Treatment of invasive fungal disease: A case report

Table 1 Criteria for proven invasive fungal disease except for endemic mycoses

Analysis and specimen	Molds1	Yeasts1
Microscopic analysis: Sterile material	Histopathologic, cytopathologic, or direct microscopic examination2 of a specimen obtained by needle aspiration or biopsy in which hyphae or melanized yeast-like forms are seen accompanied by evidence of associated tissue damage	Histopathologic, cytopathologic, or direct microscopic examination2 of a specimen obtained by needle aspiration or biopsy from a normally sterile site (other than mucous membranes) showing yeast cells - for example, Cryptococcus species indicated by encapsulated budding yeasts or Candida species showing pseudohyphae or true hyphae3
Culture; Sterile material	Recovery of a mold or “black yeast” by culture of a specimen obtained by a sterile procedure from a normally sterile and clinically or radiologically abnormal site consistent with an infectious disease process, excluding bronchoalveolar lavage fluid, a cranial sinus cavity specimen, and urine	Recovery of a yeast by culture of a sample obtained by a sterile procedure [including a freshly placed (< 24 h ago) drain] from a normally sterile site showing a clinical or radiological abnormality consistent with an infectious disease process
Blood	Blood culture that yields a mold4 (e.g., Fusarium species) in the context of a compatible infectious disease process	Blood culture that yields yeast (e.g., Cryptococcus or Candida species) or yeast- like fungi (e.g., Trichosporon species)
Serological analysis: CSF	Not applicable	Cryptococcal antigen in CSF indicates disseminated cryptococcosis

¹If culture is available, append the identification at the genus or species level from the culture results.

²Tissue and cells submitted for histopathologic or cytopathologic studies should be stained by Grocott-Gomorri methenamine silver stain or by periodic acid Schiff stain, to facilitate inspection of fungal structures. Whenever possible, wet mounts of specimens from foci related to invasive fungal disease should be stained with a fluorescent dye (e.g., calcofluor or blankophor).

³Candida, Trichosporon, and yeast-like Geotrichum species and Blastoschizomyces capitatus may also form pseudohyphae or true hyphae.

⁴Recovery of Aspergillus species from blood cultures invariably represents contamination. CSF: Cerebrospinal fluid.

Table 2 Criteria for probable invasive fungal disease except for endemic mycoses

Host factors1

Recent history of neutropenia [< 0.5 × 109 neutrophils/L (< 500 neutrophils/mm3] for > 10 d] temporally related to the onset of fungal disease

Receipt of an allogeneic stem cell transplant

Prolonged use of corticosteroids (excluding among patients with allergic bronchopulmonary aspergillosis) at a mean minimum dose of 0.3 mg/kg/d of prednisone equivalent for > 3 wk

Treatment with other recognized T cell immunosuppressants, such as cyclosporine, TNF-α blockers, specific monoclonal antibodies (such as alemtuzumab), or nucleoside analogues during the past 90 d

Inherited severe immunodeficiency (such as chronic granulomatous disease or severe combined immunodeficiency)

Clinical criteria2

Lower respiratory tract fungal disease3

The presence of one of the following three signs on CT:

Dense, well-circumscribed lesions(s) with or without a halo sign

Air-crescent sign

Cavity

Tracheobronchitis

Tracheobronchial ulceration, nodule, pseudomembrane, plaque, or eschar seen on bronchoscopic analysis

Sinonasal infection

Imaging showing sinusitis plus at least one of the following three signs:

Acute localized pain (including pain radiating to the eye)

Nasal ulcer with black eschar

Extension from the paranasal sinus across bony barriers, including into the orbit

CNS infection

One of the following two signs:

Focal lesions on imaging

Meningeal enhancement on MRI or CT

Disseminated candidiasis4

At least one of the following two entities after an episode of candidemia within the previous 2 wk:

Small, target-like abscesses (bull's-eye lesions) in liver or spleen

Progressive retinal exudates on ophthalmologic examination

Mycological criteria

Direct test (cytology, direct microscopy, or culture)

Mold in sputum, bronchoalveolar lavage fluid, bronchial brush, or sinus aspirate samples, indicated by 1 of the following:

Presence of fungal elements indicating a mold

Recovery by culture of a mold (e.g., Aspergillus, Fusarium, Zygomycetes, or Scedosporium species)

Indirect tests (detection of antigen or cell-wall constituents)5

Aspergillosis

Galactomannan antigen detected in plasma, serum, bronchoalveolar lavage fluid, or CSF

Invasive fungal disease other than cryptococcosis and zygomycoses

β-D-glucan detected in serum

Probable IFD requires the presence of a host factor, a clinical criterion, and a mycological criterion. Cases that meet the criteria for a host factor and a clinical criterion but for which mycological criteria are absent are considered possible IFD.

¹Host factors are not synonymous with risk factors and are characteristics by which individuals predisposed to invasive fungal diseases can be recognized. They are intended primarily to apply to patients given treatment for malignant disease and to recipients of allogeneic hematopoietic stem cell and solid-organ transplants. These host factors are also applicable to patients who receive corticosteroids and other T cell suppressants as well as to patients with primary immunodeficiencies.

²Must be consistent with the mycological findings, if any, and must be temporally related to current episode.

³Every reasonable attempt should be made to exclude an alternative etiology.

⁴The presence of signs and symptoms consistent with sepsis syndrome indicates acute disseminated disease, whereas their absence denotes chronic disseminated disease.

⁵These tests are primarily applicable to aspergillosis and candidiasis and are not useful in diagnosing infections due to Cryptococcus species or Zygomycetes (e.g., Rhizopus, Mucor, or Absidia species). Detection of nucleic acid is not included, because there are as yet no validated or standardized Methods. TNF-α: Tumor necrosis factor-alpha; CT: Computed tomography; MRI: Magnetic resonance imaging; IFD: Invasive fungal disease.

Table 3 Criteria for the diagnosis of endemic mycoses

Diagnosis and criteria
Proven endemic mycosis
In a host with an illness consistent with an endemic mycosis, one of the following:
Recovery in culture from a specimen obtained from the affected site or from blood
Histopathologic or direct microscopic demonstration of appropriate morphologic forms with a truly distinctive appearance characteristic of dimorphic fungi, such as Coccidioides species spherules, Blastomyces dermatitidis thick-walled broad-based budding yeasts, Paracoccidioides brasiliensis multiple budding yeast cells, and, in the case of histoplasmosis, the presence of characteristic intracellular yeast forms in a phagocyte in a peripheral blood smear or in tissue macrophages
For coccidioidomycosis, demonstration of coccidioidal antibody in CSF, or a 2-dilution rise measured in two consecutive blood samples tested concurrently in the setting of an ongoing infectious disease process
For paracoccidioidomycosis, demonstration in two consecutive serum samples of a precipitin band to paracoccidioidin concurrently in the setting of an ongoing infectious disease process
Probable endemic mycosis
Presence of a host factor, including but not limited to those specified in Table 2, plus a clinical picture consistent with endemic mycosis and mycological evidence, such as a positive Histoplasma antigen test result from urine, blood, or CSF

Endemic mycoses include histoplasmosis, blastomycosis, coccidioidomycosis, paracoccidioidomycosis, sporotrichosis, and infection due to Penicillium marneffei. Onset within 3 mo after presentation defines a primary pulmonary infection. There is no category of possible endemic mycosis, as such, because neither host factors nor clinical features are sufficiently specific; such cases are considered to be of value too limited to include in clinical trials, epidemiological studies, or evaluations of diagnostic test. CSF: Cerebrospinal fluid.