Overview

The spectrum of clinical disease associated with Aspergillus is diverse, ranging from colonization, to allergic responses (ABPA), to invasive infections. This review will focus on invasive aspergillosis. Aspergillus species are ubiquitous and inhalations of infectious conidiae are frequent occurrences; however, tissue invasion is uncommon, occurring largely in setting of significant immunocompromise.

Risk Factors

• Prolonged neutropenia (ANC < 500 x 10 days)*
• Hematologic malignancy*
• HSCT recipients, higher following allogenic than autologous stem cell transplant*
• Prolonged corticosteroids or biologic agents (TNF alpha inhibitors)
• Solid organ transplantation, especially lung transplantation
• Advanced HIV
• Chronic granulomatous disease or other inherited immunodeficiency syndromes
• Severe COPD
• ICU patients after respiratory viral infection

Evaluation

• Invasive pulmonary aspergillosis (IPA): presents with fever, pleuritic chest pain, cough, dyspnea, and/or hemoptysis; however, many of these features may be absent due to inability to mount immune response in an immunosuppressed host and may present as isolated fever
• Rhinosinusitis: non-specific presentation similar to mucormycosis, with symptoms of fever, nasal congestion, facial pain, and blurred vision. May demonstrate proptosis or chemosis if orbit is involved
• Tracheobronchitis: presents as dyspnea, cough, wheezing with pseudomembranous or ulcerative lesions in patients with advanced HIV or at anastomosis sites in lung transplant recipients
• Disseminated aspergillosis:
  • Ocular: endophthalmitis, keratitis
  • Cutaneous lesions
  • CNS: abscesses, meningitis
  • Bone: osteomyelitis
  • Other (rare): endocarditis, GI, other sites
• Aspergillus infection is difficult to diagnose and cases are either 1) Proven or 2) Probable
  • Proven disease requires histopathology with evidence of tissue invasion and culture from an otherwise sterile site
  • Probable disease requires 3 categories:
    • Host factors (immunocompromised) and
    • Clinical factors: symptoms, compatible radiologic signs and
    • Micro: cultures, galactomannan or beta-D glucan
• Radiologic features in IPA: chest CT is the test of choice (non-contrast is sufficient); findings include lung nodules +/- halo sign (nodule with surrounding ground glass, suggestive of angioinvasion; more common in hematologic malignancy patients), wedge-shaped consolidations, cavitary lesions, air crescent sign (nodule with surrounding crescenteric area of radiolucency)
• Microbiologic findings:
  • Culture: negative cultures do not rule out invasive aspergillosis
    • BAL cultures ~50% sensitive for focal pulmonary lesions
    • Blood cultures are rarely positive
  • Antigen-based testing:
    • Galactomannan: component of Aspergillus cell wall
      • positive result = galactomannan antigen index ³ 0.5 in serum or BAL fluid
      • Serum galactomannan: sensitivity 71% (95% CI 68-74%); specificity 89% (95% CI 88-90%)
      • BAL galactomannan: sensitivity 88% (95% CI 75-100%); specificity 81% (95% CI 71-91%)
      • False positive: piperacillin-tazobactam (old formulation), IV amoxicillin-clauvulanate, other invasive mycoses (penicilliosis, fusariosis, histoplasmosis, blastomycosis)
    • Beta-D-glucan assay: fungal cell wall polysaccharide
      • Signifies invasive fungal disease but not specific for Aspergillus—also detects candidiasis, fusariosis, PCP; false positive seen with IVIG, albumin, and HD with cellulose membrane
      • Positive result = serum 1,3 beta D-glucan level ³ 60
      • Sensitivity for diagnosing invasive fungal infection 77% (95% CI 67-84); specificity 85% (95% CI 80-90%)
      • Not a preferred test for diagnosing IA given issues with specificity

Management 

ID should be consulted for all cases of suspected or proven invasive aspergillosis.

Antifungal therapy:

• Voriconazole therapy is the preferred regimen:
  • Dosing (see also dosing on IDMP): 6mg/kg IV/PO q12hrs x 2 doses then 4mg/kg IV/PO q12hrs thereafter
  • Check trough level 5 days into therapy, goal: 1.5 – 5 mcg/mL
  • Remember to check for drug-drug interactions and baseline QTc
  • Monitor for LFT abnormalities, QTc prolongation, rash, CNS side effects (e.g. hallucinations)
• Alternative primary therapies include liposomal amphotericin (Ambisome) or alternative azoles (isavuconazole, posaconazole)
  • Liposomal AmB: 5mg/kg/d IV daily (with pre- and post-infusion hydration and daily BMP/Mg)
  • Isavuconazole: 372mg of isavuconazonium sulfate ( = 200mg isavuconazole) q8hrs x 6 doses as loading dose, then 372mg/day thereafter
  • Posaconazole: 300mg PO q12h x 2 doses then 300mg PO q24h (note this is dosing for the DR tablets, which is the preferred oral formulation)
• Combination of antifungal therapy with voriconazole and echinocandin may be considered in select patients with severe disease, but primary therapy with echinocandin is not recommended
• Treatment duration of IPA is a minimum of 6-12 weeks and largely depends on degree and duration of immunosuppression and evidence of disease improvement (with ongoing monitoring of clinical symptoms and radiographic findings with CT Chest)
• Surgery may be indicated in severe focal pulmonary infections, aspergilloma, osteomyelitis, rhinosinusitis, endocarditis, cerebral lesions, and lesions adjacent to great vessels
• For patients at high risk of invasive aspergillosis, consider prophylaxis with posaconazole or voriconazole
• See also the IDSA guidelines for the management of aspergillosis: https://doi.org/10.1093/cid/ciw326

Key Points

• Definitive diagnosis is made by histopathology/culture while probable disease is suspected in immunocompromised patients with consistent clinical/radiologic and microbiologic factors
• Voriconazole is the preferred therapy

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