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Invasive Mold Disease

Source: [@Donnell2020RevisionUpdate]
- Proven IFD can apply to any patient, regardless of whether the patient is immunocompromised
- Probable invasive fungal diseases (IFD) requires the presence of at least 1 host factor, a clinical feature and mycologic evidence and is proposed for immunocompromised patients only
- Cases that meet the criteria for a host factor and a clinical feature but for which mycological evidence has not been found are considered possible IFD
- (1,3)-beta-D glucan was not considered to provide mycological evidence of any invasive mold disease

Proven

  • Microscopic (Sterile Material): Histopathologic, cytopathologic, or direct microscopic examinationb 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
  • Culture (Sterile Material): Recovery of a hyaline or pigmented mold 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 BAL fluid, a paranasal or mastoid sinus cavity specimen, and urine
  • Blood: Blood culture that yields a moldc (eg, Fusarium species) in the context of a compatible infectious disease process
  • Tissue Nucleic Acid Diagnosis: Amplification of fungal DNA by PCR combined with DNA sequencing when molds are seen in formalin-fixed paraffin-embedded tissue

Probable

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 malignancy1
  • Receipt of an allogeneic stem cell transplant
  • Receipt of a solid organ transplant
  • 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, lymphocytespecific monoclonal antibodies, immunosuppressive nucleoside analogues during the past 90 days
  • Treatment with recognized B-cell immunosuppressants, such as Bruton’s tyrosine kinase inhibitors, eg, 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 the gut, lungs, or liver that is refractory to first-line treatment with steroids

ICU patients [@Bassett2021EORTCMSGERC]

  • Glucocorticoid treatment with prednisone equivalent of 20 mg or more per day
  • Qualitative or quantitative neutrophil abnormality (inherited neutrophil deficiency, absolute neutrophil count of ≤500 cells/mm3)
  • Chronic respiratory airway abnormality (chronic obstructive lung disease, bronchiectasis)
  • Decompensated cirrhosis
  • Treatment with recognized immunosuppressants (eg, calcineurin or mammalian target of rapamycin [mTOR] inhibitors, blockers of tumor necrosis factor [TNF] and similar antifungal immunity pathways, alemtuzumab, ibrutinib, nucleoside analogues) during the past 90 days
  • Hematological malignancies/HSCT
  • SOT
  • Human immunodeficiency virus infection
  • Severe influenza (or other severe viral pneumonia, such as coronavirus disease 2019 [COVID-19])

Clinical features

Pulmonary aspergillosis:

  • The presence of 1 of the following 4 patterns on CT:
    • Dense, well-circumscribed lesions(s) with or without a halo sign
    • Air crescent sign
    • Cavity
    • Wedge-shaped and segmental or lobar consolidation

Other pulmonary mold diseases:

  • As for pulmonary aspergillosis but also including a reverse halo sign

Tracheobronchitis:

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

Sino-nasal diseases:

  • 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

Central nervous system infection

1 of the following 2 signs
- Focal lesions on imaging
- Meningeal enhancement on magnetic resonance imaging or CT

Mycology evidences

  • Any mold, for example, Aspergillus, Fusarium, Scedosporium species or Mucorales recovered by culture from sputum, BAL, bronchial brush, or aspirate
  • Microscopical detection of fungal elements in sputum, BAL, bronchial brush, or aspirate indicating a mold

Tracheobronchitis

  • Aspergillus recovered by culture of BAL or bronchial brush
  • Microscopic detection of fungal elements in BAL or bronchial brush indicating a mold

Sino-nasal diseases

  • Mold recovered by culture of sinus aspirate samples
  • Microscopic detection of fungal elements in sinus aspirate samples indicating a mold

Aspergillosis only

  • Galactomannan antigen detected in plasma, serum, BAL, or CSF
    • Any 1 of the following:
      • Single serum or plasma: ≥1.0 (0.5 for ICU or COVID patients) [@Bassett2021EORTCMSGERC] [@Koehler2021Definingmanaging]
      • BAL fluid: ≥1.0 (0.8 for ICU patients)
      • Single serum or plasma: ≥0.7 and BAL fluid ≥0.8
      • CSF: ≥1.0
  • Aspergillus PCR
    • Any 1 of the following:
      • Plasma, serum, or whole blood 2 or more consecutive PCR tests positive 2
      • BAL fluid 2 or more duplicate PCR tests positive (or single with Ct < 36) 2
      • At least 1 PCR test positive in plasma, serum, or whole blood and 1 PCR test positive in BAL fluid
  • Aspergillus species recovered by culture from sputum, BAL, bronchial brush, or aspirate (+ cytology or direct microscopy for ICU patients)

Possible

  • Host factors + clinical features (for immunocompromised patients only)

References

Bassetti M, Azoulay E, Kullberg BJ, Ruhnke M, Shoham S, Vazquez J, et al. (2021) EORTC/MSGERC Definitions of Invasive Fungal Diseases: Summary of Activities of the Intensive Care Unit Working Group, Clinical Infectious Diseases, 72(Supplement_2), pp. S121–S127.

Donnelly JP, Chen SC, Kauffman CA, Steinbach WJ, Baddley JW, Verweij PE, et al. (2020) 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, Clinical Infectious Diseases, 71(6), pp. 1367–1376.

Koehler P, Bassetti M, Chakrabarti A, Chen SCA, Colombo AL, Hoenigl M, et al. (2021) Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance, The Lancet Infectious Diseases, 21(6), pp. e149–e162.

  1. Hematologic malignancy refers to active malignancy, in receipt of treatment for this malignancy, and those in remission in the recent past. These patients would comprise largely acute leukemias and lymphomas, as well as multiple myeloma, whereas patients with aplastic anemia represent a more heterogeneous group of individuals and are not included. ↩

  2. For CAPA: In case of patients with chronic obstructive pulmonary disease or chronic respiratory disease, the PCR or culture results should be confirmed by galactomannan testing to rule out colonisation or chronic aspergillosis. ↩↩