Invasive fungal infection

Microbiology

• Endemic fungi
  • Histoplasmosis
  • Blastomycosis
  • Coccidioidomycosis
  • Paracoccidioidomycosis
  • Sporotrichosis
  • Penicillium marneffei
• Other fungi
  • Molds
    • Aspergillus species
    • Zygomycosis
    • Fusarium
    • Scedosporium
  • Yeasts
    • Candida
    • Cryptococcus
• Excludes Pneumocystis

Epidemiology

• Among patients on posaconazole for a hematologic malignancy or bone marrow transplant, there is an approximately 2% rate of breakthrough infection 1

Classification (excluding endemic fungi)

• The classification for invasive fungal infections requires a combination of host factors (i.e. strong risk factor), clinical criteria (e.g. imaging), and mycological criteria (e.g. culture or serology) 2

Invasive pulmonary mold disease

• Host factors
  • Recent history of neutropenia (<0.5 × 109 neutrophils/L for >10 days) temporally related to the onset of fungal disease
  • Hematologic malignancy (active, in treatment, or recent)
  • Receipt of an allogeneic stem cell transplant
  • Prolonged use of corticosteroids (excluding ABPA) at a mean minimum dose of 0.3 mg/kg/day of prednisone equivalent for ≥3 weeks in the past 60 days
  •  Treatment with other recognized T-cell immunosuppressants, such as calcineurin inhibitors, TNF-α inhibitors, specific monoclonal antibodies (such as alemtuzumab), or nucleoside analogues during the past 90 days
  • Treatment with certain B-cell immunosuppressants, including ibrutinib
  • Inherited severe immunodeficiency, such as chronic granulomatous disease, STAT 3 deficiency, or severe combined immunodeficiency
  • Acute graft-versus-host disease grade III or IV, involving gut, lungs, or liver, which is refractory to first-line steroids
• Clinical criteria
  • Pulmonary aspergillosis: any of the following patterns on CT
    • Dense, well-circumscribed lesions with or without a halo sign
    • Air crescent sign
    • Cavity
    • Wedge-shaped and segmental or lobar consolidation
  • Other pulmonary mold disease: as above, but also including a reverse halo sign
  • Tracheobronchitis: tracheobronchial ulceration, nodule, pseudomembrane, plaque, or eschar seen on bronchoscopic analysis
  •  Sinonasal infection:
    •  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: 1 of the following 2 signs
    •  Focal lesions on imaging
    •  Meningeal enhancement on MRI or CT
• 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)
  • Tracheobronchitis
    • Aspergillus species on BAL or bronchial brush culture
    • Microscopy showing fungal elements on BAL or bronchial brush
  • Sinonasal disease
    • Mold on culture or microscopy of sinus aspirate
  • For Aspergillus species
    • Galactomannan in plasma, serum, BAL, or CSF
      • Serum or plasma ≥1
      • BAL ≥1
      • Serum or plasma ≥0.7 and BAL ≥0.8
      • CSF ≥1
    • PCR
      • Plasma, serum, or whole blood positive on 2 consecutive tests
      • BAL positive on 2 or more tests
      • At least 1 positive from plasma, serum, or whole blood and one positive from BAL

Other probable invasive diseases

Candidiasis

• Host factors
  • Recent history of neutropenia <0.5 × 109 neutrophils/L (<500 neutrophils/mm3 for >10 days) temporally related to the onset of invasive fungal disease
  • Hematologic malignancy
  • Receipt of an allogeneic stem cell transplant
  • Solid organ transplant recipient
  • Prolonged use of corticosteroids (excluding among patients with allergic bronchopulmonary aspergillosis) at a therapeutic dose of ≥0.3 mg/kg corticosteroids for ≥3 weeks in the past 60 days
  • Treatment with other recognized T-cell immunosuppressants, such as calcineurin inhibitors, tumor necrosis factor-a blockers, lymphocyte-specific monoclonal antibodies, immunosuppressive nucleoside analogues during the past 90 days
  • Inherited severe immunodeficiency (such as chronic granulomatous disease, STAT 3 deficiency, CARD9 deficiency, STAT-1 gain of function, or severe combined immunodeficiency)
  • Acute graft-versus-host disease grade III or IV involving the gut, lungs, or liver that is refractory to first-line treatment with steroids
• Clinical features
  • At least 1 of the following 2 entities after an episode of candidemia within the previous 2 weeks:
    • Small, target-like abscesses in liver or spleen (bull’s-eye lesions) or in the brain, or, meningeal enhancement
    • Progressive retinal exudates or vitreal opacities on ophthalmologic examination
• Mycological evidence
  • ß-D-glucan (Fungitell) ≥80 ng/L (pg/mL) detected in at least 2 consecutive serum samples provided that other etiologies have been excluded
  • Positive T2Candida

Cryptococcocis

• Host factors
  • HIV infection
  • Solid organ or stem cell transplant recipient
  • Hematologic malignancy
  • Antibody deficiency (eg, common variable immunoglobulin deficiency)
  • Immunosuppressive therapy (including monoclonal antibodies)
  • End-stage liver or renal disease
  • Idiopathic CD4 lymphocytopenia
• Clinical features
  • Meningeal inflammation
  • Radiological lesion consistent with cryptococcal disease
• Mycological evidence
  • Recovery of Cryptococcus from a specimen obtained from any nonsterile site

Pneumocystosis

• Host factors
  • Low CD4 lymphocyte counts <200 cells/mm3 (200 × 106 cells/L) for any reason
  • Exposure to medication (antineoplastic therapy, antiinflammatory, or immunosuppressive treatment) associated with T-cell dysfunction
  • Use of therapeutic doses of ≥0.3 mg/kg prednisone equivalent for ≥2 weeks in the past 60 days
  • Solid organ transplant
• Clinical features
  • Any consistent radiographic features particularly bilateral ground glass opacities, consolidations, small nodules or unilateral infiltrates lobar infiltrate, nodular infiltrate with or without cavitation, multifocal infiltrates, miliary pattern
  • Respiratory symptoms with cough, dyspnea, and hypoxemia accompanying radiographic abnormalities including consolidations, small nodules, unilateral infiltrates, pleural effusions, or cystic lesions on chest X-ray or computed tomography scan
• Mycological evidence
  • ß-D-glucan (Fungitell) ≥80 ng/L (pg/mL) detection in ≥2 consecutive serum samples provided other etiologies have been excluded
  • Detection of Pneumocystis jirovecii DNA by quantitative real-time polymerase chain reaction in a respiratory tract specimen

Endemic mycoses

• Host factors
  • Not applicable as these diseases affect both healthy and less healthy hosts
• Clinical features
  • Evidence for geographical or occupational exposure (including remote) to the fungus and compatible clinical illness
• Mycological evidence
  • Histoplasma or Blastomyces antigen in urine, serum, or body fluid
  • Antibody to Coccidioides in cerebrospinal fluid or 2-fold rise in 2 consecutive serum samples

Categories

Proven

• Fungal elements in biopsy of diseased tissue, or highly specific indirect assays
• Includes:
  • Aspergillus in culture
  • Histoplasma capsulatum: intracellular budding yeasts
  • Coccidioides species: spherules
  • Paracoccidioides brasiliensis: large yeasts with multiple daughter yeasts in a “pilot-wheel configuration”
  • Blastomyces dermatitidis: thick-walled, broad-based budding yeasts
• Can include Coccidioides antibodies in CSF, or Cryptococcus capsular antigen in CSF
• Does not include urine antigens

Probable

• Probable invasive fungal diseases requires at least one host factor, a clinical feature, and mycologic evidence
• Only relevant for immunocompromised patients

Possible

• Only cases with at least one host factor and at least one clinical evidence, but without supporting mycological evidence
• Not used for endemic fungi