Retrospective Comparison of Two Aspergillus IgG Enzyme Immunoassays for Diagnosing Pulmonary Aspergillosis.

Aspergillus-specific antibodies are diagnostic indicators of allergic bronchopulmonary aspergillosis (ABPA) and chronic pulmonary aspergillosis (CPA). Tests for detecting Aspergillus-specific antibodies were not used clinically in Japan, and the production of the Aspergillus precipitin test was discontinued. Thus, alternative tests for diagnosing aspergillosis are urgently needed. We retrospectively evaluated 64 patients with suspected ABPA and CPA who underwent precipitin antibody testing. Serum Aspergillus IgG levels were measured and compared using the Bordier Aspergillus fumigatus ELISA and the Platelia Aspergillus IgG (Bio-Rad) kits. Of the participants, 18 were diagnosed with CPA, and 8 were diagnosed with ABPA. Both the Bordier and Bio-Rad kits showed high sensitivity and specificity for CPA and ABPA. The area under the receiver operating characteristic curves for the Bordier and Bio-Rad kits were 0.97 and 0.95, respectively, for CPA, and 0.89 and 0.91, respectively, for ABPA. In contrast to the Bordier kit, the Bio-Rad kit showed relatively low anti-Aspergillus IgG levels and lower sensitivity to non-fumigatus Aspergillus infections. The Aspergillus-specific IgG ELISA tests showed sufficient diagnostic accuracy. Therefore, these assays are recommended as alternatives to the precipitin kit for diagnosing aspergillosis in clinical settings in Japan.

Aspergillus-sensitized asthma in children.

BACKGROUND: Asthma is the most common chronic respiratory disease in childhood. Aspergillus fumigatus sensitivity may be involved in the pathogenesis of asthma by leading to different clinical presentations. OBJECTIVE: To investigate the demographic, clinical, laboratory, and radiological characteristics of A. fumigatus sensitivity in childhood asthma and identify associated risk factors and diagnostic parameters. METHODS: A total of 259 children with asthma were included in the study, 7 (2.7%) with allergic bronchopulmonary aspergillosis (ABPA), 84 (32.4%) with A. fumigatus-sensitized asthma (Af-SA), and 168 (64.9%) with A. fumigatus-unsensitized asthma (Af-UA). RESULTS: Aspergillus sensitivity was associated with early asthma onset and longer asthma duration. Total IgE level and asthma severity are highest in ABPA and higher in Af-SA. Absolute eosinophil count was higher, and FEV1 was lower in Af-SA and ABPA. Aspergillus fumigatus was associated with greater odds of being male (odds ratio [OR], 2.45), having atopic dermatitis (OR, 3.159), Alternaria sensitivity (OR, 10.37), and longer asthma duration (OR, 1.266). The best cut-off values for detecting A. fumigatus positivity were 363.5 IU/mL for total IgE and 455 cells/µL for absolute eosinophil count. In Af-SA compared to Af-UA, centrilobular nodules and peribronchial thickening were more common, and the bronchoarterial ratio was higher. CONCLUSIONS: Aspergillus sensitivity is a strong allergic stimulus in asthma, leading to laboratory, structural, clinical, and functional consequences. Af-SA is a distinct asthma endotype independent of ABPA that is characterized by increased risk of severe clinical presentations and impaired lung function.

Detection of Specific IgE against Molds Involved in Allergic Bronchopulmonary Mycoses in Patients with Cystic Fibrosis.

CONTEXT: Allergic bronchopulmonary mycoses (ABPM) can be due to molds other than Aspergillus fumigatus in patients with cystic fibrosis (pwCF). We aimed to develop immunoassays for the detection of specific IgE (sIgE) directed against five fungal species involved in ABPM: Aspergillus terreus, Scedosporium apiospermum, Lomentospora prolificans, Rasamsonia argillacea, and Exophiala dermatitidis. MATERIALS AND METHODS: Serum samples (n = 356) from 238 pwCF, collected in eight CF care centers in France, Germany, and Italy, were analyzed by dissociated enhanced lanthanide fluorescent immunoassay (DELFIA®) to assess levels of sIgE directed against antigenic extracts of each fungus. Clinical, biological, and radiological data were collected for each episode. One hundred serum samples from healthy blood donors were used as controls. Sera were classified into four groups depending on the level of sIgE according to the quartile repartition calculated for the pwCF population. A score of 4 for values above the 3rd quartile corresponds to an elevated level of sIgE. RESULTS: PwCF showed higher levels of sIgE than controls. Based on criteria from the ABPA-ISHAM working group, with an additional criterion of "a sIgE score of 4 for at least one non-A. fumigatus mold", we were able to diagnose six cases of ABPM. CONCLUSIONS: Using 417 IU/mL as the threshold for total IgE and the same additional criterion, we identified seven additional pwCF with "putative ABPM". Detection of sIgE by DELFIA® showed good analytical performance and supports the role played by non-A. fumigatus molds in ABPM. However, commercially available kits usable in routine practice are needed to improve the diagnosis of ABPM.

Th2-skewed peripheral T-helper cells drive B-cells in allergic bronchopulmonary aspergillosis.

INTRODUCTION: Patients with allergic bronchopulmonary aspergillosis (ABPA) suffer from repeated exacerbations. The involvement of T-cell subsets remains unclear. METHODS: We enrolled ABPA patients, asthma patients and healthy controls. T-helper type 1 (Th1), 2 (Th2) and 17 (Th17) cells, regulatory T-cells (Treg) and interleukin (IL)-21+CD4+T-cells in total or sorted subsets of peripheral blood mononuclear cells and ABPA bronchoalveolar lavage fluid (BALF) were analysed using flow cytometry. RNA sequencing of subsets of CD4+T-cells was done in exacerbated ABPA patients and healthy controls. Antibodies of T-/B-cell co-cultures in vitro were measured. RESULTS: ABPA patients had increased Th2 cells, similar numbers of Treg cells and decreased circulating Th1 and Th17 cells. IL-5+IL-13+IL-21+CD4+T-cells were rarely detected in healthy controls, but significantly elevated in the blood of ABPA patients, especially the exacerbated ones. We found that IL-5+IL-13+IL-21+CD4+T-cells were mainly peripheral T-helper (Tph) cells (PD-1+CXCR5-), which also presented in the BALF of ABPA patients. The proportions of circulating Tph cells were similar among ABPA patients, asthma patients and healthy controls, while IL-5+IL-13+IL-21+ Tph cells significantly increased in ABPA patients. Transcriptome data showed that Tph cells of ABPA patients were Th2-skewed and exhibited signatures of follicular T-helper cells. When co-cultured in vitro, Tph cells of ABPA patients induced the differentiation of autologous B-cells into plasmablasts and significantly enhanced the production of IgE. CONCLUSION: We identified a distinctly elevated population of circulating Th2-skewed Tph cells that induced the production of IgE in ABPA patients. It may be a biomarker and therapeutic target for ABPA.

High Frequency of Allergic Bronchopulmonary Aspergillosis in Bronchiectasis-COPD Overlap.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is associated with frequent exacerbations and poor outcomes in chronic respiratory disease, but remains underdiagnosed. The role of fungal sensitization in bronchiectasis-COPD overlap (BCO) is unknown. RESEARCH QUESTION: What is the occurrence and clinical relevance of Aspergillus sensitization and ABPA in BCO when compared with individuals with COPD or bronchiectasis without overlap? STUDY DESIGN: Prospective, observational, cross-sectional study. METHODS: We prospectively recruited 280 patients during periods of clinical stability with bronchiectasis (n = 183), COPD (n = 50), and BCO (n = 47) from six hospitals across three countries (Singapore, Malaysia, and Scotland). We assessed sensitization responses (as specific IgE) to a panel of recombinant Aspergillus fumigatus allergens and the occurrence of ABPA in relationship to clinical outcomes. RESULTS: Individuals with BCO show an increased frequency and clinical severity of ABPA compared with those with COPD and bronchiectasis without overlap. BCO-associated ABPA is associated with more severe disease, higher exacerbation rates, and lower lung function when compared with ABPA occurring in the absence of overlap. BCO with a severe bronchiectasis severity index (BSI; > 9) is associated significantly with the occurrence of ABPA that is unrelated to underlying COPD severity. CONCLUSIONS: BCO demonstrates a high frequency of ABPA that is associated with a severe BSI (> 9) and poor clinical outcomes. Clinicians should maintain a high index of suspicion for the potential development of ABPA in patients with BCO with high BSI.

Small Molecule CCR4 Antagonists Protect Mice from Aspergillus Infection and Allergy.

The ability to regulate the recruitment of immune cells makes chemokines and their receptors attractive drug targets in many inflammatory diseases. Based on its preferential expression on T helper type 2 (Th2) cells, C-C chemokine receptor type 4 (CCR4) has been widely studied in the context of allergic diseases, but recent evidence on the expression of CCR4 in other cell types has considerably expanded the potential applications of CCR4 antagonism. However, the current number of approved indications, as well as the portfolio of CCR4-targeting drugs, are still limited. In the present study, we have assessed the potential therapeutic efficacy of a CCR4 small molecule antagonist, SP50, discovered via an in silico-based approach, against a variety of pre-clinical settings of infection with the fungus Aspergillus fumigatus. We show that SP50 efficiently worked as prophylactic vaccine adjuvant in immunocompetent mice, protected against invasive aspergillosis in immunosuppressed mice. Further, the CCR4 antagonist prevented allergic bronchopulmonary aspergillosis in susceptible mice, and in a murine model of cystic fibrosis, a genetic disorder characterized by chronic pulmonary inflammation and recurrent infections. In conclusion, our results extend the potential applications of CCR4 antagonism and prompt for the development of novel compounds with the potential to progress to clinical trials.

Aspergillus fumigatus Strain-Specific Conidia Lung Persistence Causes an Allergic Broncho-Pulmonary Aspergillosis-Like Disease Phenotype.

Aspergillus fumigatus is a filamentous fungus which can cause multiple diseases in humans. Allergic broncho-pulmonary aspergillosis (ABPA) is a disease diagnosed primarily in cystic fibrosis patients caused by a severe allergic response often to long-term A. fumigatus colonization in the lungs. Mice develop an allergic response to repeated inhalation of A. fumigatus spores; however, no strains have been identified that can survive long-term in the mouse lung and cause ABPA-like disease. We characterized A. fumigatus strain W72310, which was isolated from the expectorated sputum of an ABPA patient, by whole-genome sequencing and in vitro and in vivo viability assays in comparison to a common reference strain, CEA10. W72310 was resistant to leukocyte-mediated killing and persisted in the mouse lung longer than CEA10, a phenotype that correlated with greater resistance to oxidative stressors, hydrogen peroxide, and menadione, in vitro In animals both sensitized and challenged with W72310, conidia, but not hyphae, were viable in the lungs for up to 21 days in association with eosinophilic airway inflammation, airway leakage, serum IgE, and mucus production. W72310-sensitized mice that were recall challenged with conidia had increased inflammation, Th1 and Th2 cytokines, and airway leakage compared to controls. Collectively, our studies demonstrate that a unique strain of A. fumigatus resistant to leukocyte killing can persist in the mouse lung in conidial form and elicit features of ABPA-like disease.IMPORTANCE Allergic broncho-pulmonary aspergillosis (ABPA) patients often present with long-term colonization of Aspergillus fumigatus Current understanding of ABPA pathogenesis has been complicated by a lack of long-term in vivo fungal persistence models. We have identified a clinical isolate of A. fumigatus, W72310, which persists in the murine lung and causes an ABPA-like disease phenotype. Surprisingly, while viable, W72310 showed little to no growth beyond the conidial stage in the lung. This indicates that it is possible that A. fumigatus can cause allergic disease in the lung without any significant hyphal growth. The identification of this strain of A. fumigatus can be used not only to better understand disease pathogenesis of ABPA and potential antifungal treatments but also to identify features of fungal strains that drive long-term fungal persistence in the lung. Consequently, these observations are a step toward helping resolve the long-standing question of when to utilize antifungal therapies in patients with ABPA and fungal allergic-type diseases.

Eosinophils may serve as CEA-secreting cells for allergic bronchopulmonary aspergillosis (ABPA) patients.

Allergic bronchopulmonary aspergillosis (ABPA) is a condition characterized by an exaggerated response of the immune system to the fungus Aspergillus. This study aimed to assess the relationship between carcinoembryonic antigen (CEA) and eosinophils in ABPA patients. We describes a case of a 50-year-old patient who was diagnosed with ABPA presenting with high level of CEA and eosinophils. Besides,we used immunohistochemistry and immunofluorescence to identify eosinophils and CEA in sections which were obtained by Endobronchial ultrasound-guided transbronchial lung biopsy aspiration (EBUS-TBLB). The sections were then visualized using confocal microscopy. We also retrospectively analyzed a cohort of 37 ABPA patients between January 2013 and December 2019 in our hospital. We found the patient whose serum CEA levels were consistent with eosinophils during the follow-up (r = 0.929, P = 0.022). The positive expression of CEA and abnormal expression of eosinophils was higher in the ABPA tissue compared to the normal lung tissue. The co-localization was represented as pixels containing both red and green color in the image (with various shades of orange and yellow) which signified that eosinophils were immunohistochemically positive for CEA. Patients with higher levels of eosinophils had higher levels of CEA in the serum (P < 0.001). The results of Pearson correlation analysis showed that the levels of eosinophils were positively correlated with serum CEA levels (r = 0.459 and r = 0.506, P = 0.004 and P = 0.001). Serum CEA level is elevated in ABPA patients. The elevated serum CEA level was shown to be normalized after treatment. Increased CEA levels in ABPA patients may be positively correlated with eosinophil levels, and eosinophils may be served as CEA-secreting cells in patients with ABPA.

Optimal Aspergillus fumigatus and Asp f 1 serum IgG cut-offs for the diagnosis of allergic bronchopulmonary aspergillosis.

BACKGROUND: The presence of IgG antibodies (Abs) to Aspergillus fumigatus (Af) is a crucial diagnostic criterion for allergic bronchopulmonary aspergillosis (ABPA). Although precipitation is traditionally used to document IgG Abs, anti-Af serum IgG levels can also be measured by enzyme immunoassay (EIA). However, there are insufficient data on the optimal cut-offs to assess diagnostic performance of the EIA method. This study aimed to determine cut-off levels of IgG binding crude Af extracts or recombinant Asp f 1 (by ImmunoCAP®) and to compare their efficacy for ABPA diagnosis with Af-precipitating Abs. METHODS: The age distribution of levels of IgG to crude extracts of Af (Af-IgG) and recombinant Asp f 1 (Asp f 1-IgG) was established using sera from 694 healthy controls (HC). Receiver operating characteristic analysis for Af-IgG and Asp f 1-IgG levels for the purpose of ABPA diagnosis was performed in 306 Af-sensitized asthma patients (including 49 ABPA), and cut-offs were determined. RESULTS: An age-dependent decline in the levels of Af-IgG was observed in HC. Thus, cut-offs for Af-IgG levels were determined separately by age as 60 mg/L for patients aged <55 years, and 45 mg/L for those aged ≥55 years. For Asp f 1-IgG, 6.6 mg/L was set as the cut-off regardless of age. Although such IgG testing by EIA allowed a sufficiently good diagnostic performance, Af-precipitating Abs had better diagnostic applicability for ABPA. CONCLUSIONS: We determined cut-offs for Af-IgG and Asp f 1-IgG measured by EIA, which can be useful in clinical settings where precipitating Abs are unavailable.

Molecular allergen sensitization of Aspergillus fumigatus between allergic bronchopulmonary aspergillosis and A fumigatus-sensitized asthma in Guangzhou, Southern China.

BACKGROUND: Few studies have assessed the sensitization of mycotic allergens and Aspergillus fumigatus molecular allergens. This study aimed to investigate the relationships of A fumigatus components and mycotic allergens in allergic bronchopulmonary aspergillosis (ABPA) patients and A fumigatus (Af)-sensitized asthma patients. METHODS: Serum sIgE levels of Penicillium chrysogenum, Cladosporium herbarum, Mucor racemosus, Candida albicans, Alternaria alternata, Helminthosporium halodes, and A fumigatus allergen components (Asp f 1, Asp f 2, Asp f 3, Asp f 4, and Asp f 6) were measured via the ImmunoCAP assay in 18 ABPA and 54 Af-sensitized asthma patients in Guangzhou city, China. RESULTS: 94.44% of ABPA patients and 87.04% of Af-sensitized asthma patients were co-sensitized to at least one other fungal allergen. The positive rates of Asp f 1 (88.89% vs 59.26%, P < .05), Asp f 2 (66.67% vs 33.33%, P < .05), Asp f 4 (61.11% vs 33.33%, P < .05), and Asp f 6 (66.67% vs 14.81%, P < .001) in ABPA patients were higher than those in Af-sensitized asthma patients. IgE levels of Asp f 1 (P < .05), Asp f 4 (P < .05), and Asp f 6 (P < .001) were higher in ABPA patients than in Af-sensitized asthma patients. Optimal scale analysis showed that ABPA was more relevant to Af components (Cronbach's alpha = 90.7%). CONCLUSION: The A fumigatus components and their relationships with various mycotic allergens were different in ABPA and Af-sensitized asthma patients. This finding may help local doctors in the diagnosis and immunotherapy of fungal allergies.

[Allergic bronchopulmonary aspergillosis]. / Aspergillose bronchopulmonaire allergique.

Allergic bronchopulmonary aspergillosis (ABPA) is a specific complex immunological response to the spores of Aspergillus fumigatus (Af) colonizing the bronchi of asthmatic or cystic fibrosis patients. Recurrent episodes of bronchial obstruction and inflammation, as well as mucoid impaction cause bronchiectasis, pulmonary infiltrates and fibrotic alterations of the lung parenchyma, resulting in significant morbidity and mortality. The pathogenesis of ABPA remains incompletely understood, so it is not clear why certain colonized subjects develop hypersensitivity to Af, and why some sensitized patients develop ABPA and others do not. There is no simple and specific test for diagnosing ABPA. The diagnosis is based on the combination of clinical, radiological and immunological criteria. Systemic steroids are the cornerstone of treatment.

L'aspergillose bronchopulmonaire allergique (ABPA) est une réponse immunologique spécifique complexe contre les spores d'Aspergillus fumigatus (Af) qui colonisent les bronches de patients asthmatiques ou mucoviscidosiques. Les épisodes répétés d'obstruction et d'inflammation bronchiques et d'impactions mucoïdes génèrent des bronchiectasies, des infiltrats pulmonaires et des altérations fibrotiques du parenchyme pulmonaire, d'où une morbi-mortalité significative. La pathogenèse de l'ABPA reste mal comprise, si bien qu'on ne sait pas véritablement pourquoi certains sujets colonisés développent une hypersensibilité à Af, et pourquoi certains patients sensibilisés développent une ABPA et d'autres pas. Il n'y a pas de test simple et spécifique qui permette de diagnostiquer une ABPA. Le diagnostic se base sur l'association de critères cliniques, radiologiques et immunologiques. Les stéroïdes systémiques sont la pierre angulaire du traitement.

Th2 cells promote eosinophil-independent pathology in a murine model of allergic bronchopulmonary aspergillosis.

Repeated inhalation of airborne conidia derived from the fungus Aspergillus fumigatus (Af) can lead to a severe eosinophil-dominated inflammatory condition of the lung termed allergic bronchopulmonary aspergillosis (ABPA). ABPA affects about 5 million individuals worldwide and the mechanisms regulating lung pathology in ABPA are poorly understood. Here, we used a mouse model of ABPA to investigate the role of eosinophils and T cell-derived IL-4/IL-13 for induction of allergic lung inflammation. Selective deletion of IL-4/IL-13 in T cells blunted the Af-induced lung eosinophilia and further resulted in lower expression of STAT6-regulated chemokines and effector proteins such as Arginase 1, Relm-α, Relm-ß, and Muc5a/c. Eosinophil-deficient ΔdblGata mice showed lower IL-4 expression in the lung and the number of Th2 cells in the lung parenchyma was reduced. However, expression of the goblet cell markers Clca1 and Muc5a/c, abundance of mucin-positive cells, as well as weight gain of lungs were comparable between Af-challenged ΔdblGata and WT mice. Based on these results, we conclude that T cell-derived IL-4/IL-13 is essential for Af-induced lung eosinophilia and inflammation while eosinophils may play a more subtle immunomodulatory role and should not simply be regarded as pro-inflammatory effector cells in ABPA.

An atypical acute exacerbation of COPD due to Aspergillus fumigatus.

A 64-year-old male with a history of stabile chronic obstructive pulmonary disease (COPD) presented with increasing dyspnea and sputum for the last two months. Complete blood count showed WBC 14x103/ml, Hgb: 14.2 g/dL and eosinophilia. Blood biochemistry was normal. Chest x-ray showed hyperlucency while thorax computed tomography (CT) revealed obstructive lung disease and bronchiectasis. Pulmonary function tests demonstrated severe obstructive lung disease and a negative bronchoreversibility with a moderately reduced diffusing capacity/alveolar volume (DLCO/VA). ABG gases revealed significant hypoxemia. Sputum culture was negative. Total IgE was 1140 ng/ml. Aspergillus RAST, precipitins and aspergillusgalactomannan antigen were positive. CF genetic screening tests gave negative results. Allergic bronchopulmonary aspergillosis  (ABPA) is a hypersensitivity reaction that occurs due to bronchial aspergillus colonization. It is most common in patients with asthma and cystic fibrosis. We present a COPD case with an acute exacerbation due to Aspergillus fumigatus that lead to an aberrant clinical profile unresponsive to conventional treatment. Clinicians should consider Aspergillus fumigatus as an etiologic agent in an atypical and severe COPD exacerbation.

Serological analysis of sensitization in allergic bronchopulmonary aspergillosis: a study on allergen components and interspecies relationships.

Background: Serological testing for immunoglobulin (Ig) E or IgG is useful for diagnosing allergic bronchopulmonary aspergillosis (ABPA), as it detects type I and III allergic reactions to Aspergillus species. However, few reports have investigated the allergen component and cross-reactivity among Aspergillus species. We aimed to measure and analyze the levels of IgGs specific to each Aspergillus species and investigate the prevalence of IgEs specific to each allergen component of A. fumigatus (Af) in ABPA patients.Methods: Serum samples were collected from 12 ABPA patients who visited our hospital between February and December 2017, and 16 with Af-sensitized asthma and 41 with Af-unsensitized asthma were controls. Immuno-CAP was performed to analyze the IgEs and IgGs specific to Af, A. niger, A flavus and A. terreus, and IgEs specific to allergen components Asp f 1, 2, 3, 4 and 6.Results: The ABPA group was significantly more frequently sensitized to Asp f 1 and 2 than the control groups. Af-specific IgEs were significantly positively correlated to the IgEs specific to A. flavus, A. niger and A. terreus. Af-specific IgGs were positively correlated to the IgGs specific to all the other species.Conclusions: Tests using allergen components were useful for ABPA diagnosis. Both IgE and IgG were highly cross-reactive among the Aspergillus species. There were many patients apart from asthmatic patients with ABPA, who displayed high Aspergillus IgG values.

Asthma Phenotypes as a Guide for Current and Future Biologic Therapies.

Asthma has been increasingly recognized as being a heterogeneous disease with multiple distinct mechanisms and pathophysiologies. Evidence continues to build regarding the existence of different cell types, environmental exposures, pathogens, and other factors that produce a similar set of symptoms known collectively as asthma. This has led to a movement from a "one size fits all" symptom-based methodology to a more patient-centered, individualized approach to asthma treatment targeting the underlying disease process. A significant contributor to this shift to more personalized asthma therapy has been the increasing availability of numerous biologic therapies in recent years, providing the opportunity for more targeted treatments. When targeted biologics began to be developed for treatment of asthma, the hope was that distinct biomarkers would become available, allowing the clinician to determine which biologic therapy was best suited for which patients. Presence of certain biomarkers, like eosinophilia or antigen-specific IgE, is important features of specific asthma phenotypes. Currently available biomarkers can help with decision making about biologics, but are generally too broad and non-specific to clearly identify an asthma phenotype or the single biologic best suited to an asthmatic. Identification of further biomarkers is the subject of intense research. Yet, identifying a patient's asthma phenotype can help in predicting disease course, response to treatment, and biologic therapies to consider. In this review, major asthma phenotypes are reviewed, and the evidence for the utility of various biologics, both those currently on the market and those in the development process, in each of these phenotypes is explored.

Allergic bronchopulmonary aspergillosis.

Allergic bronchopulmonary aspergillosis (ABPA) occurs in patients with asthma or cystic fibrosis, and results in pulmonary infiltrates, tenacious mucus plugs that harbor hyphae of Aspergillus fumigatus, elevations of total serum immunoglobulin E concentration and peripheral blood and sputum eosinophilia. Bronchiectasis is an irreversible complication of ABPA. The key to early diagnosis is to consider ABPA in anyone with asthma or cystic fibrosis and with a positive skin test result for Aspergillus, and/or recurrent infiltrates on radiographs. The differential diagnosis for ABPA in patients with asthma includes diseases in which there is an overlap of asthma, peripheral blood eosinophilia, and radiographic infiltrates. Examples include chronic eosinophilic pneumonia, Churg-Strauss syndrome, drug-induced pulmonary infiltrates, infection with a parasite, asthma with atelectasis, and lymphoma. Mucus plugging that causes a "tree in bud" pattern on computerized tomography examination of the lungs may be from ABPA or other conditions, such as nontuberculous (atypical) mycobacteria (Mycobacteria avium-Mycobacteria intracellulare complex). Prednisone is indicated to clear pulmonary infiltrates, and a usual course is for 3 months. Itraconazole and voriconazole are adjunctive, and drug-drug interactions must be considered because azoles decrease elimination of various medications. Although not familial in most patients, presentation of Aspergillus fumigatus f1 (Asp f1) antigen is restricted to specific major histocompatibility complex (MHC) class II molecules, Human Leukocyte Antigen-DR2 (HLA-DR2), and HLA-DR5. There is an increased number of CD4+ T-helper type 2 lymphocytes in bronchoalveolar lavage, and A. fumigatus can serve as a growth factor of eosinophils potentiating the effects of interleukin (IL) 3, IL-5, and Granulocyte-colony stimulating factor (G-CSF). Eosinophils interact directly with A. fumigatus spores and generate extracellular traps, which can injure the bronchial epithelium.