What are the typical presentation and treatment of invasive aspergillosis?

Invasive Aspergillosis: Clinical Presentation and Treatment

Clinical Presentation

Invasive aspergillosis typically presents with fever unresponsive to broad-spectrum antibiotics in immunocompromised patients, with pulmonary involvement being the most common manifestation (56-59% of cases). 1, 2, 3

Key Clinical Features by Site

Pulmonary Disease:

• Fever is the earliest and most common sign 2
• Cough, rales, and marked pleuritic chest pain appear early in the disease course 2
• Hemoptysis typically occurs late, after neutrophil recovery 2
• Nodules are the most frequent radiographic finding (34.6% in pediatric cases) 4
• The "halo sign" and "air-crescent sign" on CT are characteristic but not diagnostic 5
• Cavitation occurs in approximately 24.5% of patients 4

Sinonasal Disease:

• Nasal obstruction, epistaxis, and facial pain 2
• Periorbital swelling and potential palate destruction 2
• Risk of direct extension into orbit, cavernous sinuses, or intracranial structures 1

Disseminated Disease:

• Occurs in approximately 19% of cases 3
• CNS involvement presents with focal neurological findings or meningism 2
• Primary cutaneous infections appear as non-purulent ulcerations, often associated with IV devices 2

High-Risk Populations

The major risk factors include:

• Bone marrow/hematopoietic stem cell transplantation (32%) 3
• Hematologic malignancies (29%) 3
• Solid organ transplantation (9%) 3
• AIDS (8%) 3
• Chronic pulmonary diseases (9%) 3
• Prolonged neutropenia and immunosuppressive therapies 4

Diagnostic Approach

High-resolution CT scan should be performed within 24 hours of clinical suspicion, combined with serum galactomannan testing (sensitivity 74%, specificity 85%) and bronchoscopy with bronchoalveolar lavage for culture and histopathology. 5

Diagnostic Algorithm:

1. Obtain high-resolution CT chest immediately when invasive aspergillosis is suspected 5
2. Send serum galactomannan (cutoff 0.5) and beta-D-glucan testing 5
3. Perform bronchoscopy with BAL for culture, galactomannan, and PCR 5
4. Consider tissue biopsy via transthoracic needle aspiration or video-assisted thoracoscopic surgery for definitive diagnosis 5
5. Blood cultures have limited utility as they are typically negative 5

Treatment

Voriconazole is the first-line treatment for invasive aspergillosis with superior efficacy and survival outcomes compared to other antifungal agents (A-I recommendation). 6

Primary Treatment Regimen

Voriconazole dosing: 1, 6

• Loading dose: 6 mg/kg IV every 12 hours for 1 day
• Maintenance: 4 mg/kg IV every 12 hours OR 200 mg oral twice daily
• Pediatric dosing: 5-7 mg/kg IV every 12 hours 1

Alternative primary therapy:

• Liposomal amphotericin B (L-AMB) 3-5 mg/kg/day IV for patients intolerant to voriconazole 6
• Isavuconazole is an acceptable alternative 6

Salvage Therapy Options

When primary therapy fails or is not tolerated:

• Lipid formulations of amphotericin B (LFAB) 6
• Itraconazole 200 mg every 12 hours 1, 6
• Caspofungin: 70 mg loading dose, then 50 mg daily 1, 6, 7
• Micafungin 100-150 mg daily 1, 6
• Posaconazole 200 mg four times daily initially, then 400 mg twice daily 1

Duration of Treatment

Continue antifungal therapy for a minimum of 6-12 weeks, extending treatment in immunosuppressed patients until radiographic lesions have resolved and immune function has recovered. 6

For specific indications:

• Candidemia: at least 14 days after last positive culture 7
• Esophageal candidiasis: 7-14 days after symptom resolution 7
• Invasive aspergillosis: based on severity, immune recovery, and clinical response 1, 6

Site-Specific Treatment Considerations

CNS Aspergillosis:

• Voriconazole is the primary recommendation (A-II) 1
• Surgical resection of accessible lesions should be strongly considered 1
• This carries the highest mortality among all invasive aspergillosis patterns 1

Sinonasal Aspergillosis:

• Combined medical and surgical approach is essential 1, 8
• Aggressive surgical debridement plus systemic antifungal therapy 8
• If organism unknown, initiate amphotericin B formulation to cover possible zygomycosis (A-III) 1
• Once Aspergillus confirmed, switch to voriconazole (B-III) 1

Cardiac Aspergillosis:

• Endocardial lesions require surgical resection 1
• Pericarditis usually requires pericardiectomy 1

Osteomyelitis/Septic Arthritis:

• Surgical resection of devitalized bone and cartilage is critical 1

Adjunctive Therapies

Surgical intervention is the only independent predictor of survival and should be considered for: 1, 4

• Lesions contiguous with great vessels or pericardium 1
• Hemoptysis from cavitary lesions 1
• Chest wall invasion 1
• Single pulmonary lesion before intensive chemotherapy or HSCT 1

Immunomodulatory approaches (B-III): 1

• G-CSF or GM-CSF for neutropenic patients not already receiving colony-stimulating factors 1
• IFN-γ for patients with chronic granulomatous disease 1
• Granulocyte transfusions (G-CSF mobilized) for profoundly neutropenic patients with refractory infection 1

Critical Management Pitfalls

Important caveats:

• Aspergillus terreus is clinically resistant to amphotericin B; use azole therapy (A-I) 6
• Therapeutic drug monitoring should be performed for azoles, particularly in treatment failure 6
• Combination therapy is NOT routinely recommended for primary treatment but may be considered for salvage (B-II) 6, 9
• Reduction of immunosuppression where feasible is essential for therapeutic success 1
• Stagger amphotericin B administration by several hours from granulocyte transfusions to avoid pulmonary toxicity 1

Treatment Outcomes

Overall mortality remains high (52.5% in contemporary series), with immune reconstitution being the best predictor of survival rather than specific antifungal choice. 4, 3

Response rates vary significantly:

• Amphotericin B alone: 25% complete response, 65% mortality 3
• Voriconazole has demonstrated superior outcomes compared to amphotericin B 6, 9
• Sequential amphotericin B followed by itraconazole: 36% mortality in less immunosuppressed patients 3
• Surgery is the only independent predictor of survival 4