Histoplasmosis due to Histoplasma capsulatum

Synonyms

North American histoplasmosis. Contrast with African histoplasmosis due to Histoplasma duboisii

Distribution of histoplasmosis in the United States

Ajellomyces capsulatus

Culture of H capsulatum BHI agar with 10% sheep blood, incubated at 35°C

Histoplasma capsulatum yeast phase from a Wright-stained sample of peripheral blood

Histoplasma capsulatum

Histoplasma capsulatum tuberculated macroconidia,grown at 25°C

Definition

Histoplasmosis refers to the condition caused by the infection with the dimorphic endemic fungi N/A(L):Histoplasma capsulatum var. capsulatum. This anamorphic fungus has a known sexual teleomorph that carries the name Ajellomyces capsulatus. The majority of acute cases of infection with this fungus follow a subclinical and benign course in normal hosts [2412]. However, a disseminated and potentially fatal picture is seen among immunosuppressed individuals, children less than 2 years old, elderly persons, and people exposed to very large inoculum [872]. Since the advent of the HIV epidemic, histoplasmosis has reemerged to become one of the most frequent opportunistic diseases in those areas of the world endemic for this soil-based fungus [2031, 2418]. The infection is acquired through inhalation of Histoplasma capsulatum microconidia. The lungs are thus the most frequently affected site and chronic pulmonary disease may occur. This clinical picture is frequently associated with preexisting chronic lung diseases such as emphysema and occurs most frequently in elderly men [871]. All stages of this disease may mimic tuberculosis. Histoplasmosis may coexist with actinomycosis, other mycoses, sarcoidosis, or tuberculosis [1823, 1838].

Forms of the disease

CATEGORIES	NOTES
Asymptomatic	Occurs in 50-90% of infected individuals
Acute & symptomatic
1.- Self-limited (Flu-like syndrome)	It usually goes unrecognized
2.- Acute Pulmonary	Diffuse or localized pneumonitis. “Buckshot” appearance on chest radiograph with subsequent calcification in cases of heavy exposure. It may be severe enough to require ventilatory support
3.- Acute Pericarditis	Frequently associated with intrathoracic adenopathy Pericardial fluid is usually sterile
4.- Rheumatologic manifestations	Arthralgias, arthritis, erythema nodosum, and/or erythema multiforme
Chronic Pulmonary	Radiologic presentations include a Ghon complex suggestive of tuberculosis, histoplasmoma, and cavitary disease
Disseminated	See Disseminated Histoplasmosis table (below)
Fibrosing Mediastinitis	Rare form that produces an intense deposition of fibrotic tissue in the mediastinum encroaching vital structures such as the superior vena cava, esophagus and trachea.

Adapted from [2412]

DISSEMINATED HISTOPLASMOSIS: CLINICAL PRESENTATIONS

ORGAN INVOLVED	CLINICAL MANIFESTATION
Lymph nodes	Lymphadenitis
Bone Marrow	Anemia Leukopenia Thrombocytopenia
Heart	Endocarditis
Adrenal glands	Enlargement without symptoms Addison’s disease
CNS	Chronic Meningitis Cerebritis Mass
GI tract	Oral ulcers Small bowel micro and macro ulcers
Eyes	Uveitis Choroiditis
Skin	Papular to nodular rash
Genitourinary tract	Hydronephrosis Bladder ulcers Penile ulcers Prostatitis

Prognosis and therapy

Special resource: You may also want to refer to the Infectious Disease Society of America-Mycoses Study Group (IDSA-MSG) Practice Guidelines for this disease. It is available at the (E):IDSA website.

Not all clinical manifestations require antifungal treatment. As mentioned above, there are self-limited pictures as well as inflammatory reactions that do not respond to specific antifungal agents. A panel of experts recently met and created a detailed set of guidelines for the treatment of histoplasmosis and the following table summarizes their recommendations [2415]:

CATEGORIES	ANTIFUNGAL TREATMENT	REGIMEN
Asymptomatic	Not indicated
Acute & symptomatic
1.- Self-limited (Flu-like syndrome)	Not indicated
2.- Acute Pulmonary	Treatment indicated ONLY IF presents with hypoxemia or lasts for >1 month	Amphotericin B +/- corticosteroids¹, follow by Itraconazole for a total of 6-12 weeks of therapy
3.- Acute Pericarditis	Not indicated	Nonsteroidal anti-inflammatory agents for 2-12 weeks. Some may want to use corticosteroids for severe cases, in which case antifungal therapy is recommended
4.- Rheumatologic manifestations	Not indicated	Nonsteroidal anti-inflammatory agents
Chronic Pulmonary	Treatment indicated	Amphotericin B followed by Itraconazole for a total of 12-24 months
Disseminated in non-AIDS	Treatment indicated	Amphotericin B followed by Itraconazole² for a total of 12 weeks
Disseminated in AIDS	Treatment for life	Amphotericin B followed by Itraconazole^2,3 for life
Fibrosis Mediastinitis	Controversial. To be considered in cases with elevated ESR or complement fixation titers >1:32	Itraconazole for 3 months

¹The use of corticosteroids is controversial
²Ketoconazole can also be used although is less well tolerated than itraconazole.
³Fluconazole can also be used although has less efficacy than itraconazole.

Histopathology

The histopathological picture in acute disseminated histoplasmosis is different from that seen in the more chronic disease, and in solitary pulmonary nodules (“coin lesion”). In the first entity, the organisms are localized in histiocytes and reticuloendothelial cells. The cells enlarge, but with no evidence of inflammation. The intracellular budding yeasts are approximately 3 µm in diameter, similar to Leishmania sp., but do not contain a kinetoplast. In addition, Leishmania does not stain with the special stains used for fungi. Older lesions show well-developed granulomata and have a central area of caseation resembling tuberculosis. The solitary pulmonary nodules are well organized and usually have a circumferential rim of calcification accounting for their visibility on chest X-ray. Fungi within these nodules are usually dead. Histoplasma capsulatum yeast are found in the center of the lesions.

Laboratory

Direct examination

The direct detection of fungi in clinical material such as bone marrow, sputum, and tissue is usually difficult. Material stained by the PAS, Giemsa, GMS or cellufluor methods is more likely to show the organisms than is a KOH preparation.

Isolation

Inoculate the clinical material onto Inhibitory Mould agar and/or yeast extract-phosphate agar and/or BHI agar with 10% sheep blood and/or a medium containing cycloheximide. Incubate cultures at 30°C and do not discard until 12 weeks.

Antigen detection

Detection of the capsular antigen of this fungus in urine or serum is a very powerful tool for the diagnosis of the disseminated forms of this disease [333, 749, 2417, 2419]. The test is useful for both diagnosis and monitoring of infection, and is available from the (E):Histoplasmosis Reference Laboratory.

Laboratory confirmation

Confirmation is necessary to ensure that the fungus is not a species of Chrysosporium or Sepedonium. This can be accomplished by mould-to-yeast conversion, exoantigen testing, or by use of DNA probes.

Susceptibility testing

Standardized testing procedures are not available. Microbiological resistance has been demonstrated with respect to fluconazole [2413], but not itraconazole. Susceptibility testing is not routinely used to guide therapy of this disease.