Allergic bronchopulmonary aspergillosis: causes, symptoms, diagnosis, treatment

Allergic bronchopulmonary aspergillosis is a hypersensitivity reaction to Aspergillus fumigatus that occurs almost exclusively in patients with asthma or, less commonly, cystic fibrosis. Immune reactions to Aspergillus antigens cause airway obstruction and, if untreated, bronchiectasis and pulmonary fibrosis.

Symptoms of allergic bronchopulmonary aspergillosis are similar to those of asthma, with the addition of productive cough and, occasionally, fever and anorexia. The diagnosis is suspected based on the anamnesis and results of instrumental examinations and is confirmed by the Aspergillus skin test and determination of the level of IgE, circulating precipitins and antibodies to A. fumigatus. Treatment of allergic bronchopulmonary aspergillosis is carried out with glucocorticoids and itraconazole in refractory cases of the disease.

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What causes allergic bronchopulmonary aspergillosis?

Allergic bronchopulmonary aspergillosis occurs when the airways of patients with asthma or cystic fibrosis become colonized by Aspergillus (a ubiquitous soil fungus). For unclear reasons, colonization in these patients triggers the production of antibodies (IgE and IgG) and cell-mediated immune responses (hypersensitivity reactions types I, III, and IV) to Aspergillus antigens, leading to frequent, recurrent asthma exacerbations. Over time, the immune responses, coupled with direct toxic effects of the fungus, lead to airway damage with dilation and, ultimately, bronchiectasis and fibrosis. Histologically, the disease is characterized by mucus plugging of the airways, eosinophilic pneumonia, infiltration of the alveolar septa by plasma and mononuclear cells, and an increase in bronchiolar mucous glands and cuboid cells. In rare cases, an identical syndrome, called allergic bronchopulmonary mycosis, is caused in the absence of asthma or cystic fibrosis by other fungi, such as Penicillum, Candida, Curvularia, Helminthosporium and/or Drechslera spp.

Aspergillus is intraluminal but not invasive. Thus, allergic bronchopulmonary aspergillosis must be distinguished from invasive aspergillosis, which occurs exclusively in immunocompromised patients; from aspergillomas, which are collections of Aspergillus in patients with known cavitary lesions or cystic lesions in the lung; and from the rare Aspergillus pneumonia that occurs in patients receiving low-dose prednisone for long periods (eg, patients with COPD ).

What are the symptoms of allergic bronchopulmonary aspergillosis?

Symptoms of allergic bronchopulmonary aspergillosis are similar to those of asthma or exacerbation of pulmonary cystic fibrosis, with the addition of cough, dirty green or brown sputum, and sometimes hemoptysis. Fever, headache, and anorexia are common systemic symptoms of severe disease. Symptoms are those of airway obstruction, with wheezing and prolonged expiration characteristic, indistinguishable from those of asthma exacerbation.

Stages of allergic bronchopulmonary aspergillosis

• I - Acute - All diagnostic criteria are present
• II - Remission - No symptoms for more than 6 months
• III - Relapse - Appearance of one or more diagnostic signs
• IV - Refractory - Glucocorticoid dependence or refractoriness to treatment
• V - Fibrosis - Diffuse fibrosis and bronchiectasis

The stages do not progress sequentially.

How is allergic bronchopulmonary aspergillosis diagnosed?

The diagnosis is suspected in patients with asthma with any frequency of exacerbations, migratory or non-resolving infiltrates on chest radiography (often due to atelectasis from mucus plug and bronchial occlusion), imaging findings of bronchiectasis, demonstration of A. fumigatus on culture, and/or marked peripheral eosinophilia. Other radiographic findings include a band- or finger-glove appearance due to mucus plugs and linear opacities indicating bronchial wall edema. These findings may also be present in bronchiectasis due to other causes, but the signet ring sign due to enlarged airways adjacent to the pulmonary vasculature distinguishes bronchiectasis from allergic bronchopulmonary aspergillosis on high-resolution CT.

Diagnostic criteria for allergic bronchopulmonary aspergillosis

• Bronchial asthma or cystic fibrosis
• Elevated levels of aspergillus-specific IgE and IgG
• Elevated serum IgE (> 1000ng/ml)
• Proximal bronchiectasis
• Papular-hyperergic reaction of the skin to aspergillosis antigens
• Blood eosinophilia (> 1 x 109)
• Serum precipitins to aspergillosis antigens
• Migratory or fixed pulmonary infiltrate
• Minimum essential criteria are noted.
• Inclusion of proximal bronchiectasis is controversial and may not be required for the diagnosis.

Several diagnostic criteria have been proposed, but in practice four essential criteria are usually assessed. If the Aspergillus antigen test is positive (immediate wheal and facial flushing), serum IgE and Aspergillus precipitins should be measured, although a positive skin test may be present in 25% of patients with asthma without allergic bronchopulmonary aspergillosis. If the IgE level is greater than 1000 ng/ml and the precipitin test is positive, specific anti-Aspergillus immunoglobulins should be measured, although up to 10% of healthy patients have circulating precipitins. Aspergillosis test: Aspergillosis antibodies in the blood can detect fungal-specific IgG and IgE antibodies at concentrations at least twice as high as in patients without allergic bronchopulmonary aspergillosis, confirming the diagnosis. Whenever the results are inconsistent, e.g. IgE is greater than 1000 ng/ml but the specific immunoglobulin tests are negative, the test should be repeated and/or the patient should be followed up over time to definitively establish or exclude the diagnosis of allergic bronchopulmonary aspergillosis.

Findings that are suggestive but not specific for the disease include the presence of mycelium in sputum, eosinophilia and/or Charcot-Leyden crystals (elongated eosinophilic bodies formed from eosinophilic granules), and a delayed-type cutaneous reaction (erythema, swelling, and tenderness within 6 to 8 hours) to Aspergillus antigens.

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Treatment of allergic bronchopulmonary aspergillosis

Treatment of allergic bronchopulmonary aspergillosis is based on the stage of the disease. Stage I is treated with prednisolone 0.5-0.75 mg/kg once daily for 2-4 weeks, then tapered over 4-6 months. Chest radiography, blood eosinophils, and IgE levels should be measured quarterly. Cure is defined as resolution of the infiltrate, a greater than 50% decrease in eosinophils, and a 33% decrease in IgE. Patients who reach stage II disease require only annual follow-up. Stage II patients with relapses (stage III) receive another course of prednisolone. Stage I or III patients who are refractory to prednisolone (stage IV) are candidates for antifungal treatment. Itraconazole 200 mg orally twice daily, fluconazole 200-400 mg daily for 4-6 months followed by 6 months of low-dose maintenance therapy are recommended instead of prednisolone and as a drug that reduces the need for glucocorticoids. Therapy with itraconazole or fluconazole requires monitoring of drug concentrations in the body, liver enzymes, triglycerides and K levels.

All patients require optimal treatment for the underlying disease, such as asthma or cystic fibrosis. In addition, patients taking long-term glucocorticoids should be monitored for complications such as cataracts, hyperglycemia, and osteoporosis, and possibly treated with medications to prevent bone demineralization and Pneumocystis jiroveci (formerly P. carinii) infection.