BY- K. Sai Manogna (MSIWM014)

Histoplasma capsulatum is a dimorphic fungus that, at ambient temperatures, stays in a mycelial shape and develops as yeast in mammals at body temperature. Histoplasmosis is caused by infection. While the fungus that causes histoplasmosis can be found worldwide in temperate climates, it is native to the U.S. valleys of the Ohio, Missouri, and Mississippi Rivers. Internationally, in North and Central America, eastern and southern Europe, and parts of Africa, East Asia, and Australia, the fungus is mainly found in river valleys. 

The soil in areas endemic to histoplasmosis provides a high organic acid damp environment that is good for mycelial development. Near regions populated by bats and birds, such as caves and chicken coops, highly infectious soil is found. Decaying trees and river banks also provide vital incubation habitats. Birds cannot be infected by fungi and do not spread the disease; bird excretions, however, contaminate the soil, enriching the mycelium growth medium. In comparison, bats may become infected, and by droppings, they spread histoplasmosis. For years, infected soil can be potentially contagious. Building and construction practices that disturb infected soil have been associated with histoplasmosis outbreaks. Moreover, as airborne spores can fly hundreds of miles, travelers to endemic areas are at risk of histoplasmosis. 

Pathophysiology: 

Life cycle:

1. H.capsulatum develops in a mycelial form in the saprobic state. 

2. On the hyphae of mycelium; macroconidia, and microconidia are formed. They are converted under temperature-controlled regulation to the yeast form. 

3. Conidia and mycelial fragments from polluted soil are aerosolized, resulting in alveolar deposition through inhalation. 

4. The host defense involves neutrophils and macrophages’ fungistatic properties. 

5. In restricting the degree of infection, T lymphocytes are essential. With weakened cellular host defenses, vulnerability to dissemination is markedly increased. 

6. Intracellularly, transfer from the mycelial to the pathogenic yeast type occurs. 

7. After macrophage phagocytosis, the yeast replicates within approximately 15-18 hours. Multiplication occurs throughout the phagosomes despite fusion with lysosomes. 

8. Proposed theories suggest that yeasts may produce proteins that inhibit the activity of lysosomal proteases. 

9. The growth of yeast stops within 1-2 weeks after exposure as the host immune response grows. 

10. Systemically, cytokines activate the fungistatic activity against intracellular yeasts in macrophages. 

11. Delayed-type hypersensitivity to histoplasmal antigens occurs with the cell-mediated response (3-6 weeks following exposure). 

12. Approximately 85-90 percent of immunocompetent people develop a positive response to the Histoplasma species skin antigen examination. 

13. The inflammatory response develops, over weeks to months, calcified fibrinous granulomas with areas of caseous necrosis. 

14. With continued exposure to large inoculums, clinical symptoms of histoplasmosis occur. The initial pulmonary infection, with hematogenous propagation, can spread systemically and produce extrapulmonary manifestations. 

15. There may be hematogenous spread to regional lymph nodes through the lymphatic or liver and spleen.

In adult hosts, which are immunocompetent, progressive disseminated histoplasmosis is rare. In patients with compromised cellular immunity, systemic spread usually occurs and generally includes the CNS, liver, spleen, and rheumatologic, ocular, and hematologic systems. 

Epidemiology: 

Sex: 

The rates of positive skin test results for exposure to H capsulatum antigens are identical in males and females. In women, rheumatologic manifestations appear to occur primarily. 

Age: 

While histoplasmosis may affect individuals of any age due to immature or degraded immune defenses, those in severe age ranges are more vulnerable to developing an infection. 

Prognosis:

A positive result is associated with acute pulmonary histoplasmosis. There is a long-term, long path of recurrent, progressive disseminated histoplasmosis, lasting for years, with long asymptomatic periods. Subacute progressive disseminated histoplasmosis progresses to death within 2-24 months if untreated. 

A 50 percent relapse rate is associated with, if treated, acute progressive disseminated histoplasmosis. With life-long antifungal maintenance, the incidence decreases to 10-20 percent. Without care, death is inevitable. 

Morbidity/mortality:

Morbidity and mortality are linked to systemic infection length and magnitude. 

Around 90 percent of acute pulmonary histoplasmosis patients are asymptomatic. In as many as 5% of symptomatic patients, acute pericarditis can happen. Generally, the pericardial fluid is exudative. In 40-60 percent of pericarditis patients, pleural effusions form. In patients with underlying lung disease, chronic pulmonary histoplasmosis occurs. Patients form cavities that can expand and result in necrosis. Progressive pulmonary fibrosis that results in cardiac failure, respiratory, and recurrent infections may result from untreated histoplasmosis. 

In infected infants, older people, and immunosuppressed people, progressive disseminated histoplasmosis occurs. In the subacute form, in untreated situations, death occurs within 2-24 months. The acute form results in death within weeks if untreated. 

Symptoms: 

Most individuals who are exposed to the Histoplasma fungus never have symptoms. Some individuals can have flu-like symptoms that typically go away by themselves. 

Histoplasmosis signs include fever, chills over, coughing, headache, fatigue, chest pain, and body pains.

In Severe Histoplasmosis: 

Histoplasmosis can evolve into a long-term lung infection in certain persons, usually those with compromised immune systems, or it can spread from the lungs to other areas of the body, such as the CNS.

Transmission: 

Usually, histoplasmosis is acquired by inhalation of airborne microconidia, often after polluted material disturbance (e.g., practices such as spelunking, chicken coop washing, or construction). It is exceedingly rare to have primary cutaneous histoplasmosis and solid organ donor-derived histoplasmosis. 

Risk and Prevention for Histoplasmosis: 

If they’ve been to a place where Histoplasma resides in the atmosphere, everyone can get histoplasmosis. Activities that disturb the soil, particularly soil containing bird or bat droppings, are often associated with histoplasmosis. Some classes of individuals are at greater risk of developing extreme types of histoplasmosis: 

For example, people who have weakened immune systems, individuals who: 

a. Have HIV/AIDS

b. Who took corticosteroids or TNF inhibitors

c. Children and adults of age 55 years above

d. Who had an organ transplant.

Histoplasmosis is unable to propagate between individuals or between people and animals from the lungs. However, the infection can be passed by an organ transplant of an infected organ in rare cases. 

Diagnosis: 

The most commonly used and most sensitive tool for diagnosing disseminated histoplasmosis and acute pulmonary histoplasmosis following exposure to a large inoculum is Histoplasma antigen detection in urine and serum. Antibody studies, culture, and microscopy are other methods.

Detection of antigens: Enzyme immunoassay (EIA) is typically performed on serum and urine, but also be used for bronchoalveolar lavage in cerebrospinal fluid.

Antibody testing: Antibody tests are not as effective as antigen detection tests for the diagnosis of acute histoplasmosis or for immunosuppressed individuals that may not have an excellent immune response, as it may take two to six weeks to develop antibodies to Histoplasma.

Immunodiffusion (ID): checks for the presence of precipitin bands of H (indicating chronic or severe acute infection) and M (developing within weeks of critical illness and can linger for months to years after the disease has ended); sensitivity of approximately 80%. 

Complement Fixation (CF): After infection, complement-fixing antibodies can take up to 6 weeks to appear. CF is more sensitive than immunodiffusion but less precise. 

Culture: May be done on tissue, blood, and other body fluids. They may take up to 6 weeks to become positive; most useful in diagnosing severe histoplasmosis types. You may use a commercially available DNA probe to confirm this. 

Microscopy: Low sensitivity in tissue or body fluids for the detection of budding yeast, but can provide a quick, proven diagnosis if positive.

Polymerase Chain Reaction (PCR): PCR is still experimental but promising for the identification of Histoplasma directly from clinical specimens. 

Histoplasmosis Treatment: 

Mild histoplasmosis cases confined to the lungs will be cured in about a month without special treatment. Treatment with antifungal medications is needed for severe infections or disseminated cases of histoplasmosis. Antifungal drugs that treat histoplasmosis are itraconazole, fluconazole, and amphotericin B. For several months, a person might need to continue treatment.

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