Histoplasmosis is a global disease endemic to regions of all six inhabited continents. The areas of highest endemicity lie within the Mississippi and Ohio River Valleys of North America and parts of Central and South America. As a result of climate change and anthropogenic land utilization, the conditions suitable for Histoplasma capsulatum are changing, leading to a corresponding change in epidemiology. The clinical manifestations of histoplasmosis are protean, variably resembling other common conditions such as community-acquired pneumonia, tuberculosis, sarcoidosis, Crohn's disease, or malignancy. Making a successful diagnosis is contingent on a thorough understanding of epidemiology, common clinical presentations, and best testing practices for histoplasmosis. While most subclinical or self-limited diseases do not require treatment in immunocompetent patients, all immunocompromised patients and those with progressive disseminated disease or chronic pulmonary disease should be treated. Liposomal amphotericin B is the preferred agent for severe or disseminated disease, while itraconazole is adequate for milder cases and “step-down” therapy following response to amphotericin B. In this review, we discuss the current evidence-based approaches to the epidemiology, diagnosis, and management of histoplasmosis.

Although fibrotic disorders are frequently assumed to be linked to TH2 cells, quantitative tissue interrogation studies have rarely been performed to establish this link and certainly many fibrotic diseases do not fall within the type 2/allergic disease spectrum. We have previously linked two human autoimmune fibrotic diseases, IgG4-related disease and systemic sclerosis, to the clonal expansion and lesional accumulation of CD4+CTLs. In both these diseases TH2 cell accumulation was found to be sparse. Fibrosing mediastinitis linked to Histoplasma capsulatum infection histologically resembles IgG4-related disease in terms of the inflammatory infiltrate and fibrosis, and it provides an example of a fibrotic disease of infectious origin in which the potentially profibrotic T cells may be induced and reactivated by fungal Ags. We show in this study that, in this human disease, CD4+CTLs accumulate in the blood, are clonally expanded, infiltrate into disease lesions, and can be reactivated in vitro by H. capsulatum Ags. TH2 cells are relatively sparse at lesional sites. These studies support a general role for CD4+CTLs in inflammatory fibrosis and suggest that fibrosing mediastinitis is an Ag-driven disease that may provide important mechanistic insights into the pathogenesis of idiopathic fibrotic diseases.

Introduction: Mediastinal granuloma (MG) is a postinfectious complication of histoplasmosis that remains a rare diagnosis in the pediatric literature. This case series presents a well phenotyped population to further characterize this disease process.Methods: Thirty cases of MG in children under 21 years-of-age presenting over a 16-year period were retrospectively analyzed.Results: Seventy-five percent of patients presented with respiratory symptoms.Histoplasma antigen was negative in 90%. Histoplasma antibody was positive in 100%. Fine needle aspirates were positive for histoplasma in 31% whereas excisional biopsy was positive in 71%. Bronchoalveolar lavage (BAL) was negative for histoplasma in all cases where performed. Computed tomography revealed 53% of MGs were right paratracheal, 60% had internal calcifications, and 23% had splenic calcifications. Sixteen patients (53%) were managed with medical therapies only, with 7 (44%) treated with steroids and antifungals and 7 (44%) with antifungals alone. The remaining 14 patients (47%) underwent surgical excision and 9 were also treated with antifungals (64%). Bronchial compression was the most common comorbidity within the medically managed only group whereas vascular compression and fistulation were most common within the surgically managed group. Conclusion:Respiratory symptoms should raise suspicion for MG. Diagnostic evidence of MG includes positive histoplasma serologies, right paratracheal location, internal calcifications, and splenic calcifications. Bronchoscopy, BAL and needle biopsies provide minimal diagnostic benefit. Antifungals are used in the majority of cases, whereas steroids are used most often in non-surgically managed patients with airway compression. Indications for surgical resection are less defined, but include vascular compression and fistulation unresponsive to medical treatment.