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Allergic Bronchopulmonary Aspergillosis FREE TO VIEW

Ritesh Agarwal, MD, DM, FCCP
Author and Funding Information

*From the Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

Correspondence to: Ritesh Agarwal, MD, DM, FCCP, Assistant Professor, Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Sector-12, Chandigarh 160012, India; e-mail: riteshpgi@gmail.com


The author has no conflicts of interest to disclose.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).


Chest. 2009;135(3):805-826. doi:10.1378/chest.08-2586
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Allergic bronchopulmonary aspergillosis (ABPA) is an immunologic pulmonary disorder caused by hypersensitivity to Aspergillus fumigatus. Clinically, a patient presents with chronic asthma, recurrent pulmonary infiltrates, and bronchiectasis. The population prevalence of ABPA is not clearly known, but the prevalence in asthma clinics is reported to be around 13%. The disorder needs to be detected before bronchiectasis has developed because the occurrence of bronchiectasis is associated with poorer outcomes. Because many patients with ABPA may be minimally symptomatic or asymptomatic, a high index of suspicion for ABPA should be maintained while managing any patient with bronchial asthma whatever the severity or the level of control. This underscores the need for routine screening of all patients with asthma with an Aspergillus skin test. Finally, there is a need to update and revise the criteria for the diagnosis of ABPA. This review summarizes the advances in the diagnosis and management of ABPA using a systematic search methodology.

Figures in this Article

Aspergillus is a ubiquitous mold representing between 0.1% and 22% of the total air spores sampled.1 There are approximately 250 species of Aspergillus, but only a few are human pathogens.2,3 Depending on the host immunity and the organism virulence, the respiratory diseases caused by Aspergillus are classified as saprophytic (aspergilloma), allergic (allergic Aspergillus sinusitis, allergic bronchopulmonary aspergillosis [ABPA], and hypersensitivity pneumonias) and invasive (airway invasive aspergillosis, chronic necrotizing pulmonary aspergillosis, and invasive aspergillosis).4 ABPA is an allergic pulmonary disorder caused by hypersensitivity to Aspergillus fumigatus clinically manifesting as chronic asthma, recurrent pulmonary infiltrates, and bronchiectasis.513 The condition has immunologic features of immediate hypersensitivity (type I), antigen-antibody complexes (type III), and eosinophil-rich inflammatory cell responses (type IVb), based on the revised Gell and Coombs classification of immunologic hypersensitivity.14,15 The disorder was first described by Hinson et al16 in 1952 in the United Kingdom. Occasionally, patients can develop a syndrome similar to ABPA, but it is caused by fungi other than A fumigatus and is called allergic bronchopulmonary mycosis.17 The prevalence of ABPA is believed to be about 1 to 2% in patients with asthma and 2 to 15% in patients with cystic fibrosis (CF).13 The condition remains underdiagnosed in many countries with reports of mean diagnostic latency of even 10 years between the occurrence of symptoms and the diagnosis.18 In the past two decades, there has been an increase in the number of cases of ABPA due to the heightened physician awareness and the widespread availability of serologic assays.1923 This review provides a summary of the advances in the field of ABPA. For the purpose of this review, a systematic search of PubMed and EmBase was performed for relevant studies published from 1952 to 2008. A total of 250 articles were reviewed for the purpose of this article.

Epidemiology of ABPA

Aspergillus hypersensitivity (AH) is defined by the presence of an immediate-type cutaneous hypersensitivity to A fumigatus antigens, and it is the first step in the development of ABPA.24 Only a minority of patients with AH develop the complete clinical picture of ABPA.25 The population prevalence of ABPA in asthma, generally referred to as 1 to 2%,5,13,26,27 is based on the inference of only three studies (one peer-reviewed and two non–peer-reviewed studies).28,29 In the only peer-reviewed study,28 14 patients with allergic bronchopulmonary mycosis were identified from a total of 1,390 new referrals in a catchment area population of half a million, estimating a period prevalence of just above 1%. The other two non–peer-reviewed questionnaire-based studies suggested a maximum prevalence of ABPA of 1% in the United States.29 In a recent metaanalysis,30 we demonstrated a prevalence of AH and ABPA in asthma of 28% and 12.9%, respectively. The limitation noted in this review was that all the studies were performed in specialized clinics and may not be representative of the general population. Thus the exact population prevalence of ABPA remains speculative but is likely to be fairly high in patients attending asthma clinics. Table 1 summarizes the prevalence of ABPA in patients with asthma reported in various studies20,23,3136 over the last two decades. The prevalence of ABPA in patients admitted with acute severe asthma is even higher. In a recent study of 57 patients with acute severe asthma admitted in the respiratory ICUs, we demonstrated the prevalence of AH and ABPA to be around 51% and 39%, respectively.37 The occurrence of AH and ABPA was significantly higher in patients with acute asthma compared to the outpatient bronchial asthma (around 39% and 21%, respectively).23

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Table 1 Studies Describing the Prevalence of AH and/or ABPA in Patients with Bronchial Asthma Over the Last Two Decades*

* Criteria for ABPA: Major (A = asthma, R = radiologic opacities, T = immediate positive skin test, E = eosinophilia, P = precipitins to A fumigatus, I = IgE elevated, C = central bronchiectasis, S = specific IgG/IgE to A fumigatus); Minor (C = sputum cultures of A fumigatus, S = type III skin test positivity, B = brownish black mucus plugs).

Pathogenesis of ABPA

The susceptibility of asthmatic patients to develop ABPA is not fully understood (Fig 1). Some authors have reported that exposure to large concentrations of spores of A fumigatus may cause ABPA.16,3841 Environmental factors are not considered the main pathogenetic factors because not all asthmatics develop ABPA despite being exposed to the same environment. In a genetically predisposed individual4254 (Table 2), inhaled conidia of A fumigatus persist and germinate into hyphae with release of antigens that compromise the mucociliary clearance, stimulate and breach the airway epithelial barrier, and activate the innate immunity of the lung.5558 This leads to inflammatory cell influx and a resultant early- and late-phase inflammatory reaction.59,60 The antigens are also processed presented to T-cells with activation of Th2 CD4+ T-cell responses.42,6163 The Th2 cytokines (interleukin [IL]-4, IL-5, and IL-13) lead to total and A fumigatus-specific IgE synthesis, mast cell degranulation, and promotion of a strong eosinophilic response. This causes the characteristic pathology of ABPA.

Figure Jump LinkFigure 1 A line diagram depicting the pathogenesis of allergic bronchopulmonary aspergillosis. Th = T-helper.Grahic Jump Location
Table Graphic Jump Location
Table 2 Genetic Factors Involved in the Pathogenesis of ABPA*

*HLA = human leukocyte antigen; TNF = tumor necrosis factor; CFTR = CF transmembrane conductance regulator.

Pathology of ABPA

The pathology of ABPA varies from patient to patient, and in different areas of the lung in the same patient (Fig 2).64,65 Histologic examination reveals the presence of mucus, fibrin, Curschmann spirals, Charcot-Leyden crystals, and inflammatory cells. Scanty hyphae can often be demonstrated in the bronchiectatic cavities. The bronchial wall in ABPA is usually infiltrated by inflammatory cells, primarily the eosinophils.65 The peribronchial parenchyma shows an inflammatory response with conspicuous eosinophilia. Occasionally, fungal growth in the lung parenchyma can occur in some patients with ABPA.66 Patients can also demonstrate a pattern similar to that of bronchiolitis obliterans with organizing pneumonia.67 Bronchocentric granulomatosis, the presence of noncaseating granulomas containing eosinophils and multinucleated giant cells centered on the airway, are also seen.68,69 Rarely, invasive aspergillosis complicating the course of ABPA has also been described.7074

Figure Jump LinkFigure 2 Histopathologic findings in a patient with allergic bronchopulmonary aspergillosis. Top left, A: photomicrograph showing bronchial lumen containing allergic mucin (hematoxylin-eosin, original ×100). Top right, B: high-magnification photomicrograph of allergic mucin having variegated appearance, necrotic eosinophils, Charcot-Leyden crystals (thin arrow), and an occasional septate fungal hyphae indicated by a thick arrow (hematoxylin-eosin, original ×200). Bottom left, C: photomicrograph showing eosinophilic pneumonia. There is filling of the alveolar spaces by eosinophils admixed with variable number of macrophages (hematoxylin-eosin, original ×200). Bottom right, D: photomicrograph showing bronchocentric granulomatosis. There is partial replacement of bronchial epithelium by palisading histiocytes (hematoxylin-eosin, original ×100).Grahic Jump Location
Clinical Features

There is no gender predilection and majority of the cases present in the third to fourth decade. A family history of ABPA may be elicited occasionally.75Table 3 summarizes the clinical features of ABPA encountered in three large series from our institute.19,21,23 Most present with low-grade fever, wheezing, bronchial hyperreactivity, hemoptysis, or productive cough. Expectoration of brownish black mucus plugs is seen in 31 to 69% of patients.21,23,34 The symptoms of hemoptysis, expectoration of brownish black mucus plugs, and history of pulmonary opacities in an asthmatic patient suggests ABPA. Patients can occasionally be asymptomatic, and the disorder is diagnosed on routine screening of asthmatic patients.22,23,33 Physical examination can be normal or may reveal polyphonic wheeze. Clubbing is rare, seen in only 16% of patients. On auscultation, coarse crackles can be heard in 15% of patients.23 Physical examination can also detect complications such as pulmonary hypertension and/or respiratory failure.76 During exacerbations of ABPA, localized findings of consolidation and atelectasis can occur that needs to be differentiated from other conditions.

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Table 3 Clinical Features Encountered in Three Large Case Series of ABPA Published From the Author's Institute*

*AEC = absolute blood eosinophil count.

Laboratory Findings
Aspergillus Skin Test:

The Aspergillus skin test is performed using an A fumigatus antigen, either commercial (eg, Aspergillin; Hollister-Stier Laboratories; Spokane, WA) or locally prepared. The test is read every 15 min for 1 h, and then after 6 to 8 h. The reactions are classified as type I if a wheal and erythema developed within 1 min, reaches a maximum after 10 to 20 min, and resolves within 1 to 2 h. A type III reaction is read after 6 h, and any amount of subcutaneous edema is considered a positive result. An immediate cutaneous hypersensitivity to A fumigatus antigens is a characteristic finding of ABPA and represents the presence A fumigatus- specific IgE antibodies, whereas a type III skin reaction probably represents the immune complex hypersensitivity reaction, although its exact significance remains unclear. The test can be performed using either a skin-prick test or intradermal injection with the latter being more sensitive.30,77,78 A skin-prick test should be performed for Aspergillus skin testing, and if the results are negative should be confirmed by an intradermal test.30 There is no difference on the outcome of the test and the type of antigen (locally prepared or commercial) used for performance of the test.30

Total Serum IgE Levels:

The total IgE level is the most useful test for diagnosis and follow-up of ABPA. A normal serum IgE level excludes ABPA as the cause of the patient's current symptoms. The only situation where IgE levels can be normal in active ABPA is when the patient is already on glucocorticoid therapy for any reason and investigation for IgE levels has been conducted. After treatment with glucocorticoids, the serum IgE levels decline, and a 35 to 50% decrease is taken as a criteria for remission.79 The serum IgE determination is also used for follow-up, and a doubling of the patient's baseline IgE levels indicates relapse of ABPA.80,81

Serum IgE and IgG Antibodies Specific to A fumigatus:

An elevated level of A fumigatus-specific antibodies measured by fluorescent enzyme immunoassay is considered the hallmark of ABPA.22 A cutoff value of IgG/IgE more than twice the pooled serum samples from patients with AH can greatly help in the differentiation of ABPA from other conditions.82

Radiologic Investigations:

A wide spectrum of radiographic appearances can occur in ABPA (Table 4). The chest radiographic findings of ABPA include transient or fixed pulmonary opacities (Fig 3), tramline shadows, finger-in-glove opacities, and toothpaste shadows.8387 Findings noted on high-resolution CT (HRCT) include central bronchiectasis, mucoid impaction, mosaic attenuation, presence of centrilobular nodules, and tree-in-bud opacities (Fig 4).88,89 High-attenuation mucoid impaction (mucus visually denser than the paraspinal muscle) is a pathognomonic finding encountered in patients with ABPA.23,9095 Central bronchiectasis with peripheral tapering of bronchi on HRCT is believed to be a sine qua non for the diagnosis of ABPA. Bronchiectasis may not be present in all patients with ABPA, may be present in patients with CF without ABPA, and almost 40% of the bronchiectatic segments can also have associated peripheral bronchiectasis.22,96 Minimal bronchiectasis can also be seen in asthma,97,98 but the findings of bronchiectasis affecting three or more lobes, centrilobular nodules, and mucoid impaction are highly suggestive of ABPA.99 The uncommon radiologic manifestations of ABPA include miliary nodular opacities,100 perihilar opacities simulating hilar lymphadenopathy,84,101,102 pleural effusions,103105 and pulmonary masses.106111

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Table 4 Radiologic Findings Encountered in Patients With ABPA
Figure Jump LinkFigure 3 Chest radiograph showing transient pulmonary opacities in the right lower lobe (left) in a patient with allergic bronchopulmonary aspergillosis that have spontaneously disappeared (right).Grahic Jump Location
Figure Jump LinkFigure 4 HRCT images of different patients with allergic bronchopulmonary aspergillosis. Top right: bilateral central bronchiectasis with centrilobular nodules and tree-in-bud opacities in the left lung. Top left: bilateral central bronchiectasis with many mucus-filled bronchi. Bottom, left and right: images from the same patient show high-attenuation mucoid impaction. Bottom right: the mucoid impaction in the right lung is visually denser than the paraspinal skeletal muscle.Grahic Jump Location
Serum Precipitins Against A fumigatus:

The precipitating IgG antibodies are elicited from crude extracts of A fumigatus and can be demonstrated using the double gel diffusion technique.112,113 They can also be present in other pulmonary disorders and thus represent supportive not diagnostic evidence for ABPA.112114

Peripheral Eosinophilia:

A blood absolute eosinophil count > 1,000 cells/μL is also a major criterion for the diagnosis of ABPA. However, 53% of patients in our series22 had an absolute eosinophil count < 1,000 cells/μL, and thus a low eosinophil count does not exclude the diagnosis of ABPA.

Sputum Cultures for A fumigatus:

Culture of A fumigatus in the sputum is supportive but not diagnostic of ABPA. The fungus can also be grown in patients with other pulmonary diseases due to the ubiquitous nature of the fungi. We rarely perform sputum cultures for the diagnosis of ABPA.

Pulmonary Function Tests:

These tests help categorize the severity of the lung disease but have no diagnostic value in ABPA and need not constitute the basis for screening.22 The usual finding is an obstructive defect of varying severity.115117

Role of Specific Aspergillus Antigens:

Patients with ABPA are evaluated with crude extracts from Aspergillus, which lack reproducibility and consistency, and they frequently cross-react with other antigens.118 The advances in molecular techniques have enabled detection and cloning of specific Aspergillus antigens. The recombinant allergens Asp f1, Asp f2, Asp f3, Asp f4, and Asp f6 have been evaluated for their diagnostic performance in serologic studies in asthmatic patients119122 and in patients with CF121,123125 Preliminary data suggest a promising role of these antigens in the diagnosis of ABPA. Further studies are required before they can be implemented in routine clinical practice.

Diagnosis and Diagnostic Criteria

The Rosenberg-Patterson criteria6,9 are most often used for the diagnosis (Table 5). There are also a set of minimal diagnostic criteria for ABPA (Table 5).32,33 These criteria continue to be challenged and modified because there is lack of evidence on the number of criteria that should be present to make the diagnosis. The differentiation of patients with ABPA from patients with AH can also be problematic. Serum precipitins to A fumigatus is present in 69 to 90% of patients with ABPA23,112,116,126,127 but also in 9% of asthmatics.112 Central bronchiectasis can be seen in patients with asthma without ABPA.9799 There are no cutoffs for total IgE levels with many using 1,000 IU/mL,8,9,22,23,82,128130 and others using 1,000 ng/mL (equivalent to 417 IU/mL).5,27,33,34 The total IgE levels may also be elevated in patients with AH without ABPA. As the understanding of ABPA has evolved, it is clear that patients with AH may present with less than the full complement of diagnostic criteria.131 Thus, a cutoff value of 1,000 ng/mL IgE will probably lead to an overdiagnosis of ABPA.131 The use of A fumigatus-specific IgE and IgG levels can help in confirming the diagnosis of ABPA because values of IgG/IgE more than twice the pooled serum samples from patients with asthma are raised only in ABPA.113,132

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Table 5 Criteria Used for the Diagnosis of ABPA

We currently use a cutoff value of 1,000 IU/mL for the diagnosis of ABPA.22,23 While investigating a patient with asthma, we first perform an Aspergillus skin test. Once it is positive, the total serum IgE levels are done.131 If the value is > 1,000 IU/mL, we perform the other tests (Fig 5). If the value is between 500 and 1,000 IU/mL, the next step is analysis of A fumigatus-specific IgE and IgG antibodies. If the levels are raised, the patient is followed up every 6 weeks with total IgE levels. If the absolute value rises > 1,000 IU/mL or there is a rising trend with clinical deterioration, the treatment is started. If the value is between 500 and 1,000 IU/mL and IgE and IgG specific to A fumigatus are not raised, the patient is followed up with a yearly total IgE levels (Fig 5).

Figure Jump LinkFigure 5 Algorithm followed in the diagnostic workup for allergic bronchopulmonary aspergillosis in the author's chest clinic.Grahic Jump Location
Natural History

The natural history of ABPA is not well characterized.9,128,133136 An early diagnosis and initiation of systemic corticosteroids are essential to prevent irreversible damage.137 The natural course of ABPA can be best understood if we recognize the two important classification schemes (Tables 6 and 7) of ABPA: (1) classification of ABPA into five stages as described by Patterson et al8, and (2) classification of ABPA into ABPA-S (seropositive ABPA) and ABPA-CB (ABPA with central bronchiectasis) described by Greenberger et al.12

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Table 6 Stages of ABPA8,22
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Table 7 Radiologic Classification of ABPA*

*Both the classification schemes believe that patients without CB and ORF have serologically milder disease, but it has been shown that there is no difference in clinical, spirometric, and serological severity between patients with and without bronchiectasis (see text for details).

Staging of ABPA:

ABPA has been classified into five stages, but a patient does not necessarily progress from one stage to the other sequentially (Table 6). Patients in stage I or III (depending on whether or not the disorder has been previously diagnosed) are generally symptomatic with radiographic infiltrates, raised IgE levels, and elevated A fumigatus-specific IgG/IgE.23 With glucocorticoid therapy, there is clearing of radiographic opacities with a 35 to 50% decline in IgE levels by 6 weeks that defines remission or stage II. The aim of glucocorticoid therapy is not normalization of total IgE levels because the immunologic process goes in remission with just 35 to 50% decline in IgE levels, and in many patients the IgE levels do not come to down to normal values. The test needs to be often repeated during therapy to determine the lowest level for an individual patient that serves as the baseline for that particular patient. Treatment is continued for 6 to 9 months, and if there are no exacerbations over the next 3 months after stopping therapy, we label it as “complete remission.” Patients in complete remission are followed up by serial IgE levels every 6 months for the first year and then annually. Even in patients with complete remission, the IgE levels decline to normal in only a minority of patients,128,133 and the aim of glucocorticoid therapy is not achievement of normal IgE levels.79 A complete remission does not imply a permanent remission because exacerbations can occur several years after remission.135 Almost 25 to 50% of the patients have relapse/exacerbation of the disease, defined by doubling of the baseline IgE levels (stage III).8,9,22 Patients in stage IV require oral glucocorticoids for control of asthma (glucocorticoid-dependent asthma) or ABPA (glucocorticoid-dependent ABPA).10,22 Patients in stage V are those with widespread bronchiectasis and varying degrees of pulmonary dysfunction. We define patients in stage V if they have hypercapnic respiratory failure (Pao2 < 60 mm Hg and Paco2 ≥ 45 mm Hg) and/or cor pulmonale. Even in stage V ABPA, the disease can be clinically as well as immunologically active requiring long-term glucocorticoid therapy.136,138

Radiologic Classification of ABPA:

ABPA is classified as ABPA-S or ABPA-CB, respectively, depending on the absence or presence of bronchiectasis or as ABPA-S (mild), ABPA-CB (moderate), and ABPA-CB-ORF (other radiologic findings) (Table 7). Patients with ABPA-S probably represent the earliest stage of the disorder. It is believed that patients with ABPA-S have a milder clinical course and less severe immunologic findings when compared to ABPA-CB based on the inference of three studies (total of 124 patients).12,139,140 In the largest of these three studies (76 patients), only the A fumigatus-specific IgG levels were higher in patients with ABPA-CB compared to ABPA-S. Other immunologic parameters were not significantly different between the two groups.12 In our study of 126 patients, the clinical, spirometric, and immunologic findings were not significantly different when classifying ABPA into ABPA-S and ABPA-CB or as ABPA-S, ABPA-CB, and ABPA-CB-ORF.22

However, the course of patients with ABPA-S is likely to be less severe when compared to those with ABPA-CB. In a multivariate analysis of 155 patients with ABPA, we demonstrated that the severity of bronchiectasis and presence of hyperattenuating mucoid impaction on HRCT-predicted relapses of ABPA and the severity of bronchiectasis was an independent predictor of failure to achieve long-term remission.23 Thus it may not be important to stage the severity of ABPA based on the presence or absence of CB, but it remains prudent to diagnose and treat ABPA early to prevent the development of bronchiectasis because it increases the probability of a smoother course of this relapsing-remitting disorder.

Management

The management of ABPA includes two important aspects: institution of glucocorticoids to control the immunologic activity and close monitoring for detection of relapses. Another possible target is the use of antifungal agents to attenuate the fungal burden secondary to the fungal colonization in the airways.

Systemic Glucocorticoid Therapy:

Oral corticosteroids are the treatment of choice for ABPA. They not only suppress the immune hyperfunction but are also antiinflammatory. There are no data to guide the dose and duration of glucocorticoids, and different regimens of glucocorticoids have been used (Table 8). The use of lower doses of glucocorticoids was associated with frequent relapses or corticosteroid dependence (45%).9 We use a higher dosage of glucocorticoids for a longer duration and observed higher remission rates and a lower prevalence of glucocorticoid-dependent ABPA (13.5%).22 This raises the possibility of a higher dose and prolonged duration of corticosteroid therapy being associated with better outcomes. However, there are no direct comparisons between the two regimens, and the selection is a matter of personal preference. The clinical effectiveness of steroid therapy is reflected by marked decreases in the patient's total serum IgE levels (there seems to be no correlation between serum levels of A fumigatus-specific IgE levels and disease activity141) along with symptom and radiographic improvements. The goal of therapy is not to attempt normalization of IgE levels but to decrease the IgE levels by 35 to 50%, which leads to clinical and radiographic improvement. One should also establish a stable serum level of total IgE to serve as a guide to future detection of relapse.

Table Graphic Jump Location
Table 8 Treatment Protocols for the Management of ABPA
Inhaled Corticosteroids:

Although small case studies suggest some benefit of inhaled corticosteroids in the management of ABPA,142145 a double-blind multicenter placebo-controlled trial in 32 patients suggested no superiority over placebo.146 We use inhaled corticosteroids only for the control of asthma once the oral prednisolone dose is reduced to < 10 mg/day.

Oral Itraconazole:

Ketoconazole has been tried in the past147 and has been replaced by the less toxic agent, itraconazole.130,141,148160 Only two randomized controlled studies (84 patients) have evaluated the role of itraconazole in ABPA.130,156 Pooled analysis showed that itraconazole could significantly decrease the IgE levels by ≥ 25% when compared to placebo but did not cause significant improvement in lung function.161 A major limitation was that neither of the studies reported long-term outcomes in ABPA. Thus longer term trials are required before a firm recommendation can be made for the use of itraconazole in ABPA. We currently use itraconazole only after the first relapse of ABPA despite glucocorticoid therapy or in patients with glucocorticoid-dependent ABPA (Table 8). In the limited numbers of patients in whom we have used the drug, there was no observable advantage.22 Itraconazole not only has numerous adverse effects,162 but it also inhibits the metabolism of methylprednisolone (but not prednisolone) with resultant increased frequency of steroid side effects including adrenal insufficiency.163 Adrenal suppression has also been reported with the concomitant use of itraconazole and inhaled budesonide.164,165

Other Therapies:

There is a single patient case report of ABPA treated with inhaled amphotericin and budesonide.166 Similarly, there is another case record on the use of omalizumab for the management of ABPA.167 One author has also used pulse doses of IV methylprednisolone for the treatment of severe ABPA.168 Recently, voriconazole has also been tried in the treatment of ABPA.169171

Differential Diagnosis and Complications

The disorder needs to be differentiated from the following conditions: Aspergillus hypersensitive bronchial asthma, pulmonary tuberculosis in endemic areas, community-acquired pneumonia (especially acute presentations), and other inflammatory pulmonary disorders such as eosinophilic pneumonia, bronchocentric granulomatosis, and Churg-Strauss syndrome. The complications of ABPA include recurrent asthma exacerbations and, if untreated, the development of bronchiectasis with subsequent pulmonary hypertension and respiratory failure. In fact, this is the reason why routine screening is recommended in bronchial asthma to prevent the complications just described.

ABPA in Special Situations
ABPA Complicating CF:

The association of ABPA and CF was first reported in 1965.172 The occurrence of ABPA in CF is associated with deterioration of lung function, higher rates of microbial colonization, pneumothorax, massive hemoptysis, and poorer nutritional status.153,173,174 A key element in the immunopathogenesis may be exposure to high levels of Aspergillus allergens due to abnormal mucus properties.175 The recognition of ABPA in CF can be difficult because ABPA shares many clinical characteristics with poorly controlled CF lung disease. Presence of wheezing, pulmonary infiltrates, bronchiectasis, and mucus plugging are common manifestations of CF-related pulmonary disease without ABPA. The prevalence of AH in patients with CF has been reported between 29% and 53%,176180 and the prevalence of ABPA as 1 to 15%. Atopy seems to be an important risk factor for ABPA in CF, with ABPA observed in 22% of atopic patients but only 2% of nonatopic patients.153,181183

To determine the prevalence of AH/ABPA in CF, a systematic search was performed. The search yielded 28 studies (16 studies [1,391 patients] describing the prevalence of AH in CF and 23 studies [32,589 patients] describing the prevalence of ABPA in CF) that have described the prevalence of AH and/or ABPA in patients with CF (Table 9).153,173,174,176200 A proportion metaanalysis of these studies suggested the prevalence of AH in CF of 34% (95% confidence interval, 27 to 41) and the prevalence of ABPA of 7.8% (95% confidence interval, 5.8 to 10) using a random effects model [Figs 6 and 7]. There was no uniformity in the diagnostic criteria between different studies with varying criteria used for diagnosis of AH and ABPA. This fact has also been previously reported in a questionnaire-based study, which revealed a considerable variability in the criteria used for the diagnosis of ABPA in CF.201 Therefore, prospective reporting of cases with uniform criteria would be the only way to reliably identify the true prevalence of ABPA in CF.

Table Graphic Jump Location
Table 9 Studies Describing Prevalence of AH and/or ABPA in Patients With CF

* ABPA: Studies have used different inclusion criteria for diagnosing ABPA. See text for further details.

† AH: Defined as immediate cutaneous hypersensitivity to Aspergillus antigen or a positive specific IgE in serum against A fumigatus (radioallergosorbent test class ≥ 2) and/or increased specific IgE in serum against rAsp f1 > 9.6 EU/mL, with normal values for rAsp f4 (< 8.4 EU/mL) and rAsp f6 (< 7.2 EU/mL)

Figure Jump LinkFigure 6 Proportion metaanalysis showing the prevalence of Aspergillus hypersensitivity in patients with cystic fibrosis (random effects model).Grahic Jump Location
Figure Jump LinkFigure 7 Proportion metaanalysis showing the prevalence of allergic bronchopulmonary aspergillosis in patients with CF (random effects model).Grahic Jump Location

Although a high proportion of CF patients develop sensitization to A fumigatus, many demonstrate a spontaneous decline in many immunologic parameters, including IgE levels.192 The diagnosis of ABPA in CF should not be based solely on serology and skin test results, and prolonged testing might be required to make a definite diagnosis (Table 10). The treatment of ABPA in CF is not very different from that of ABPA in bronchial asthma, except minimal data are available to formulate conclusive treatment recommendations for ABPA in CF. The treatment issues are further complicated because pulmonary exacerbations in a patient with ABPA and CF could be related to ABPA or pulmonary infection, and hence continuous assessment may be required over months with repeat performance of all the serologic investigations for ABPA before a decision to treat an individual case is made.202

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Table 10 Consensus Conference Proposed Diagnostic and Screening Criteria for ABPA in CF202
ABPA Without Bronchial Asthma:

ABPA may occasionally develop in an individual without preexisting asthma. We have performed a systematic MEDLINE search for the occurrence of ABPA without bronchial asthma.100 In total they included 36 cases reported across the globe; two cases demonstrated bronchodilator reversibility,203 and one showed airway hyperresponsiveness to methacholine challenge.204 Most of the cases demonstrated hypersensitivity to A fumigatus, but three cases showed hypersensitivity to Helminthosporium,203 and one case each to Aspergillus niger.205,206 Because of the absence of bronchial asthma, these cases are often mistaken initially for other pulmonary disorders like bronchogenic carcinoma206208 or pulmonary tuberculosis.100

ABPA Complicating Other Conditions:

Occasionally ABPA has been reported to complicate other lung diseases like idiopathic bronchiectasis,209 post-tubercular bronchiectasis,210 bronchiectasis secondary to Kartagener syndrome,211 COPD,212 and in patients with chronic granulomatous disease and hyper IgE syndrome.213 However, these are case reports or small case studies, and larger observations are required to definitely establish an association.

Coexistence of ABPA and Aspergilloma:

The serologic findings of ABPA have also been reported in patients with aspergilloma214224 and chronic necrotizing pulmonary aspergillosis.225 This ABPA-like syndrome probably represents a true hypersensitivity reaction consequent to the colonization of Aspergillus in long-standing pulmonary cavities and the continuous release of Aspergillus antigens that leads to immunologic activation.214,215 Most patients show a brisk response to glucocorticoids.214217,224

Allergic Bronchopulmonary Mycosis:

Allergic bronchopulmonary mycosis is the occurrence of an ABPA-like syndrome due to non-A fumigatus fungal organisms. A variety of fungal agents (Table 11) have been reported to cause this syndrome, but the frequency is far less when compared to ABPA.218,226240

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Table 11 Fungi Implicated in the Causation of Allergic Bronchopulmonary Mycosis
ABPA and Allergic Aspergillus Sinusitis:

Allergic Aspergillus sinusitis (AAS) is a clinical entity in which mucoid impaction akin to that of ABPA occurs in the paranasal sinuses.241 The pathogenesis is also similar to ABPA and represents an allergic hypersensitivity response to the presence of fungi within the sinus cavity.242 The patient is often asymptomatic or can manifest with symptoms of nasal obstruction, rhinorrhea, headache, and epistaxis. Occasionally, the allergic fungal sinusitis may extend into adjacent spaces such as the orbit and manifest as proptosis.243 Although in many patients with ABPA, sinusitis can often be radiologically demonstrated, it may not be possible to confirm the diagnosis of AAS because many patients decline to undergo the diagnostic procedures required to establish the diagnosis. We currently label the patients with ABPA as having concomitant AAS if there is combination of hyperattenuating mucus and/or bony erosion on a paranasal CT scan. Treatment is initiated for ABPA with patients receiving additional intranasal glucocorticoids. If the symptoms persist or are troublesome, surgical management may be required for the management of AAS.

A high index of suspicion for ABPA should be maintained while managing any patient with bronchial asthma whatever the severity or the level of control. Host immunologic responses are central to the pathogenesis, and they are the primary determinants of the clinical, biologic, pathologic, and radiologic features of this disorder. ABPA may precede the clinical recognition of the disorder for many years or even decades, and it is often misdiagnosed as a variety of pulmonary diseases. Because a patient with ABPA can be minimally symptomatic or asymptomatic, all patients with bronchial asthma should be routinely screened with an Aspergillus skin test. In patients with Aspergillus hypersensitivity, further immunologic studies are warranted to diagnose ABPA before the development of bronchiectasis because bronchiectasis is a poor prognostic marker in the natural history of this disease.

AAS

allergic Aspergillus sinusitis

ABPA

allergic bronchopulmonary aspergillosis

ABPA-CB

allergic bronchopulmonary aspergillosus with central bronchiectasis

ABPA-CB-ORF

allergic bronchopulmonary aspergillosus with central bronchiectasis and other radiological findings

ABPA-S

seropositive allergic bronchopulmonary aspergillosus

AH

Aspergillus hypersensitivity

CF

cystic fibrosis

HRCT

high-resolution CT

IL

interleukin

The author wishes to thank Dr. Amanjit Bal, Assistant Professor, Department of Histopathology, PGIMER, Chandigarh for providing the histopathology photographs.

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Figures

Figure Jump LinkFigure 1 A line diagram depicting the pathogenesis of allergic bronchopulmonary aspergillosis. Th = T-helper.Grahic Jump Location
Figure Jump LinkFigure 2 Histopathologic findings in a patient with allergic bronchopulmonary aspergillosis. Top left, A: photomicrograph showing bronchial lumen containing allergic mucin (hematoxylin-eosin, original ×100). Top right, B: high-magnification photomicrograph of allergic mucin having variegated appearance, necrotic eosinophils, Charcot-Leyden crystals (thin arrow), and an occasional septate fungal hyphae indicated by a thick arrow (hematoxylin-eosin, original ×200). Bottom left, C: photomicrograph showing eosinophilic pneumonia. There is filling of the alveolar spaces by eosinophils admixed with variable number of macrophages (hematoxylin-eosin, original ×200). Bottom right, D: photomicrograph showing bronchocentric granulomatosis. There is partial replacement of bronchial epithelium by palisading histiocytes (hematoxylin-eosin, original ×100).Grahic Jump Location
Figure Jump LinkFigure 3 Chest radiograph showing transient pulmonary opacities in the right lower lobe (left) in a patient with allergic bronchopulmonary aspergillosis that have spontaneously disappeared (right).Grahic Jump Location
Figure Jump LinkFigure 4 HRCT images of different patients with allergic bronchopulmonary aspergillosis. Top right: bilateral central bronchiectasis with centrilobular nodules and tree-in-bud opacities in the left lung. Top left: bilateral central bronchiectasis with many mucus-filled bronchi. Bottom, left and right: images from the same patient show high-attenuation mucoid impaction. Bottom right: the mucoid impaction in the right lung is visually denser than the paraspinal skeletal muscle.Grahic Jump Location
Figure Jump LinkFigure 5 Algorithm followed in the diagnostic workup for allergic bronchopulmonary aspergillosis in the author's chest clinic.Grahic Jump Location
Figure Jump LinkFigure 6 Proportion metaanalysis showing the prevalence of Aspergillus hypersensitivity in patients with cystic fibrosis (random effects model).Grahic Jump Location
Figure Jump LinkFigure 7 Proportion metaanalysis showing the prevalence of allergic bronchopulmonary aspergillosis in patients with CF (random effects model).Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 Studies Describing the Prevalence of AH and/or ABPA in Patients with Bronchial Asthma Over the Last Two Decades*

* Criteria for ABPA: Major (A = asthma, R = radiologic opacities, T = immediate positive skin test, E = eosinophilia, P = precipitins to A fumigatus, I = IgE elevated, C = central bronchiectasis, S = specific IgG/IgE to A fumigatus); Minor (C = sputum cultures of A fumigatus, S = type III skin test positivity, B = brownish black mucus plugs).

Table Graphic Jump Location
Table 2 Genetic Factors Involved in the Pathogenesis of ABPA*