COVID-19-associated pulmonary aspergillosis

Background

• Defined as invasive pulmonary aspergillosis following COVID-19
• Similar to influenza-associated pulmonary aspergillosis

Pathophysiology

• Viral infection damages airway epithelium, allowing Aspergillus to invade
• May also be a component of immune dysfunction, with COVID-19 affecting T cells
• Probably also made more likely by treatment for COVID-19, including corticosteroids and IL-6 inhibitors

Clinical Manifestations

• The diagnosis should be considered in any critically ill patient with COVID-19 who has any of the following
  • Refractory fever lasting more than 3 days or a new fever after defervescing for more than 48 hours while on appropriate antibiotics
  • Hemoptysis
  • Pleural friction rub or chest pain
• Typically occurs within 1 to 3 weeks or intubation

Prognosis

• Mortality increased 16 to 25% compared to patients without aspergillosis

Investigations

• CT chest for COVID-19 can mimic IPA and vice-versa, made more complicated in patients with ARDS
  • Multiple pulmonary nodules or lung cavitation is suggestive, since they are less likely to be due to COVID-19 alone
  • Halo sign indicates local infarction, which can occur with COVID-19 even in the absence of IPA
• BAL for galactomannan is highly suggestive of IPA
• Serum galactamannan is insensitive (positive in about 20% of patients)

Diagnosis

• Diagnostic criteria have been developed by ECMM/ISHAM1
• Criteria only apply to patients with COVID-19 needing intensive care and who have a temporal relationship
• Proven tracheobronchitis or other pulmonary form:
  • At least one of the following:
    • Histopathological or direct microscopic detection of fungal hyphae, showing invasive growth with associated tissue damage
    • Aspergillus recovered by culture or microscopy or histology or PCR obtained by a sterile aspiration or biopsy from a pulmonary site
• Probable tracheobronchitis
  • Tracheobronchitis, indicated by tracheobronchial ulceration, nodule, pseudomembrane, plaque, or eschar seen on bronchoscopy
  • At least one of the following:
    • Microscopic detection of fungal elements in BAL, indicating a mold
    • Positive BAL culture or PCR
    • Serum galactomannan >0.5 or serum LFA >0.5
    • BAL galactomannan ≥1 or BAL LFA ≥1
• Probable pulmonary forms excluding tracheobronchitis
  • Pulmonary infiltrate, preferably documented by CT chest, or cavitating infiltrate, not attributed to another cause
  • At least one of the following:
    • Microscopic detection of fungal elements in BAL, indicating a mold
    • Positive BAL culture
    • Serum galactomannan >0.5 or serum LFA >0.5
    • BAL galactomannan ≥1 or BAL LFA ≥1
    • Two or more positive Aspergillus PCR tests in plasma, serum, or whole blood
    • A single positive Aspergillus PCR on BAL <36 cycles
    • A single positive Aspergillus PCR in plasma, serum, or whole blood, plus a single positive PCR in BAL
• Possible pulmonary forms excluding tracheobronchitis
  • Pulmonary infiltrate, preferably documented by CT chest, or cavitating infiltrate, not attributed to another cause
  • At least one of the following:
    • Microscopic detection of fungal elements in non-bronchoscopic lavage indicating a mould; positive non-bronchoscopic lavage culture
    • Single non-BAL galactomannan index >4.5
    • Non-BAL galactomannan index >1.2 twice or more
    • Non-BAL galactomannan index >1.2 plus another non-BAL mycology test positive (non-BAL PCR or LFA)

Management

• Either voriconazole or isavuconazole is recommended for possible, probable, and proven CAPA1
  • Voriconazole 6 mg/kg bid for 2 doses followed by 4 mg/kg bid
  • Isavuconazole 300 mg tid for 6 doses followed by 200 mg daily
• Liposomal amphotericin B is the recommended salvage therapy
• Alternatives include posaconazole and echinocandins, though the latter should ideally not be used as monotherapy