Histoplasmosis AKA Ohio River Valley Fever or Darling s Disease

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1 Histoplasmosis AKA Ohio River Valley Fever or Darling s Disease By Rosalia Lopez de Alda Histoplasmosis; etiologic agent Histoplasma capsulatum (1). Transmission: Histoplasmosis is a non-communicable disease and infection is transmitted through the inhalation of airborne spores of Histoplasma capsulatum (1). Reservoirs: It grows in soil and material contaminated with bat and bird droppings (1). Taxonomy: Eukaryota -> Opisthokonta -> Fungi -> Dikarya -> Ascomycota -> Saccharomyceta -> Pezizomycotina -> Leotiomyceta -> Eurotiomycetes -> Eurotiomycetidae -> Onygenales -> Ajellomycetaceae -> Histoplasma -> Histoplasma capsulatum (11). General Characteristics: Histoplasma capsulatum is a slow-growing dimorphic fungus that takes mycelial form at room temperature, 25 C and yeast form at body temperature, 37 C. It causes disease ranging in severity from focal and asymptomatic/mildly symptomatic to disseminated and fatal. Those who are immunocompromised are especially at risk for disseminated histoplasmosis. The best way to identify H. capsulatum is by culture. The fungus can be placed on Sabouraud agar and incubated at 25 C for 6 to 12 weeks. The colonies are initially smooth, but become filamentous, cottony, and brownish over time. For an accurate diagnosis, it is necessary to convert H. capsulatum from mold phase to the yeast phase. This can be done using enriched media such as blood agar or Brainheart infusion agar (BHI) with cysteine incubated at C. The colonies are smooth white to brown (4). For a non-culture diagnosis, anti-h and anti-m antibodies may be detected in serum with the use of histoplasmin (HMIN) that functions as the antigenic marker that is extracted from H. capsulatum mycelial culture. C, M, and H are the antigens to which antibodies respond. The M antigen is a catalase and the H antigen is a β-glucosidase. The C antigen is a carbohydrate (galactomannan) that is largely responsible for the cross-reactions observed with other fungal species therefore is not a deciding factor in the fungal identification. Immunodiffusion (ID) is highly specific for the detection of anti-m and anti-h antibodies 4 6 weeks after infection. Anti-H antibodies, which appear after anti-m

2 antibodies, are present in only 7% of patients with acute disease. They tend to disappear more quickly than anti-m antibodies although they may still be detected 1 2 years after the infection has resolved. Anti-M antibodies appear soon after infection and can indicate prior infection, acute disease or a chronic progressive disease. They may remain in serum up to 3 years after disease has resolved and can also be stimulated after skin testing with histoplasmin in people who have never had contact with H. capsulatum or infection. The presence of both the anti-h and anti-m antibodies is considered to be conclusive for the diagnosis of histoplasmosis along with clinical assessment of the patient (4). Complement fixation (CF) measures antibodies to either the mycelial (HMIN) antigen or yeast form. Titers between 1:8 and 1:16 are considered weakly positive and are observed in almost one quarter of patients serum of healthy persons from regions where histoplasmosis is endemic. A high titer (1:32 or greater) or a fourfold increase in titer over time indicates active histoplasmosis (4). False-positive and false-negative results can occur in both ID and CF. False-positive serologic tests may be seen in patients with other disseminated fungal infections, while false-negative results may occur in immunocompromised individuals who cannot produce an antibody response (5,7). Because of this, antigen detection tests in urine and serum samples may be more effective (especially in those with disseminated histoplasmosis) using a radioimmunoassay for the detection of a polysaccharide antigen from H. capsulatum (HPA). Histopathologic analysis of biopsy material from the bone marrow (preferred)/lung, sputum, urine or skin lesions is also useful in patients with chronic or acute disseminate infection. 10% KOH and Parker ink or calcofluor-white mounts are used to examine skin scrapings, exudates and body fluids. Tissue sections are stained using PAS (Periodic Acid Schiff) digest, Grocott s methenamine silver (GMS) or Gram stain for examination. In mycelial form, you would see hyaline septate hyphae with micro and macroconidias and smooth-walled spherical shaped microconidia between 2μm to 6μm in diameter. As yeast, cells are generally ovoid and thick-walled (4, 7). Other forms of testing: HMIN Skin testing HMIN inserted intra-dermally to test for reactivity. Immunoenzymatic assays To detect antibodies (i.e. Western Blot and ELISA). PCR - Targeted the internal transcribed spacer region of the rrna gene complex and used hybridization probes and fluorescent resonance energy transfer technology (5). Historical Information: Samuel Taylor Darling was the first to isolate Histoplasma capsulatum in 1906 while working on a team headed by William Gorgas in Ancon Hospital in Panama City, Panama, initially proposing that they were protozoans. The team s mission was to control malaria and yellow fever that had been affecting workers during their efforts in the construction of the Panama Canal. He performed various autopsies after

3 workers deaths from disease and noticed some workers had distinct presentations to those that died from malaria or yellow fever like pustules, ulcers and granulomas in their lungs, spleen, liver and bone marrow. Smears revealed an intense invasion of large endothelial-like cells by small round or oval microorganisms that were encapsulated (3). He published his observations in 6 papers between 1906 and 1909 and histoplasmosis became known as Darling s Disease. Darling later recognized the mistake in his conclusion that histoplasmosis members were protozoans and encapsulated after finding flagellated forms of the microorganism and comparing them to Leishmania, which had appeared simultaneously with histoplasmosis in In 1912, the Brazilian pathologist, Henrique da Rocha-Lima, obtained tissue from Darling s Panama patients and compared the organisms to Leishmaniasis. He showed the microorganism s similarity to the fungus Cryptoccocus farciminosus Rivolta that causes epizootic lymphangitis in horses and concluded that Histoplasma capsulatum was a fungus rather than a protozoan (3). Signs and Symptoms: Symptoms of histoplasmosis range in severity and appear 3-17 days after the fungal spores and inhaled. The mildest form of histoplasmosis generally produces no signs or symptoms. Symptoms of more severe infections (usually occur in immunosuppressed patients) include fever, cough, fatigue, chills, headache, chest pain and body aches usually lasting between few weeks to a month. If symptoms persist past 1-3 months the case may become chronic which is characterized by additional hemoptysis, night sweats, shortness of breath or secondary complications like pneumonia (8). The clinical manifestations are similar to those with community acquired pneumonia and TB and include identification of pulmonary nodules and mediastinal lymphadenopathy on CT scan/radiography. In cases of progressive disseminated histoplasmosis, the severity varies with the degree of immune deficiency. Symptoms continue to include fever, shortness of breath and weight loss. Examination may show pustules, ulcers, hepatomegaly, splenomegaly or lymphadenopathy and lab tests may reveal hepatitis or suppression of bone marrow. In the most severe cases, it can ultimately lead to shock and multi-organ failure (2). Virulence Mechanism: H. capsulatum s dimorphic abilities allow it to survive in different conditions: in mycelial form in soil, 25 C, and the pathogenic yeast form once it enters the body, 37 C. While in the body, the yeast form of H. capsulatum is known for releasing a calcium binding protein (CBP) in vitro. While CBP s exact mechanism is unknown, its structure suggests that it inhibits phagocytic function, which allows the yeast to replicate in the cell and survive. H. capsulatum s cell wall also contains a polysaccharide, α-glucan, on its surface that prevents it s recognition by macrophages and the protein Yps3 that is believed to be responsible for the progression of histoplasmosis to the disseminated stage in the spleen and liver. This protein interacts with chitin in the cell wall and is made during the fungus s transition from mycelial to yeast form (6).

4 Control/Treatment: H. capsulatum is susceptible to Amphotericin B, Ketoconazole, Itraconazole, and Fluconazole. Patients with acute histoplasmosis receive Amphotericin for 1-2 weeks followed by Itraconazole for 3 days. If patients symptoms persist for longer than one month, they may extend Itraconazole intake for 6-12 weeks. In severe cases, antifungals like Voriconazole and Posaconazole may be given intravenously. Patients who are asymptomatic do not require treatment (9). Prevention: There are no immunizations or prophylactic treatment for histoplasmosis. The best way to prevent acquiring the disease is by avoiding being in areas were the fungi is prevalent or wearing a mask while working in unknown soils or near bird or bat guano (8,9). Current Cases/Outbreaks: Most histoplasmosis cases are not associated with outbreaks. During the 1940s 1950s skin tests were done in the US to find histoplasmosis-endemic areas (2) with the highest percentages of positive reactions (60% 90%) around the Ohio and Mississippi River valleys. There were a decreased amount of reactions with increasing distance from these areas (13). According to the CDC, histoplasmosis is reportable in the following US territories: Arkansas, Delaware, Illinois, Indiana, Kentucky, Michigan, Minnesota, Nebraska, Pennsylvania, Puerto Rico, and Wisconsin (8). During , a total of 105 outbreaks involving 2,850 cases were reported in 26 states and the territory of Puerto Rico. In 77% of the outbreaks, birds, bats, or their droppings were reportedly present, and 41% of the outbreaks reported workplace exposures (12). Internationally, many people have been infected in South and Central America reportedly in Brazil, French Guiana, Argentina, Colombia, Venezuela and Panama as well as Asia (India, Malaysia, Indonesia, Singapore, Thailand, Vietnam and Japan), Africa and Europe (Italy and Switzerland) (13). The latest histoplasmosis outbreak occurred in the Dominican Republic in 2015 claiming 3 lives of a group of 28 workers who were cleaning the tunnels of a dam (14). Works Cited: 1. "Histoplasmosis: MedlinePlus." MedlinePlus Trusted Health Information for You. U.S. National Library of Medicine, 21 Dec Web. 26 Feb Wheat, Joseph L., MD, and Chadi A. Hage, MD. "Histoplasma Capsulatum (Histoplasmosis)."Histoplasma Capsulatum (Histoplasmosis) - Infectious Disease and

5 Antimicrobial Agents. E-Sun Technologies, Inc., Web. 01 Mar Hagan, Teresa. "The Discovery and Naming of Histoplasmosis-Samuel Taylor Darling." Antimicrobe, n.d. Web. 27 Feb Darling.pdf 4. Guimarães, Allan Jefferson, Joshua D. Nosanchuk, and Rosely Maria Zancopé- Oliveira. "DIAGNOSIS OF HISTOPLASMOSIS." Brazilian Journal of Microbiology : [publication of the Brazilian Society for Microbiology]. U.S. National Library of Medicine, Jan Web. 27 Feb Martagon-Villamil, Jose, Nabin Shrestha, Mary Sholtis, Carlos M. Isada, Gerri S. Hall, Terry Bryne, Barbara A. Lodge, Barth L. Reller, and Gary W. Procop. "Identification of Histoplasma Capsulatum from Culture Extracts by Real-Time PCR." Journal of Clinical Microbiology. American Society for Microbiology, Mar Web. 27 Feb Edwards, Jessica A., and Chad A. Rappleye. "Histoplasma Mechanisms of Pathogenesis One Portfolio Doesn t Fit All." FEMS Microbiology Letters. U.S. National Library of Medicine, 09 Aug Web. 01 Mar "Fungal Tests." Lab Tests Online: Empower Your Health. Understand Your Tests. A Public Resource on Clinical Laboratory Testing. American Association for Clinical Chemistry, 4 Oct Web. 01 Mar "Histoplasmosis." Centers for Disease Control and Prevention: Fungal Diseases. Centers for Disease Control and Prevention, 21 Nov Web. 28 Feb "Free Safety Data Sheet Index: Histoplasma Capsulatum." MSDSonline. Public Health Agency of Canada, Nov Web. 01 Mar "Epidemiology of Histoplasmosis Outbreaks, United States, : Discussion."Medscape. Centers for Disease Control, Web. 1 Mar "Histoplasma Capsulatum - NCBI Taxonomy - Overview." Encyclopedia of Life. EOL, n.d. Web. 03 Mar

6 12. Benedict, Kaitlin, and Rajal K. Mody. "Epidemiology of Histoplasmosis Outbreaks, United States, " Emerging Infectious Diseases. Centers for Disease Control and Prevention, Mar Web. 05 Mar Benedict, Kaitlin, and Rajal K. Mody. "Epidemiology Of Histoplasmosis Outbreaks, United States, " American Journal of Epidemiology (1978): Medscape, LLC, 10 Jan Web. 28 Feb "Histoplasmosis -Dominican Republic (02): (Santiago) Tunnel Cleaners, Update."ProMED-mail. International Society for Infectious Diseases, 22 Sept Web. 06 Mar