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Histoplasma capsulatum and Histoplasmosis

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1 Histoplasma capsulatum and Histoplasmosis
Brandon Hang

2 Outline Characteristics Pathogenesis Histoplasmosis Pulmonary
Disseminated Treatment Future challenges

3 Characteristics Member of the phylum Ascomycota Worldwide distribution
Naturally found in fecal-contaminated soils Birds and bats appear to be reservoirs Etiologic agent of histoplasmosis

4 Characteristics (cont.)
Dimorphic fungus Sexual multi-cellular saprophytic mycelia Asexual single-celled parasitic yeast Mycelial form is most commonly found in the environment Heterothallic species Tightly coiled septate hyphae (A) Globose cleistothecia (C) Pear-shaped asci (E) Smooth, hyaline, spherical ascospores (F) A C E F

5 Characteristics (cont.)
Yeast form is the infectious agent in humans Form asexual macro- and microconidia Also borne by hyphae in the mycelial form (B) Conidia germinate via non/polar budding Yeast cells have white, thin-walled, oval bodies (A) A B

6 Pathogenesis Infection begins with inhalation of microconidia or hyphal fragments Mycelial form transforms into yeast form Triggered by elevated temperatures and increased cysteine levels 3-stage process Heat shock phenomenon Restimulation of cellular respiration Increase of RNA & protein synthesis

7 Pathogenesis (cont.) Yeast cells are phagocytized by host immune system M. capsulatum is able to survive phagocytosis Calcium-binding protein, a cytoplasmic enzyme, a peroxisomal enzyme, and immunogenic M antigen are involved Apoptosis of infected macrophages allow M. capsulatum to spread Infection is usually self-limiting in immunocompetent individuals

8 Histoplasmosis 2 major forms of histoplasmosis
Pulmonary and disseminated Pulmonary histoplasmosis occurs when microconidia or mycelial fragments are inhaled Form lesions in the hilar and/or mediastinal nodes Many types of pulmonary histoplasmosis Asymptomatic pulmonary histoplasmosis Acute pulmonary histoplasmosis Mediastinal granuloma Fibrosing mediastinitis Chronic cavitary pulmonary histoplasmosis

9 Pulmonary Histoplasmosis
Asymptomatic pulmonary histoplasmosis Low level exposure to H. capsulatum 99% of infected people display no symptoms May display a mild “illness” not recognized as histoplasmosis Diagnosed using radiography, CT scans, or biopsies

10 Pulmonary Histoplasmosis (cont.)
Acute pulmonary histoplasmosis Higher level exposure to H. capsulatum Patients display fever, malaise, headache, dyspnea, and other respiratory problems Diagnosed using radiography, BAL, CF, or ID

11 Pulmonary Histoplasmosis (cont.)
Mediastinal granuloma Substantial enlargement of a large number of mediastinal lymph nodes Can impede airways or the superior vena cava Often matted together and necrotic Patients have severe chest pain when breathing Diagnosed using radiography or CT scans

12 Pulmonary Histoplasmosis (cont.)
Fibrosing mediastinitis Uncontrolled immune response to necrotizing nodes causes fibrosis around mediastinal lymph nodes Patients display worsening dyspnea, cough, hemoptysis, and chest pain Superior vena cava obstruction and heart failure can occur Diagnosed using radiography and CT scans

13 Pulmonary Histoplasmosis (cont.)
Chronic cavitary pulmonary histoplasmosis Exclusive to older patients with emphysema H. capsulatum infection near emphysematous bullae form a cavity The cavity progressively grows and spreads from lobe to lobe to form more cavities Patients display fatigue, fever, anorexia, weight loss, hemoptysis, and dyspnea Diagnosed using radiography and bronchoscopy

14 Disseminated Histoplasmosis
Occurs primarily in immunocompromised individuals In healthy individuals, H. capsulatum is similar to tuberculosis While the infection is usually resolved, the fungus is still present Constantly kept in check by T lymphocytes In immunocompromised individuals, H. capsulatum is able to spread from the lungs into other organs Patients display fever, malaise, and occasionally petechiae or skin lesions (cutaneous histoplasmosis) Tests often reveal mucous membrane ulcerations, simultaneous enlargement of the liver and spleen, and enlarged lymph nodes

15 Disseminated Histoplasmosis (cont.)
Diagnosis is performed by demonstrating the presence of the fungus in extrapulmonary tissue Blood cultures, bronchoscopy, BAL, ID, CF, and positive antigen tests are commonly performed Elevated levels of lactate dehydrogenase and ferritin in AIDS patients

16 Treatment Treatment is not required in most cases
Itraconazole and/or amphotericin B in more serious cases No effective treatment for fibrosing mediastinitis Amphotericin B Itraconazole

17 Future Challenges Treatment of fibrosing mediastinitis continues to be difficult and ineffective Quick and accurate identification of H. capsulatum in infected patients needs to be addressed Developing a broad spectrum vaccine may be a step in the right direction to address some of these concerns

18 Questions?

19 References Conant, N. F. (1941). Cultural study of the life-cycle of Histoplasma capsulatum Darling Journal of Bacteriology, 41(5), Deacon, J. W. (2005). Fungal biology (4th ed.). Malden, MA: Wiley-Blackwell. Frías De León, M. G., Arenas López, G, Taylor, M. L., Acosta Altamirano, G., & Reyes-Montes, M. del R. (2012). Development of specific sequence-characterized amplified region markers for detecting Histoplasma capsulatum in clinical and environmental samples. Journal of Clinical Microbiology, 50(3), Hage, C. A., Wheat, L. J., Loyd, J., Allen, S. D., Blue, D., & Knox, K. S. (2008). Pulmonary histoplasmosis. Seminars in Respiratory and Critical Care Medicine, 29(2), Inglis, D. O., Berkes, C. A., Hocking Murray, D. R., & Sil, A. (2010). Conidia but not yeast cells of the fungal pathogen Histoplasma capsulatum trigger a type I interferon innate immune response in murine macrophages. Infection and Immunity, 78(9), Kauffman, C. A. (2007). Histoplasmosis: A clinical and laboratory update. Clinical Microbiology Reviews, 20(1), Keath, E. J., & Abidi, F. E. (1994). Molecular cloning and sequence analysis of yps-3, a yeast-phase-specific gene in the dimorphic fungal pathogen Histoplasma capsulatum. Microbiology, 140(4), Khasawneh, F. A., Ahmed, S., & Halloush, R. A. (2013). Progressive disseminated histoplasmosis presenting with cachexia and hypercalcemia. International Journal of General Medicine, 6, Kwon-Chung, K. J. (1972). Sexual stage of Histoplasma capsulatum. Science, 175(4019), 326. Maresca, B., & Kobayashi, G. S. (1989). Dimorphism in Histoplasm capsulatum: A model for the study of cell differentiation in pathogenic fungi. Microbiological Reviews, 53(2), Newman, S. L., Bucher, C., Rhodes, J., & Bullock, W. E. (1990). Phagocytosis of Histoplasma capsulatum yeasts and microconidia by human cultured macrophages and alveolar macrophages. The Journal of Clinical Investigation, 85(1), Pal, J., Ray, A. N., Sherpa, P., Majumdar, B. B., Modak, D., Chatterjee, S., & Sarkar, P. (2013). Primary cutaneous histoplasmosis simulating Molluscum contagiosum. Journal of the Association of Physicians of India, 61, Rossi, S. E., McAdams, H. P., Rosado-de-Christenson, M. L., Franks, T. J., & Galvin, J. R. (2001). Fibrosing mediastinitis. RadioGraphics, 21(3), 736. Sebghati, T. S., Engle, J. T., & Goldman, W. E. (2000). Intracellular parasitism by Hisoplasma capsulatum: Fungal virulence and calcium dependence. Science, 290(5495), Takahashi, K., Sasaki, T., Nabaa, B., van Beek, E. J., Stanford, W., & Aburano, T. (2012). Pulmonary lymphatic drainage to the mediastinum based on computed tomographic observations of the primary complex of pulmonary histoplasmosis. Acta Radiologica, 53(2), Tobón, A. M., Agudelo, C. A., Rosero, D. S., Ochoa, J. E., de Bedout, C., Zuluaga, A., Restrepo, A. (2005). Disseminated histoplasmosis: A comparative study between patients with acquired immunodeficiency syndrome and non-human immunodeficiency virus-infected individuals. The American Journal of Tropical Medicine and Hygiene, 7(3), Wheat, L. J., Freifeld, A. G., Kleiman, M. B., Baddley, J. W., McKinsey, D. S., Loyd, J. E., & Kauffman, C. A. (2007). Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the infectious diseases society of America. Clinical Infectious Diseases, 45(7), Woods, J. P. (2002). Histoplasma capsulatum molecular genetics, pathogenesis, and responsiveness to its environment. Fungal Genetics and Biology, 35(2),

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