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Chapter 229 Aspergillus
Luise E. Rogg, William J. Steinbach
The aspergilli are ubiquitous fungi whose normal ecological niche is that of a soil saprophyte that recycles carbon and nitrogen. The genus Aspergillus contains approximately 185 species, but most human disease is caused by A. fumigatus, A. flavus, A. niger, A. terreus, and A. nidulans. Invasive disease is most commonly caused by A. fumigatus. Aspergillus reproduces asexually via production of sporelike conidia. Most cases of Aspergillus disease (aspergillosis) are due to inhalation of airborne conidia that subsequently germinate into fungal hyphae and invade host tissue. People are likely exposed to conidia on a daily basis. When inhaled by an immunocompetent person, conidia are rarely deleterious, presumably because they are efficiently cleared by phagocytic cells. Macrophage- and neutrophil-mediated host defenses are required for resistance to invasive disease. Disease can develop in hosts with neutropenia or suppressed macrophage function or after exposure to unusually high doses of conidia.
Aspergillus is a relatively unusual pathogen in that it can create very different disease states depending on the host characteristics, including allergic (hypersensitivity), saprophytic (noninvasive), or invasive disease. Immunodeficient hosts are at risk for invasive disease, whereas immunocompetent hosts tend to develop allergic disease. Disease manifestations include primary allergic reactions; colonization of the lungs or sinuses; localized infection of the lung or skin; invasive pulmonary disease; or widely disseminated disease of the lungs, brain, skin, eye, bone, heart, and other organs. Clinically, these syndromes often manifest with mild, nonspecific, and late-onset symptoms, particularly in the immunosuppressed host, complicating accurate diagnosis and timely treatment.
229.1 Allergic Disease (Hypersensitivity Syndromes)
Attacks of atopic asthma can be triggered by inhalation of Aspergillus spores, producing allergic responses and subsequent bronchospasm. Exposure to fungi, especially Aspergillus, needs to be considered as a trigger in a patient with an asthma flare.
Extrinsic alveolar alveolitis is a hypersensitivity pneumonitis that occurs due to repetitive inhalational exposure to inciting materials, including Aspergillus conidia. Symptoms typically occur shortly after exposure and include fever, cough, and dyspnea. Neither blood nor sputum eosinophilia is present. Chronic exposure to the triggering material can lead to pulmonary fibrosis.
Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity disease resulting from immunologic sensitization to Aspergillus antigens. It is primarily seen in patients with asthma or cystic fibrosis. Inhalation of conidia produces noninvasive colonization of the bronchial airways, resulting in persistent inflammation and development of hypersensitivity inflammatory responses. Disease manifestations are due to abnormal immunologic responses to A. fumigatus antigens and include wheezing, pulmonary infiltrates, bronchiectasis, and even fibrosis.
There are 7 primary diagnostic criteria for ABPA: episodic bronchial obstruction, peripheral eosinophilia, immediate cutaneous reactivity to Aspergillus antigens, precipitating antibodies to Aspergillus antigen, elevated IgE, pulmonary infiltrates, and central bronchietasis. Secondary diagnostic criteria include repeated detection of Aspergillus from sputum by identification of morphologically consistent fungal elements or direct culture, coughing up brown plugs or specks, elevated Aspergillus antigen–specific immunoglobulin E (IgE) antibodies, and late skin reaction to Aspergillus antigen. Radiologically, bronchial wall thickening, pulmonary infiltrates, and central bronchiectasis can be seen.
Treatment depends on relieving inflammation via an extended course of systemic corticosteroids. Addition of the antifungal agent itraconazole is used to decrease the fungal burden and diminish the inciting stimulus for inflammation. Because disease activity is correlated with serum IgE levels, these levels are used as one marker to define duration of therapy. An area of research interest is the utility of anti-IgE antibody therapy in the management of ABPA.
Allergic Aspergillus sinusitis is thought to be similar in etiology to ABPA. It has been primarily described in young adult patients with asthma and may or may not be seen in combination with ABPA. Patients often present with symptoms of chronic sinusitis or recurrent acute sinusitis, such as congestion, headaches, and rhinitis, and are found to have nasal polyps and opacification of multiple sinuses on imaging. Laboratory findings can include elevated IgE levels, precipitating antibodies to Aspergillus antigen, and immediate cutaneous reactivity to Aspergillus antigens. Sinus tissue specimens might contain eosinophils, Charcot-Leyden crystals, and fungal elements consistent with Aspergillus species. Surgical drainage is an important aspect of treatment, often accompanied by courses of either systemic or inhaled steroids. Use of an antifungal agent may also be considered.
Bibliography
Agarwal R. Allergic bronchopulmonary aspergillosis. Chest. 2009;135:805-826.
De Almeida MB, Bussamra MHF, Rodrigues JC. Allergic bronchopulmonary aspergillosis in paediatric cystic fibrosis patients. Paediatr Resp Rev. 2006;7:67-72.
229.2 Saprophytic (Noninvasive) Syndromes
Aspergillomas are masses of fungal hyphae, cellular debris, and inflammatory cells that proliferate without vascular invasion, generally in the setting of pre-existing cavitary lesions or ectatic bronchi. These cavitary lesions can occur as a result of infections such as tuberculosis, histoplasmosis, or resolved abscesses or secondary to congenital or acquired defects such as pulmonary cysts or bullous emphysema. Patients may be asymptomatic, with diagnosis made through imaging for other reasons, or they might present with hemoptysis, cough, or fever. On imaging, there may be thickening of the walls of a cavity initially, or later, a solid round mass separated from the cavity wall, as the fungal ball develops. Detection of Aspergillus antibody in the serum suggests this diagnosis. Treatment is indicated for control of complications, such as hemoptysis. Surgical resection is the definitive treatment but has been associated with significant risks. Systemic antifungal treatment with azole-class agents may be indicated in certain patients.
Chronic aspergillosis can occur in patients with normal immune systems or mild degrees of immunosuppression. Three categories have been proposed to describe different manifestations of chronic aspergillosis. The first is chronic cavitary pulmonary aspergillosis (CCPA), which is similar to aspergilloma, except that multiple cavities form and expand with occupying fungal balls. The second is chronic fibrosing pulmonary aspergillosis, where the multiple individual lesions progress to significant pulmonary fibrosis. The final is chronic necrotizing pulmonary aspergillosis (CNPA), also known as subacute invasive or semi-invasive pulmonary aspergillosis, a slowly progressive subset found in patients with mild to moderate immune impairment.
Management of CCPA can sometimes be via surgical resection, though long-term antifungal therapy, as for invasive aspergillosis, is indicated. Management of CNPA is similar to that of invasive pulmonary aspergillosis; however, the disease is more indolent, and thus there is a greater emphasis on oral therapy. Direct instillation of antifungals into the lesion cavity has been employed with some success.
Sinus aspergillosis typically manifests with chronic sinus symptoms that are refractory to antibacterial treatment. Imaging can demonstrate mucosal thickening in the case of Aspergillus sinusitis or a single mass within the maxillary or ethmoid sinus in the case of sinus aspergilloma. If untreated, sinusitis can progress and extend into the ethmoid sinuses and orbits. Therapy of sinusitis depends on surgical débridement and drainage, including surgical removal of the fungal mass in cases of sinus aspergilloma.
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