Objectives

1. Identify the typical clinical signs, symptoms, and laboratory findings in allergic bronchopulmonary aspergillosis (ABPA).
2. Understand the basics of the immunopathogenesis of ABPA.
3. Identify the diagnostic criteria for ABPA.
4. Identify the clinical stages of ABPA.
5. Understand the therapeutic options for ABPA.

Key words

allergic bronchopulmonary aspergillosis; Aspergillus; asthma; azoles; corticosteroids; therapy

Abbreviations

ABPA = allergic bronchopulmonary aspergillosis; ABPA-CB = allergic bronchopulmonary aspergillosis with central bronchiectasis; ABPA-S = serologic allergic bronchopulmonary aspergillosis; CF = cystic fibrosis; IL = interleukin; Th2 = T-helper type 2

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity disease of the lungs virtually always related to Aspergillus fumigatus. This disease is seen in patients who have cystic fibrosis (CF) or poorly controlled asthma. The natural history is that of chronic immunologic, clinical, and radiologic episodes of relapse and remission.¹ Therapy for ABPA involves prophylaxis against and treatment of acute exacerbations, as well as prevention of end-stage fibrotic disease.^2,3 The disease is often undiagnosed for several years, and this may result in the development of permanent lung damage before appropriate therapy is initiated. This lesson will outline the clinical features, diagnostic criteria, and current treatment strategies for ABPA.

Clinical Features of ABPA

Clinical Presentation

ABPA was initially described as a disease characterized by episodic wheezing, pulmonary infiltrates, sputum and blood eosinophilia, pyrexia, and sputum containing brown flecks or plugs.⁴ Almost all ABPA patients have clinical asthma. The inflammatory response of ABPA is associated with tenacious sputum that cannot be expectorated by the patient.⁵ This mucus is usually not removable even with vigorous bronchoscopy.⁵ This mucoid impaction, usually coupled with central bronchiectasis, typically results in radiographic abnormalities (vide infra) that suggest the diagnosis. Patients with ABPA are highly atopic in that several other allergic conditions—such as allergic rhinitis, exercise induced asthma, and immediate cutaneous reactivity to non-Aspergillus skin testing—are often present.^5,6

Epidemiology

ABPA is most commonly diagnosed between the third and fifth decades of life, but has been recognized in infants, young adults, and the elderly.⁷ The disease may remain undiagnosed for years, as it is often mistaken for “routine” asthma or another atopic condition.^7,8 There is no sex or racial predilection.⁸ Virtually all patients with ABPA have asthma that ranges from mild to corticosteroiddependent, severe asthma. Approximately 3 to 5% of patients in asthma clinics have ABPA.⁹ More than half of ABPA patients have corticosteroid-dependent asthma,¹⁰ and 7 to 14% of corticosteroid-dependent asthmatics in the United States have ABPA.¹¹ Many patients with CF have airway colonization with Aspergillus spp, and ABPA develops in 7 to 9% of them.^12,13

Radiographic Features

The radiographic features of ABPA often distinguish it from a routine case of asthma, and therefore are important clues to the diagnosis. Typically, the chest radiograph in ABPA reveals transient areas of consolidation. These consolidations were reported to be more common in the upper lobes,^14-16 although some series suggest that there may not be a specific lobar predominance.^17,18 The consolidations may be bilateral.¹⁴ These opacifications are caused by bronchial obstruction with mucus plugs. A bronchus filled with mucus may form a band shadow or glove-finger shadow (Fig 1).¹⁴ These fleeting shadows are a characteristic feature of the disease and may be relieved by coughing up a mucus plug. A ring sign or parallel shadows (tram lines), representing inflamed bronchi, may be seen on chest radiographs (Fig 2). Although bronchiectasis is characteristically central in location in ABPA, asthmatic patients without ABPA may also have central bronchiectasis.^1,19 Nonetheless, CT findings of central bronchiectasis, bronchiectasis affecting three or more lobes, and mucoid impaction (Fig 3) are highly suggestive of ABPA in asthmatic patients,^16,19,20 and warrant further diagnostic testing.¹ On occasion, the CT scan findings may be entirely normal in ABPA.¹⁶

Immunopathogenesis

The immunopathogenesis of ABPA is not completely understood. It is thought that the airways are initially colonized with A fumigatus, which produces at least 15 to 20 antigens that are recognized by IgE molecules on mast cells.^1,2 Interaction of these antigens with IgE causes mast cell degranulation, releasing mediators that cause vasodilation and vascular leakage so that serum components, including anti-Aspergillus IgG, enter the bronchi and combine with Aspergillus antigen to form IgG-containing immune complexes.² These complexes cause activation of the complement cascade, leading to inflammation and pulmonary damage.² Specific Aspergillus antigens have been identified that cause IgE and IgG responses in ABPA patients but not in non-ABPA asthma patients.^21,22 In addition to a type I and type III immune response, ABPA is also associated with an abnormal T-lymphocyte cellular immune response. A fumigatus antigens are processed by antigen presenting cells and presented to T lymphocytes. The T- lymphocyte response in ABPA is skewed towards a T-helper type 2 (Th2) response, manifested by the production of Th2 cytokines, including interleukin-4 (IL-4), IL-5, IL-10, and IL-13,²³ causing an allergic inflammatory pattern. IL-4 may induce a positive feedback response to further stimulate Th2 lymphocytes.²⁴ These abnormal T lymphocytes may be related to a genetic defect, as studies have shown that ABPA patients have a high frequency of the major histocompatability class II alleles that are associated with abnormalities of Th2 lymphocytes.²⁵

Histologic Findings

Because the diagnosis of ABPA is made largely by clinical evaluation and laboratory testing, the study of lung biopsy specimens to confirm ABPA is usually not required.^26,27 There are two distinct pathologic processes, one centered on the airways and the other affecting the lung parenchyma.²⁸ The bronchi contain tenacious mucus consisting of fibrin, Curschmann’s spirals, Charcot-Leyden crystals, eosinophils, and mononuclear cells.²⁷ Fungal hyphae may be seen in the bronchial lumen, and Aspergillus may be isolated in culture.²⁷ Giant cells may be observed in the bronchial lumen. Bronchiectasis may occur in the segmental and subsegmental bronchi.²⁹ Bronchocentric granulomatosis, in which the bronchiolar wall is replaced with granulomatous inflammation consisting of palisading histiocytes surrounded by lymphocytes, plasma cells, and eosinophils,²⁶ is commonly observed.

The distal lung may show inflammatory cells, granulomata, multinucleated giant cells, and eosinophilic infiltration. Distal lung inflammation is not thought to result in permanent lung damage; however, such damage may occur in the airways in the form of proximal bronchiectasis and irreversible airway obstruction.²⁸

Diagnostic Criteria

The diagnostic criteria for ABPA have evolved over several decades.^30,31 Table 1 lists the diagnostic clinical, laboratory, and serologic findings consistent with a diagnosis of ABPA.³¹ Each of the tests in Table 1 has an imperfect sensitivity and specificity for the diagnosis of ABPA; therefore, there are no absolute criteria to diagnose or exclude the disease.⁸

Another classification scheme has been proposed (Table 2)³ wherein the diagnosis can be made by serologic or clinical criteria. According to this scheme, the presence of asthma, eosinophilia, fleeting infiltrates on chest radiograph, and central bronchiectasis would be virtually diagnostic of ABPA even without serologic confirmation. In addition, Table 2 shows that the diagnosis of ABPA can be made serologically (if all four tests in Table 2 are positive) without the presence of bronchiectasis. These patients are classified as having serologic ABPA (ABPA-S) in distinction to ABPA with central bronchiectasis (ABPA-CB).

Rarely, ABPA may be caused by an Aspergillus sp other than A fumigatus or by a non-Aspergillus sp.^29,32,33 In these instances, the serologic tests in relation to A fumigatus will be negative.

A diagnostic algorithm has been proposed for ABPA (Fig 4).¹ Clinical clues that suggest ABPA include refractory asthma, asthma with radiographic infiltrates, asthma with bronchiectasis, asthma with prominent peripheral eosinophilia, CF with a prominent symptom of wheezing, and asthma with expectoration of brown plugs.

Clinical Stages and Natural History of ABPA

Clinical experience in treating patients with ABPA has resulted in an understanding that the disease may progress through various stages. The stages are based on clinical, serologic, and radiographic findings. These stages are not phases of the disease and need not occur in order.³¹ The first four stages are potentially reversible with no long-term sequelae. However, the fifth stage, in which bronchiectasis or fibrosis develops, is not reversible.¹⁰

Stage 1: Acute Stage

This stage is associated with moderate or severe asthma, productive cough (mucus plugs may be expectorated), and pulmonary infiltrates on chest radiograph. These findings disappear completely with corticosteroid treatment.³¹

Stage 2: Remission

During remission, the patient continues to be asymptomatic or has mild asthma after discontinuation of corticosteroid therapy. The serum IgE level usually remains elevated at half of the peak IgE level during the acute stage.³¹ The patient may remain in remission permanently or for a variable period of time.

Stage 3: Recurrent Exacerbation

This exacerbation is usually apparent, with recurrence of the same findings as in stage I. However, in some cases the exacerbation is marked by serology (total IgE) because clinical findings may be subacute and radiographic findings may be absent.³¹ Serum IgE rises to at least double the baseline level, and such an increase often antedates clinical or radiographic worsening.³¹

Stage 4: Corticosteroid-Dependent Asthma

The disease may evolve to this stage from any of the previous stages.³¹ Exacerbations marked by worsening asthma, radiographic changes, and an increase in IgE level may occur.³¹

Stage 5: Fibrotic Lung Disease

Changes of central bronchiectasis and pulmonary fibrosis occur that are irreversible. Pulmonary function tests demonstrate a restrictive pattern alone or with superimposed obstruction. Patients at this stage may still have asthma, but findings of restriction and cor pulmonale predominate.³¹

This classification scheme for ABPA differentiates ABPA-S into stages 1 through 4, while those with stage 5 have ABPA-CB. Regardless of which classification system is used, it has been proposed that patients with ABPA who do not have bronchiectasis are in an early phase of ABPA and that early treatment of initial disease and subsequent exacerbations may prevent progression to lung fibrosis and bronchiectasis.² Obviously, it is advantageous for ABPA to be diagnosed before permanent lung injury has occurred.

Pharmacotherapy

The main goals of therapy for APBA are to treat acute exacerbations of disease and prevent the development of the fibrotic stage and bronchiectasis. Therefore, an important part of therapy is to establish the diagnosis of ABPA early, before permanent lung damage has occurred. Pharmacotherapy for ABPA involves the use of systemic (oral) corticosteroids, metered-dose inhaler medications, and antifungal therapy. General guidelines for therapy are outlined in Table 3.

Corticosteroids

The cornerstone of treatment of ABPA has been to use systemic corticosteroids to suppress the inflammatory response provoked by A fumigatus, rather than removing the organism.^30,34,35 This may require prolonged treatment with high doses of corticosteroids.³⁵

Although corticosteroids are the primary therapy for ABPA, most of the supportive data have come from uncontrolled trials involving small numbers of patients.^30,35-38 These studies have shown that corticosteroids control asthma symptoms, treat exacerbations, and prevent exacerbations.³⁵ It is not known if corticosteroids prevent loss of lung function or disease progression.³⁵

Recommended corticosteroid doses for acute exacerbations of disease are 0.5 to 1.0 mg/kg of prednisone equivalent daily for 1 to 2 weeks, followed by 0.5 mg/kg every other day for 6 to 12 weeks; after that, the dose is tapered in an attempt to wean the patient off corticosteroids.^10,30,39 Symptoms of wheezing, dyspnea, and cough usually remit rapidly with this regimen. As the dose of prednisone is decreased, patients may develop symptoms of mild asthma that can be controlled with inhaled bronchodilators and inhaled corticosteroids in many instances.³⁰ However, some patients—8 of 25 (32%) in one series³⁹—require an increase in their prednisone dose. Some patients cannot be successfully weaned off corticosteroids without developing exacerbations. One study of 28 corticosteroid-dependent ABPA patients treated with a mean daily dose of 7.4 mg of prednisolone for 11 years showed no deterioration in forced vital capacity or FEV₁, suggesting that corticosteroids may prevent progression to end-stage fibrotic disease.³⁶

Monitoring the Need for Corticosteroid Therapy

It is recommended that the physician regularly monitor the serum IgE level in ABPA patients,^31,40 although the importance of this test is controversial. Longterm follow-up of ABPA patients has demonstrated that clinical symptoms and airway obstruction are not always reliable indicators of disease activity.^41,42 Regular determination of serum IgE helps to identify flares, and levels often increase prior to exacerbations of ABPA.³¹ However, it is unknown if detecting and treating these asymptomatic flares alters the outcome of ABPA. Serum IgE levels decline with a clinical response to corticosteroids.³¹ Baseline levels should be determined when the disease has been controlled with corticosteroid therapy, and levels should be measured every 1 to 2 months thereafter.¹⁰ The total serum IgE usually does not return to normal, and corticosteroids should not be continued only to “treat” this laboratory result. Consideration should be given to reinstitution of corticosteroids, even in asymptomatic patients, if the serum IgE doubles from baseline values.¹⁰

A less controversial reason for treatment of ABPA is the development of radiographic findings of pulmonary fibrosis, mucoid impaction, pulmonary infiltrates, and bronchiectasis.²⁶ Lung damage is occurring in these patients, and they should be given a trial of corticosteroids. Many of these patients require chronic low-dose corticosteroids.²⁶ If corticosteroids are discontinued in these patients, they should be closely monitored with frequent pulmonary function testing, chest radiography, and serum IgE levels; patients should be treated with corticosteroids if these parameters worsen.⁴³ It has been recommended that a daily corticosteroid dose of ≥ 7.5 to 10 mg of prednisone be used in such patients,^36-38 and that chest radiographs be obtained every 3 months during the first year of follow-up and yearly thereafter.²⁷ Pulmonary function tests are recommended on a yearly basis.²⁷

Inhaled Corticosteroids

Three studies have directly addressed the use of inhaled corticosteroids for ABPA, and the results have been conflicting. A double-blind, placebo-controlled study of inhaled beclomethasone 400 µg daily demonstrated better control of asthma symptoms in 32 ABPA patients.⁴⁴ However, radiographic deterioration and pulmonary eosinophilia were not lessened by inhaled corticosteroids, suggesting that these medications alleviate asthmatic symptoms but not the underlying destructive inflammatory mechanisms of ABPA. In contrast, two other studies have suggested that inhaled corticosteroids may be beneficial for patients with ABPA. In one study, 87% of ABPA patients (13/15) treated with 400 µg/d of inhaled beclomethasone experienced symptomatic improvement.45 Of the 10 patients who had been receiving long-term systemic corticosteroid therapy, 8 (80%) were able to discontinue this therapy within 2 weeks of starting inhaled corticosteroids. Radiographic clearing occurred within 1 month of starting inhaled corticosteroids in 7 of the 9 patients who had infiltrates (78%). Another study followed 5 patients with ABPA for a mean of 15 years.⁴⁶ All were treated with inhaled corticosteroids, and they used only short courses of oral corticosteroids for symptomatic exacerbations. None of the patients demonstrated deterioration of spirometry results, although 2 of the 5 may have developed some localized bronchiectasis. None developed any respiratory impairment.

Based on these limited data, the use of inhaled corticosteroids may be considered in ABPA patients to control break-through asthma symptoms as the corticosteroid dose is decreased. Often these symptoms can be controlled with inhaled corticosteroids and inhaled bronchodilators. In ABPA patients who cannot be weaned off corticosteroids, it is reasonable to attempt to use inhaled corticosteroids in weaning. In this situation, the clinician must continue to be vigilant that the underlying disease is under control in asymptomatic patients by monitoring serum IgE levels, chest radiographs, and pulmonary function because lung damage may occur in asymptomatic patients.

Antifungal Therapy

It has been hypothesized that reducing the fungal burden in the respiratory tract of ABPA patients would decrease chronic antigenic stimulation, reduce the inflammatory response, ameliorate symptoms, and possibly reduce the longterm risk of progression.¹ This has been the rationale for investigating the use of antifungal therapy for ABPA.

Several studies of antifungal agents, oral or inhaled, have been performed and have recently been reviewed.^1,35,47 Inhaled nystatin, inhaled natamycin, inhaled amphotericin B, hamycin, miconazole, clotrimazole, ketoconazole, and itraconazole have all been effective.^1,35,47 Itraconazole has been studied the most.^13,48-58 Itraconazole has been effective in improving symptoms, reducing the baseline corticosteroid dose, allowing patients to discontinue corticosteroids, decreasing Aspergillus titers, improving radiographic abnormalities, and improving pulmonary function. Recently, a double-blind, placebo-controlled trial of oral itraconazole, 200 mg twice daily, for ABPA was conducted.⁵⁵ Statistically and clinically significant improvement was seen in pulmonary symptoms, pulmonary function, chest radiographs, and serum IgE levels in the itraconazole group compared with those receiving placebo.

On the basis of these data, itraconazole should be considered as adjunctive therapy in ABPA. It should probably not be used for an initial bout of ABPA. However, it should be strongly considered for ABPA patients who relapse and for corticosteroid-dependent patients in attempt to reduce or discontinue corticosteroid therapy. It is intuitive that fungal serology and fungal culture and sensitivity may be important to ensure that fungus implicated in a case of ABPA is sensitive to itraconazole. Voriconazole has not yet been studied for ABPA, but it is likely to be effective given its excellent activity against A fumigatus.^59-61

b-Agonists/Other Therapy

No clinical trials have been conducted to determine the role of bronchodilators such as b-agonists, anticholinergics, and leukotriene antagonists in ABPA. At the present time, a rational approach would be to use inhaled corticosteroids and bronchodilators to treat asthma symptoms as recommended by the National Institutes of Health asthma guidelines.⁶²

Although it has been shown that there are more ABPA exacerbations during seasons with peak mold counts,⁶³ Aspergillus is ubitquitous and cannot be avoided. However, patients should avoid environments with high mold counts, such as work in organic farming and moldy living quarters.³¹

ABPA in Cystic Fibrosis

ABPA is common in CF patients, although it is problematic to estimate the prevalence because the diagnostic criteria are not standardized. ABPA and CF share many clinical and laboratory findings, so differentiation is difficult. As previously mentioned, 7 to 9% of CF patients develop ABPA.^12,13,64 Observational studies from large CF databases show a much lower prevalence, which suggests that ABPA is underdiagnosed in CF.⁶⁵ Exacerbations of both diseases may present with infiltrates, acute increased wheezing, and sputum production, often accompanied by fever, weight loss, and fatigue.⁶⁶ Proximal bronchiectasis is also common to both, and a bronchiectatic flare with hemoptysis may herald either recurrence of ABPA or a bacterial infection in CF.⁶⁶

The diagnosis of ABPA in CF is further complicated by the fact that certain immunologic findings, such as positive Aspergillus precipitins and peripheral blood eosinophilia can be found in CF patients sensitized to Aspergillus antigens with and without ABPA.^66,67 Both clinical symptoms and serologic data must be assessed in establishing the diagnosis of ABPA in CF patients.⁶⁶ Table 4 lists the criteria for the diagnosis of ABPA in a CF patient.¹³

CF patients with ABPA appear to have more severe pulmonary disease. Compared with CF patients who do not have ABPA, patients with CF and ABPA have worse spirometry, more frequently have hemoptysis, and are more likely to have a pneumothorax.⁶⁴

The treatment of ABPA in CF patients is similar to those without CF. As mentioned previously, it is important to attempt to differentiate a bacterial exacerbation of CF from an ABPA flare before embarking on corticosteroid treatment. A serologic assessment is essential as part of this evaluation. Itraconazole has been recommended as adjunctive therapy for ABPA flares in CF.^13,68

Summary

ABPA is a form of asthma related to a hypersensitivity reaction to Aspergillus. ABPA needs to be considered and diagnosed at an early stage because proper therapy may prevent permanent lung damage. Monitoring patients with ABPA is likewise important to avoid permanent sequelae. Oral corticosteroids are the cornerstone of therapy for ABPA. Inhaled corticosteroids and antifungal agents, such as itraconazole, are promising and should be considered in the treatment of ABPA, especially in corticosteroid-dependent patients. Bronchodilators are an adjunctive therapy and should be used for asthmatic symptoms.

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