Exploring Histoplasma species seroprevalence and risk factors for seropositivity in The Gambia's working equid population: Baseline analysis of the Tackling Histoplasmosis project dataset.

Introduction: Exposure rates to Histoplasma species, the causative agent of equine epizootic lymphangitis (EL), are unknown amongst working equids in The Gambia. The primary aims of this study were to estimate anti-Histoplasma antibody seroprevalence in the equid population in rural The Gambia and to explore risk factors for seropositivity. Methods: A nationwide cross-sectional study was conducted (February-July 2022), representing baseline measurements of a longitudinal cohort study. Horses (n = 463) and donkeys (n = 92) without EL signs were recruited in 18 study sites. Following informed owner consent, equid clinical and management data were recorded. Blood samples were collected by jugular venepuncture, and sera were subject to the IMMY Latex Agglutination Histoplasma test (LAT). Seropositivity risk factors were explored by multi-level, multivariable logistic regression analysis. Study site and household variance were described using a latent-variable approach. Whole blood DNA extractions were subject to nested ITS-PCR to detect Histoplasma capsulatum var. farciminosum (HCF), and agreement with LAT results was measured using Cohen's kappa statistic. Results: Anti-Histoplasma antibody seroprevalence in horses and donkeys was 79.9% [95% confidence interval (CI) 76.0-83.5%] and 46.7% (95% CI 36.3-57.4%), respectively. In horses, two multivariable models explained the maximum amount of data variability. Model 1 demonstrated increased odds of seropositivity in mares [odds ratio (OR) = 2.90 95% CI 1.70-4.95, p < 0.001] and decreased odds in horses <2.5 years (OR = 0.46 95% CI 0.22-0.95, p = 0.04; reference: ≥4.5 years). Model 2 demonstrated increased odds in horses recruited during the rainy season (OR = 2.03 95% CI 1.08-3.84, p = 0.03) and those owned by farmers reporting previous EL in their equids (OR = 1.87 95% CI 1.04-3.37, p = 0.04). Decreased odds were measured in horses <2.5 years (OR = 0.37 95% CI 0.18-0.78, p = 0.01) and horses reported to transport firewood (OR = 0.45 95% CI 0.28-0.74, p = 0.001). On multivariable analysis of donkeys, decreased odds of seropositivity were demonstrated amongst donkeys owned by households which also owned horses (OR = 0.23 95% CI 0.06-0.85, p = 0.03). HCF infection prevalence in horses and donkeys was 22.0% (n = 102/463, 95% CI 18.3-26.1%) and 5.4% (n = 5/92, 95% CI 1.8-12.2%), respectively. No significant agreement was measured between LAT and nested ITS-PCR results (κ < 0.00). Conclusion: High Histoplasma spp. exposure was demonstrated amongst equids in The Gambia. Investigation of risk factors, including equid husbandry and management strategies, as well as geoclimatic variations, is warranted. Outcomes may inform sustainable and equitable EL control strategies in The Gambia and comparable settings worldwide.

Disseminated Histoplasmosis Diagnosed in an Immunocompetent Patient from a Non-Endemic Area: Neglected or Emerging Disease?

Histoplasma capsulatum (H. capsulatum) is considered to be one of the most extensively spread dysmorphic fungi worldwide. Histoplasmosis primarily impacts patients with weakened immune systems and can result in a diverse range of clinical manifestations. In immunocompetent patients, the disease may manifest as a self-limiting or asymptomatic infection; however, in immunocompromised individuals, it can occur as a debilitating, disseminated disease. Diagnosing histoplasmosis may be challenging. A medical professional that specializes in treating endemic fungal illnesses is better able to assist with an accurate and timely diagnosis since they have a deeper grasp of these illnesses. Consequently, the process of diagnosing histoplasmosis might be difficult for less experienced physicians. The case presented is an example of the myriad faces that histoplasmosis can take on, mimicking other common infectious or malignant conditions, leading to extensive work-up and invasive procedures in establishing the diagnosis of this otherwise benign condition. We hereby report the case of disseminated histoplasmosis in a young immunocompetent female patient.

A Rare Case of Simultaneous Histoplasmosis and Coccidioidomycosis.

Histoplasma and Coccidioides are fungi that can cause serious infections in immunocompromised patients. Histoplasma is primarily endemic to the central and eastern United States, while Coccidioides is primarily endemic to the southwestern United States. Here, we present a case of simultaneous histoplasmosis and coccidioidomycosis. A 69-year-old female with a past medical history of rheumatoid arthritis and polymyalgia rheumatica on immunosuppression presented to the emergency department (ED) with fevers, malaise, and confusion. She initially developed these symptoms a month prior while visiting her son in Tennessee. During this time, she lived in his basement where mold exposure was confirmed. Her symptoms gradually improved but recurred, prompting her to come to the ED. In the ED, her vital signs were as follows: temperature of 36.5˚C, heart rate of 88, respiratory rate of 16, blood pressure of 158/88, and oxygen saturation of 94% on room air. She was alert and oriented without focal neurologic deficits. Heart sounds were regular rate and rhythm, lungs were clear to auscultation bilaterally and abdomen was soft, non-tender, and non-distended. No skin rashes were observed either. Laboratory work revealed an elevated C-reactive protein (CRP), thrombocytopenia, and transaminitis. Chest X-ray showed patchy airspace disease in the left lower lobe, and she underwent a lumbar puncture which was negative for meningitis. Due to her travel to Tennessee, a urine Histoplasma antigen test was ordered which resulted positive, along with a beta-1,3-D-glucan level >500 picograms per milliliter (pg/mL), indicating disseminated histoplasmosis. Coccidioides antibodies also resulted positive, pointing to concurrent coccidioidomycosis. The patient was subsequently started on intravenous amphotericin B. Over the following days, the patient's transaminitis and thrombocytopenia improved, and she was ultimately discharged on oral itraconazole with outpatient infectious disease follow-up. Although the patient's exposure to mold was likely the source of her histoplasmosis, the source of her coccidioidomycosis is less clear given its endemicity. Even rarer is the coinciding infections, and to the best of our knowledge, this is one of the very few known cases. Immunocompromised patients who present with infectious symptoms should have a low threshold for a fungal infection workup, as prompt treatment is crucial to limiting the morbidity and mortality of these infections. Furthermore, geographic location should not narrow one's workup to endemic fungi only, as evidenced by this patient's simultaneous infections.

Respiratory Compromise Related to Primary Histoplasmosis Infection in Two Pediatric Patients.

Primary infection related to the fungus, histoplasmosis, is generally asymptomatic in immunocompetent hosts. Calcified granulomas may be noted incidentally on radiologic imaging such as chest radiographs or computed tomography imaging. However, even in immunocompetent hosts, these primary infections occasionally result in end-organ involvement including respiratory compromise. Histoplasmosis should be included in the differential diagnosis of patients presenting with respiratory involvement and mediastinal adenopathy. We present two pediatric-aged patients who developed pulmonary involvement related to a primary histoplasmosis infection that resulted in mediastinal and tracheal lymphadenopathy. These led to respiratory compromise due to pleural effusion in the first patient and tracheal compression in the second. In this paper, the basic microbiology of Histoplasma capsulatum is presented, previous reports of primary respiratory involvement presented, and diagnostic and therapeutic options discussed.

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.

An overview of various stages and morphology of Histoplasma capsulatum var. farciminosum in the horse.

This article describes the development of the pathogenic dimorphic fungus Histoplasma capsulatum var. farciminosum (HCF), which is the causative agent of Equine epizootic lymphangitis (EEL), from the mycelial form in the soil to the yeast form in the horse. In this study, the stages and morphology of HCF were identified through histopathological analysis and culture with various samples collected in Ethiopia from 15 horses showing clinical signs of EEL. In equids, especially cart horses in Ethiopia, poor-quality harnesses cause cutaneous wounds, which often attract flies facilitating the transmission of the fungus. Also, HCF infection occurs through open wounds or ocular mucous membranes when horses roll on contaminated damp soil. Respiratory histoplasmosis can occur through inhaling fungal spores, which is rare. HCF microconidia enter the lungs and skin wounds and are phagocytized by tissue-resident macrophages. The spores undergo intracellular replication within the macrophages transitioning into yeasts. The infected macrophages undergo lysis releasing pathogenic yeast cells into the surrounding tissue. Consequently, yeast-rich purulent exudate is produced, contaminating the soil in stables where yeast cells germinate into the mycelial form, and the entire process starts from the beginning.

Fatal misdiagnosis of progressive disseminated histoplasmosis.

Disseminated histoplasmosis is the form of a mycosis caused by the fungus Histoplasma capsulatum that mainly occurs in immunosuppressed hosts, usually with non-specific symptoms. In non-endemic areas, where the disease is rarely involved in the differential diagnosis, a delay in treatment may lead to severe medical complications. Due to the rising prevalence of disseminated histoplasmosis in these areas, a thorough medical history is regarded as the decisive factor in prompt diagnosis of the disease. We, herein, report the case of an immunocompetent Greek farmer with disseminated histoplasmosis whose condition was initially misdiagnosed, and the consequential inadequate treatment led to his death.

The Association of Chronic Pulmonary Aspergillosis and Chronic Pulmonary Histoplasmosis with MDR-TB Patients in Indonesia.

In Indonesia, 2.4% of all new tuberculosis patients had multi-drug resistant disease (MDR-TB); an estimated 24,000 incidences. Historical case series of MDR-TB described a high frequency of cavitation and poor prognosis. The diagnosis of chronic pulmonary aspergillosis (CPA) relies on raised levels of Aspergillus IgG antibodies, and detectable Histoplasma IgG antibodies are suspicious for chronic pulmonary histoplasmosis (CPH). We investigated whether MDR-TB patients might have concurrent CPH or CPA. This was a cross-sectional study with 50 MDR-TB patients. ELISA was used to detect Histoplasma IgG antibodies and lateral flow assay was used to detect Aspergillus IgG/IgM antibodies. Several other possible disease determinants were assessed by multivariate analysis. Of the 50 MDR-TB patients, 14 (28%) and 16 (32%) had positive Histoplasma or Aspergillus serology; six patients (12%) had dual antibody reactivity. Radiological abnormalities in positive patients included diffuse or local infiltrates, nodules, consolidation, and apical cavities, consistent with CPH and CPA. Patients with detectable fungal antibodies tended to have worse disease, and 4 of 26 (15.3%) died in the first 5 months of dual infection (p = 0.11 compared with no deaths in those with only MDR-TB). The criteria for the diagnosis of CPH and CPA were fulfilled in those with moderately and far advanced disease (13 of 14 or 93%) and 12 of 16 (75%), respectively. Damp housing was the only determinant associated with Histoplasma antibodies (PR 2.01; 95%CI 0.56-7.19), while pets were associated with the Aspergillus antibody (PR 18.024; 95%CI 1.594-203.744). CPA or CPH are probably frequent in MDR-TB patients in Indonesia and may carry a worse prognosis.

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.

Histoplasmosis in patients living with HIV in Europe: review of literature.

Histoplasma capsulatum (var. capsulatum Hcc and duboisii Hcd), is a dimorphic fungus that causes histoplasmosis. It usually affects people coming from endemic areas, causing a variety of clinical manifestations up to progressive disseminated histoplasmosis (PDH), especially among people living with HIV (PLWH). We conducted a systematic review to assess histoplasmosis burden of PLWH in Europe. The review follows PRISMA guidelines, with protocol registered in PROSPERO (CRD42023429779). Seventy-eight articles were selected, including 109 patients (32 women). On overall, median age was 37 years. Forty-six patients were Americans, 39 Africans, 17 Europeans, 5 Asians, in 2 cases nationality was not specified. Cases were mainly diagnosed in Italy (28.4%), France (17.3%) and Spain (17.4%), with a north-south gradient. Six cases lacked epidemiologic links with endemic areas. Concerning CDC HIV staging at diagnosis, the information was available for 60 PLWH (55%) and all subjects were at stage C3 except for two subjects at stage B3. PDH was the AIDS-presenting illness in 39 patients. Most patients had a PDH (80.7%); other common extrapulmonary forms were isolated cutaneous histoplasmosis (7.3%), or lymphatic localization (2.7%). In 30 cases, the diagnosis was made by analyzing only one sample. For the remaining 79 cases, multiple samples were collected from each patient. Regarding the biological sample more frequently used for the diagnosis of histoplasmosis, bronchoalveolar lavage sample was taken from 39 patients, and tested positive in 51.3% of cases; 36 patients underwent a skin biopsy which was positive in 86.1% of cases and 28 patients performed bone-marrow biopsy, which led to the diagnosis of histoplasmosis in 92.9% of cases. The identification of Histoplasma capsulatum was available in 97 PLWH through examination of different samples: Hcc and Hcd were identified in 89 and 8 PLWH, respectively. Concerning therapies, 67.9% were treated with liposomal amphotericin B, 18.3% with itraconazole, 10 died pre-treatment. The overall mortality rate was 23.6%. Non-survivors exhibited more frequently gastrointestinal symptoms (p = 0.017), while cutaneous signs correlated with better survival (p = 0.05). Untreated patients faced higher mortality (p < 0.001). Histoplasmosis should be considered amongst opportunistic infection in PLWH, even in Europe, especially if patients originate from or have travelled to endemic areas. Systematic review registration: The registration number is CRD42023429779.

Disseminated histoplasmosis: Long journey of a febrile young man.

A 19-year-old non-diabetic, non-HIV male presented with eighteen months of fever, weight loss, skin rash and lymphadenopathy. He was treated with anti-tubercular medication for more than twelve months in multiple institutions based on repeated biopsy reports of lymph nodes showing granuloma suggestive of tuberculosis. Before he was diagnosed at Bangabandhu Sheikh Mujib Medical University (BSMMU) with disseminated histoplasmosis at eighteen months of his disease, he already lost twenty kg weight, developed multiple small joint pain, back pain, and cough along with previously mentioned symptoms. Extensive investigations at BSMMU revealed biopsy material from multiple sites showed noncaseating granulomas with Periodic acid-Schiff (PAS) stain positive for budding oval yeast cells, and fungal culture revealed growth of dimorphic fungus suggestive of Histoplasma after three weeks. After treatment with intravenous liposomal amphotericin B with continuous itraconazole, the patient's fever completely subsided, his well-being improved, joint pain reduced, started to gain weight, and skin lesions started to heal. This case serves as a significant reminder that it is imperative to consider alternative diagnoses in patients who fail to show improvement with conventional antitubercular treatment.

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.

Development of a TaqMan probe-based multiplex real-time PCR for the simultaneous detection of four clinically important filamentous fungi.

Filamentous fungi present significant health hazards to immunocompromised individuals globally; however, the prompt and precise identification of them during infection remains challenging. In this study, a TaqMan probe-based multiplex real-time PCR (M-qPCR) assay was developed to detect simultaneously the target genes of four important pathogenic filamentous fungi: ANXC4 gene of Aspergillus fumigatus, EF1-α gene of Fusarium spp., mitochondrial rnl gene of Mucorales, and hcp100 gene of Histoplasma capsulatum. In this M-qPCR assay, the limit of detection (LoD) to all four kinds of fungi was 100 copies and the correlation coefficients (R2) were above 0.99. The specificity of this assay is 100%, and the minimum detection limit is 100 copies/reaction. In conclusion, an M-qPCR detection assay was well established with high specificity and sensitivity for rapid and simultaneous detection on four important filamentous fungi in the clinic. IMPORTANCE: World Health Organization developed the first fungal priority pathogens list (WHO FPPL) in 2022. Aspergillus fumigatus, Mucorales, Fusarium spp., and Histoplasma spp. are the four types of pathogenic fungi with filamentous morphology in the critical priority group and high priority group of WHO FPPL. These four filamentous fungal infections have become more common and severe in immunocompromised patients with the increase in susceptible populations in recent decades, which resulted in a substantial burden on the public health system. However, prompt and precise identification of them during infection remains challenging. Our study established successfully a TaqMan probe-based multiplex real-time qPCR assay for four clinically important filamentous fungi, A. fumigatus, Fusarium spp., Mucorales, and Histoplasma capsulatum, with high sensitivity and specificity, which shows promising potential for prompt and precise diagnosis against fungal infection.

Common virulence factors between Histoplasma and Paracoccidioides: Recognition of Hsp60 and Enolase by CR3 and plasmin receptors in host cells.

Over the last two decades, the incidence of Invasive Fungal Infections (IFIs) globally has risen, posing a considerable challenge despite available antifungal therapies. Addressing this, the World Health Organization (WHO) prioritized research on specific fungi, notably Histoplasma spp. and Paracoccidioides spp. These dimorphic fungi have a mycelial life cycle in soil and a yeast phase associated with tissues of mammalian hosts. Inhalation of conidia and mycelial fragments initiates the infection, crucially transforming into the yeast form within the host, influenced by factors like temperature, host immunity, and hormonal status. Survival and multiplication within alveolar macrophages are crucial for disease progression, where innate immune responses play a pivotal role in overcoming physical barriers. The transition to pathogenic yeast, triggered by increased temperature, involves yeast phase-specific gene expression, closely linked to infection establishment and pathogenicity. Cell adhesion mechanisms during host-pathogen interactions are intricately linked to fungal virulence, which is critical for tissue colonization and disease development. Yeast replication within macrophages leads to their rupture, aiding pathogen dissemination. Immune cells, especially macrophages, dendritic cells, and neutrophils, are key players during infection control, with macrophages crucial for defense, tissue integrity, and pathogen elimination. Recognition of common virulence molecules such as heat- shock protein-60 (Hsp60) and enolase by pattern recognition receptors (PRRs), mainly via the complement receptor 3 (CR3) and plasmin receptor pathways, respectively, could be pivotal in host-pathogen interactions for Histoplasma spp. and Paracoccidioides spp., influencing adhesion, phagocytosis, and inflammatory regulation. This review provides a comprehensive overview of the dynamic of these two IFIs between host and pathogen. Further research into these fungi's virulence factors promises insights into pathogenic mechanisms, potentially guiding the development of effective treatment strategies.

Purulent Streptococcus intermedius Pericarditis in the Setting of Histoplasma Mediastinal Lymphadenitis: A Case Report and Literature Review.

Purulent pericarditis is a rare and potentially life-threatening condition characterized by infection of the pericardial space. We describe a case of purulent bacterial pericarditis in a 41-year-old male with no significant medical or surgical history who had concomitant pulmonary Histoplasma infection. Streptococcus intermedius was the bacteria directly responsible for the pericardial infection, though co-infection with histoplasmosis likely predisposed him to develop purulent pericarditis. We hypothesize histoplasmosis caused mediastinal lymphadenopathy, facilitating contact between a necrotic lymph node and the pericardium and contiguous suppuration of bacteria to the pericardial space. We treated S. intermedius and Histoplasma capsulatum with ceftriaxone and amphotericin B, respectively. Additionally, the patient presented in cardiac tamponade requiring emergent pericardiocentesis and drain placement. His course was also complicated by pericardial constriction. Cardiac magnetic resonance confirmed this, showing inflamed pericardium and abnormal septal motion with inspiration, and he had symptoms refractory to antimicrobials and anti-inflammatories. As such, he required pericardiectomy. This case demonstrates maintaining suspicion for secondary infectious foci as a contributor to the pathogenesis of purulent pericarditis is important, as pulmonary histoplasmosis played a pivotal role in allowing S. intermedius to spread to the pericardium but was not the primary infection. It also highlights the multifaceted evaluation and management of purulent pericarditis, highlighting the role of echocardiography and emergent pericardial drainage if cardiac tamponade is present, the importance of targeted antimicrobial therapy, the superior ability of cardiac magnetic resonance to identify pericardial constriction as a sequela of purulent pericarditis, and indications for pericardiectomy.

Histoplasmosis in Taiwan: Case Summary and Literature Review.

Histoplasmosis is a global infection caused by the thermally dimorphic fungus, Histoplasma capsulatum complex. It is endemic in the United States, as well as in Central and South America. In Taiwan, histoplasmosis is rare, with the first reported case not occurring until 1977. We summarized a total of 17 cases reported in Taiwan over the past 40 years and provided detailed descriptions for four probable indigenous cases. Due to the lack of rapid diagnostic tools and clinical suspicion, histoplasmosis may be underdiagnosed in Taiwan. We recognize that a limitation of our review is the lack of data on the environmental surveillance for H. capsulatum complex in Taiwan. Conducting a further phylogenetic analysis on both environmental and clinical isolates would provide valuable evidence for the region.

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.

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.