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: ten patients had acute pulmonary histoplasmosis (APH), one had chronic pulmonary histoplasmosis (CPH), two had progressive disseminated (PD) presentation, and six had the chronic disseminated (CD) form. The median age of our sample was 32.7 years old [IQR: 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. The lung images of APH were characterized by nodules, enlarged hilar/mediastinal lymph nodes, and patches, and three patients were initially treated empirically for pulmonary tuberculosis; one death was registered. 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 CD form 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 heath 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 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.

Gastrointestinal Bleeding and Hemorrhagic Shock in a Patient Diagnosed With Disseminated Histoplasmosis.

A 63-year-old patient with HIV/AIDS and hepatitis B virus was found to have disseminated histoplasmosis with gastrointestinal bleeding. The patient was initially treated for sepsis, but the infectious workup was negative. Computed tomography of the abdomen and pelvis showed diffuse mesenteric and retroperitoneal lymphadenopathy, with plan for biopsy. Unfortunately, the patient had a Code Blue after having profuse hematochezia. Esophagogastroduodenoscopy disclosed actively bleeding duodenal ulcer; computed tomography angiography showed gastric and jejunal extravasation. The patient expired, and autopsy revealed histoplasmosis of duodenum and jejunum. Esophagogastroduodenoscopy is particularly helpful for timely diagnosis in immunocompromised patients with gastrointestinal bleed from suspected infections or malignancy.

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.

Disseminated Cutaneous Histoplasmosis and Its Recurrence in an Apparently Immunocompetent Patient.

Histoplasmosis is a fungal infection caused by the fungus Histoplasma capsulatum. It can manifest in various ways, ranging from pulmonary to disseminated presentations. Most of the disseminated cases are seen in immunocompromised patients; here, we present an unusual case of an 81-year-old Mexican male with a history of cave exposure in his childhood, with 75 years of incubation period of the disease, who developed disseminated cutaneous histoplasmosis with no evident immunocompromising conditions. We considered the hypotheses of transient immunosuppression, CD4+ T lymphocytopenia, and immune senescence as the cause of this manifestation. The present case is also notable for its recurrence following therapy. This report underscores the challenges in diagnosing histoplasmosis in immunocompetent individuals and highlights the importance of long-term treatment and follow-up.

Histoplasmosis Beyond Human Immunodeficiency Virus (HIV): Clinical Characteristics and Outcomes in a Non-HIV Population.

Histoplasmosis is an endemic and invasive mycosis caused by Histoplasma capsulatum. We conducted a retrospective study comparing immunosuppressed patients without human immunodeficiency virus (HIV) with a historical cohort of people with HIV and histoplasmosis. We included 199 patients with proven or probable histoplasmosis, of which 25.1% were people without HIV. Diabetes mellitus, chronic kidney disease, hematologic neoplasms, rheumatologic diseases, and transplantations were more frequent among people without HIV (P < .01). Forty-four percent of immunocompromised patients without HIV died within the first 6-week period following their diagnosis. A high suspicion index for histoplasmosis should be kept in immunosuppressed patients.

Spontaneous rupture of a mycotic splenic artery pseudoaneurysm secondary to histoplasmosis: a case report.

BACKGROUND: A splenic artery pseudoaneurysm is a rare pathology that occurs mainly secondary to pancreatitis, abdominal trauma, peptic ulcers, pancreatic and gastric cancers, and infections. It is best diagnosed using computed tomography angiography and typically treated using endovascular embolization and, in some cases, open or laparoscopic surgery. In this report, we present a case of a ruptured mycotic splenic artery pseudoaneurysm containing Histoplasma capsulatum, which to our knowledge is the first case to report a mycotic splenic artery pseudoaneurysm of this nature. CASE PRESENTATION: We report a case of a 42-year-old white male with past medical history of Hepatitis C and IV drug abuse who presented to the Emergency Department with a 24-h history of severe diffuse abdominal pain. He was tachycardic and peritonitic on exam. Work-up demonstrated leukocytosis and lactic acidosis. Computed tomography of the abdomen and pelvis with intravenous contrast showed hemoperitoneum and active extravasation of contrast from the splenic artery into the splenic hilum, associated with a surrounding hematoma measuring 5.3 × 5.0 cm, concerning for ruptured splenic artery pseudoaneurysm. The patient was taken emergently for exploratory laparotomy, where a large intraperitoneal hematoma was evacuated. A ruptured splenic artery pseudoaneurysm was identified, isolated, and controlled, followed by completion splenectomy. Final pathology demonstrated a 3.0 × 1.3 × 0.3 cm pseudoaneurysm wall and a 14 × 9.5 × 5.5 cm spleen containing multiple necrotizing granulomata positive for the presence of Histoplasmosis species. The patient recovered appropriately and was discharged on post-operative day five. CONCLUSIONS: This case demonstrates a successful approach to a ruptured mycotic splenic artery pseudoaneurysm resulting in a positive outcome. It is a unique case as it highlights, to our knowledge, the first report of splenic artery aneurysm secondary to Histoplasma capsulatum infection. This report helps further the understanding of the pathophysiology as well as the natural history of mycotic splenic pseudoaneurysms.

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.

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 Non-HIV Infected Patients: Another Neglected Infection in French Guiana.

(1) Background: Only a few studies on histoplasmosis in immunocompetent patients have been reported in French Guiana. Therefore, we conducted a detailed clinical description of hospitalized patients suffering with histoplasmosis among non-HIV patients. (2) Methods: This is a single-center, retrospective study conducted at Cayenne Hospital Center between 2008 and 2022. (3) Results: Our cohort was composed of 31 (91%) adults (>18 years of age) and 3 (9%) children, with a sex ratio, M:F, of 1:2. The median age was higher among the women than among the men (70 versus 54 years). The collection of respiratory samples constituted the majority of the performed examinations (38%). Fever (>37 °C) was found in 56% of patients. Surprisingly, the histoplasmosis was disseminated in 82% of patients with an overall case fatality rate of 14.7%. However, immunosuppressive conditions were found in 52% (16/31) of the adult patients, including lymphoid hemopathies, diabetes and immunosuppressive drugs. Conclusions: This disease, though rare and usually considered a mostly benign disease in non-HIV patients, presented a relatively high mortality rate in our cohort. Thus, histoplasmosis should be suspected, screened and investigated as a first line of defense in highly endemic areas, even in immunocompetent and non-HIV patients, especially those with fever or chronic respiratory symptoms.

Histoplasmosis around the world: A global perspective on the presentation, virulence factors, and treatment of histoplasmosis.

Histoplasmosis is a systemic infection caused by an endemic dimorphic fungus, Histoplasma capsulatum. Though prevalent in the eastern United States of America, near the Ohio and Mississippi River Valleys, the evidence underlying the global prevalence of histoplasmosis, especially in immunocompromised populations, is underappreciated. This article highlights the global epidemiology, risk factors, microbiology and pathophysiological characteristics, pulmonary and extrapulmonary manifestations, prevention measures, radiographic patterns, diagnostic techniques, and antifungal treatment approaches for Histoplasma capsulatum.

Histoplasmosis Causing Overt Inflammation Presenting as Pericarditis: A Case Report.

Histoplasma capsulatum is a well-known cause of pulmonary infections, but in the right patient population or host environment, it can cause a vast array of symptoms. The fungus possesses a special set of virulence factors that allows it to evade host immunity and cause infection, particularly in immunosuppressed hosts. Pericarditis is a known presentation of histoplasmosis, but it can be difficult to diagnose and is often treated based on suspicion. We present a case of a healthy young male who mounted a robust inflammatory response to histoplasmosis resulting in pericarditis.

Disseminated Histoplasmosis presenting with panniculitis and macrophage activation syndrome in a patient undergoing immunosuppressive therapy for Mixed Connective Tissue Disease (MCTD).

Histoplasmosis, a fungal infection caused by Histoplasma capsulatum, is endemic in many parts of the world. However, this is not common in Japan. We herein present a unique case of military histoplasmosis in a 45-year-old female with mixed connective tissue disease (MCTD) who was receiving immunosuppressive therapy. The histological findings coupled with molecular confirmation led to final a diagnosis. This case emphasizes the diagnostic challenges associated with histoplasmosis in immunocompromised patients and underscores the importance of considering it in the differential diagnosis of any atypical presentation in rheumatic patients.

Should Histoplasmosis be Screened for Before Initiation of Tumour Necrosis Factor Alpha Inhibitors?

Histoplasmosis is a soil-based dimorphic fungus endemic to the Midwest and Southeastern United States and is responsible for infection through inhalation of conidia. Infection is usually asymptomatic, as the fungal growth is contained by formation of granulomas. However, dissemination can occur in immunocompromised hosts due to the lack of optimal activity of interferon gamma, tumour necrosis factor alpha (TNF-alpha) and interleukin-17. There is a significant overlap between the symptomatology of histoplasmosis and granulomatosis with polyangiitis (GPA). We report a case of a 48-year-old female who presented with high-grade fever, worsening generalised weakness and tachycardia. She had a previous history of bilateral cavitary lung lesions for which she was evaluated at an outside facility. As her entire infectious investigation was negative and found to be positive for antineutrophil cytoplasmic antibody (ANCA), a diagnosis of GPA was made, and she was initiated on rituximab infusions 7 weeks prior to her presentation to our facility. Repeat infectious investigations at our facility were positive for (1-3)-ß-D-glucan test and urine histoplasma antigen. Prompt discontinuation of rituximab and initiation of systemic antifungal therapy led to clinical improvement. Based on this experience, we highlight the association of histoplasma with ANCA positivity along with the importance of closely monitoring these patients for possible clinical worsening after the initiation of TNF-alpha inhibitors, despite the negative infectious work-up. Also routine screening or pre-emptive therapy for histoplasmosis before the initiation of TNF-inhibitors is not recommended. LEARNING POINTS: Histoplasmosis is associated with ANCA positivity.Despite the negative investigations for histoplasmosis and criteria for GPA being met, patients should be closely monitored for possible clinical worsening after the initiation of immunosuppressive therapy, especially TNF-alpha inhibitors.Current guidelines are not recommending routine screening or pre-emptive therapy for histoplasmosis before initiation of TNF-alpha inhibitors.

Management of disseminated histoplasmosis in a high-complexity clinic in Cali, Colombia.

Histoplasmosis presents a substantial clinical challenge globally, with a particular prevalence in South America, especially among patients with concurrent Human Immunodeficiency Virus (HIV) infection. Despite itraconazole's established efficacy, investigating alternative therapeutic approaches remains imperative. This is the largest study in our region to date, assessing the effectiveness of the less explored posaconazole treatment. This observational study, conducted at Fundación Valle del Lili (FVL) from 2016 to 2022, encompassed adults with disseminated histoplasmosis. Patients (n = 31) were treated with liposomal amphotericin B as an initial treatment, followed by consolidation treatment with posaconazole or itraconazole. Patients with single-organ cases, those lacking microbiological diagnosis, those who received initial treatment with antifungals other than liposomal Amphotericin B and those with < 6 months follow-up were excluded (Figure 1). Analyses considered population characteristics, treatments, and outcomes. Patients (average age: 45.6; 58.1% female) had common comorbidities (HIV 38.7%, solid organ transplantation 29% and oncologic disease 12.9%). Lungs (48.4%) and lymph nodes (16.1%) were commonly affected. Biopsy (64.5%) was the primary diagnostic method. Initial treatment with liposomal amphotericin B (100%) was given for 14 days on average. Follow-up indicated 71% completion with 19.4% requiring treatment modifications. Notably, 70.9% completed a posaconazole consolidation regimen over 350 days on average. Drug interactions during consolidation (80.6%) were common. No relapses occurred, and three deaths unrelated to histoplasmosis were reported. Traditionally, itraconazole has been the prevalent initial treatment; however, in our cohort, 55.9% of patients received posaconazole as the primary option. Encouragingly, posaconazole showed favorable tolerance and infection resolution, suggesting its potential as an effective and well-tolerated alternative for consolidation treatment. This finding prompts further exploration of posaconazole, potentially leading to more effective patient care and better outcomes.

Histoplasmosis is a critical concern in South America, notably among human immunodeficiency virus patients, leading to high mortality rates. This study, the largest in our region, investigates the effectiveness of posaconazole as an alternative treatment to itraconazole. The results offer the potential for enhanced patient care and improved outcomes.

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.

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.

Proceedings of the Second International Meeting on Endemic Mycoses of the Americas (IMEMA), and First International Symposium on Implantation Mycoses (ISIM).

The Second International Meeting on Endemic Mycoses of the Americas (IMEMA) and the First International Symposium on Implantation Mycoses (ISIM) took place in Santiago del Estero, Argentina during September 25-27th, 2023. The conference provided a platform for researchers, clinicians, and experts to discuss the latest developments in the field of endemic and implantation mycoses. Topics included epidemiology, diagnostic advances, treatment strategies, and the impact of environmental factors in the spread of these fungal diseases. IMEMA and ISIM contributed to the regional discourse on the mycoses, emphasizing the importance of international cooperation in addressing these public health challenges.

IMEMA/ISIM, held in Santiago del Estero, Argentina, convened experts to discuss endemic and implantation mycoses, covering topics such as epidemiology, diagnostics, treatment, and advocacy. The event highlighted ongoing efforts in combating these diseases.

Cardiac Implications of Itraconazole Therapy in Histoplasmosis Patients.

A male patient in his 60s, with a history of tobacco use, presented with fever, weight loss, and cough, and was ultimately diagnosed with histoplasmosis. Initial treatment with itraconazole (ITZ) led to symptom improvement. However, two months later, he returned with lower extremity swelling and dyspnea. Imaging showed pleural effusions and reduced ejection fraction, suggesting itraconazole-induced cardiac toxicity. Transition to voriconazole and initiation of guideline-directed medical therapy improved symptoms. This case report delves into the cardiac side effects of itraconazole, notably heart failure, and elucidates the potential underlying mechanisms. Our goal is to emphasize the importance of monitoring patients on itraconazole for potential cardiac complications, necessitating timely intervention to mitigate adverse outcomes.