Allergic bronchopulmonary aspergillosis' diagnosis remains a challenge

INTRODUCTION: Allergic bronchopulmonary aspergillosis (ABPA) is a complex disease, triggered by a hypersensitivity reaction to the allergens of Aspergillus fumigatus, a fungus that opportunistically colonizes the lungs of patients with asthma. The diagnosis of ABPA is difficult. A major problem is the lack of standardized allergens used in the determination of specific IgE, but the use of recombinant allergens has been proposed to overcome this. The aim of the present study is to evaluate whether serological tests for IgE specific to recombinant allergens of A. fumigatus (rAsp) can aid in the detection of sensitization to this fungus and in the diagnosis of ABPA. METHODS: This was an observational, cross-sectional study. The diagnosis of ABPA, using classical criteria, was searched in 65 asthmatics patients with immediate cutaneous reactivity to A. fumigatus. After that, serum titers of IgE against rAsp f 1, rAsp f 2, rAsp f 3, rAsp f 4 and rAsp f 6 were determined. In order to compare the differences between patients with confirmed and excluded diagnosis of ABPA, the two-tailed Fisher's exact test was used. RESULTS: Although 19 of 65 patients had IgE against at least one recombinant, the disease was diagnosed in only six patients by classical criteria. One of them had IgE against all recombinant allergens tested and another one had antibody against Asp f 3. DISCUSSION: The determination of serum IgE against recombinant A. fumigatus allergens in this group was not helpful to make the diagnosis of ABPA, neither to detect sensitization to fungus.     

变应性支气管肺曲霉病血清学诊断的研究进展

变应性支气管肺曲霉病(allergic bronchopulmonary Aspergillosis,ABPA)在囊性纤维化或哮喘患者中是一种常见的临床综合征,可导致不可逆的支气管扩张、肺纤维化,甚至死亡.ABPA的早期诊断及治疗可预防不可逆的肺部损伤.尽管多个APBA的诊断标准被先后提出,然而其临床和影像学特点与囊性纤维化、哮喘曲霉过敏有部分重叠,所以诊断上仍存在一定困难.因此,有效的血清标志物对于ABPA的诊断非常关键.从众所周知的标志物如总血清免疫球蛋白E(immunoglobulin E,IgE)、烟曲霉特异性IgE、烟曲霉特异性免疫球蛋白G(immunoglobulin G, IgG)、沉淀素到新的血清生物标志物如曲霉菌抗原重组体(recombinant Aspergillus fumigatus allergen,rAsp)、胸腺活性调节趋化因子(thymus gland activity regulating chemokine,TARC)、嗜碱细胞活性试验(basophilic cells activity test,BAT)、细胞过敏原刺激实验(cell allergen stimulation test,CAST),结合文献复习上述血清标志物在提高APBA早期发现及诊断中的地位及有效性.     

Chemokines indicate allergic bronchopulmonary aspergillosis in patients with cystic fibrosis

RATIONALE: Allergic bronchopulmonary aspergillosis (ABPA) is characterized by a Th2 immune response. Mouse models suggest a critical role for the Th2 chemokines thymus- and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) in ABPA. OBJECTIVES: To determine whether serum levels of TARC and MDC characterize ABPA in patients with cystic fibrosis (CF) and to examine longitudinally if levels of TARC and MDC indicate ABPA exacerbations in patients with CF. METHODS: Levels of TARC and MDC and levels of Th1 (IL-12 and IFN-gamma) and Th2 (IL-4, IL-5, and IL-13) cytokines were analyzed in serum of 16 patients with CF with ABPA, six non-CF patients with asthma with ABPA, 13 patients with CF colonized with Aspergillus fumigatus, six patients with CF sensitized to A. fumigatus, 12 atopic patients with CF, and 13 non-CF atopic control subjects by ELISA. The longitudinal course of TARC, MDC, and IgE levels was assessed during ABPA episodes. RESULTS: Patients with ABPA had significantly higher serum levels of TARC compared with the other patient groups. Cytokine levels did not differ among the patient groups. Longitudinally, levels of TARC indicated ABPA exacerbations in patients with CF more clearly than IgE levels. In patients with CF and ABPA, levels of TARC correlated positively with specific IgE to A. fumigatus and rAsp f4. CONCLUSIONS: Serum levels of TARC differentiate patients with CF or patients with asthma with ABPA from patients with CF colonized with or sensitized to A. fumigatus, atopic patients with CF, and atopic control subjects. Longitudinally, levels of TARC indicate ABPA exacerbations, suggesting TARC as a marker for identification and monitoring of ABPA in patients with CF.     

Allergic bronchopulmonary mycosis complicating cystic fibrosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity lung disease caused by bronchial colonization with Aspergillus fumigatus that affects approximately 10% of patients with cystic fibrosis (CF). The diagnosis in CF patients is difficult because the cardinal symptoms of ABPA occur frequently in CF, ie, pulmonary infiltrates and wheezing, as well as the frequent colonization with A fumigatus that leads to humoral reactivity. If left untreated, ABPA leads to bronchiectasis and pulmonary fibrosis. The pathogenesis of ABPA seems to be a prolonged asthmatic late-phase reaction orchestrated by CD4+ Th2-like T cells in response to persistent pulmonary A fumigatus allergen exposure. Thus, polyclonal and A fumigatus-specific IgE antibodies (and IgA and IgG) and blood pulmonary eosinophilia are stimulated by Th2-derived cytokines such as IL-4 and IL-5. In addition, IL-4 would also promote pulmonary transendothelial migration of eosinophils, basophils, and lymphocytes via induction of cell adhesion molecules and their ligands. IgE mast cell interactions would also contribute to the bronchial reactivity and inflammation. Recent advances have begun to identify immunodominant A fumigatus allergens. Evaluation of the quantity of IgE antibodies (and IgA and IgG) and T-cell cytokine responses to specific A fumigatus allergens should aid in the diagnosis and immunopathogenesis of ABPA, especially in CF patients.     

Potential role of the cellular allergen stimulation test (CAST) in diagnosis of allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis

Allergic bronchopulmonary aspergillosis (ABPA) is a severe complication in cystic fibrosis (CF), which is difficult to identify because of overlapping unspecific diagnostic features with common CF-manifestations. The cellular allergen stimulation test (CAST) is used in diagnosis of allergic and pseudoallergic reactions. This assay is based on the determination of sulfidoleukotrienes, which are produced by allergen-stimulated basophils in vitro. The potential role of CAST in diagnosis of ABPA was evaluated in this study. The CAST assay was applied in 27 CF-patients including eight subjects with positive clinical and serological signs of ABPA. Additional to the Nelson-criteria for diagnosis of ABPA specific IgE against recombinant Aspergillus antigens (rAsp f 1, 2, 3, 4, and 6) were assessed. The CAST results were positive in all ABPA-patients and in five controls without any sign of ABPA except positive specific IgE against Aspergillus fumigatus (sensitivity of 100%, specificity of 74%). Specific IgE against rAsp f 4 and/or f 6 were positive in six of the eight ABPA-patients, but not in the controls. Positive CAST results, total serum IgE > 500 U/ml and positive IgE antibodies against rAsp f 4 and/or f 6 were only found in ABPA-patients (specificity of 100%). The CAST assay on its own includes high sensitivity with lower specificity. For the discrimination of ABPA from sensitization to Aspergillus, the CAST, the highly elevated total serum IgE and rAsp in combination are potential auxiliary diagnostic parameters.     

Molecular characterization of aspergillus fumigatus allergens

Aspergillus fumigatus (Af) is ubiquitous saprophytic fungus associated with a broad spectrum of diseases in humans. These diseases range from benign colonization of the lung to life threatening diseases such as allergic bronchopulmonary aspergillosis (ABPA) and invasive aspergillosis. Af is the etiologic agent identified in most of the Aspergillus related human diseases and is therefore of particular clinical importance. Af induced obstructive airway diseases may be due to transient exposure to fungal spores resulting in a T helper 2 response. The IgE mediated inflammatory reaction could be due to colonization of bronchial airway epithelium by Af. Early and precise diagnosis of Aspergillus induced respiratory allergy is essential for preventing irreversible lung damages. The major problems in the diagnosis of A. fumigatus induced diseases are due to the lack of standardized and well characterized fungal extracts. The advent of molecular cloning technology and the development of phage surface display technology for cloning genes have facilitated the isolation of more relevant recombinant allergens. Using these techniques, a panel of different Af allergens having distinct IgE binding with various groups of Af sensitized patients have been cloned and characterized. These allergens can be categorized functionally as secreted and cytoplasmic proteins. The distinct IgE binding property of these purified and well characterized recombinant Af allergens may be useful for the differential diagnosis of Af related pulmonary complications.     

Effect of allergic bronchopulmonary aspergillosis on lung function in children with cystic fibrosis

RATIONALE: The relationship between sensitization to Aspergillus fumigatus and progression of pulmonary function is not yet established in cystic fibrosis (CF). OBJECTIVES: We aimed to evaluate onset of A. fumigatus sensitization and development of allergic bronchopulmonary aspergillosis (ABPA), as well as to determine the physiologic factors of lung function influencing these mechanisms in CF. METHODS: Serial annual lung function tests performed in 122 children with CF (62 males; 60 females; age: 6-18 yr) provided data pertaining to FRC measured by plethysmography, lung clearance index, volume of trapped gas, effective specific airway resistance, and forced expiratory indices (FEV1, FEF at 50% VC). Specific IgE to recombinant A. fumigatus allergens, rAspf1 and rAspf3, served as marker for sensitization, and to rAspf4 and rAspf6 as indications for a serologic ABPA, were clinically diagnosed (Nelson criteria). By linear mixed-effect model analysis, five patient groups, (1) not sensitized and free from Pseudomonas aeruginosa, (2) intermittently P. aeruginosa colonized, (3) chronically P. aeruginosa infected, (4) sensitized, and (5) with ABPA, were retrospectively evaluated. MEASUREMENTS AND MAIN RESULTS: A. fumigatus sensitization was best reflected by increased rAspf1+3-specific IgE levels, whereas, in most patients, sensitization was preceded by P. aeruginosa infection. Patients with ABPA demonstrated the most severe progression in all lung function parameters, and FEF at 50% VC, volume of trapped gas, and effective specific airway resistance were the best predictors (p < 0.0001). However, regarding distinction between sensitization to A. fumigatus and development of ABPA in the course of CF, chronic P. aeruginosa infection has to be taken into account. CONCLUSIONS: Airway narrowing, gas trapping, and small airway disease are the major targets for functional derangement in ABPA.     

Allergic bronchopulmonary aspergillosis (ABPA)

ABPA is the most common allergic bronchopulmonary mycosis in humans. The diagnosis of the complex disease is based on defined criteria. Five clinical stages of ABPA were proposed. The extend of the defined criteria varies in the different stages, thus making diagnosis difficult. Particularly the discrimination of ABPA in remission stage (stage II) and allergic asthma with A--sensitisation may be an important problem. Early diagnosis in stages without persistent changes of bronchial wall and lung parenchyma is needed to prevent severe end stages of ABPA. The up to now widely used commercial (crude) allergen extracts for in vitro and in vivo diagnosis show batch to batch variation, insufficient standardization and lack of reproducibility. Potentials and limitations of routine diagnostic procedures in ABPA are described. The production of a panel of recombinant allergens of A. fumigatus and their evaluation for in vivo and particularly in vitro use has brought an important step forward in the early and precise diagnosis of ABPA. A panel of recombinant allergens is now available for routine assay in CAP-System.     

Allergic bronchopulmonary aspergillosis (ABPA)

Allergic bronchopulmonary aspergillosis (ABPA) is the most common allergic bronchopulmonary mycosis in humans. The diagnosis of the complex disease is based on defined criteria. Five clinical stages of ABPA were proposed. The extent of the defined criteria varies in the different stages, thus making diagnosis difficult. Particularly the discrimination of ABPA in remission stage (stage II) and allergic asthma with A. fumigatus-sensitisation may be an important problem. Early diagnosis in stages without persistent changes of bronchial wall and lung parenchyma is needed to prevent severe end stages of ABPA. The up to now widely used commercial (crude) allergen extracts for in vitro and in vivo diagnosis show batch to batch variation, insufficient standardization and lack of reproducibility. Potentials and limitations of routine diagnostic procedures in ABPA are described. The production of a panel of recombinant allergens of A. fumigatus and their evaluation for in vivo and particularly in vitro use has brought an important step forward in the early and precise diagnosis of ABPA. A panel of recombinant allergens is now available for routine assay in CAP-System. Glucocorticosteroids play a central role in therapy of ABPA. The approach in exacerbation phase and the long term therapy are described and also the indication for antimycotic drugs.     

Surfactant protein D in serum from patients with allergic bronchopulmonary aspergillosis.

Surfactant protein D (SP-D) interacts with Aspergillus fumigatus and is strongly increased in the lavage from animals with acute allergic reactions to the fungus, suggesting a central role for SP-D. As the course of cystic fibrosis (CF) is often complicated by an allergic bronchopulmonary aspergillosis (ABPA), the authors hypothesised that SP-D may also be increased in serum during an ABPA, potentially assisting in its diagnosis and follow-up. In 22 patients with CF (11 with ABPA, 11 matched without ABPA) and 19 control patients without a pulmonary disease, SP-D concentrations in serum were assessed by an enzyme immunoassay. Serum SP-D in CF patients (130 +/- 16 ng x mL(-1) (mean +/- SEM)) was significantly higher than in the controls without lung disease (66 +/- 8 ng x mL(-1)). During the whole ABPA-episode, SP-D level did not change significantly, despite large changes of total serum immunoglobulin E. There was a clear negative correlation between SP-D concentration and overall lung function, i.e. forced expiratory volume in one second and forced vital capacity. Serum level of surfactant protein D may be of value to follow pulmonary function and lung injury in cystic fibrosis patients. Surfactant protein D serum levels are not helpful for the diagnosis and follow-up of an allergic bronchopulmonary aspergillosis episode, contrary to what was expected from animal experiments.     

An overview of allergic bronchopulmonary aspergillosis with some new insights.

Allergic bronchopulmonary aspergillosis (ABPA) occurs as a complication of bronchial asthma or cystic fibrosis (CF). The diagnostic criteria speak to an exaggerated type I hypersensitivity response to the ubiquitous organism Aspergillus fumigatus. Immunologic parameters indicative of Aspergillus sensitization in CF may be lost spontaneously. Therefore, it is important that the diagnosis of ABPA in CF include clinical parameters. CF transmembrane regulator gene mutations may occur in asthmatic ABPA patients indicating a subset of ABPA patients that warrant further study to exclude the diagnosis of CF. The extensive tissue damage seen in ABPA may, in part, be caused by proteases released from aspergillus. Host characteristics may predispose to the development of ABPA. It appears that human leukocyte antigen DR2 and particularly DRB1*1503 and *1501 alleles represent significant ABPA susceptibility genes with the possibility that human leukocyte antigen DQ2 allele confers protection in the non-ABPA population. These findings may offer an additional clinical aid in early diagnosis and provide insight into T-cell reactivity in ABPA that may lead to the development of specific immunotherapy.     

变态反应性支气管肺曲霉病研究进展

变态反应性支气管肺曲霉病(allergic bronchopulmonary aspergillosis,ABPA)与烟曲霉引起的变态反应相关,常发生在哮喘和肺囊性纤维化患者中.ABPA可引起血清总IgE水平升高,外周血嗜酸粒细胞增多,肺浸润和中心性支气管扩张,严重者可导致肺纤维化等肺组织的不可逆破坏.故ABPA的早期明确诊断和及时治疗十分重要.本文将对近年来ABPA的发病机制、临床分期、诊断标准、辅助检查及治疗研究新进展进行介绍.     

Aspergillus bronchitis in cystic fibrosis

Aspergillus fumigatus, a widely distributed spore-bearing fungus, is commonly grown in sputum cultures of patients with cystic fibrosis (CF). A fumigatus may cause allergic bronchopulmonary aspergillosis (ABPA), a complex condition that leads to worsening of airway inflammation and progressive damage and is diagnosed by specific criteria. In this report, we present six CF patients with respiratory deterioration that did not respond to appropriate antibiotic treatment. All had had A fumigatus in sputum cultures but did not fulfill the criteria of ABPA. Treatment with antifungal agents was followed by improvement in clinical condition. We suggest that in patients with CF, A fumigatus should be considered as a pathogen that may directly cause respiratory exacerbations. Antifungal therapy should be considered when deteriorating respiratory function is not responding to antibacterial therapy and A fumigatus is growing in sputum cultures.     

变态反应性支气管肺曲霉病的诊断与治疗

变态反应性支气管肺曲霉病是哮喘和囊性纤维化患者常见的并发症,由机体对曲霉的变态反应引起,表现为喘息、肺部浸润、支气管扩张和肺纤维化;病理改变包括黏液嵌塞、中心性支气管肉芽肿、嗜酸细胞肺炎和慢性或渗出性毛细支气管炎;诊断依靠临床表现、实验室以及影像学改变等标准,并分为囊性纤维化和非囊性纤维化两组;治疗主要是口服激素联合依曲康唑。     

Increased antigen-specific Th-2 response in allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis

The majority of patients with cystic fibrosis (CF) become colonized with Aspergillus fumigatus (A. fumigatus) in the lower respiratory tract, the prevalence being up to 60%. Between 1-11% of CF patients develop allergic bronchopulmonary aspergillosis (ABPA). Previous studies of ABPA in selected patients suffering from cystic fibrosis or atopic asthma have suggested a pathogenic role for antigen-specific "Th2-like" T lymphocytes. The aim of this study was to evaluate the quantitative importance of such Th2 cells, using improved techniques for measuring interleukin-4 (IL-4) and IL-5 secretion in unseparated peripheral blood mononuclear cell (PBMC) suspensions from CF patients with ABPA and from a control group without ABPA. Thus, 20 patients with CF, heavily colonized with A. fumigatus in the lower respiratory tract, were studied: 10 patients with ABPA, and 10 without. Unseparated PBMC were stimulated in vitro by A. fumigatus antigen and by an unrelated antigen (tetanus toxoid) as a control. After 6 days of stimulation, IL-4 and IL-5 (markers for Th2 cell activity) and interferon-gamma (IFN-gamma) (marker for Th1 cell activity) were quantified in the supernatants by enzyme-linked immunosorbent assay. PBMC from ABPA patients secreted significantly higher amounts of IL-4, i.e., 0.48 (0.15-0.8) ng/mL (median (range)), and IL-5, 37.64 (0.32-82.85) ng/mL, compared to secretions obtained in non-ABPA CF controls of 0.07 (0.04-0.16) ng/mL and 3.00 (0.10-5.09) ng/mL, respectively (P < 0.01 for both). IFN-gamma secretion was similar in the two groups, amounting to 21.5 (2.05-72.5) ng/mL in ABPA patients vs. 20.75 (1.80-54.0) ng/mL in non-ABPA patients (P = 0.47). No significant differences were obtained in the cytokine secretion induced by tetanus toxoid stimulation between the two groups. We conclude that ABPA in CF patients is associated with an antigen-specific, Th2-like T-cell immune response, as indicated by excessive secretion of IL-4 and IL-5.     

烟曲霉特异性免疫球蛋白E阳性患者临床特点及吸入性过敏原过筛试验对变应性支气管肺曲霉菌病的诊断价值研究

背景变应性支气管肺曲霉菌病(ABPA)临床辨识度低,诊断困难,误诊、漏诊率高。而吸入性过敏原过筛试验(Phadiatop)可检测吸入性过敏原混合物的特异性免疫球蛋白E(sIgE)。目前Phadiatop在烟曲霉sIgE阳性人群及ABPA人群临床诊治中的应用尚未普及。目的探讨烟曲霉sIgE阳性患者的临床特点及Phadiatop对ABPA的诊断价值。方法本研究为横断面观察性研究。回顾性选取上海交通大学附属第一人民医院2018—2019年收治的烟曲霉sIgE阳性患者122例为研究对象。根据血清总免疫球蛋白E(TIg E),将患者分为ABPA组(血清TIg E> 1 000 k U/L,44例)和单纯曲霉致敏组(血清TIg E≤1 000 k U/L,78例)。比较两组患者性别、年龄、实验室检查指标、sIgE及Phadiatop滴度。分析烟曲霉sIgE阳性患者烟曲霉sIgE与外周血嗜酸粒细胞计数、血清TIg E、Phadiatop滴度的相关性。分析Phadiatop滴度对ABPA的诊断价值。结果 122例患者中,男99例(81.1%),平均年龄(66.3±14.5)岁。ABPA组患者烟曲霉sIgE、混合霉菌sIgE、户尘螨sIgE、粉尘螨sIgE、德国小蠊sIgE、猫毛屑sIgE、狗毛屑sIgE、树花粉sIgE、杂草花粉sIgE、Phadiatop滴度高于单纯曲霉致敏组(P <0.05)。烟曲霉sIgE阳性患者烟曲霉sIgE与外周血嗜酸粒细胞计数、血清TIg E、Phadiatop滴度均呈弱相关(rs值分别为0.232、0.336、0.395,P值分别为0.011、<0.001、<0.001)。Phadiatop滴度诊断ABPA的曲线下面积(AUC)为0.79[95%CI(0.71,0.88)],临界值为1.00 KUA/L,灵敏度为69.01%,特异度为77.50%,阳性似然比为2.50,阴性似然比为3.07。结论烟曲霉sIgE阳性患者以男性多见,老年人为主。当Phadiatop滴度> 1.00 KUA/L时,应当警惕ABPA的发生,Phadiatop对ABPA有一定的诊断价值。     

Serologic IgE immune responses against Aspergillus fumigatus and Candida albicans in patients with cystic fibrosis

OBJECTIVES: The objectives of this study were to determine the prevalence of Aspergillus fumigatus and Candida albicans in the sputa of patients with cystic fibrosis (CF), to assess serologic IgE responses of these patients to the presence of fungi in the sputum, to evaluate what effect this may have on clinical status, and to determine how the above-mentioned factors relate to allergic bronchopulmonary aspergillosis (ABPA). PATIENTS: Seventy-six CF patients (40 male and 36 female patients; age, 15.3 plus minus 8.7 years [mean plus minus SD]) were studied. Measurements and results: A total of 1,239 sputum samples from 66 patients were cultured for fungi. A fumigatus was grown in 256 sputum specimens (20.7%), and C albicans was grown in 588 sputum samples (47.5%). Forty patients (60.6%) had at least one positive culture finding for A fumigatus, and 58 patients (87.9%) had at least one positive culture finding for C albicans. Forty-nine patients (64.5%) were sensitized to A fumigatus, and 20 patients (26.7%) were sensitized to C albicans. No correlation was found between the finding of A fumigatus in sputum and IgE to A fumigatus. Only patients who had at least one positive culture finding for C albicans had IgE to C albicans develop. Lung function values and chest radiograph scores were not significantly lower in patients sensitized to either A fumigatus or C albicans as compared to nonsensitized patients. Of the 20 patients sensitized to C albicans, 10 patients had confirmed ABPA and 10 patients had some immunologic characteristics of ABPA. CONCLUSIONS: A high prevalence of colonization and sensitization to A fumigatus and C albicans in CF patients was observed. The sensitization to these fungi was not related to the clinical severity. IgE to C albicans may be an immunologic marker related to the development of ABPA in patients with CF.     

Allergic bronchopulmonary aspergillosis in cystic fibrosis. A European epidemiological study. Epidemiologic Registry of Cystic Fibrosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a disease resulting from a hypersensitivity response to Aspergillus fumigatus, although the pathogenesis of the disease is unknown and its prevalence in cystic fibrosis (CF) is still poorly defined. Data from the Epidemiologic Registry of Cystic Fibrosis (ERCF) on 12,447 CF patients gathered from 224 CF centres in nine European countries were analysed. The ERCF definition of ABPA diagnosis is a positive skin test and serum precipitins to A. fumigatus, together with serum immunoglobulin (Ig)E levels >1,000 U x mL(-1) and additional clinical or laboratory parameters. The overall prevalence of ABPA in the ERCF population was 7.8% (range: 2.1% in Sweden to 13.6% in Belgium). Prevalence was low <6 yrs of age but was almost constant approximately 10% thereafter. No sex differences were observed. ABPA affected 8.0% of patients with a deltaF508/deltaF508 genotype and 5-6% with deltaF508/G551D, deltaF508/G542X and deltaF508/N1303K genotypes. ABPA patients presented a lower forced expiratory volume in one second (FEV1) than those without ABPA at any age and the prevalence ranged from 6.6% in patients with FEV1 > or =20-12.9% in those with FEV1 <40%. ABPA was associated with higher rates of microbial colonization, pneumothorax and massive haemoptysis, and with higher IgG serum levels and poorer nutritional status. A mixed model regression analysis of lung function showed that FEVI decline during the follow-up period was not substantially different in ABPA patients compared with non-ABPA patients for any subgroups based on age or disease severity at enrollment. To conclude, allergic bronchopulmonary aspergillosis is a frequent complication in cystic fibrosis patients, particularly after the age of 6 yrs, and it is generally associated with a poorer clinical condition. However, any clear independent influence of allergic bronchopulmonary aspergillosis on the rate of lung function decline in the short term was not shown.     

Correlation of IgE antibody titer to Aspergillus fumigatus with decreased lung function in cystic fibrosis

Obstructive pulmonary disease is a typical feature of cystic fibrosis (CF) and is often associated with bronchial hyperreactivity. Positive skin-test reactions to Aspergillus fumigatus antigens are frequently seen even in nonatopic patients with CF. Full-fledged allergic bronchopulmonary aspergillosis (ABPA) has been estimated to occur in 10% of patients with CF. The relationship between lung function and presence of IgE antibodies to Aspergillus antigens in patients without ABPA is not clear. In 148 outpatients with CF (aged 6-34 years) specific immunoglobulin E (IgE) to Aspergillus fumigatus antigens, basic lung-function parameters, and bronchial response to salbutamol were measured. Multiple regression was performed for age, weight as percentile for actual height (indicating general condition), and Aspergillus RAST. Aspergillus IgE was present in 46% of patients; 19% had RAST class 3 or 4. Independent negative correlations of Aspergillus RAST with FEV1, FEF50%, FEF25%, RV, Chrispin Norman score, and sRaw (P less than 0.05) were found. Bronchodilator sensitivity did not correlate significantly with age and weight percentile. However, Aspergillus RAST did correlate significantly with bronchodilator response measured by sRaw (P less than 0.05). High titers of Aspergillus RAST might serve as a selective criterion for patients to be included in future studies evaluating broncholytic or antiphlogistic therapies.     

Pathogenesis of allergic bronchopulmonary aspergillosis and an evidence-based review of azoles in treatment

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is a complex condition that affects people with asthma and cystic fibrosis (CF). It results from exposure to the fungus Aspergillus fumigatus, which leads to worsening airway inflammation and progressive damage to the lungs. The aim of this review is to outline the pathogenesis of the disorder, diagnostic criteria and to discuss the use of anti-fungal agents in its treatment. METHODS: The Cochrane library of systematic reviews and the Cochrane database of controlled trials were searched for controlled trials on ABPA and its treatment in both asthma and CF. In addition, articles included within the reviews were examined separately, and a separate search carried out using Medline. RESULTS: A systematic review for the use of azole anti-fungal agents in ABPA was identified for their use in both CF and non-CF-related disease. The review of ABPA alone identified two randomized-controlled trials of itraconazole in chronic disease. These trials demonstrated improvements in symptoms and immune activation, but were short-term trials and failed to show a significant change in lung function. No trials were identified in CF. CONCLUSIONS: The use of anti-fungal agents in ABPA seems to be a rational one, with short-term efficacy demonstrated for the use of itraconazole. Further investigations are required to identify individuals who will benefit most from treatment and to establish the correct dose and means of delivering treatment in ABPA. Longer-term studies are required to demonstrate that treatment modifies the progressive decline in lung function seen with the disease.