Invasive fungal infection

Background

Microbiology

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

Epidemiology

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

Classification

• 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
• It excludes endemic fungi

Invasive Pulmonary Mold Disease

• Interpretation
  • Possible IFD requires a host factor and a clinical feature, without mycological evidence
  • Probable IFD requires the presence of at least 1 host factor, a clinical feature, and mycologic evidence, and is relevant for immunocompromised patients only
  • Proven IFD is based on histopathology and can apply to any patient, regardless of whether the patient is immunocompromised
• 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 features
  • 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 evidence
  • 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 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
    • 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 Invasive Fungi

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

Cryptococcosis

• 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: 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

Further Reading

• Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Clin Infect Dis. 2020 Sep 12;71(6):1367-1376. doi: 10.1093/cid/ciz1008. PMID: 31802125; PMCID: PMC7486838.