Aspergillosis is a spectrum of diseases that may be caused by a number of Aspergillus species. Aspergillus species are ubiquitous saprobes in nature, and aspergillosis occurs worldwide. A. fumigatus is the most common human pathogen, but many others, including Aspergillus flavus, Aspergillus niger, Aspergillus terreus, and Aspergillus lentulus, may cause disease. This mold produces abundant small conidia that are easily aerosolized. Following inhalation of these conidia, atopic individuals often develop severe allergic reactions to the conidial antigens. In immunocompromised patients— especially those with leukemia, stem cell transplant patients, and individuals taking corticosteroids—the conidia may germinate to produce hyphae that invade the lungs and other tissues.

Morphology and Identification

Aspergillus species grow rapidly, producing aerial hyphae that bear characteristic conidial structures: long conidiophores with terminal vesicles on which phialides produce basipetal chains of conidia (see Figure 1). The species are identified according to morphologic differences in these structures, including the size, shape, texture, and color of the conidia.

Fig1. A. fumigatus. Phialides form on top of a swollen vesicle at the end of a long conidiophore. The basal conidia are the youngest. Mature conidia have rough walls. 400×.

Pathogenesis

In the lungs, alveolar macrophages are able to engulf and destroy the conidia. However, macrophages from corticosteroid-treated animals or immunocompromised patients have a diminished ability to contain the inoculum. In the lung, conidia swell and germinate to produce hyphae that have a tendency to invade preexisting cavities (aspergil loma or fungus ball) or blood vessels.

Clinical Findings

A. Allergic Forms

 In some atopic individuals, development of IgE antibodies to the surface antigens of Aspergillus conidia elicits an immediate asthmatic reaction upon subsequent exposure. In others, the conidia germinate, and hyphae colonize the bronchial tree without invading the lung parenchyma. This phenomenon is characteristic of allergic bronchopulmonary aspergillosis, which is clinically defined as asthma, recurrent chest infiltrates, eosinophilia, and both type I (immediate) and type III (Arthus) skin test hypersensitivity to Aspergillus antigen. Many patients produce sputum with Aspergillus and serum precipitins. They have difficulty breathing and may develop permanent lung scarring. Normal hosts exposed to massive doses of conidia can develop extrinsic allergic alveolitis.

B. Aspergilloma and Extrapulmonary Colonization

Aspergilloma occurs when inhaled conidia enter an existing cavity, germinate, and produce abundant hyphae in the abnormal pulmonary space. Patients with previous cavitary disease (eg, tuberculosis, sarcoidosis, and emphysema) are at risk. Some patients are asymptomatic; others develop cough, dyspnea, weight loss, fatigue, and hemoptysis. Cases of aspergilloma rarely become invasive. Localized, noninvasive infections (colonization) by Aspergillus species may involve the nasal sinuses, the ear canal, the cornea, or the nails.

C. Invasive Aspergillosis

Following inhalation and germination of the conidia, invasive disease develops as an acute pneumonic process with or without dissemination. Patients at risk are those with lymphocytic or myelogenous leukemia and lymphoma, stem cell transplant recipients, and especially individuals taking corticosteroids. The risk is much greater for patients receiving allogeneic (rather than autologous) hematopoietic stem cell transplants. In addition, AIDS patients with CD4 cell counts less than 50 CD4 cells/µL are predisposed to invasive aspergillosis. Symptoms include fever, cough, dyspnea, and hemoptysis. Hyphae invade the lumens and walls of blood vessels, causing thrombosis, infarction, and necrosis. From the lungs, the disease may spread to the gastrointestinal tract, kidney, liver, brain, or other organs, producing abscesses and necrotic lesions. Without rapid treatment, the prognosis for patients with invasive aspergillosis is grave. Persons with less compromising underlying disease may develop chronic necrotizing pulmonary aspergillosis, which is a milder disease.

Diagnostic Laboratory Tests

A. Specimens, Microscopic Examination, and Culture

 Sputum, other respiratory tract specimens, and lung biopsy tissue provide good specimens. Blood samples are rarely positive. On direct examination of sputum with KOH or calcofluor white or in histologic sections, the hyphae of Aspergillus species are hyaline, septate, and uniform in width (about 4 µm) and branch dichotomously (Figure 2). Aspergillus species grow within a few days on most media at room temperature. Species are identified according to the morphology of their conidial structures (see Figure1).

Fig2. Invasive aspergillosis. A: Uniform, branching septate hyphae (ca. 4 µm in width) of A. fumigatus in lung tissue stained with Gomori methenamine silver. 400×. B: Similar preparation with Grocott stain. 1000×.

B. Serology

 The ID test for precipitins to A. fumigatus is positive in over 80% of patients with aspergilloma or allergic forms of aspergillosis, but antibody tests are not helpful in the diagnosis of invasive aspergillosis. For the latter, the serologic test for circulating cell wall galactomannan is diagnostic, although not entirely specific for aspergillosis (see Table 1). In addition to testing for circulating galactomannan, the detection of β-glucan is also helpful in diagnosing invasive aspergillosis as well as candidiasis.

Table1. Laboratory Tests for Fungal Antigens in Clinical Specimens

Treatment

Aspergilloma is treated with itraconazole or amphotericin B and surgery. Invasive aspergillosis requires rapid administration of either the native or lipid formulation of amphotericin B or voriconazole, often supplemented with cytokine immunotherapy (eg, granulocyte-macrophage colony-stimulating factor or interferon Γ). Amphotericin B-resistant strains of A. terreus and other species, including A. flavus and A. lentulus, have emerged at several leukemia treatment centers, and the new triazole, posaconazole, may be more effective for these infections. The less severe chronic necrotizing pulmonary disease may be treatable with voriconazole or itraconazole. Allergic forms of aspergillosis are treated with corticosteroids or disodium cromoglycate.

Epidemiology and Control

 For persons at risk for allergic disease or invasive aspergillosis, efforts are made to avoid exposure to the conidia of Aspergillus species. Most bone marrow transplant units employ filtered air-conditioning systems, monitor airborne contaminants in patients’ rooms, reduce visiting, and institute other measures to isolate patients and minimize their risk of exposure to the conidia of Aspergillus and other molds. Some patients at risk for invasive aspergillosis are given pro phylactic low-dose amphotericin B or itraconazole.

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