Aspergillosis

Essentials of Diagnosis

• Most common cause of noncandidal invasive fungal infection in transplant recipients and in patients with hematologic malignancies

• Predisposing factors for invasive disease: leukemia, bone marrow or organ transplantation, corticosteroid use, advanced AIDS

• Lungs, sinuses, and CNS are most common disease sites

• Detection of galactomannan in serum or other body fluids is useful for early diagnosis in at-risk patients

General Considerations

• Aspergillus fumigatus is the usual cause of aspergillosis, although many species of Aspergillus can cause disease

• Clinical illness results from abnormal immune response or tissue invasion

• Allergic bronchopulmonary aspergillosis (ABPA) occurs in persons with asthma or cystic fibrosis

• Invasive aspergillosis

  • Usually occurs in profound immunodeficiency, particularly in patients

    • Who have undergone hematopoietic stem cell transplantation

    • With prolonged severe neutropenia

  • Can occur among critically ill immunocompetent patients

• Allergic forms of aspergillosis

  • ABPA causes worsening bronchospasm in patients with asthma or cystic fibrosis

  • Allergic aspergillus sinusitis produces a chronic sinus inflammation characterized by eosinophilic mucous and noninvasive hyphal elements

• Chronic aspergillosis

  • Cough

  • Shortness of breath

  • Weight loss

  • Malaise

• Invasive aspergillosis

  • Pulmonary disease most common

  • Invasive sinus disease

• ABPA

  • Eosinophilia

  • High levels of total IgE, and IgE and IgG specific for Aspergillus in the blood

• Chronic aspergillosis

  • Disease manifestations range from aspergillomas that develop in a lung cavity to chronic fibrosing pulmonary aspergillosis in which the majority of lung tissue is replaced with fibrosis

• Invasive aspergillosis

  • Definitive diagnosis requires demonstration of Aspergillus in tissue or culture from a sterile site

  • Indirect diagnostic assays include detection of galactomannan in bronchoalveolar lavage fluid or serum, or serum assays for (1, 3)-beta-D-glucan (though the latter is not specific for Aspergillus); the diagnostic utility of Aspergillus DNA by PCR is debated

  • To improve the reliability of galactomannan testing, multiple determinations should be done, though sensitivity is decreased in patients receiving anti-mold prophylaxis (ie, voriconazole or posaconazole)

  • Galactomannan levels and Aspergillus DNA PCR can be tested in serum or in bronchoalveolar lavage fluid, which may be more sensitive than serum

  • Isolation of Aspergillus from pulmonary secretions does not necessarily imply invasive disease, although its positive predictive value increases with more advanced immunosuppression

  • CT scanning of the chest may aid in early detection and help direct additional diagnostic procedures

  • Common radiologic findings include

    • Nodules

    • Wedge-shaped infarcts

    • Characteristic "halo sign," a zone of diminution of ground glass around a consolidation

• ABPA

  • For acute exacerbations, prednisone, 0.5 mg/kg/day orally tapered slowly over several months

  • Itraconazole, 200 mg orally once daily for 16 weeks, appears to improve pulmonary function and decrease corticosteroid requirements

  • Voriconazole is an alternative agent

• Allergic aspergillus sinusitis

  • Topical corticosteroids cornerstone of therapy

  • Itraconazole is best studied agent

• Chronic aspergillosis

  • Surgical resection is most effective therapy for symptomatic aspergilloma

  • Other forms of chronic aspergillosis are generally treated with at least 4–6 months of oral azole therapy

    • Itraconazole, 200 mg twice daily

    • Voriconazole, 200 mg twice daily

    • Posaconazole, 300 mg daily

• Invasive aspergillosis

  • Voriconazole

    • Intravenous dose: 6 mg/kg intravenously twice on day 1 and then 4 mg/kg every 12 hours thereafter considered as optimal therapy for invasive aspergillosis

    • Oral dosing: 4 mg/kg twice daily can be used for less serious infections or as a step-down strategy after intravenous therapy

  • Isavuconazole (200 mg intravenously every 8 hours for six doses, then 200 mg daily) or voriconazole may be first-line therapy based on data from a randomized controlled trial demonstrating noninferiority of isavuconazole in terms of treatment outcomes and with fewer adverse events

  • In a randomized controlled trial, no overall benefit was found by adding anidulafungin (200 mg on day 1, then 100 mg daily) to voriconazole; however, among patients in whom galactomannan was detected, those who received combination therapy had better outcomes

  • Other alternatives include

    • A lipid formulation of amphotericin B (3–5 mg/kg/day)

    • Caspofungin (70 mg intravenously on day 1, then 50 mg/day thereafter)

    • Micafungin (100–150 mg intravenously daily)

    • Posaconazole oral tablets (300 mg twice daily on day 1 then 300 mg daily thereafter)

  • Antifungal susceptibility testing of Aspergillus isolates is recommended in patients

    • Who are unresponsive to therapy or

    • In whom azole-resistance is clinically suspected

Prevention

• Posaconazole (300 mg orally daily) and voriconazole (200 mg orally twice daily) are best studied agents

Prognosis

• Invasive aspergillosis

  • Can be life-threatening, particularly in profound immunodeficiency and prolonged severe neutropenia

  • Reversal of underlying immunosuppression is key to patient outcome

  • Higher galactomannan levels correlate with increased mortality and failure of galactomannan levels to fall in response to therapy portends a worse outcome