Aspergillosis represents an important group of pulmonary diseases that span the spectrum from asymptomatic colonization to IgE-mediated hypersensitivity reactions or tissue invasion with dissemination and death. Since aspergillosis is encountered frequently in the acute care setting, it is important that you recognize the clinical patterns of disease and understand the principles of therapy.

The spectrum of illness caused by Aspergillus is related to the presence or absence of hypersensitivity structural lung disease, and immune factors. Otherwise healthy persons do not generally encounter problems with this organism if they are not allergic or hypersensitive. Patients with bullae, cysts, or cavities are at risk for mycetomas. Immunosuppressed persons can experience any of the more invasive types of illness.

This article will focus on the diagnosis and treatment of allergic bronchopulmonary aspergillosis (ABPA) and mycetomas. In a coming issue of The Journal of Respiratory Diseases, Drs Khurana and Kane will review chronic necrotizing (chronic invasive) pulmonary aspergillosis, acute invasive pulmonary aspergillosis, and pulmonary aspergillosis in HIV-infected patients.

Aspergillus

Since fungi of the Aspergillus genus are ubiquitous and grow on decaying matter, exposure to their spores is inevitable. (1) The organism, its fruiting body, and the spores that can be aerosolized into the environment are shown in Figure 1. Although there are more than 300 species of Aspergillus, only a few affect humans. Aspergillus fumigatus is the most common, followed by Aspergillus flavus. Rarely encountered species include Aspergillus niger, Aspergillus clavatus, and Aspergillus nidulans.

Although Micheli first recognized Aspergillus as an organism in 1729, the first cases in humans were not noted until the mid19th century. (2) Approximately 100 years later, invasive aspergillosis was first described as an opportunistic infection. (3)

Currently, the range of aspergillosis is expanding, and the incidence of invasive disease seems to be rising, largely because of increased use of immunosuppressive therapies and transplantation. Despite repeated exposure to this group of organisms, disease as a result of tissue invasion is relatively uncommon. Neutropenia and corticosteroid use are the most common risk factors. (45)

Allergic bronchopulmonary aspergillosis

In some persons, hypersensitivity to Aspergillus species can cause asthma, hypersensitivity pneumonitis (HP) (extrinsic allergic alveolitis), and ABPA. HP that is caused by Aspergillus is indistinct clinically from HP caused by other pathogens, except that the inciting antigen must be aerosolized from Aspergillus growing on decaying organic matter. HP is also known as malt workers lung or farmers lung, although the more specific entities are caused by hypersensitivity to other pathogens, namely the thermophilic organisms. (6)

Allergic asthma associated with inhalation of Aspergillus is rare and is clinically distinct from ABPA. Patients with classic IgE-mediated allergic asthma have serum IgE levels that range from 10 to 250 ug/L. (7) Markedly elevated levels of IgE, usually exceeding 500 to 1000 ug/L, characterize ABPA. (6,8)

* Diagnosis: Although the diagnosis of ABPA does not require all of the following clinical characteristics, the first 5 usually are present: asthma, peripheral blood eosinophilia, markedly elevated IgE levels, immediate skin test reactivity to Aspergillus antigen, precipitating antibodies to Aspergillus species in the serum, pulmonary infiltrates that may be migrating, and central bronchiectasis (Table). A series of radiographic findings obtained from a patient who had ABPA with fleeting pulmonary infiltrates and migratory lobar collapse (secondary to mucous plugging) are shown in Figure 2. A follow-up thoracic CT scan of the same patient showed bronchiectatic changes (Figure 3).

The clinical course of ABPA is characterized by recurrent acute episodes with intervening remission (duration is difficult to predict). During remission, underlying asthma often requires treatment. Recurrent acute flares can lead to severe bronchiectasis or end-stage fibrosis. (6)

ABPA was first recognized as a common disease in the United Kingdom. (9) Initially, in the United States, ABPA was thought to be quite rare, (10) but now it is common in the Midwest, (11) with a lower incidence in the mid-Atlantic region. ABPA associated with cystic fibrosis is seen often in Great Britain (12) but is seen less in North America. (6)

* Treatment: Systemic corticosteroids should be used to treat ABPA. Prednisone (0.5 mg/kg) for 2 to 6 weeks will effect radiographic clearing of infiltrates in most patients. After this, prednisone can be tapered to alternate-day dosing for several months. (8) The total duration of therapy is based on symptoms, eosinophilia, and the serum IgE level. We recommend frequent checking of the IgE level during the first year of therapy, establishing a baseline to use for ongoing monitoring. (13) The IgE level rarely returns to the normal range, but the new baseline level should be significantly lower than the pretreatment level.

Asthma flares with a significant rise in the IgE level or new infiltrates indicate an exacerbation of ABPA and the need to resume oral corticosteroids. Inhaled corticosteroids are not effective in the acute flares of the illness but are helpful in treating underlying asthma during remission. Some physicians suggest periodic plain radiographic imaging for patients in remission, because infiltrates can recur with minimal symptoms. (14)

Use of itraconazole has been controversial, although anecdotal reports of response to treatment with rapid resolution of symptoms and a decline in serum IgE levels have suggested an adjunctive therapeutic role. (15,16) In 2000, Stevens and colleagues (17) reported on a double-blind, placebo-controlled trial of itraconazole in corticosteroid-dependent patients with ABPA. At reputable centers, 55 patients were randomized to itraconazole, 200 mg twice daily, or placebo. Patients receiving itraconazole had further reduction in corticosteroid dose and greater improvement in lung function and exercise tolerance than those receiving placebo. The drug was well tolerated without significant toxicity.

Thus, itraconazole may have a potential role in corticosteroid-dependent patients with ABPA. However, its use cannot be recommended in all patients until further studies have been reported. Currently, we believe itraconazole should be used in patients with ABPA who require daily corticosteroid treatment for more than 3 months because of continuing symptoms.

Mycetomas

Usually, this form of Aspergillus infection is seen after the occurrence of isolated hemoptysis without constitutional symptoms. It may be evident on routine radiologic imaging of patients with various chronic lung diseases, such as emphysema or sarcoidosis.

Generally, this form of aspergillosis occurs in preexisting cysts or cavities, leading to the formation of mycetomas or fungus balls. Rarely, mycetomas may remain as the residua of invasive parenchymal aspergillosis after reversal of the immune defect and stabilization with antifungal therapy.

* Diagnosis: The classic radiographic appearance is a cavitary lesion with an intracavitary mass of variable size (diameter, 1 to 20 cm) formed by a collection of fungal hyphae. A fumigatus is the species identified most often, but others (A flavus, A niger, Pseudallescheria boydii) may be encountered. Certain bacteria can mimic the appearance of a fungus ball, such as Actinomyces israelii (a filamentous gram-positive rod that can cause the air-crescent sign) in pulmonary actinomycosis. (18)

The worst complication of mycetomas is massive hemorrhage, which usually occurs unexpectedly and often requires emergent management decisions. Episodes may occur without warning and can be fatal. The presence of fungus causes bleeding from the epithelialized lining of the cavity wall without significant tissue invasion. The exact mechanism remains controversial. Mycetomas also can become suppurative locally.

The cause of the underlying cavitary lung disease may be inflammatory, infectious, or neoplastic. Cavities resulting from pulmonary tuberculosis were once common; however, the incidence of mycetomas from tuberculosis has decreased over the last 50 years. Generally, sarcoidosis leads to upper lobe fibrosis and subsequent cyst or cavity formation in the areas of destroyed lung. These areas are possible sites for aspergilloma formation. (19) Other causes include bronchial cysts, bronchiectasis, emphysematous bullae, and neoplasm. (20) Aspergilloma may occur in the setting of cystic fibrosis. (21) The colonized cysts range in diameter, from 2 to 20 cm.

The characteristic radiologic appearance of a mycetoma makes it identifiable readily, particularly if an air-crescent sign is seen (Figure 4). Movement of the intracavitary mass with change in the patient's position helps make the diagnosis.

However, mycetomas may be hidden in scarred or fibrotic lung, making the diagnosis difficult on plain radiographic films and CT scans. Aspergillomas may be unchanged for years, grow, or gradually resolve.

Typically, the diagnosis of an aspergilloma is suggested by the radiographic appearance; however, confirmation requires the culture of the organism from the lesion (needle or bronchoscopic biopsy) or demonstration of precipitins that are invariably present when testing is done in reliable laboratories. Radiologic criteria alone are not always sufficient because neoplasms or lung abscesses can produce similar rounded masses surrounded by a halo. Examination of sputum usually does not reveal the causative organism.

When the presenting symptom is hemoptysis, bronchoscopy frequently is recommended for localization of the bleeding site. Pursel and Lindskog (22) reported successful bronchoscopic localization of the source of bleeding in 86% of patients with active bleeding. However, when parenchymal disease occurs bilaterally and bleeding is profuse, this may not be possible. Use caution in acutely bleeding patients with diffuse or bilateral disease to avoid resection of the wrong lobe or lesion. Decisions are easier in patients with isolated radiographic lesions, although bronchoscopic localization generally is still recommended. In our experience, some patients confidently can sense the side with bleeding, but this alone cannot form the basis for guiding surgery

* Treatment: Because hemorrhage is unpredictable, treatment of mycetomas is difficult. At our institution, at least 7 known fatalities have resulted from hemorrhage in patients with sarcoidosis. (19) The goal of therapy is to control acute, severe episodes of hemorrhage and prevent recurrence in patients with known mycetomas.

In patients with unilateral lesions and good lung function (forced vital capacity, more than 50% of predicted), surgery is often the treatment of choice. Surgical resection for patients with bilateral pulmonary parenchymal disease must be considered on an individual basis. (19) Rates of hemorrhage may be as high as 74%, (20) with massive hemoptysis (more than 600 mL/24 h) and fatality occurring in 10% to 28% of patients. (19,23) We are not aware of a predictive model using clinical criteria that can help identify patients at risk for major bleeding.

Consider alternative measures for acute ongoing bleeding in patients who are unfit for surgical resection. Unfortunately, therapeutic options are based on limited studies consisting primarily of case reports or small case series. Intravenous amphotericin B has no therapeutic benefit for acute bleeding. There are anecdotal reports of improvement from intracavitary instillation of amphotericin B, (24,25) but this approach is not widely used.

A report of successful treatment of life-threatening bleeding in 11 cases by intracavitary instillation of iodides requires corroboration. (26) Lung cavities were flushed 3 times daily for 3 to 4 weeks via the percutaneous or transcricothyroid route. With the absence of a control group for comparison, it is difficult to draw conclusions from this study.

Although itraconazole has been used in treating patients with aspergilloma and recurrent bleeding, it has not been used in the setting of acute bleeding. Limited case series and individual reports have demonstrated both clinical and radiographic response, but relapse can occur in patients when the drug is discontinued. (27-29) Embolization to control active bleeding is difficult, but it has proved effective in experienced hands. Long-term control and prevention of rebleeding is not necessarily achieved with embolization. (30,31)

Since no prospective trials have addressed the management issues that arise in patients with bleeding aspergilloma, there is little consensus on management. The options--surgery, antifungal chemotherapy, instillation of antifungal agents via catheter, or observation--must be weighed on an individual basis, with consideration of local available resources.

For more information contact:
Dr. Rajiv R. Sahay
(800) 422-7873 ext. 204
iaq@pureaircontrols.com