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School of Molecular & Biomedical Science
The University of Adelaide
AUSTRALIA 5005

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Dr David Ellis
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Aspergillosis

Description:

Aspergillosis is a spectrum of diseases of humans and animals caused by members of the genus Aspergillus. These include (1) mycotoxicosis due to ingestion of contaminated foods; (2) allergy and sequelae to the presence of conidia or transient growth of the organism in body orifices; (3) colonisation without extension in preformed cavities and debilitated tissues; (4) invasive, inflammatory, granulomatous, narcotising disease of lungs, and other organs; and rarely (5) systemic and fatal disseminated disease. The type of disease and severity depends upon the physiologic state of the host and the species of Aspergillus involved. The etiological agents are cosmopolitan and include Aspergillus fumigatus, A. flavus, A. niger, A. nidulans and A. terreus.

Clinical manifestations:

1. Pulmonary Aspergillosis: including allergic, aspergilloma and invasive aspergillosis.

The clinical manifestations of pulmonary aspergillosis are many, ranging from harmless saprophytic colonisation to acute invasive disease.

Allergic aspergillosis is a continuum of clinical entities ranging from extrinsic asthma to extrinsic allergic alveolitis to allergic bronchopulmonary aspergillosis (hypersensitivity pneumonitis) caused by the inhalation of Aspergillus conidia. Features include asthma, intermittent or persistent pulmonary infiltrates, peripheral eosinophilia, positive skin test to Aspergillus antigenic extracts, positive immunodiffusion precipitin tests for antibody to Aspergillus, elevated total IgE, and elevated specific IgE against Aspergillus. Plug expectoration and a history of chronic bronchitis are also common. Symptoms may be mild and without sequelae, but recurrent episodes frequently progress to bronchiectasis and fibrosis.

Non-invasive aspergillosis or aspergilloma (fungus ball), is caused by the saprophytic colonisation of pre-formed cavities, usually secondary to tuberculosis or sarcoidosis. Features often include hemoptysis with blood stained sputum, positive immunodiffusion precipitin tests for antibody to Aspergillus, and elevated specific IgE against Aspergillus. However, many cases are asymptomatic and are usually found by routine chest roentenogram.

Aspergilloma

Aspergilloma formed by the colonisation of a pre-formed lung cavity.

Acute invasive pulmonary aspergillosis. Predisposing factors include prolonged neutropenia, especially in leukemia patients or in bone marrow transplant recipients, corticosteroid therapy, cytotoxic chemotherapy and to a lesser extent patients with AIDS or chronic granulomatous disease. Clinical symptoms may mimic acute bacterial pneumonia and include fever, cough, pleuritic pain, with hemorrhagic infarction or a narcotising bronchopneumonia. The typical patient is granulocytopenic and receiving broad-spectrum antibiotics for unexplained fever. Radiological features may be non-specific and tests for serum antibody precipitins are also usually negative. Clinical recognition is essential as this is the most common form of aspergillosis in the immunosuppressed patient.

Chronic narcotising aspergillosis is an indolent, slowly progressive, "semi-invasive" form of infection seen in mildly immunosuppressed patients, especially those with a previous history of lung disease. Diabetes mellitus, sarcoidosis and treatment with low-dose glucocorticoids may be other predisposing factors. Common symptoms include fever, cough and sputum production; positive serum antibody precipitins may also be detected.

2. Disseminated Aspergillosis:

Hematogenous dissemination to other visceral organs may occur, especially in patients with severe immunosuppression or intravenous drug addiction. Abscesses may occur in the brain (cerebral aspergillosis), kidney (renal aspergillosis), heart, (endocarditis, myocarditis), bone (osteomyelitis), and gastrointestinal tract. Ocular lesions (mycotic keratitis, endophthalmitis and orbital aspergilloma) may also occur, either as a result of dissemination or following local trauma or surgery.

3. Aspergillosis of the paranasal sinuses:

Two types of paranasal sinus aspergillosis are generally recognised. (1) A non-invasive "aspergilloma" form, primarily seen in non-immunosuppressed individuals. Predisposing factors include a history of chronic sinusitis and poorly draining sinuses with excessive mucus. (2) An invasive form, usually seen in the immunosuppressed patient. This form has a similar clinical setting to that seen in rhinocerebral zygomycosis; and symptoms include fever, rhinitis and signs of invasion into the orbit.

4. Cutaneous Aspergillosis:

Cutaneous aspergillosis is a rare manifestation that is usually a result of dissemination from primary pulmonary infection in the immunosuppressed patient. However, cases of primary cutaneous aspergillosis also occur, usually as a result of trauma or colonisation. Lesions manifest as erythematous papules or macules with progressive central necrosis.

Laboratory diagnosis:

1. Clinical material: Sputum, bronchial washings and tracheal aspirates from patients with pulmonary disease and tissue biopsies from patients with disseminated disease.

2. Direct Microscopy: (a) Sputum, washings and aspirates make wet mounts in either 10% KOH & Parker ink or Calcofluor and/or Gram stained smears; (b) Tissue sections should be stained with H&E, GMS and PAS digest. Note Aspergillus hyphae may be missed in H&E stained sections. Examine specimens for dichotomously branched, septate hyphae.

dichotomously branched, septate hyphae conidial head of A. fumigatus
Aspergillosis of the lung. Methenamine silver stained tissue section showing dichotomously branched, septate hyphae (left) and a conidial head of A. fumigatus (right).

Interpretation: The presence of hyaline, branching septate hyphae, consistent with Aspergillus in any specimen, from a patient with supporting clinical symptoms should be considered significant. Biopsy and evidence of tissue invasion is of particular importance. Remember direct microscopy or histopathology does not offer a specific identification of the causative agent.

3. Culture: Clinical specimens should be inoculated onto primary isolation media, like Sabouraud's dextrose agar. Colonies are fast growing and may be white, yellow, yellow-brown, brown to black or green in colour.

A. fumigatus growing in a hen

A. fumigatus growing in air sacs of a hen during epidemic aspergillosis in poultry.

Interpretation: Aspergillus species are well recognised as common environmental airborne contaminants, therefore a positive culture from a non-sterile specimen, such as sputum, is not proof of infection. However, the detection of Aspergillus (especially A. fumigatus and A. flavus) in sputum cultures, from patients with appropriate predisposing conditions, is likely to be of diagnostic importance and empiric antifungal therapy should be considered. Unfortunately, patients with invasive pulmonary aspergillosis, often have negative sputum cultures making a lung biopsy a prerequisite for a definitive diagnosis.

4. Serology: Immunodiffusion tests for the detection of antibodies to Aspergillus species have proven to be of value in the diagn.osis of allergic, aspergilloma, and invasive aspergillosis. However, they should never be used alone, and must be correlated with other clinical and diagnostic data. Mixed and individual antigenic extracts and antisera to the common Aspergillus species are commercially available from a number of sources. Reliable antigen detection tests for invasive aspergillosis are currently not available.

5. Identification: Aspergillus colonies are usually fast growing, white, yellow, yellow-brown, brown to black or shades of green, and they mostly consist of a dense felt of erect conidiophores. Conidiophores terminate in a vesicle covered with either a single palisade-like layer of phialides (uniseriate) or a layer of subtending cells (metulae) which bear small whorls of phialides (the so-called biseriate structure). The vesicle, phialides, metulae (if present) and conidia form the conidial head. Conidia are one-celled, smooth- or rough-walled, hyaline or pigmented and are basocatenate, forming long dry chains which may be divergent (radiate) or aggregated in compact columns (columnar). Some species may produce Hülle cells or sclerotia.

Causative agents:

Aspergillus flavus, Aspergillus fumigatus, Aspergillus nidulans, Aspergillus niger, Aspergillus terreus.

Treatment Guidelines

 

Further reading:

Chandler FW., W. Kaplan and L. Ajello. 1980. A colour atlas and textbook of the histopathology of mycotic diseases. Wolfe Medical Publications Ltd. London.

Kwon-Chung KJ and JE Bennett 1992. Medical Mycology Lea & Febiger.

Richardson MD and DW Warnock. 1993. Fungal Infection: Diagnosis and Management. Blackwell Scientific Publications, London.

Rippon JW. 1988. Medical Mycology WB Saunders Co.

Warnock DW and MD Richardson. 1991. Fungal infection in the compromised patient. 2nd edition. John Wiley & Sons.