ASPERGILLOSIS

ASPERGILLOSIS - Rodney D. Adam, MD
BASICS
DESCRIPTION
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: (1,2)[C]
- Pulmonary infiltrates, mucous plugging; secondary to allergic reaction to fungus (3)[C]
• Aspergillomas: "Fungus ball" saprophytic colonization within pre-existing pulmonary cavities
• Invasive aspergillosis: Most common and severe in BMT and neutropenic patients. Also occurs with increased frequency in other immunocompromised persons, such as those with AIDS, solid-organ transplant, or high-dose corticosteroids; commonly fatal (3,4)[C]
• System(s) Affected: Cardiovascular; Gastrointestinal; Musculoskeletal; Nervous, Pulmonary
• Synonym(s): Hypersensitivity pneumonitis; Fungus ball
GENERAL PREVENTION
• Allergic: Avoid exposure.
• Aspergillomas: Treatment of underlying diseases (e.g., chronic obstructive pulmonary disease [COPD])
EPIDEMIOLOGY
• Predominant age: Depends on subtype:
- Allergic: Tends to occur in patients 35 years
- Aspergillomas: Older patients with chronic lung disease
- Invasive: All ages
• Predominant sex: Male = Female
Prevalence
Rare
RISK FACTORS
• Allergic
- Exposure
- Asthma
• Aspergillomas
- COPD
- Bronchiectasis
- Tuberculosis (TB)
- Malignancy
• Invasive
- Neutropenia
- Corticosteroid therapy
- Graft Versus Host disease in recipients of bone marrow transplant
- AIDS
Genetics
No known genetic pattern
ETIOLOGY
Aspergillus species in decreasing order of frequency
• Aspergillus fumigatus
• Aspergillus flavus
• Aspergillus niger
ASSOCIATED CONDITIONS
• Allergic: Asthma
• Aspergillomas
- COPD
- TB
- Pulmonary mycoses
- Silicosis
- Sarcoidosis
- Nontuberculous mycobacteria
- Ankylosing spondylitis
- Malignancy
• Invasive: Neutropenia

DIAGNOSIS
SIGNS AND SYMPTOMS
• Allergic
- Cough
- Wheezing
- Constitutional symptoms
- Plug expectoration
• Aspergillomas
- Hemoptysis
- Manifestations of underlying disease
• Invasive
- Fever
- Cough
- Rales
- Rhonchi
- Toxicity
- CNS signs
- GI bleeding
TESTS
• Allergic bronchopulmonary aspergillosis
• Invasive: None
Lab
• Allergic bronchopulmonary aspergillosis
- Eosinophilia
- 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 Aspergillus fumigatus
• Invasive
- Sputum culture
- Cultures of bronchoalveolar lavage or bronchial washings
- Biopsy is definitive.
- Blood cultures almost never positive
Imaging
Chest radiographs
Fleeting infiltrates (allergic bronchopulmonary aspergillosis)
Round intracavity mass (aspergillomas)
Nodular or patchy infiltrates progressing to diffuse consolidation and cavitation (invasive)
Nodular, cavitary, or pleural-based wedge-shaped lesions
Diagnostic Procedures/Surgery
• 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.
Pathological Findings
• Necrotizing pneumonia
• Hemorrhagic infarcts
• Blood vessel invasion
• Branching septate hyphae if organism seen microscopically
DIFFERENTIAL DIAGNOSIS
• Allergic: Other causes of asthma and hypersensitivity pneumonitis
• Aspergillomas
- Neoplasm
- TB
• Invasive
- Bacterial pneumonia
- Pulmonary hemorrhage
- Drug toxicity
- Malignancy
- Mucor (sinuses)
TREATMENT
GENERAL MEASURES
• Allergic
- Usually outpatient
- Extrinsic allergic alveolitis: Drug therapy, exposure avoidance
- Allergic bronchopulmonary aspergillosis: Corticosteroids
• Aspergillomas
- Usually outpatient
- Individualized therapy ranging from no therapy to surgical resection of cavities in cases of severe hemoptysis
- Systemic antifungal therapy seldom useful
• Invasive
- Inpatient
- High-dose intravenous antifungal therapy (prognosis tends to be poor)
- Treatment of underlying disease
- Adjunctive cytokine therapy to reverse neutropenia
Diet
No special diet
Activity
As tolerated
MEDICATION (DRUGS)
First Line
• Allergic
- Extrinsic allergic alveolitis: Bronchodilators, cromolyn, steroids
- Allergic bronchopulmonary aspergillosis: Steroids are the mainstay of therapy. Antifungal agents (itraconazole or voriconazole) are being used increasingly as adjunctive agents.
• Aspergillomas: None
• Invasive: High-dose lipid formulation of amphotericin B (5 mg/kg/day and frequently higher). 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.
• Caspofungin: 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.
• Voriconazole: Superior to conventional amphotericin in a large study; well absorbed orally
• Contraindications: Refer to manufacturer's literature.
• Precautions
- Amphotericin B (including the 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.
- Voriconazole: Hepatically metabolized drugs, serum levels may be altered
- Itraconazole: Hepatically metabolized drugs, serum levels altered
Second Line
• Itraconazole occasionally useful as alternative agent
• Note: Because of frequent failure of single-drug therapy, combination therapy is frequently proposed.
FOLLOW-UP
PROGNOSIS
• Allergic
- With treatment: Good
- Untreated: Can progress to severe fibrosis, COPD
• Aspergillomas: Prognosis more related to underlying disease
• Invasive: Poor
COMPLICATIONS
• Allergic
- Bronchiectasis
- Pulmonary fibrosis
- Obstructive lung disease
• Aspergillomas: Hemoptyses
• Invasive
- Metastatic infection of CNS, GI tract, and other organs
- Death
PATIENT MONITORING
• Allergic
- Extrinsic allergic alveolitis: Spirometry
- Allergic bronchopulmonary aspergillosis: Chest radiograph, IgE levels
• Aspergillomas: Chest radiograph, symptoms
• Invasive: Chest radiograph, CBC
REFERENCES
1. Greenberger PA. Allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol. 110:685-692.
2. Zander DS. Allergic bronchopulmonary aspergillosis: An overview. Arch Pathol Lab Med. 129:924-928,l.
3. Soubani AO, Chandrasekar PH. The clinical spectrum of pulmonary aspergillosis. Chest. 2002;121:1988-1999.
4. Lin S, Schranz J, Teutsch S. Aspergillosis case-fatality rate: Systematic review of the literature. Clin Infect Dis. 2001;32:358-366.
5. Herbrecht R, Denning DW, Patterson TF, et al. Invasive Fungal Infections Group of the European Organisation for Research and Treatment of Cancer and the Global Aspergillus Study Group. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347:408-415.