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Histoplasmosis

by Sanjay G. Revankar, MD, Jack D. Sobel, MD

Histoplasmosis is a pulmonary and hematogenous disease caused by Histoplasma capsulatum; it is often chronic and usually follows an asymptomatic primary infection. Symptoms are those of pneumonia or of nonspecific chronic illness. Diagnosis is by identification of the organism in sputum or tissue or use of specific serum and urine antigen. Treatment, when necessary, is with amphotericin B or an azole.

(See also the Infectious Diseases Society of America’s Practice Guidelines for the Management of Patients with Histoplasmosis .)

Histoplasmosis occurs worldwide.

In the US, the endemic area for histoplasmosis includes

  • The Ohio–Mississippi River valleys extending into parts of northern Maryland, southern Pennsylvania, central New York, and Texas

Microfoci have been noted in other states, such as Florida, and along the St. Lawrence and Rio Grande rivers.

H. capsulatum grows as a mold in nature or in culture at room temperature but converts to a small (1 to 5 μm in diameter) yeast cell at 37° C and during invasion of host cells. Infection follows inhalation of conidia (spores produced by the mycelial form of the fungus) in soil or dust contaminated with bird or bat droppings. Severe disease is more common after heavy, prolonged exposure and in men, infants, or people with compromised T-cell–mediated immunity.

Initial infection occurs in the lungs and usually remains there but may spread hematogenously to other organs if it is not controlled by normal cell-mediated host defenses. Progressive disseminated histoplasmosis is one of the defining opportunistic infections for AIDS.

Symptoms and Signs

Most histoplasmosis infections are asymptomatic or so mild that patients do not seek medical attention. The disease has 3 main forms.

Acute primary histoplasmosis is a syndrome with fever, cough, myalgias, chest pain, and malaise of varying severity. Acute pneumonia (evident on physical examination and chest x-ray) sometimes develops.

Chronic cavitary histoplasmosis is characterized by pulmonary lesions that are often apical and resemble cavitary TB. Manifestations are worsening cough and dyspnea, progressing eventually to disabling respiratory dysfunction. Dissemination does not occur.

Progressive disseminated histoplasmosis characteristically includes generalized involvement of the reticuloendothelial system, with hepatosplenomegaly, lymphadenopathy, bone marrow involvement, and sometimes oral or GI ulcerations. The course is usually subacute or chronic, with only nonspecific, often subtle symptoms (eg, fever, fatigue, weight loss, weakness, malaise); the condition of HIV-positive patients may inexplicably worsen. The CNS may become involved, causing meningitis or focal brain lesions. Adrenal infection is rare but may result in Addison disease. Severe pneumonia is rare, but patients with AIDS may develop severe acute pneumonia with hypoxia suggesting Pneumocystis jirovecii infection, as well as hypotension, mental status changes, coagulopathy, or rhabdomyolysis.

Fibrosing mediastinitis, a chronic but rare form, ultimately causes circulatory compromise.

Patients with histoplasmosis may lose vision, but organisms are not present in ocular lesions, antifungal chemotherapy is not helpful, and the link to H. capsulatum infection is unclear.

Diagnosis

  • Histopathology and cultures

  • Antigen testing

The index of suspicion must be high because symptoms are nonspecific. Chest x-rays should be done and may show the following:

  • In acute infection: Normal or a diffuse nodular or miliary pattern

  • In chronic pulmonary histoplasmosis: Cavitary lesions in most patients

  • In progressive disease: Hilar adenopathy with diffuse nodular infiltrates in about 50% of patients

Bronchoalveolar lavage or tissue biopsy may be necessary to obtain histology specimens; serologic testing and culture of urine, blood, and sputum specimens are also done. Because culturing Histoplasma can pose a severe biohazard to laboratory personnel, the laboratory should be notified of the suspected diagnosis.

Microscopic histopathology can strongly suggest the diagnosis, particularly in patients with AIDS and extensive infections; in such patients, intracellular yeasts may be seen in Wright- or Giemsa-stained peripheral blood or buffy coat specimens. Fungal culture confirms the diagnosis. Lysis-centrifugation or culture of buffy coat improves the yield from blood specimens.

A test for H. capsulatum antigen is sensitive and specific, particularly when simultaneous serum and urine specimens are tested; however, cross-reactivity with other fungi ( Coccidioides immitis, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Penicillium marneffei) has been noted.

Prognosis

The acute primary form is almost always self-limited, although very rarely, death occurs after massive infection. Chronic cavitary histoplasmosis can cause death due to severe respiratory insufficiency. Untreated progressive disseminated histoplasmosis has a mortality rate of > 90%.

Treatment

  • Sometimes no treatment

  • For mild to moderate infection, itraconazole

  • For severe infection, amphotericin B

Acute primary histoplasmosis requires no antifungal therapy unless there is no spontaneous improvement after 1 mo; itraconazole 200 mg po is given tid for 3 days, then once/day for 6 to 12 wk. Fluconazole is less effective, and other azoles are not well-studied but have been used successfully. Severe pneumonia requires more aggressive therapy with amphotericin B.

For chronic cavitary histoplasmosis , itraconazole 200 mg po is given tid for 3 days, then once/day or bid for 12 to 24 mo. Other azoles or amphotericin B is used if patients are seriously ill or do not respond to or tolerate itraconazole.

For severe disseminated histoplasmosis , liposomal amphotericin B 3 mg/kg IV once/day (preferred) or amphotericin B 0.5 to 1.0 mg/kg IV once/day for 2 wk or until the patient is clinically stable is the treatment of choice. Patients can then be switched to itraconazole 200 mg po tid for 3 days, then twice/day continued for 12 mo after they become afebrile and require no ventilatory or BP support. For mild disseminated disease, itraconazole 200 mg po tid for 3 days, then twice/day for 12 mo can be used. In patients with AIDS, itraconazole is given indefinitely to prevent relapse or until CD4 cell counts are > 150. Blood levels of itraconazole and Histoplasma antigen levels should be monitored during therapy. Fluconazole may be less effective, but voriconazole and posaconazole are very active against H. capsulatum and may be effective in the treatment of patients with histoplasmosis. Further data and experience are required to determine which drug is the best in each clinical situation.

Key Points

  • Histoplasmosis is a common fungal infection acquired by inhaling spores.

  • It is endemic to the Ohio–Mississippi River valleys, extending into parts of northern Maryland, southern Pennsylvania, central New York, and Texas.

  • It may cause an acute primary pulmonary infection, a chronic cavitary pulmonary infection, or progressive disseminated infection.

  • Diagnose using histopathology, cultures, and/or antigen testing.

  • Acute primary infection is almost always self-limited.

  • Untreated progressive disseminated histoplasmosis has a mortality rate of > 90%.

  • For mild to moderate infection, use itraconazole.

  • For severe infection, use liposomal amphotericin B, followed by itraconazole.

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Drugs Mentioned In This Article

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  • VFEND
  • DIFLUCAN
  • SPORANOX
  • NOXAFIL

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