Background

Ubiquitous saprophytic molds, Aspergillus species are common on decaying material throughout the world. More than 900 species are included in the genus Aspergillus. The agent responsible for more than 90% of human infections is Aspergillus fumigatus. Aspergillus flavus accounts for about 10% of invasive disease; Aspergillus niger and Aspergillus terreus each are responsible for approximately 2% of all invasive diseases. Other pathogens of interest include Aspergillus amstelodami, Aspergillus avenaceus, Aspergillus caesiellus, Aspergillus carneus, Aspergillus clavatus, Aspergillus oryzae, Aspergillus versicolor, and Aspergillus wentii. The most common cause of sinusitis is A flavus; the predominant cause of otomycosis is A niger.

Aspergillus species are characterized by dichotomously branching septate hyphae. Conidiophores are tubular structures arising from the hyphae, and the terminal ends of these widen to form vesicles. Spores or conidia are formed from long chains of sterigmata, which cover these vesicles. Abundant sporulation is demonstrated by every conidial head producing numerous conidia. These conidia are easily airborne, and their small size (ie, 2-3 µm) aids access to the lower respiratory tract. Characteristically, A fumigatus organisms are identified by the morphology of the conidia and conidiophores. A fumigatus organisms have green echinulate conidia produced basipetally from greenish phialides.

Pathophysiology

In most patients, the respiratory tract is the usual portal of entry and site of infection. Disease is classified by the site involved within the respiratory tract and by the extent of mycelial colonization or invasion of tissue, both of which are influenced by the host's immune status. Allergic disease (eg, allergic sinusitis, asthma, alveolitis) occurs following repeated exposure to Aspergillus conidia or antigens in patients without mycelial colonization or invasion. In contrast, allergic bronchopulmonary aspergillosis (ABPA), aspergilloma, and invasive aspergillosis syndrome involve mycelial growth in the body of the host.

Noninvasive aspergillosis is usually seen in immunocompetent individuals, whereas invasive aspergillosis is seen in immunocompromised patients.^[1]Noninvasive disease usually manifests as allergic bronchopulmonary aspergillosis, aspergilloma, and allergic sinusitis, whereas invasive disease can lead to widespread organ involvement, including pulmonary, cerebral, ocular, and cutaneous disease.

The histopathologic/cytopathologic view of invasive aspergillosis from a needle aspiration or biopsy demonstrates septate acutely branching hyphae or spherule formation (filamentous fungi without yeast forms), with evidence of associated tissue damage (either microscopically or unequivocally by imaging). Probable cases of invasive aspergillosis have been defined to include those with a clinically documented site of infection, and a culture from this site positive for Aspergillus species. Clinically documented infection is defined when fever is accompanied by cellulitis, sinusitis, pneumonia, or esophagitis. Possible invasive aspergillosis is defined as a clinically documented infection with undetermined microbiological etiology that did not respond to antibacterial therapy during persistent neutropenia.

Allergic bronchopulmonary aspergillosis

The pathogenesis of ABPA involves allergic reactions to Aspergillus species. Patients with chronic respiratory disease (eg, asthma, cystic fibrosis [CF]) may trap A fumigatus in their tenacious secretions, leading to an immune response that exacerbates their respiratory symptoms. Chronic mucosal colonization with A fumigatus causes elevated immunoglobulin G (IgG) and immunoglobulin E (IgE) levels, which lead to recurrent bronchospasm. ABPA occurs in 1-2% of patients with asthma and in 11% of patients with CF.

Aspergilloma

Aspergilloma is a nonallergic colonization by Aspergillus species in patients who are immunocompetent. Preexisting pulmonary cavities form a nidus for aspergilloma. These include cavities caused by tuberculosis, sarcoidosis, and chronically obstructed paranasal sinuses.

Invasive aspergillosis

Aspergillus disseminates by means of conidia, which disperse readily throughout the environment because of their lightweight. Airborne conidia enter the human host via inhalation or inoculation. An increase in the environmental load of conidia leads to increased risk of disease. Construction or renovation of hospital buildings or demolition of air-handling ducts near hospitals may lead to outbreaks of aspergillosis, especially in patients who are immunocompromised because these actions release concentrated bursts of conidia, which contaminate the surroundings.

Phagocytic cells, including pulmonary macrophages and neutrophils, are the first lines of defense against the conidia that are inhaled into the respiratory tract. Hyphae are destroyed by neutrophils, and macrophages ingest the conidia. This is why patients with immunocompromising conditions (eg, patients preparing for bone marrow transplantation, patients with graft versus host disease or graft rejection) have the highest risk of developing invasive aspergillosis.

Aspergillus species are second only to candida organisms as the cause of opportunistic infections in patients who are immunocompromised. Profound neutropenia (ie, polymorphonuclear leucocytes < 100/μL) and prolonged neutropenia (>12-15 d) create significant risks of patients developing invasive aspergillosis. Patients on corticosteroid therapy, cytotoxic chemotherapy, intravenous drug use, and broad-spectrum antimicrobial therapy also have increased susceptibility to invasive aspergillosis. Allogenic hematopoietic stem cell transplantation (HSCT) recipients are at much higher risk of invasive aspergillosis compared with autologous HSCT recipients, especially in the first month of conditioning regimens, which usually lead to profound neutropenia.

Functional neutrophil defects, including defective oxidative killing, are responsible for invasive aspergillosis that occurs in chronic granulomatous disease. Defects in cell-mediated immunity alone rarely predispose patients to invasive aspergillosis. For example, invasive aspergillosis occurs only in patients with advanced acquired immunodeficiency syndrome (AIDS) when significant neutrophil dysfunction occurs.

In patients who are immunosuppressed, widespread dissemination of Aspergillus is secondary to vascular invasion. This angiotropism is associated with infarction and tissue necrosis. In addition to pulmonary involvement, other sites of infection include the brain, skin, GI tract, kidneys, and peritoneum.

Frequency

United States

Frequency in the United States is similar to international frequency.

International

The incidence of invasive aspergillosis varies according to the underlying condition. The incidence is 19-26% in patients who have undergone heart and lung transplantation, 25-40% in patients with chronic granulomatous disease, 5-24% in patients with acute leukemia, and 3-7% in patients undergoing bone marrow transplantation. ABPA incidence rates are unavailable; however, the frequency of ABPA is increasing because of the increasing incidence of asthma. The incidence of aspergillomas is declining.

Mortality/Morbidity

The mortality rate of invasive aspergillosis ranges from 45-94%. CNS involvement is invariably fatal.

Race

Aspergillosis equally affects all races.

Sex

Aspergillosis equally affects both sexes.

Age

Aspergillosis may affect individuals at any age.

Clinical Presentation

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