Dermatologic Fungal Neglected Tropical Diseases-Part I. Epidemiology and Clinical Features.

In this part 1 of a 2-part continuing medical education series, the epidemiology, clinical features, and diagnostic methods for fungal skin neglected tropical diseases (NTDs), which include eumycetoma, chromoblastomycosis, paracoccidioidomycosis, sporotrichosis, emergomycosis, talaromycosis, and lobomycosis, are reviewed. These infections, several of which are officially designated as NTDs by the World Health Organization (WHO), cause substantial morbidity and stigma worldwide and are receiving increased attention due to the potential for climate change-related geographic expansion. Domestic incidence may be increasing in the setting of global travel and immunosuppression. United States dermatologists may play a central role in early detection and initiation of appropriate treatment, leading to decreased morbidity and mortality.

Disseminated Blastomycosis in an Immunocompetent Patient.

Blastomycoses dermatitidis is a dimorphic fungus that can cause disseminated blastomycosis with varying clinical manifestations and multiorgan involvement. While blastomycosis commonly causes pulmonary disease, extrapulmonary spread can result in skin, bone, and central nervous system involvement. Cutaneous blastomycosis can present as pustular lesions that evolve into ulcerative or verrucous plaques. We present a case of disseminated blastomycosis in an immunocompetent patient with both pulmonary and cutaneous features. The patient developed hypoxic respiratory failure and was subsequently diagnosed with disseminated blastomycosis after undergoing bronchoscopy with bronchial washing. He was found to have ulcerative nasal lesions as part of his disseminated disease. He was successfully treated with amphotericin B and ultimately discharged from the hospital.

Dermatologic Fungal Neglected Tropical Diseases-Part II. Management and Morbidity.

In this part 2 of a 2-part continuing medical education series, the management, outcomes, and morbidities for fungal skin neglected tropical diseases (NTDs), including eumycetoma, chromoblastomycosis, paracoccidioidomycosis, sporotrichosis, emergomycosis, talaromycosis, and lobomycosis are reviewed. While fungal skin NTDs are associated with poverty in resource-limited settings, they are more often associated with immunosuppression and global migration in the United States. These infections have a high morbidity burden, including disfigurement, physical disability, coinfection, malignant transformation, mental health issues, and financial impact. For most fungal skin NTDs, management is difficult and associated with low cure rates. Dermatologists play a central role in initiating appropriate treatment early in disease course in order to improve patient outcomes.

Atypical Pleural Effusion in an Immunocompetent Patient With Valley Fever: A Case Study and Review of the Literature.

Valley fever is a fungal infection, commonly of the lungs, caused by Coccidioides immitis or Coccidioides posadasii. This disease is endemic to the southwestern United States, Central America, and South America. Infected individuals are typically asymptomatic but may develop community-acquired pneumonia. On rare occasions, coccidioidomycosis can present with severe complications in addition to the pulmonary manifestation. In this study, a 58-year-old immunocompetent male presented to the Emergency Department with a cough, night sweats, and pleuritic chest pain. Despite the administration of broad-spectrum antimicrobials, he developed a large right pleural effusion that did not resolve following thoracentesis. Serology was positive for Coccidioides, and the patient was referred to a thoracic surgeon due to persistent effusion. It is rare for patients with coccidiomycosis to develop a large pleural effusion requiring surgical intervention, especially in immunocompetent individuals. This case highlights the importance of monitoring patients with unresolved acute pneumonia in endemic areas and considering Coccidioides as a possible etiology.

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.

Chromoblastomycosis in French Guiana: Epidemiology and Practices, 1955-2023.

Chromoblastomycosis (CBM) is a chronic neglected fungal disease, usually met in tropical areas. French Guiana is a South American territory with limited epidemiological data. This retrospective study concerned all patients with CBM proven by at least one paraclinical examination and diagnosed in French Guiana between 1950 and 2023. In total, 23 patients were included, mostly males (87%) of Creole origin, living in the coastal region (87%) and involved in outdoor occupations (74%). Lesions were mostly observed on the lower limbs (78.3%), with a median time to diagnosis of four years. Laboratory tests included positive direct microscopic examinations (78.3%) and mycological cultures (69.6%), identifying 14 cases of Fonsecaea pedrosoi and one case of Exophiala janselmei. Various treatments were employed, including antifungals, surgery and combinations of both. In conclusion, CBM in French Guiana involves a different population than other subcutaneous mycoses such as Lobomycosis or Paracoccidioidomycosis, mostly found in the forest hinterland. Surgery should be recommended for recent and limited lesions. Itraconazole and terbinafine should systematically be proposed, either in monotherapy or in combination with surgery or cryotherapy.

MSG-15: Super-Bioavailability Itraconazole Versus Conventional Itraconazole in the Treatment of Endemic Mycoses-A Multicenter, Open-Label, Randomized Comparative Trial.

Background: Invasive fungal disease caused by dimorphic fungi is associated with significant morbidity and mortality. Super-bioavailability itraconazole (SUBA-itra) is a novel antifungal agent with pharmacokinetic advantages over currently available formulations. In this prospective comparative study, we report the outcomes of patients with endemic fungal infections (histoplasmosis, blastomycosis, coccidioidomycosis, and sporotrichosis). Methods: This open-label randomized trial evaluated the efficacy, safety, and pharmacokinetics SUBA-itra compared with conventional itraconazole (c-itra) treatment for endemic fungal infections. An independent data review committee determined responses on treatment days 42 and 180. Results: Eighty-eight patients were enrolled for IFD (SUBA-itra, n = 42; c-itra, n = 46) caused by Histoplasma (n = 51), Blastomyces (n = 18), Coccidioides (n = 13), or Sporothrix (n = 6). On day 42, clinical success was observed with SUBA-itra and c-itra on day 42 (in 69% and 67%, respectively, and on day 180 (in 60% and 65%). Patients treated with SUBA-itra exhibited less drug-level variability at days 7 (P = .03) and 14 (P = .06) of randomized treatment. The concentrations of itraconazole and hydroxyitraconazole were comparable between the 2 medications (P = .77 and P = .80, respectively). There was a trend for fewer adverse events (AEs; 74% vs 87%, respectively; P = .18) and serious AEs (10% vs 26%; P = .06) in the SUBA-itra-treated patients than in those receiving c-itra. Serious treatment-emergent AEs were less common in SUBA-itra-treated patients (12% vs 50%, respectively; P < .001). Conclusions: SUBA-itra was bioequivalent, well tolerated, and efficacious in treating endemic fungi, with a more favorable safety profile than c-itra. Clinical Trials Registration: NCT03572049.

Pulmonary endemic mycoses.

While rare, the likelihood of encountering a case of a pulmonary endemic mycosis (PEM) in the UK is increasing. Diagnosis may be challenging, often leading to considerable delay to appropriate treatment. Clinical suspicion must be present for respiratory disease, particularly in the immunocompromised or in those not responding to empiric treatment approaches, and an extended travel history should be obtained. This article summarises the epidemiology of PEM, key clinical features, diagnostic strategies and management.

Pericardial effusion in an immunocompetent host- a unique presentation of histoplasmosis.

Histoplasma capsulatum infection is infrequently considered in the differential diagnoses for acute pericarditis in immunocompetent hosts when presenting with tamponade physiology, given its gradual infective nature. We describe a case of a young male presenting solely with acute pericarditis with pericardial effusion and early cardiac tamponade physiology secondary to a pulmonary histoplasmosis infection. Our patient had no pulmonary symptoms; the only pulmonary manifestation of histoplasmosis included incidental findings of subcarinal lymphadenopathy and a left lingular nodule abutting the pericardium. Given failure of symptom improvement with pericardiocentesis and first-line therapy for idiopathic/viral pericarditis, further workup of the pulmonary nodule was pursued. Histopathologic analysis of tissue showed caseating granulomas and fungal Grocott-Gömöri's methenamine silver stain revealed yeast consistent with Histoplasma species. The patient improved with itraconazole therapy. Learning objective: Pulmonary histoplasmosis has potential to present as a pericardial effusion in the immunocompetent individual. In addition to pericardiocentesis, antifungal therapy can be curative.

The Current and Future States of Diagnostic Tests for Histoplasmosis with a Focus on People with HIV and Disseminated Histoplasmosis.

Histoplasmosis is caused by Histoplasma capsulatum and, although endemic in large parts of the world, is often underrecognized in many locations. In addition to underrecognition, inadequate availability of diagnostic tests is a major contributor to poor outcomes in disseminated disease in people with HIV. For those with advanced HIV and disseminated disease, antibody testing is less useful. Culture and histopathology can be useful in this situation, but each has limitations, including variable sensitivity by site and, in the case of culture, the need for a biosafety level three laboratory and a long period of growth. Antigen testing has proven useful for disseminated histoplasmosis due to the excellent sensitivity of urine. Yet, turnaround is slower than ideal due to use in a limited number of centers. The development of lateral flow assays has the potential to make for true rapid point-of-care assays for histoplasmosis, but in order to meet that promise, the tests must be widely available and affordable.

Epidemiology of Coccidioidomycosis in the Veterans Health Administration, 2013-2022.

We describe the epidemiology of coccidioidomycosis among a national cohort of Veterans. Using electronic health record data from adults tested for coccidioidomycosis between 1 January 2013 and 31 December 2022, we analyzed differences in baseline demographics (age, sex, race/ethnicity, birth country, comorbidities, residence, and Charlson Comorbidity Index score) between 4204 coccidioidomycosis-test-positive and 63,322 test-negative Veterans. Log-binomial regression models with adjusted risk ratios (aRRs) were used to evaluate risk factors associated with coccidioidomycosis including dissemination, hospitalization, and mortality. Case counts and incidence rates were highest in select counties in Arizona and California where Coccidioides is endemic. Coccidioidomycosis-positive Veterans were younger, more likely to be male, and Philippine-born. The risk factors most highly associated with being coccidioidomycosis-positive included Native Hawaiian/Pacific Islander (aRR 1.068 [95%CI: 1.039-1.098]), Asian (aRR 1.060 [95%CI: 1.037-1.083]), Black (aRR 1.029 [95%CI: 1.022-1.036]), American Indian/Alaska Native (aRR 1.026 [95%CI: 1.004-1.048]) race, and Hispanic/Latino ethnicity (aRR 1.021 [95%CI: 1.013-1.028]). Black race (aRR: 1.058 [95%CI: 1.037-1.081]) and Hispanic/Latino ethnicity (aRR 1.018 [95%CI: 1.0003-1.036]) were also associated with disseminated coccidioidomycosis, strengthening the evidence for the association of coccidioidomycosis, including severe infections, with specific racial and ethnic groups. There were no statistically significant differences in hospitalization within 45 days of testing or 30-day all-cause mortality. Improving our understanding of coccidioidomycosis risk factors is important for targeted prevention strategies and to reduce delays in diagnosis and ineffective treatment.

Development and validation of a new quantitative reverse transcription PCR assay for the diagnosis of human sporotrichosis.

Sporotrichosis is an emergent public health problem. The mycological diagnosis of this infection is based on culture, which is fastidious and may represent a biohazard for technicians. Although not widely implemented in routine diagnosis, molecular methodologies are fast, have good accuracy, and can be easily standardized, aiding in the early diagnosis of neglected mycoses. This study aimed at implementing a new pan-Sporothrix quantitative reverse transcription PCR (RT-qPCR) assay, and then validating it on clinical samples from confirmed human sporotrichosis cases. A total of 68 human samples with culture-confirmed diagnosis of sporotrichosis were collected from 64 patients followed at a Brazilian reference center for endemic mycoses. These samples were submitted to whole nucleic acid extraction, followed by an RT-qPCR protocol. The limit of detection was 244 fg, the efficiency was 2.0 (100%), and the assay could amplify the genetic material of the three major clinically relevant species of the genus Sporothrix. Among the 68 samples analyzed, 62 were positive in RT-qPCR, showing an overall sensitivity of 91.18%, which variated according to the type of biological sample: 96.72% in skin samples (n = 61) and 100% in respiratory samples (n = 3), whereas all cerebrospinal fluid specimens (n = 4) were negative. The specificity was 100% when tested in 25 samples from patients with other mycoses and tuberculosis. In addition, DNA from 93 fungal species did not yield positive results, confirming the high specificity of this test. Our RT-qPCR presented high sensitivity and specificity, representing an excellent tool for a fast and reliable diagnosis of human sporotrichosis.

Sporotrichosis is a deep mycosis with limited laboratorial techniques for fast diagnosis. We developed an assay able to detect the genetic material of fungal agents of sporotrichosis, and validated it in human specimens from patients with this disease, obtaining high positivity and specificity.

Blastomycosis in New England: 5 Cases and a Review.

The geographic range of blastomycosis is thought to include New England, but documentation is sparse. We report 5 cases of infection with Blastomyces dermatitidis that were likely acquired in New England between 2011 and 2021. Our experience suggests that chart coding for the diagnosis of blastomycosis is imprecise and that mandatory reporting might help resolve uncertainties about the prevalence and extent of blastomycosis.

Diagnosis and Treatment of Pulmonary Coccidioidomycosis and Paracoccidioidomycosis.

Coccidioidomycosis (CM) and paracoccidioidomycosis (PCM) are systemic mycoses that are highly endemic in Latin America and have recently been included on the World Health Organization (WHO) Fungal Priority Pathogens List. Coccidioides immitis and Coccidioides posadasii are recognized as etiological agents of CM, with peculiarities in their geographic distribution. The genus Paracoccidioides now includes Paracoccidioides lutzii and the Paracoccidioides brasiliensis complex, which encompasses four phylogenetic species. In both diseases, pulmonary signs and symptoms are the main reasons for patients to seek medical assistance, and they are frequently misdiagnosed as tuberculosis. In this paper, we present a critical view of the strategies for diagnosis and clinical management of CM and PCM. Over the past few decades, there has been an increase in the number of reports of endemic fungal infections in areas previously thought to be "non-endemic" due to climate change and increased travel, among other factors. Learning to recognize their main epidemiological aspects and clinical manifestations is crucial so that clinicians can include them in the differential diagnosis of lung disease and avoid late diagnosis.

Review: Emergomycosis.

Purpose of Review In this review, we provide an overview of emergomycosis from a clinical perspective and discuss the taxonomy and classification of the pathogens, epidemiology, pathophysiology of infection and mechanisms of pathogenesis, immunology, clinical manifestations, laboratory culture and diagnosis, molecular characterisation, therapy and prognosis. Recent Findings While Emergomyces pasteurianus is the most geographically-widespread species, Emergomyces africanus is endemic to Southern Africa and causes disseminated disease with cutaneous involvement primarily among patients with advanced human immunodeficiency virus (HIV) disease. Summary Emergomycosis, a disseminated clinical disease resulting from infection with dimorphic fungi in the genus Emergomyces, occurs primarily among immunocompromised patients. Further knowledge is needed on the pathophysiology, diagnosis and management of emergomycosis.

The Geographic Distribution of Dimorphic Mycoses in the United States for the Modern Era.

BACKGROUND: The dimorphic mycoses (DMs) of the United States-Histoplasma, Coccidioides, and Blastomyces-commonly known as endemic mycoses of North America (in addition to Paracoccidioides) are increasingly being diagnosed outside their historical areas of endemicity. Despite this trend, the maps outlining their geographic distributions have not been updated in more than half a century using a large, nationwide database containing individual-patient-level data. METHODS: This was a retrospective analysis of >45 million Medicare fee-for-service beneficiaries from 1 January 2007 through 31 December 2016. Diagnoses of histoplasmosis, coccidioidomycosis, and blastomycosis were defined by International Classification of Diseases, Ninth/10th Revision, codes. The primary outcome was the incidence of histoplasmosis, coccidioidomycosis, and blastomycosis for each US county. Clinically meaningful thresholds for incidence were defined as 100 cases/100 000 person-years for histoplasmosis and coccidioidomycosis and 50 cases/100 000 person-years for blastomycosis. RESULTS: There were 79 749 histoplasmosis, 37 726 coccidioidomycosis, and 6109 blastomycosis diagnoses in unique persons from 2007-2016 across 3143 US counties. Considering all US states plus Washington, DC, 94% (48/51) had ≥1 county above the clinically relevant threshold for histoplasmosis, 69% (35/51) for coccidioidomycosis, and 78% (40/51) for blastomycosis. CONCLUSIONS: Persons with histoplasmosis, coccidioidomycosis, and blastomycosis are diagnosed in significant numbers outside their historical geographic distributions established >50 years ago. Clinicians should consider DM diagnoses based on compatible clinical syndromes with less emphasis placed on patients' geographic exposure. Increased clinical suspicion leading to a subsequent increase in DM diagnostic testing would likely result in fewer missed diagnoses, fewer diagnostic delays, and improved patient outcomes.

Can fluconazole be used for inpatient re-treatment of coccidioidomycosis among patients with past fluconazole exposures?

BACKGROUND: Coccidioides spp. may cause significant disease requiring hospitalisation, but optimal antifungal therapy among inpatients following outpatient fluconazole exposures is unknown. OBJECTIVES: The objective of this study is to describe the effectiveness of fluconazole among patients hospitalised for coccidioidomycosis despite recent outpatient fluconazole treatment. PATIENTS/METHODS: Patients were admitted to an academic medical center in Phoenix, Arizona from 1 January 2013 through 31 December 2020 for coccidioidomycosis following at least 30 days of outpatient treatment and re-initiation of fluconazole upon admission. The primary outcome was the proportion of patients with an improved response per the change in the modified Mycosis Study Group (MSG) score (a composite of symptoms, serology and radiographic findings) and clinician impressions. RESULTS: Sixty-seven patients were included, with most (54%) admitted to the intensive care unit. Meningitis was the most common infectious presentation (55%), 17 patients (25%) had multiple infection sites, and 23 (34%) were culture-positive for Coccidioides. Upon admission, the median (IQR) MSG score was 11 (9-14), which dropped to 4 (1-7) at end of therapy or last follow-up. Overall, after initiation of fluconazole therapy at a median daily dose of 800 mg, 48 patients (72%) improved in overall status, 10 (15%) showed stable disease and 9 (13%) were unresponsive. Improved response rates were high across all infection sites, including meningitis (68%) and bone infection (71%). There was no significant difference in response rates between patients with and without reported outpatient fluconazole nonadherence. CONCLUSIONS: The majority of patients admitted to the hospital for coccidioidomycosis appeared responsive to fluconazole therapy despite past outpatient exposures.

Chest Imaging in Systemic Endemic Mycoses.

Endemic fungal infections are responsible for high rates of morbidity and mortality in certain regions of the world. The diagnosis and management remain a challenge, and the reason could be explained by the lack of disease awareness, variability of symptoms, and insidious and often overlooked clinical presentation. Imaging findings are nonspecific and frequently misinterpreted as other more common infectious or malignant diseases. Patient demographics and clinical and travel history are important clues that may lead to a proper diagnosis. The purpose of this paper is to review the presentation and differential diagnosis of endemic mycoses based on the most common chest imaging findings.

Updates on Histoplasmosis in Solid Organ Transplantation.

Purpose of Review: Histoplasmosis remains a challenging infection in solid organ transplantation. This review provides a topic update with emphasis on the changing Histoplasma epidemiology, along with new diagnostic and treatment innovations. Recent Findings: Recent years have observed expanding Histoplasma geographic distribution due to climate change, environmental disruption, and host factors. Early clinical experience also suggests a relationship between COVID-19 infection and histoplasmosis, particularly among immunocompromised individuals. Advances in diagnostic methods, such as newer enzyme immunoassays and molecular techniques, have broadened the capability for expedient and highly specific pathogen identification. Novel drug innovations, including the development of new formulations of existing antifungal agents, extended-spectrum azoles and new antifungal drug classes have expanded therapeutic options. Summary: Advances in organ transplantation have largely outpaced those for histoplasmosis. However, these emerging insights enhance our understanding of this pathogen and management of clinical infection, particularly for transplant recipients with a higher incidence and severity of disease.