- Disease caused by a ubiquitous mold; primarily involves lungs
- Frequently lethal in neutropenic and bone marrow transplant (BMT) patients. Syndromes include:
- Allergic aspergillosis:
- Extrinsic allergic alveolitis: Hypersensitivity pneumonitis in individuals repeatedly exposed to fungus
- Allergic bronchopulmonary aspergillosis (ABPA) (1,2)[C]
- Pulmonary infiltrates, mucous plugging; secondary to allergic reaction to fungus (3)[C]
- Aspergillomas: “Fungus ball” saprophytic colonization within preexisting pulmonary cavities
- Invasive aspergillosis (IA): Most commonly seen in BMT and neutropenic patients. Increased frequency: AIDS, solid-organ transplant, or high-dose corticosteroids; commonly fatal (3,4)[C]
- Allergic aspergillosis:
- System(s) affected: Cardiovascular; Gastrointestinal; Musculoskeletal; Nervous; Pulmonary
- Synonym(s): Hypersensitivity pneumonitis; Fungus ball
- Predominant age: Depends on subtype:
- Allergic: Tends to occur in patients <35 years
- Aspergillomas: Older patients with chronic lung disease
- Invasive: All ages
- Predominant gender: Male = Female
Rare (for invasive disease)
Rare (for invasive disease)
- Chronic obstructive pulmonary disease (COPD)
- Tuberculosis (TB)
- Corticosteroid therapy
- Graft-versus-host disease in BMT recipients
- AIDS (not particularly common in AIDS, but increased over general population)
- Chronic granulomatous disease
No known genetic risk factors
- Allergic: Avoid exposure
- Aspergillomas: Treatment of underlying diseases (e.g., COPD)
- Invasive: Prophylaxis with fluconazole or posaconazole reduces invasive fungal infections and decreases mortality (5)[A].
- Allergic bronchopulmonary aspergillosis symptoms result from the immune response to pulmonary fungal colonization.
- Invasive disease results from a combination of direct extension and hematogenous spread of the fungus.
Aspergillus species in decreasing order of frequency:
- Aspergillus fumigatus
- A. flavus
- A. niger
- A. terreus
Commonly Associated Conditions
- Allergic: Asthma
- COPD, TB, pulmonary mycoses, silicosis, sarcoidosis, nontuberculous mycobacteria, anklyosing spondylitis, malignancy
- Constitutional symptoms
- Chest tightening
- Plug expectoration
- Often asymptomatic but patients may experience:
- Manifestations of underlying lung disease
- Often asymptomatic but patients may experience:
- Productive cough
- Sternal retractions
- Prolonged expirations
- No specific abnormalities
- Central nervous system (CNS) signs
- Gastrointestinal (GI) bleeding
Diagnostic Tests & Interpretation
Initial lab tests
- Allergic bronchopulmonary aspergillosis:
- Arterial blood gas (ABG) shows decreased PCO2 and PO2
- Eosinophilia and moderate leukocytosis
- Immediate skin reactivity to Aspergillus antigen
- Precipitating-serum antibodies (precipitins) against Aspergillus antigens
- Elevated serum IgE concentrations
- Elevated serum IgE and IgG antibodies specific to A. fumigatus
- Invasive aspergillosis:
- Sputum culture
- Cultures of bronchoalveolar lavage or bronchial washings
- Biopsy with growth of Aspergillus species from specimen is definitive.
- Blood cultures almost never positive
- Serum galactomannan levels by enzyme immunoassay have sensitivity as high as 90% and specificity as high as 95% for invasive disease. This is especially helpful in patients with a high a priori suspicion of invasive disease in whom more invasive testing is impossible (6)[B].
- Bronchoalveolar lavage (BAL) of galactomannan (BAL-GM) has been shown to be 90% sensitive and 94% specific in identifying IA (7)[B].
Chest x-rays (CXRs):
- Fleeting infiltrates, overinflation (allergic bronchopulmonary aspergillosis)
- Round intracavity mass (aspergillomas)
- Nodular or patchy infiltrates progressing to diffuse consolidation and cavitation
- Nodular, cavitary, or pleural-based wedge-shaped lesions
- “Halo-sign” can be seen, which illustrates nodules surrounded by ground-glass appearance (IA)
- Bronchoscopy, bronchial washings, bronchoalveolar lavage, or transthoracic needle aspiration may be helpful in isolating organism in invasive disease
- Open-lung biopsy is diagnostic but often not possible in severely ill, ventilated patients
- Branching septate hyphae if organism seen microscopically
- Hemorrhagic infarcts, blood vessel invasion (IA)
- Bronchial smooth muscle hypertrophy, mucous hyperplasia, airways with viscid mucus containing shed epithelial cell casts (Curschmann spirals), or eosinophils containing Charcot-Leyden crystals
- Allergic: Other causes of asthma and hypersensitivity pneumonitis
- Wegener granulomatosis
- Hydatid cyst
- Bacterial pneumonia
- Pulmonary hemorrhage
- Drug toxicity
- Mucor (sinuses)
- Extrinsic allergic alveolitis: Bronchodilators, cromolyn, steroids
- Allergic bronchopulmonary aspergillosis: Itraconazole 200 mg b.i.d. in addition to corticosteroids as needed (1)[A]. Other azoles with activity against Aspergillus species are reasonable alternatives if itraconazole is contraindicated or not tolerated.
- Aspergillomas: Consider an azole with anti-Aspergillus activity (3)[B]
- Voriconazole 6 mg/kg q.12h. for 1 day, then 4 mg/kg q.12h. for up to 1 week, followed by an equivalent oral dose (e.g., 200 mg b.i.d. or t.i.d.): Superior to conventional amphotericin in a large study; well absorbed orally (1)[A]
- Voriconazole: Hepatically metabolized drugs, serum levels may be altered
- Pediatric population:
- From available trials that compared antifungal agents, there was no clear difference in efficacy regarding antifungal therapy in children (8)[A].
- A. terreus is resistant to amphotericin B
- Amphotericin B (including lipid formulations) can cause significant renal insufficiency and electrolyte abnormalities. Saline infusion at time of amphotericin B administration may decrease nephrotoxicity.
- Itraconazole: Normal, low gastric pH necessary for absorption
- Significant possible interactions:
- Amphotericin B: Other nephrotoxic drugs (e.g., aminoglycosides, cyclosporine) accelerate development of renal insufficiency.
- Amphotericin B: Diuretics accelerate electrolyte depletion
- Itraconazole: Serum levels of hepatically metabolized drugs may be altered.
- Invasive: High-lipid formulation of amphotericin B (3–5 mg/kg/d). The lipid formulations of amphotericin B (Abelcet, AmBisome) are preferred over standard amphotericin because of reduced nephrotoxicity in view of high doses required and perhaps better efficacy. In a recent study of invasive mycoses, primarily aspergillosis, low-dose AmBisome (3 mg/kg/d) was as effective and less toxic than high-dose (10 mg/kg/d).
- Posaconazole (200 mg PO 3-4x daily) has similar activity as Voriconazole against Aspergillus.
- Itraconazole (200 mg PO 3× daily for 3 days, then 200 mg PO 2× daily) is useful as alternative agent but rarely used in immunosuppressed patients.
- Caspofungin (70 mg IV once, then 50 mg IV once daily): Echinocandin approved for patients with aspergillosis unresponsive to other therapy or who have unacceptable toxicity to other agents. Micafungin and anidulafungin are other echinocandins that have been approved for treatment of candidiasis and are expected to have efficacy for treatment of aspergillosis.
- Note: Because of frequent failure of single drug therapy, combination therapy is frequently proposed. No published data support or refute this approach.
- Allergic (usually outpatient):
- Extrinsic allergic alveolitis: Drug therapy, exposure avoidance
- ABPA: Corticosteroids
- Aspergillomas (usually outpatient):
- Individualized therapy ranging from no therapy to oral antifungal therapy to surgical resection of cavities in cases of severe hemoptysis
- Invasive (inpatient):
- Intravenous antifungal therapy
- Treatment of underlying disease
- Adjunctive cytokine therapy to reverse neutropenia
Issues for Referral
Patients with invasive disease should be followed by specialists with experience in treating invasive fungal infections.
Resection of localized disease in life-threatening locations may be required.
For invasive disease, begin antifungal therapy as soon as there is strong suspicion of invasive disease.
Most patients with invasive disease should be treated as inpatients.
- Extrinsic allergic alveolitis: Spirometry
- Allergic bronchopulmonary aspergillosis: CXR, IgE levels
- Aspergillomas: CXR, symptoms
- Invasive: CXR, CT of chest or other involved parts of body
- With treatment: Good
- Untreated: Can progress to severe fibrosis, COPD
- Aspergillomas: Prognosis more related to underlying disease
- Invasive: Guarded; response to treatment can be monitored by serum galactomannan index.
- Pulmonary fibrosis
- Obstructive lung disease
- Metastatic infection of CNS, GI tract, and other organs
1. Walsh, TJ, et al. Treatment of Aspergillosis: Clinical Practice Guidelines of the Infectious Diseases Society of America. C Infect Dis 2008;46:327–360.
2. Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis. 2001;32:358–66
3. Herbrecht R, Denning DW, Patterson TF et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347:408–15
4. Cornely OA, Maertens J, Bresnik M et al. Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial). Clin Infect Dis. 2007;44:1289–97
5. Playford EG, Webster AC, Sorrell TC, Craig JC. Antifungal agents for preventing fungal infections in non-neutropenic critically ill patients. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD004920. DOI: 10.1002/14651858.CD004920.pub2
6. Leeflang MM, Debets-Ossenkopp YJ, Visser CE, Scholten RJPM, Hooft L, Bijlmer HA, Reitsma JB, Bossuyt PMM, Vandenbroucke-Grauls CM. Galactomannan detection for invasive aspergillosis in immunocompromized patients. Cochrane Database of Systematic Reviews 2008, Issue 4. Art. No.: CD007394. DOI: 10.1002/14651858.CD007394
7. Guo YL, Chen YQ, Wang K, Qin SM, Wu C, Kong JL, et al. Accuracy of bronchoalveolar lavage galactomannan in diagnosing invasive aspergillosis: a bivariate meta-analysis and systematic review. Chest. 2010
8. Blyth CC, Palasanthiran P, O’Brien TA, et al. Antifungal therapy in children with invasive fungal infections: a systematic review. Pediatrics. 2007;119:772–84
Singh N. Evidence-based approach to challenging issues in the management of invasive aspergillosis. Med Mycol. 2009;:1–5
Zander DS. Allergic bronchopulmonary aspergillosis: an overview. Arch Pathol Lab Med. 2005;129:924–8
- 117.3 Aspergillosis
- 495.9 Unspecified allergic alveolitis and pneumonitis
- 65553006 Aspergillosis (disorder)
- 37471005 extrinsic allergic alveolitis (disorder)
- Allergic aspergillosis tends to occur in younger patients (< 35).
- Eosinophilia is present with aspergillosis.
- Although aspergillus is ubiquitous, most immunocompetent people will not aquire disease.