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Allergic Bronchopulmonary Aspergillosis (ABPA)

by Matthew C. Miles, MD, Stephen P. Peters, MD, PhD

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to Aspergillus species (generally A. fumigatus) that occurs almost exclusively in patients with asthma or, less commonly, cystic fibrosis. Immune responses to Aspergillus antigens cause airway obstruction and, if untreated, bronchiectasis and pulmonary fibrosis. Symptoms and signs are those of asthma with the addition of productive cough and, occasionally, fever and anorexia. Diagnosis is suspected based on history and imaging tests and confirmed by Aspergillus skin testing and measurement of IgE levels, circulating precipitins, and A. fumigatus–specific antibodies. Treatment is with corticosteroids and, in patients with refractory disease, itraconazole.

ABPA develops when airways of patients with asthma or cystic fibrosis become colonized with Aspergillus sp (ubiquitous fungi in the soil).

Pathophysiology

For unclear reasons, colonization in these patients prompts vigorous antibody (IgE and IgG) and cell-mediated immune responses (type I, III, and IV hypersensitivity reactions) to Aspergillus antigens, leading to frequent, recurrent asthma exacerbations. Over time, the immune reactions, combined with direct toxic effects of the fungus, lead to airway damage with dilatation and, ultimately, bronchiectasis and fibrosis. The disorder is characterized histologically by mucoid impaction of airways, eosinophilic pneumonia, infiltration of alveolar septa with plasma and mononuclear cells, and an increase in the number of bronchiolar mucous glands and goblet cells. Rarely, other fungi, such as Penicillium, Candida, Curvularia, Helminthosporium, and Drechslera spp, cause an identical syndrome called allergic bronchopulmonary mycosis in the absence of underlying asthma or cystic fibrosis.

Aspergillus is present intraluminally but is not invasive. Thus, ABPA must be distinguished from invasive aspergillosis, which occurs in immunocompromised patients; from aspergillomas, which are collections of Aspergillus in patients with established cavitary lesions or cystic airspaces; and from the rare Aspergillus pneumonia, which occurs in patients who take low doses of prednisone long term (eg, patients with COPD). Although the distinction can be clear, overlap syndromes have been reported.

Symptoms and Signs

Symptoms are those of asthma or pulmonary cystic fibrosis exacerbation, with the addition of cough productive of dirty-green or brown plugs and, occasionally, hemoptysis. Fever, headache, and anorexia are common systemic symptoms in severe disease. Signs are those of airway obstruction, specifically, wheezing and prolonged expiration, which are indistinguishable from asthma exacerbation.

Diagnosis

  • History of asthma

  • Chest x-ray or high-resolution CT

  • Skin prick test with Aspergillus antigen

  • Aspergillus precipitins in blood

  • Positive sputum culture for Aspergillus species (or, rarely, other fungi)

  • IgE levels

The diagnosis is suspected in patients with asthma with recurrent asthma exacerbations, migratory or nonresolving infiltrates on chest x-ray (often due to atelectasis from mucoid plugging and bronchial obstruction), evidence of bronchiectasis on imaging studies (see Bronchiectasis : Diagnosis), sputum cultures positive for A. fumigatus, or notable peripheral eosinophilia.

Several criteria have been proposed for the diagnosis (see Table: Diagnostic Criteria for Allergic Bronchopulmonary Aspergillosis), but in practice not all criteria are assessed in every case. When the diagnosis is suspected, a skin prick test with Aspergillusantigen is the best first step. An immediate wheal-and-flare reaction should prompt measurement of serum IgE and Aspergillus precipitins because up to 25% of patients with asthma without ABPA may have a positive skin test. An IgE level > 1000 ng/mL (> 417 IU/mL) and positive precipitins suggest the diagnosis, which should be confirmed by measurement of specific anti- Aspergillus immunoglobulins (up to 10% of healthy patients have circulating precipitins). When ABPA is suspected, a finding of A. fumigatus–specific IgG and IgE antibodies in concentrations at least twice those found in patients without ABPA establishes the diagnosis. Whenever test results diverge, such as when serum IgE is elevated but no A. fumigatus–specific immunoglobulins are found, testing should be repeated and the patient should be monitored over time to definitively establish or exclude the diagnosis.

Diagnostic Criteria for Allergic Bronchopulmonary Aspergillosis

Asthma or cystic fibrosis*

Elevated Aspergillus-specific IgE and IgG*

Elevated serum IgE (> 1000 ng/mL or > 417 IU/mL)*

Proximal bronchiectasis

Wheal-and-flare skin reaction to Aspergillus antigen*

Blood eosinophilia (> 1000 cells/μL

Serum precipitins to Aspergillus antigen

Transient or fixed pulmonary infiltrates

*Indicates minimal essential criteria.

Inclusion of proximal bronchiectasis is controversial and may not be necessary for diagnosis.

Treatment

  • Prednisone

  • Sometimes antifungal drugs

Treatment is based on disease stage (see Table: Stages of Allergic Bronchopulmonary Aspergillosis*). Stage I is treated with prednisone 0.5 to 0.75 mg/kg po once/day for 2 to 4 wk, then tapered over 4 to 6 mo. Chest x-ray, blood eosinophil count, and IgE levels should be checked quarterly for improvement, defined as resolution of infiltrates, 50% decline in eosinophils, and 33% decline in IgE. Patients who achieve stage II disease require annual monitoring only. Stage II patients who relapse (stage III) are given another trial of prednisone. Stage I or III patients who do not improve with prednisone (Stage IV) are candidates for antifungal treatment. Itraconazole 200 mg po bid for 4 to 6 mo with a 6-mo taper is recommended as a substitute for prednisone and as a corticosteroid-sparing drug. Itraconazole therapy requires checking drug levels and monitoring liver enzymes and triglyceride and potassium levels.

Stages of Allergic Bronchopulmonary Aspergillosis*

Stage

Description

Criteria

I

Acute

All diagnostic criteria present

II

Remission

Symptoms resolved for > 6 mo

III

Relapse

Recurrence of 1 of the diagnostic criteria

IV

Refractory

Corticosteroid-dependent or refractory to treatment

V

Fibrosis

Diffuse fibrosis and bronchiectasis

*Stages do not progress sequentially.

All patients should be optimally treated for their underlying asthma or cystic fibrosis. In addition, patients taking long-term corticosteroids should be monitored for complications, such as cataracts, hyperglycemia, and osteoporosis, and possibly prescribed treatments to prevent bone demineralization and Pneumocystis jirovecii lung infection.

Key Points

  • Consider ABPA if a patient with asthma or cystic fibrosis develops frequent exacerbations for unclear reasons, has migratory or nonresolving infiltrates on chest x-ray, evidence of bronchiectasis on imaging studies, persistent blood eosinophilia, or if a sputum culture reveals Aspergillus.

  • Begin testing with a skin prick using Aspergillus antigen, followed usually by serologic testing.

  • Treat initially with prednisone.

  • If ABPA persists despite prednisone, treat with an antifungal such as itraconazole.

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