are crucial for the accurate identification and typing of pathogens as well as the discovery of novel microorganisms in veterinary microbiology.

Using multilocus sequence analysis with four concatenated housekeeping gene loci, at least two distinct phylogenetic clades, namely Eurasia clade and Africa clade, of Histoplasma capsulatum sensu lato were confirmed to be circulating in Ethiopian horses with epizootic lymphangitis.

Histoplasma capsulatum urinary antigen detection in a kidney transplant recipient with acute paracoccidioidomycosis: Case study and literature review.

BACKGROUND: Paracoccidioidomycosis (PCM) and histoplasmosis are endemic fungal diseases in South America. Both can lead to lung involvement with fungal dissemination progressing to systemic and severe clinical manifestations, especially in immunosuppressed hosts. As the population of immunosuppressed individuals has been rising, a higher occurrence of fungal infections is predicted in this setting. This poses challenges regarding the differential diagnosis due to overlapping clinical and laboratorial findings, hampering the management of cases. OBJECTIVES: In this study, the authors discuss the occurrence of a false-positive Histoplasma urinary antigen detection in a kidney transplant recipient with acute PCM. Given the scarce information about this subject, a review on literature data is provided. METHODS: A comprehensive literature search was conducted to investigate previous studies that found cross-reactivity between Histoplasma urinary antigen assays in human patients with confirmed diagnosis of PCM. Additionally, an update of PCM in transplant recipients is provided. FINDINGS: The included studies reported 120 samples from patients with PCM tested for Histoplasma antigen, presenting an overall cross-reactivity of 51.67% and 17 cases of PCM in transplant recipients. CONCLUSIONS: The galactomannan urinary antigen developed to diagnose histoplasmosis can cross react with PCM, which may represent a concern in countries where both mycoses overlap.

Systematic Review of Prevalence of Histoplasma Antigenuria in Persons with HIV in Latin America and Africa.

Histoplasmosis is a fungal disease associated with substantial mortality rates among persons with advanced HIV disease. Our systematic review synthesized data on the global prevalence of Histoplasma--caused antigenuria in persons with HIV. We searched PubMed/Medline, Embase, and Scopus databases on January 3, 2023, to identify cross-sectional and cohort studies evaluating Histoplasma antigenuria prevalence among adults with HIV infection. We calculated point estimates and 95% CIs to summarize prevalence. Of 1,294 studies screened, we included 15. We found Histoplasma antigenuria among 581/5,096 (11%; 95% CI 11%-12%) persons with HIV and 483/3,789 persons with advanced HIV disease (13%; 95% CI 12%-14%). Among persons with HIV and symptoms consistent with histoplasmosis, Histoplasma antigenuria prevalence was 14% (95% CI 13%-15%; 502/3,631 participants). We determined that persons with advanced HIV disease, inpatients, and symptomatic persons might benefit from a systematic approach to early detection of histoplasmosis using urine antigen testing.

SUBA-itraconazole in the treatment of systemic fungal infections.

Conventional itraconazole (c-ITZ) can be used for a variety of fungal infections although variable absorption has been a significant limitation. Super-bioavailable itraconazole (SUBA-ITZ) is a novel formulation that overcomes absorption concerns by utilizing a polymer-matrix to disperse active drug and facilitate dissolution. The pH-driven matrix allows concurrent proton pump inhibitor administration without significant effects on drug concentrations. The enhanced bioavailability of SUBA-ITZ allows for lower dosing, while achieving similar serum concentrations as c-ITZ and SUBA-ITZ is now US FDA approved in the treatment of blastomycosis, histoplasmosis and aspergillosis. Common side effects of SUBA-ITZ include gastrointestinal disorders, peripheral edema and drug-induced hypertension. Given the significant differences in pharmacokinetics between the formulations, c-ITZ and SUBA-ITZ capsules are not considered interchangeable. It is important to note that drug errors may occur when transitioning a patient from one formulation to another.

Itraconazole is an antifungal agent used in the treatment of a number of mycoses. Prior formulations (versions) of itraconazole required strict dietary requirements and often had poor absorption. A new itraconazole formulation has since been developed ­ super bioavailable itraconazole (SUBA-itraconazole). This has no food requirements, has superior absorption and maintains effectiveness against a number of fungal infections.

Histoplasmosis in non-immunosuppressed patients from an endemic area in Northeastern Brazil.

Differently from immunocompromised patients, very little information is available in the literature regarding the clinical presentation, epidemiology, and outcomes of histoplasmosis in non-immunosuppressed individuals living in endemic areas. This retrospective case series study was carried out by reviewing the medical records of non-immunocompromised patients with histoplasmosis, residents in a hyperendemic area in northeastern Brazil, between 2011 and 2022. Thirty HIV-negative patients were identified with histoplasmosis, and 19 cases met the inclusion criteria: three had acute, five subacute and one chronic pulmonary forms; two with mediastinal picture and eight had disseminated disease (two with severe symptoms). The median age of our sample was 32.7 years old [interquartile range: 24-45]. Most of the patients were male (male-to-female ratio = 15:4) and resided in the state capital (n = 9). The majority had a previous history of exposure to well-known risk factors for Histoplasma infection. Pulmonary nodules were observed in all subacute form, two patients (acute and subacute forms) were initially treated empirically for pulmonary tuberculosis; one death was registered in the subacute form. The chronic pulmonary form of histoplasmosis was diagnosed in one patient only after the symptoms persisted despite specific treatment. The primary clinical manifestations of the moderate form of DH were enlarged lymph nodes, with histopathology being the main diagnostic method. The cases were detected as isolated occurrences and not as an outbreak, suggesting that exposure to Histoplasma can be more widespread than presumed. Despite the self-limiting nature of the disease, death can occur even in previously heathy patients.

This study aimed to describe the presentation of histoplasmosis outside the context of immunosuppression, including the diagnostic methods, epidemiology, and main radiological and clinical features. A better understanding of the various forms of this disease will help improve case management.

Histoplasmosis in a fingolimod-treated patient: case report and scoping review.

Fingolimod is a sphingosine-1-phosphate receptor modulator used to treat multiple sclerosis. While fingolimod has been associated with an increased risk of cryptococcal meningitis, its correlation with other deep mycoses remains unclear. In this study, we conducted a scoping review of fingolimod associated with histoplasmosis, based on a case report, a literature review, and data from the FDA Adverse Events Reporting System (FAERS) as of January 24th, 2023. A 30-year-old Brazilian woman diagnosed with relapsing-remitting multiple sclerosis, receiving a daily dose of 0.5 mg of fingolimod, presented with a two-month history of fever and unintended weight loss, accompanied by lymphadenopathy, splenomegaly, and lung involvement was investigated. Biopsy of a lung nodule revealed fungal structures suggestive of Histoplasma sp. Additionally, serological testing yielded positive for Histoplasma capsulatum. Disseminated histoplasmosis should be considered in the differential diagnosis of febrile syndromes in patients undergoing fingolimod therapy for multiple sclerosis, particularly in the Americas, where this mycosis is endemic. Treatment with itraconazole and modification of immunotherapy can achieve excellent clinical outcomes.

Antifungal efficacy and immunomodulatory effect of PLGA nanoparticle-encapsulated itraconazole in histoplasmosis in vivo model.

INTRODUCTION: Histoplasma capsulatum is the etiological agent of histoplasmosis, the most common endemic pulmonary mycosis. Itraconazole (ITZ) is the choice for mild disease and a step-down therapy in severe and disseminated clinical presentations. Drug encapsulation into nanoparticles (NPs) is an alternative to improve drug solubility and bioavailability, reducing undesirable interactions and drug degradation and reaching the specific therapeutic target with lower doses. OBJECTIVE: evaluate the antifungal and immunomodulatory effect of ITZ encapsulated into poly(lactic-co-glycolic acid) (PLGA) NPs, administrated orally and intraperitoneally in an in vivo histoplasmosis model. RESULTS: After intranasal infection and treatment of animals with encapsulated ITZ by intraperitoneal and oral route, fungal burden control, biodistribution, immune response, and histopathology were evaluated. The results showed that the intraperitoneal administered and encapsulated ITZ has an effective antifungal effect, significantly reducing the Colony-Forming-Units (CFU) after the first doses and controlling the infection dissemination, with a higher concentration in the liver, spleen, and lung compared to the oral treatment. In addition, it produced a substantial immunomodulatory effect on pro- and anti-inflammatory cytokines and immune cell infiltrates confirmed by histopathology. CONCLUSIONS: Overall, results suggest a synergistic effect of the encapsulated drug and the immunomodulatory effect contributing to infection control, preventing their dissemination.

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.

A commercial whole blood polymerase chain reaction assay failed to diagnose histoplasmosis in cats confirmed by cytology or urine antigen detection.

OBJECTIVE: To determine the sensitivity and specificity of a commercial whole blood real-time PCR assay (RT-PCR) for the diagnosis of histoplasmosis when compared to direct organism identification and/or urine antigen quantification by enzyme immunoassay (UA-EIA). A secondary objective was to compare the sensitivity and specificity of RT-PCR to anti-Histoplasma immunoglobulin G antibody detection by enzyme immunoassay (IgG-EIA) and IgG-EIA to UA-EIA. ANIMALS: Cats presented to the Kansas State University Veterinary Health Center from February through September of 2023 in which histoplasmosis was diagnosed or suspected. METHODS: From February through September of 2023, cats were tested by RT-PCR, IgG-EIA, and UA-EIA if histoplasmosis was diagnosed cytologically or was a differential diagnosis for the presenting clinical signs. Cats were excluded if all 3 tests were not submitted or if the diagnosis of histoplasmosis could not be excluded despite a negative UA-EIA result. Cats with cytologically or histologically confirmed histoplasmosis were designated as proven histoplasmosis cases, and cats with a positive UA-EIA result without cytological or histological confirmation were designated as probable histoplasmosis cases. RESULTS: 10 cats were diagnosed with either proven (n = 6) or probable (4) histoplasmosis, and 10 cats were considered true negatives. Whole blood RT-PCR results were negative in all 20 cats (sensitivity, 0%; 95% CI, 0% to 30.85%). The IgG-EIA was 90% sensitive (95% CI, 55.50% to 99.75%) and 70% specific (95% CI, 34.75% to 93.33%). The UA-EIA results were positive in all cats with proven histoplasmosis. CLINICAL RELEVANCE: This commercial RT-PCR is insensitive when used on whole blood collected in EDTA and should not be used to diagnose feline histoplasmosis. Further studies are required to determine whether alternate RT-PCR protocols for EDTA-collected whole blood could be useful for diagnosing histoplasmosis in cats.

Improving disseminated histoplasmosis diagnosis in HIV/AIDS patients in Suriname: The role of a urine lateral flow assay.

Histoplasmosis is a frequent cause of infections in people living with HIV/AIDS (PLWHA). This study introduces the application of a Histoplasma capsulatum urine antigen lateral flow assay (LFA) for diagnosing disseminated histoplasmosis in PLWHA in Suriname. The LFA's diagnostic accuracy was compared with the current diagnostic approach, aiming to assess whether this test resulted in improved early detection and management. Additionally, the prevalence of histoplasmosis among advanced stage HIV patients without clinical suspicion of infection was evaluated using the same LFA. In total, 98 patients were included in the study, of which 58 were classified as "possible disseminated histoplasmosis (DH)" based on clinical criteria and 40 as "controls". Of these possible DH cases, only 19 (32.7%) had a positive LFA. During the study, decisions for treatment were made without the treating physician being aware of the LFA result. Only 55% of the patients who started treatment for histoplasmosis based on clinical criteria had a positive LFA, and 21% of untreated patients had a positive LFA. This study shows that combining clinical signs with LFA results enhances diagnostic accuracy and is cost effective, resulting in better treatment decisions.

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.