Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (492 page)

   
Immunocompromised patients
: Invasive and disseminated infection is most common in immunocompromised patients; patients with severe and prolonged neutropenia are at greatest risk. Immunocompromised patients with fusariosis usually present with sepsis, associated with positive blood cultures and skin lesions. Skin lesions may occur as a primary site of infection but are the most common site of disseminated infection, occurring in a significant majority of patients with systemic disease. Patients typically present with multiple, painful lesions. Papular or nodular lesions are most common on the extremities. They commonly develop central necrosis with surrounding erythema.

   Laboratory Findings

Histopathology
: Hyaline, segmented hyphae with acute and right-angle branching are seen in tissues. Hyphae cannot be confidently differentiated from other opportunistic fungi, like
Aspergillus
and
Scedosporium
, but the presence of adventitious sporulation in vivo is not seen in
Aspergillus
and suggests
Fusarium
or
Scedosporium
infection. Angioinvasion may be evident, with distal necrosis due to vascular compromise.

Culture
:
Fusarium
species grow well on nonselective media for fungal isolation. Accurate speciation relies on specialized testing, like nucleic acid sequencing or specific PCR, and is not widely available. Standardized antifungal susceptibility testing is available.

Other
: The (1,3)-β-D-glucan assay is usually positive in invasive disease but is not specific for fusariosis. The galactomannan test is negative.

HISTOPLASMOSIS

   Definition

Histoplasmosis is caused by the thermally dimorphic fungus
Histoplasma capsulatum
. There are two variants,
H. capsulatum
var
capsulatum
and
H. capsulatum
var
duboisii
.
Histoplasma capsulatum
var
capsulatum
is endemic in the eastern United States (Mississippi, Ohio, and St. Lawrence River basins) and Latin America.
Histoplasma capsulatum
var
duboisii
occurs in Africa (Gabon, Uganda, and Kenya) and is associated with a lower frequency of pulmonary infection but more frequent skin and bone infection. The natural habitat of
H. capsulatum
is soil with high nitrogen content, such as found near roosting areas of birds or in caves, where the organism proliferates in its mold phase. Infection is transmitted by inhalation of conidia or mycelial fragments.

   Who Should Be Suspected?

Most infections are asymptomatic. Patients with defects in T-cell–mediated immune mechanisms are at increased risk for dissemination, reactivation of latent infection, or reinfection. Heavy exposure may result in acute pulmonary histoplasmosis and increased risk of disseminated disease. Conditions associated with disseminated disease include AIDS, chemotherapy for malignancy, glucocorticoid therapy, primary immunodeficiency disease, solid organ transplantation, and treatment with tumor necrosis factor blockers. Pulmonary histoplasmosis may mimic TB, other endemic mycoses, or other subacute or chronic pulmonary diseases. Histoplasmosis should be considered in patients with pneumonia at epidemiologic risk.

   Laboratory Findings

Direct detection
: Direct detection is most useful for acute histoplasmosis by detection of yeast-like cells in infected patient specimens. Small budding yeast (2–5 μm), often within mononuclear cells, may be seen by wet mount preparations or histology.

Culture
: Culture of the lung, skin, and mucosal lesions, sputum, BAL, gastric washings, blood, or bone marrow may provide a specific diagnosis. Fungal culture of blood is recommended for all patients with histoplasmosis. Two or three specimens may be needed for sensitive detection. Fungal culture of bone marrow is positive in a majority of patients with cytopenias or other signs of marrow failure. Blood and bone marrow cultures are positive in 50–70% of patients. Respiratory culture is positive in <40% of acute pulmonary cases but in up to 85% of patients with chronic pulmonary disease. Culture of tissue from infected sites is positive in 25–30% of patients. Culture is positive in approximately 50% of patients with meningitis, but a large volume of CSF is needed to detect CNS histoplasmosis by culture. Repeat culture on several occasions is recommended. Cultures may take up to 8 weeks to yield positive results, so initial therapeutic decisions are often based on clinical and other laboratory results.

Histology
: Granulomas, lymphohistiocytic aggregates, and mononuclear cell infiltrates are most commonly seen histopathologically using routine staining methods; staining to enhance fungi, like methenamine silver or periodic acid–Schiff, improves detection of yeast cells in tissue. Biopsy (specially stained) of skin and mucosal lesions, bone marrow, and RE system provides initial diagnosis in approximately 45% of cases. Demonstration of
H. capsulatum
in smears of peripheral blood, buffy coat, bone marrow (25–60% positive), or respiratory secretions is often the most rapid method of diagnosis; fungal culture is recommended to improve sensitivity of detection.

Antigen detection
:

   
Histoplasma capsulatum
–specific antigen may provide accurate diagnosis in early acute histoplasmosis, especially in patients with severe and progressive disease. The sensitivity of antigen detection is increased by submission of urine, blood, BAL fluid, and specimens from other potentially infected sites. Antigen may be detected in ≥75% of patients with diffuse acute pulmonary histoplasmosis.

   Antigen detection is especially useful in disseminated disease in which patients may not show significant antibody response. Urine antigen is positive in approximately 90% of patients with disseminated disease, approximately 20% of patients with acute self-limited disease, and <10% of patients with chronic pulmonary cavitary disease.

   Serum antigen testing is less sensitive than urine and is positive in approximately 70% of patients with disseminated disease. Antigen is detected in CSF in <50% of patients with meningitis; positive antigen must be interpreted with caution, as cross-reactions are seen in coccidioidal meningitis. (CSF antibodies may also cross-react.) Antigen is positive in BAL fluid in approximately 70% of patients with pulmonary histoplasmosis.