Allergic Bronchopulmonary Aspergillosis Exacerbations Research Articles

Revised ISHAM-ABPA working group clinical practice guidelines for diagnosing, classifying and treating allergic bronchopulmonary aspergillosis/mycoses.

The International Society for Human and Animal Mycology (ISHAM) working group proposed recommendations for managing allergic bronchopulmonary aspergillosis (ABPA) a decade ago. There is a need to update these recommendations due to advances in diagnostics and therapeutics. An international expert group was convened to develop guidelines for managing ABPA (caused by Aspergillus spp.) and allergic bronchopulmonary mycosis (ABPM; caused by fungi other than Aspergillus spp.) in adults and children using a modified Delphi method (two online rounds and one in-person meeting). We defined consensus as ≥70% agreement or disagreement. The terms "recommend" and "suggest" are used when the consensus was ≥70% and <70%, respectively. We recommend screening for A. fumigatus sensitisation using fungus-specific IgE in all newly diagnosed asthmatic adults at tertiary care but only difficult-to-treat asthmatic children. We recommend diagnosing ABPA in those with predisposing conditions or compatible clinico-radiological presentation, with a mandatory demonstration of fungal sensitisation and serum total IgE ≥500 IU·mL-1 and two of the following: fungal-specific IgG, peripheral blood eosinophilia or suggestive imaging. ABPM is considered in those with an ABPA-like presentation but normal A. fumigatus-IgE. Additionally, diagnosing ABPM requires repeated growth of the causative fungus from sputum. We do not routinely recommend treating asymptomatic ABPA patients. We recommend oral prednisolone or itraconazole monotherapy for treating acute ABPA (newly diagnosed or exacerbation), with prednisolone and itraconazole combination only for treating recurrent ABPA exacerbations. We have devised an objective multidimensional criterion to assess treatment response. We have framed consensus guidelines for diagnosing, classifying and treating ABPA/M for patient care and research.

CT Imaging Assessment of Response to Treatment in Allergic Bronchopulmonary Aspergillosis in Adults With Bronchial Asthma

BackgroundOne of the major challenges in managing allergic bronchopulmonary aspergillosis (ABPA) remains consistent and reproducible assessment of response to treatment. Research questionWhat are the most relevant changes in computed tomography (CT-scan) parameters over time for assessing response to treatment? Study Design and MethodsIn this ancillary study of a randomized clinical trial (NEBULAMB), asthmatic patients with available CT-scan and without exacerbation during a 4-month ABPA exacerbation treatment period (corticosteroids and itraconazole) were included. Changed CT-scan parameters were assessed by systematic analyses of CT-scan findings at initiation (M0) and end of treatment (M4). CT-scans were assessed by two radiologists blinded to the clinical data. Radiological parameters were determined by selecting those showing significant changes over time. Improvement of at least one, without worsening of the others, defined the radiological response. Agreement between radiological changes, clinical and immunologic responses was likewise investigated. ResultsAmong the 139 originally randomized patients, 132 were included. We identified 5 CT-scan parameters showing significant changes at M4: mucoid impaction extent, mucoid impaction density, centrilobular micronodules, consolidation/ground-glass opacities and bronchial wall thickening (P<0.05). These changes were only weakly associated with one another, except for mucoid impaction extent and density. No agreement was observed between clinical or immunologic and radiological responses, assessed as an overall response, or considering each of the parameters (Cohen’s κ, -0.01 to 0.24). InterpretationChanges in extent and density of mucoid impactions, centrilobular micronodules, consolidation/ground-glass opacities and thickening of the bronchial walls were found to be the most relevant CT-scan parameters to assess radiological response to treatment. A clinical, immunologic and radiological multidimensional approach should be adopted to assess outcomes, probably with a composite definition of response to treatment.

Long-term follow-up of allergic bronchopulmonary aspergillosis treated with glucocorticoids: A study of 182 subjects.

The long-term outcomes of allergic bronchopulmonary aspergillosis (ABPA) are poorly characterised. We retrospectively included treatment-naïve subjects of acute stage ABPA-complicating asthma from three randomised trials. All the subjects received oral prednisolone for 4 months and were monitored every 6 weeks for 6 months and then every 6 months. Our primary objective was to estimate the incidence rate and the frequency of subjects experiencing ABPA exacerbation. The key secondary objectives were to evaluate the factors predicting ABPA exacerbation and the changes in serum total IgE seen during treatment. We included 182 subjects. Eighty-one (44.5%) patients experienced 120 exacerbations during 512 patient-years of follow-up. The incidence rate of ABPA exacerbations was 234/1000 patient-years. Most (73/81, 90.1%) subjects experienced ABPA exacerbation within three years of stopping therapy. On multivariate logistic regression analysis, peripheral blood eosinophil count ≥1000 cells/μL (adjusted odds ratio [aOR] 2.43; 95% confidence interval (CI), 1.26-4.67), the extent of bronchiectasis (aOR 1.10; 95% CI, 1.03-1.18), age (aOR 0.97; 95% CI, 0.94-0.99), and female sex (aOR 2.16; 95% CI, 1.10-4.24) independently predicted ABPA exacerbation after adjusting for serum total IgE and high-attenuation mucus. The best cut-off for serum total IgE after 6 weeks for identifying treatment response and ABPA exacerbations was a 20% decline and a 50% increase, respectively. ABPA exacerbations were common within 3 years of stopping treatment. Age, female sex, peripheral blood eosinophilia and the extent of bronchiectasis predicted ABPA exacerbations. The optimal serum total IgE cut-off for defining ABPA response and exacerbations is a 20% decline and a 50% increase, respectively.

Allergic bronchopulmonary aspergillosis in identical twins: Effectiveness of dupilumab

Allergic bronchopulmonary aspergillosis in identical twins: Effectiveness of dupilumab

Is voriconazole more efficacious than itraconazole in children with acute exacerbation of allergic bronchopulmonary aspergillosis? A systematic review of literature and evidence-based guideline recommendation

Is voriconazole more efficacious than itraconazole in children with acute exacerbation of allergic bronchopulmonary aspergillosis? A systematic review of literature and evidence-based guideline recommendation

Clinical Characteristics and Prognosis of Allergic Bronchopulmonary Aspergillosis: A Retrospective Cohort Study

BackgroundThe clinical features, treatment, and prognosis of allergic bronchopulmonary aspergillosis (ABPA) are not well-defined.ObjectiveWe aimed to investigate the clinical characteristics, therapy, and prognosis of ABPA to aid its clinical recognition.MethodsA total of 232 patients with ABPA were analyzed retrospectively. The characteristics of ABPA in terms of its misdiagnosis, computed tomography classification, therapy, and its relationship with asthma were analyzed, and risk factors for acute exacerbation of ABPA were analyzed based on follow-up data.ResultsOf the 232 ABPA patients, 132 had a history of misdiagnosis. Compared with the misdiagnosed patients, ABPA patients with central bronchiectasis, a high total eosinophil count, and mucus plugs were less likely to be misdiagnosed. Compared with serological ABPA, ABPA with central bronchiectasis was more likely to occur in older people and in patients with mucus plugs, and decreased forced vital capacity and diffusing capacity for carbon monoxide. ABPA patients with asthma were more likely to have bronchiectasis, decreased lung function in 1 s FEV1 and FEV1/FVC, and shorter time to first acute exacerbation compared with ABPA patients without asthma. Patients receiving glucocorticoids plus antifungal therapy had a longer time to first exacerbation than those receiving glucocorticoid therapy alone. Univariate and multivariate analyses revealed that duration of asthma history, duration of misdiagnosis, mucus plugs, and poor pulmonary function were risk factors for acute exacerbation of ABPA.ConclusionTo our knowledge, this is the largest sample size study of ABPA in China. ABPA patients with a history of asthma and/or central bronchiectasis on high-resolution computed tomography are prone to frequent acute exacerbations. The use of glucocorticoids combined with antifungal drugs can prolong the time to the first acute exacerbation in ABPA patients. Longer durations of asthma history and misdiagnosis, mucus plugs, and poor pulmonary function are risk factors for acute exacerbation of ABPA.

Epidemiology and outcomes of allergic bronchopulmonary aspergillosis in the elderly.

The prevalence and outcomes of allergic bronchopulmonary aspergillosis (ABPA) in the elderly remain unknown. We reviewed our database to identify the proportion of subjects diagnosed with ABPA at ≥60years of age (ABPA-elderly). We compared the clinical features, treatment and outcomes of ABPA-elderly versus the non-elderly (ABPA diagnosed at <60years of age). Between 2007 and 2019, we encountered 810 ABPA subjects with a mean age of 34.9years (49.4% women). Of these, 43 (5.3%) were aged ≥60years (ABPA-elderly). There was a trend towards lower median (interquartile range [IQR]) serum total IgE (4900 [2659-10000] vs. 7156 [23360-11963] IU/mL; P=.06) and Aspergillus fumigatus-specific IgE (12.3 [4.8-29.6] vs. 22.4 [7.7-41.5] kUA/L; P=.06) in the elderly than the non-elderly. Eosinophil counts were similar in the two groups. The median [IQR] number of segments involved by bronchiectasis (5 [2-9] vs. 7 [4-11]) was significantly lower in the ABPA-elderly (P=.001). The proportion of subjects experiencing ABPA exacerbations was significantly (P=.047) lower in the elderly (25.6%) vs. the non-elderly (40.8%). There was also a tendency towards a lower mean number of exacerbations in the elderly (155 vs. 208 exacerbation per 1000 person-years) than the non-elderly (P=.09). There was also a trend towards longer mean time to first exacerbation in the ABPA-elderly than the non-elderly (1612 vs. 1159days). ABPA was uncommon in the elderly. The bronchiectasis is less extensive with a trend towards lower immunological severity and fewer exacerbations in the elderly than the non-elderly subjects with ABPA.

Characterising the allergic profile of children with cystic fibrosis.

BackgroundCystic fibrosis (CF) is a genetic condition that affects multiple organ systems. Allergic bronchopulmonary aspergillosis (ABPA) is a well‐recognised problem but other allergic conditions are less well documented in CF.ObjectiveTo characterise the allergic profile of a cohort of children with CF, with a focus on those with ABPA.MethodsA cohort of children with CF were interviewed and retrospective data were collected regarding their allergic histories and other relevant clinical features.ResultsThe cohort included 37 children with median age of 9 years (interquartile range: 6‐12). There was a history of ≥1 allergic condition(s) in 28/37 children (76%). The most common allergic condition was allergic rhinitis (AR) in 21/37 (57%) and 16 of these 21 children (76%) had another allergic condition. All children with ABPA (8) had another allergic condition. In some children ABPA exacerbations appeared to be seasonal, suggesting possible cross‐sensitisation between Aspergillus fumigatus and aeroallergens associated with seasonal AR. Allergic conditions were also common in children with Pseudomonas aeruginosa infection.

Anti-IgE therapy for allergic bronchopulmonary aspergillosis in people with cystic fibrosis.

Cystic fibrosis is an autosomal recessive multisystem disorder with an approximate prevalence of 1 in 3500 live births. Allergic bronchopulmonary aspergillosis is a lung disease caused by aspergillus-induced hypersensitivity with a prevalence of 2% to 15% in people with cystic fibrosis. The mainstay of treatment includes corticosteroids and itraconazole. The treatment with corticosteroids for prolonged periods of time, or repeatedly for exacerbations of allergic bronchopulmonary aspergillosis, may lead to many adverse effects. The monoclonal anti-IgE antibody, omalizumab, has improved asthma control in severely allergic asthmatics. The drug is given as a subcutaneous injection every two to four weeks. Since allergic bronchopulmonary aspergillosis is also a condition resulting from hypersensitivity to specific allergens, as in asthma, it may be a candidate for therapy using anti-IgE antibodies. Therefore, anti-IgE therapy, using agents like omalizumab, may be a potential therapy for allergic bronchopulmonary aspergillosis in people with cystic fibrosis. This is an updated version of the review. To evaluate the efficacy and adverse effects of anti-IgE therapy for allergic bronchopulmonary aspergillosis in people with cystic fibrosis. We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews. Last search: 09 September 2021. We searched two ongoing trial registries (Clinicaltrials.gov and the WHO trials platform). Date of latest search: 16 August 2021. Randomized and quasi-randomized controlled trials comparing anti-IgE therapy to placebo or other therapies for allergic bronchopulmonary aspergillosis in people with cystic fibrosis. Two review authors independently extracted data and assessed the risk of bias in the included study. They planned to perform data analysis using Review Manager. Only one study enrolling 14 participants was eligible for inclusion in the review. The double-blind study compared a daily dose of 600 mg omalizumab or placebo along with twice daily itraconazole and oral corticosteroids, with a maximum daily dose of 400 mg. Treatment lasted six months but the study was terminated prematurely and complete data were not available. We contacted the study investigator and were told that the study was terminated due to the inability to recruit participants into the study despite all reasonable attempts. One or more serious side effects were encountered in six out of nine(66.67%) and one out of five(20%) participants in omalizumab group and placebo group respectively. There is lack of evidence for the efficacy and safety of anti-IgE (omalizumab) therapy in people with cystic fibrosis and allergic bronchopulmonary aspergillosis. There is a need for large prospective randomized controlled studies of anti-IgE therapy in people with cystic fibrosis and allergic bronchopulmonary aspergillosis with both clinical and laboratory outcome measures such as steroid requirement, allergic bronchopulmonary aspergillosis exacerbations and lung function.

A randomised trial of prednisolone versus prednisolone and itraconazole in acute-stage allergic bronchopulmonary aspergillosis complicating asthma.

Whether a combination of glucocorticoid and antifungal triazole is superior to glucocorticoid alone in reducing exacerbations in patients with allergic bronchopulmonary aspergillosis (ABPA) remains unknown. We aimed to compare the efficacy and safety of prednisolone-itraconazole combination versus prednisolone monotherapy in ABPA. We randomised subjects with treatment-naïve acute-stage ABPA complicating asthma to receive either prednisolone alone (4 months) or a combination of prednisolone and itraconazole (4 and 6 months, respectively). The primary outcomes were exacerbation rates at 12 months and glucocorticoid-dependent ABPA within 24 months of initiating treatment. The key secondary outcomes were response rates, percentage decline in serum total IgE at 6 weeks, time to first ABPA exacerbation and treatment-emergent adverse events (TEAEs). We randomised 191 subjects to receive either prednisolone (n=94) or prednisolone-itraconazole combination (n=97). The 1-year exacerbation rate was 33% and 20.6% in the prednisolone monotherapy and prednisolone-itraconazole combination arms, respectively (p=0.054). None of the participants progressed to glucocorticoid-dependent ABPA. All of the subjects experienced a composite response at 6 weeks, along with a decline in serum total IgE (mean decline 47.6% versus 45.5%). The mean time to first ABPA exacerbation (417 days) was not different between the groups. None of the participants required modification of therapy due to TEAEs. There was a trend towards a decline in ABPA exacerbations at 1 year with the prednisolone-itraconazole combination versus prednisolone monotherapy. A three-arm trial comparing itraconazole and prednisolone monotherapies with their combination, preferably in a multicentric design, is required to define the best treatment strategy for acute-stage ABPA.

Pregnancy complicated by allergic bronchopulmonary aspergillosis: A case-control study.

Whether allergic bronchopulmonary aspergillosis (ABPA) affects maternal and perinatal outcomes during pregnancy or vice versa is unknown. To evaluate the course of ABPA and its consequence on maternal and perinatal outcomes during pregnancy. We retrospectively included pregnant women with ABPA (cases) and compared them with non-pregnant ABPA subjects (controls). We recorded the following details in cases and controls: demographical characteristics, radiological findings, pulmonary function, duration of symptoms and the number of asthma and ABPA exacerbations during follow-up. We also recorded the maternal and perinatal outcomes in the cases. We included nine cases and 38 controls with a similar age range. All the cases had achieved remission of ABPA before pregnancy and were receiving inhaled medications for asthma control. Serum total IgE levels, the extent of bronchiectasis on CT thorax and pulmonary function were comparable in the two groups. The mean number of asthma (53 vs 7) and ABPA (62 vs 16) exacerbations per 100 person-years was significantly higher in cases compared to the controls. We did not observe any maternal complications. One neonate had low birthweight. The risk of asthma and ABPA exacerbations is significantly higher in pregnant subjects with ABPA than non-pregnant women with ABPA. However, maternal and perinatal outcomes are good.

EXACERBATIONS IN ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS: IDENTIFICATION OF RISK FACTORS AND DEVELOPING A PREDICTION MODEL

SESSION TITLE: Tuesday Abstract Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM PURPOSE: The course of allergic bronchopulmonary aspergillosis (ABPA), an immunological disorder complicating asthma and cystic fibrosis, is characterized by recurrent exacerbations. However, the factors predisposing to ABPA exacerbations remain unknown. Herein, we explore the risk factors and develop a prediction model to identify subjects at increased risk of exacerbation METHODS: We reviewed our database over a ten-year period to identify treatment-naïve subjects of ABPA having a minimum follow-up of 12 months. Clinical details, spirometry, IgE levels (total and Aspergillus fumigatus-specific IgE), and imaging findings (the number of lobes, and segments involved by bronchiectasis, presence of high-attenuation mucus [HAM]) were all retrieved. We reviewed the treatment details and the number of exacerbations during follow-up. We then compared the baseline parameters of subjects with and without exacerbation. Binomial logistic regression analysis was performed to identify factors predicting an exacerbation. Using the prediction model, we obtained the probability of exacerbation for each subject and a receiver operating characteristics (ROC) curve was constructed to predict an exacerbation. The degree of agreement between the model’s estimated probability of relapse and the actual relapse was assessed using the Hosmer-Lemeshow test for goodness-of-fit RESULTS: We included 428 subjects (median age 35.1 years, 54.4% men) with a median (IQR) follow-up of 40.6 (25-66.5) months. 206 subjects (48.1%) experienced a median (IQR) of 2 (1-2) exacerbations. The duration of asthma, symptom profile, the severity of obstruction, total IgE levels, and eosinophil counts were similar in subjects with and without ABPA exacerbation. The presence of bronchiectasis was also similar. However, the number of lobes and segments affected by bronchiectasis (median [IQR] of 7 [4-10] vs. 5 [2-9], p=0.008) were significantly higher in ABPA subjects experiencing exacerbations. Majority of the included subjects (79.2%) were treated with glucocorticoids, and this was not significantly different in the two study groups. The number of segments involved by bronchiectasis (OR [95% CI], 1.08 [1.02-1.14]) and the presence of HAM (OR [95% CI], 1.63 [1.01-2.62]) were the only factors independently associated with the development of ABPA exacerbation after adjusting for lung function, total and A.fumigatus-specific IgE levels. The model was moderate in predicting the occurrence of exacerbation (AUROC, 0.611) CONCLUSIONS: Exacerbations occur in nearly half of the patients with ABPA during follow-up. The presence of HAM at baseline and the number of segments affected by bronchiectasis independently predict the risk of developing an exacerbation CLINICAL IMPLICATIONS: The current model is moderately accurate in predicting future risk of exacerbation in ABPA. There may be factors other than HAM and bronchiectasis, resulting in exacerbation. DISCLOSURES: No relevant relationships Added 03/13/2019 by Ritesh Agarwal, source=Web Response, value=Consulting fee Removed 03/15/2019 by Ritesh Agarwal, source=Web Response No relevant relationships by Ashutosh Aggarwal, source=Web Response No relevant relationships by valliappan muthu, source=Web Response

Allergic bronchopulmonary aspergillosis (ABPA) sans asthma: A distinct subset of ABPA with a lesser risk of exacerbation.

Allergic bronchopulmonary aspergillosis (ABPA) is a complex immunological disorder complicating asthma. Uncommonly, ABPA presents without underlying asthma. Herein, we describe the outcomes of ABPA with and without asthma. Of the 530 subjects (median follow-up, 39 months), 37 (7%) were ABPA sans asthma. Bronchiectasis was more frequent (97.3%vs. 83.2%, P = .02), and the lung function was significantly better in ABPA sans asthma. The incidence-rate of ABPA exacerbation was higher in those with asthma than without (112vs. 242 per 1000 person-years, P = .0001). ABPA sans asthma appears to be a distinct subset of ABPA, with a better lung function and fewer exacerbations.

A randomised trial of vitamin D in acute-stage allergic bronchopulmonary aspergillosis complicating asthma.

Vitamin D has been demonstrated to have an immunomodulatory role in cystic fibrosis with allergic bronchopulmonary aspergillosis (ABPA). Herein, we evaluate supplemental vitamin D in acute-stage ABPA complicating asthma. Thirty subjects were randomised to receive either prednisolone (n=15, control) or prednisolone and oral vitamin D (n=15, intervention arm). Serum vitamin D levels were significantly higher in the intervention versus the control arm, following therapy. The mean decline in total IgE at 2months (primary outcome) was 10% higher in the intervention arm than the control arm; however, this was not statistically significant (48.6% vs 38.1%, P=0.27). The percentage decline in total IgE after 4 and 6months of randomisation was also similar in the two arms. There was no difference in asthma exacerbations (0 vs 2, intervention vs control; P=0.16). No ABPA exacerbation occurred in either arm. The other outcomes including the Th2 (IL-4, IL-6 and IL-10) and Th17 (IL-17) cytokine levels were similar in the two groups. None of the participants experienced hypervitaminosis D. There was no significant improvement in the clinical or immunological outcomes following vitamin D supplementation. A larger trial is required to ascertain the role of vitamin D in ABPA complicating asthma [Clinicaltrials.gov: NCT03133299].

Anti-IgE therapy for allergic bronchopulmonary aspergillosis in people with cystic fibrosis.

Cystic fibrosis is an autosomal recessive multisystem disorder with an approximate prevalence of 1 in 3500 live births. Allergic bronchopulmonary aspergillosis is a lung disease caused by aspergillus-induced hypersensitivity with a prevalence of 2% to 15% in people with cystic fibrosis. The mainstay of treatment includes corticosteroids and itraconazole. The treatment with corticosteroids for prolonged periods of time, or repeatedly for exacerbations of allergic bronchopulmonary aspergillosis, may lead to many adverse effects. The monoclonal anti-IgE antibody, omalizumab, has improved asthma control in severely allergic asthmatics. The drug is given as a subcutaneous injection every two to four weeks. Since allergic bronchopulmonary aspergillosis is also a condition resulting from hypersensitivity to specific allergens, as in asthma, it may be a candidate for therapy using anti-IgE antibodies. Therefore, anti-IgE therapy, using agents like omalizumab, may be a potential therapy for allergic bronchopulmonary aspergillosis in people with cystic fibrosis. This is an updated version of the review. To evaluate the efficacy and adverse effects of anti-IgE therapy for allergic bronchopulmonary aspergillosis in people with cystic fibrosis. We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews. Last search: 29 September 2017.We searched two ongoing trial registries (Clinicaltrials.gov and the WHO trials platform). Date of latest search: 24 January 2018. Randomized and quasi-randomized controlled trials comparing anti-IgE therapy to placebo or other therapies for allergic bronchopulmonary aspergillosis in people with cystic fibrosis. Two review authors independently extracted data and assessed the risk of bias in the included study. They planned to perform data analysis using Review Manager. Only one study enrolling 14 participants was eligible for inclusion in the review. The double-blind study compared a daily dose of 600 mg omalizumab or placebo along with twice daily itraconazole and oral corticosteroids, with a maximum daily dose of 400 mg. Treatment lasted six months but the study was terminated prematurely and complete data were not available. We contacted the study investigator and were told that the study was terminated due to the inability to recruit participants into the study despite all reasonable attempts. One or more serious side effects were encountered in six out of nine(66.67%) and one out of five(20%) participants in omalizumab group and placebo group respectively. There is lack of evidence for the efficacy and safety of anti-IgE (omalizumab) therapy in people with cystic fibrosis and allergic bronchopulmonary aspergillosis. There is a need for large prospective randomized controlled studies of anti-IgE therapy in people with cystic fibrosis and allergic bronchopulmonary aspergillosis with both clinical and laboratory outcome measures such as steroid requirement, allergic bronchopulmonary aspergillosis exacerbations and lung function.

Allergic Bronchopulmonary Aspergillosis

Allergic bronchopulmonary aspergillosis (ABPA) is an immunologic bronchopulmonary inflammation due to an immune response of the lower respiratory tract against Aspergillus fumigatus. The major clinical features of ABPA include asthma, recurrent pulmonary infiltrates, immediate wheal and flare skin reactivity to A. fumigatus, elevated total serum IgE levels, detectable serum precipitating antibodies to A. fumigatus, peripheral blood eosinophilia, elevated levels of Aspergillus-specific serum IgE and central bronchiectasis with normal distal structures. The diagnosis of ABPA should be considered in asthmatics of all ages. Evolution of the disease comprises five stages from the acute to the fibrotic stage including pulmonary fibrosis and respiratory insufficiency. The goals of ABPA treatment are to control patient's asthma and prevent exacerbations of ABPA. During the acute stage, prednisone should be administered. Antifungals agents (itraconazole) may be useful to prevent exacerbations of the disease.

Allergic bronchopulmonary aspergillosis in patients with cystic fibrosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a pulmonary disorder that often occurs in patients with asthma or cystic fibrosis (CF) and is characterized by a hypersensitivity response to the allergens of the fungus Aspergillus fumigatus. In patients with CF, growth of A. fumigatus hyphae within the bronchial lumen triggers an immunoglobulin E (IgE)-mediated hypersensitivity response that results in airway inflammation, bronchospasm, and bronchiectasis. In most published studies, the prevalence of ABPA is about 8.9% in patients with CF. Since the clinical features of this condition overlap significantly with that of CF, ABPA is challenging to diagnose and remains underdiagnosed in many patients. Diagnosis of ABPA in CF patients should be sought in those with evidence of clinical and radiologic deterioration that is not attributable to another etiology, a markedly elevated total serum IgE level (while off steroid therapy) and evidence of A. fumigatus sensitization. Management of ABPA involves the use of systemic steroids to reduce inflammation and modulate the immune response. In patients who do not respond to steroids or cannot tolerate them, antifungal agents should be used to reduce the burden of A. fumigatus allergens. Recent studies suggest that omalizumab may be an effective option to reduce the frequency of ABPA exacerbations in patients with CF. Further randomized controlled trials are needed to better establish the efficacy of omalizumab in managing patients with CF and ABPA.

A pilot randomized trial of nebulized amphotericin in patients with allergic bronchopulmonary aspergillosis

Background and aim: Nebulized amphotericin B (NAB) has been used in the management of acute stage and exacerbations of allergic bronchopulmonary aspergillosis (ABPA). Whether NAB can prevent exacerbations of ABPA is not known. Herein, we evaluate the efficacy and safety of NAB in subjects with ABPA complicating asthma. Methods: Consecutive subjects of ABPA with recurrent exacerbations were randomized to receive either NAB plus nebulized budesonide (NEB) or NEB alone. The primary outcome was the time-to-first exacerbation of ABPA. The secondary outcomes were the number of subjects with ABPA exacerbations, ACQ7 scores, lung function, IgE levels, and adverse effects of treatment. Results: Twenty-one subjects (14 men; mean age, 32.3 years) were randomized to either the NAB (n = 12) or the NEB (n = 9) arm. The baseline characteristics were similar in the two groups. The time-to-first exacerbation was similar in the two groups. At one year, the numbers of patients experiencing exacerbation was significantly lower in the NAB arm (1/12 [8.3%] vs. 6/9 [66.7%]; p = 0.016). The other secondary end points were not different between the two groups. There were no major adverse events leading to discontinuation of any of the study drugs. Three patients experienced bronchospasm after first dose of NAB; however, the subsequent doses were well tolerated. Conclusions: NAB seems to be beneficial in decreasing the frequency of exacerbations in patients with ABPA complicating asthma. Larger trials are required to confirm our study results.

Measuring total IgE is useful in detecting exacerbations in patients with allergic bronchopulmonary aspergillosis receiving omalizumab

The pathogenesis of allergic bronchopulmonary aspergillosis (ABPA), a hypersensitivity reaction to Aspergillus fumigatus antigens, is complex and not yet fully clarified.Moreover, the diagnosis might sometimes represent a challenge because there is no universal consensus on the diagnostic criteria originally proposed by Rosenberg et al. Nonetheless, IgE plays a key pathogenic role in the disease, and is currently accepted as a marker of both initial diagnosis and disease activity. Systemic corticosteroids are required to suppress the immunological response, but ABPA is a chronic and progressive disease, associated with repeated exacerbations after successful treatment with steroids and/or antifungal agents. The well-known adverse effects of steroids have prompted clinicians to look for other therapeutic options. Hence, omalizumab, an mAb that binds to circulating IgE, has been repeatedly reported to successfully control ABPA within the initial months of treatment, both in retrospective case series and in a recent placebo-controlled registered clinical trial, but no long-term information is currently available. Another problem is that the ability to assess adequate reductions in total IgE levels afterward, or even to detect further exacerbations, on the basis of indicator and predictor value of serum IgE in ABPA, represents a concern in all patients receiving omalizumab. This occurs given that measuring the total IgE level through commercially available methods is considered not quite reliable in patients receiving omalizumab, and measuring free IgE is both controversial and, above all, not available for most clinicians. The aim of this communication was to describe the long-term clinical follow-up and serial measured total and specific IgE levels in 3 adult patients with ABPA while receiving treatment with omalizumab. All 3 patients have severe asthma according to the European Respiratory Society/American Thoracic Society criteria, and central bilateral bronchiectasis on chest computed tomography. The main clinical, laboratory, and spirometric parameters of the 3 patients are summarized in Table I. The pattern of total IgE levels over time is shown in Figure 1. Patient 1 (male, 44 years old) met commonly used criteria for ABPA since 1999, with multiple severe exacerbations requiring systemic corticosteroids and itraconazole (on average 3/year), a mean baseline total IgE level of 1000 KU/L (ImmunoCAP Phadia, Uppsala, Sweden), rising up to 4000 KU/L during exacerbations, and lung function impairment (mean baseline FEV1 70% of predicted, decreasing down to 43% during exacerbations). In 2010, he was started on omalizumab, with clinical and lung function improvement and a decrease in the total IgE level to 315 KU/L within the first year, being stable afterward and without ABPA exacerbations for almost 2 years. Still on omalizumab, in 2013 he had an ABPA relapse consisting of clinical and spirometrical decline, blood eosinophilia up to 1393/mm, increase in specific IgE and IgG levels to Aspergillus fumigatus, and also an almost 10-fold increase (from 400 to 3788 IU/mL) in measured total IgE level, which decreased progressively after initiating treatment with oral corticosteroids and itraconazole, coinciding with clinical improvement and progressive steroid step-down. Patient 2 (female, 50 years old) has aspirin-exacerbated respiratory disease (chronic rhinosinusitis with recurrent nasal polyps, difficult-to-control asthma, and aspirin hypersensitivity) since 1983; therefore, off-label treatment with omalizumab was started in 2008, achieving clinical and spirometrical stability (mean FEV1, 70%-75% of predicted) and no further need of sinus surgery. Every now and then she presented blood eosinophilia up to 900/mm, but the total IgE level was always around 400 KU/L, specific IgE and IgG for Aspergillus spp had always been negative, and Churg-Strauss and other autoimmune vasculitis had also been excluded. Almost 6 years after starting omalizumab, the patient experienced progressively worsening asthma symptoms and FEV1 decline down to 54% predicted. Chest X-ray was normal. The skin prick test performed to A fumigatus was positive (6 8 mm), and blood work revealed a total IgE level of 2402 KU/L, specificAspergillus IgG of 66mgA/L, and r Asp f 4 of 212 KU/L. The total IgE level decreased after starting oral steroids and itraconazole in July 2014, with progressive clinical and spirometric improvement up to previous values (FEV1 79% predicted). One year later (July 2015), she maintains asthma control (Asthma Control Test: 24 points), with no further exacerbations and having suspended oral steroids. Patient 3 (male, 34 years old) has early-onset allergic bronchial asthma. At age 20 years, he was diagnosed with ABPA, experiencing frequent and severe exacerbations, some of them requiring hospital admission. In 2008, he was started on omalizumab with consequent clinical improvement and stability for almost 3 years. In 2011, he was referred for a moderate clinical worsening (Asthma Control Test value decreased from 25 to 19 points). The total IgE level increased from 1132 kU/L to 2425 KU/L. One month after starting oral steroids, the total IgE level decreased to 964 KU/L, and clinical and lung function

Anti-IgE therapy for allergic bronchopulmonary aspergillosis in people with cystic fibrosis.

Cystic fibrosis is an autosomal recessive multisystem disorder with an approximate prevalence of 1 in 3500 live births. Allergic bronchopulmonary aspergillosis is a lung disease caused by aspergillus-induced hypersensitivity with a prevalence of 2% to 15% in people with cystic fibrosis. The mainstay of treatment includes corticosteroids and itraconazole. The treatment with corticosteroids for prolonged periods of time, or repeatedly for exacerbations of allergic bronchopulmonary aspergillosis, may lead to many adverse effects. The monoclonal anti-IgE antibody, omalizumab, has improved asthma control in severely allergic asthmatics. The drug is given as a subcutaneous injection every two to four weeks. Since allergic bronchopulmonary aspergillosis is also a condition resulting from hypersensitivity to specific allergens, as in asthma, it may be a candidate for therapy using anti-IgE antibodies. Therefore, anti-IgE therapy, using agents like omalizumab, may be a potential therapy for allergic bronchopulmonary aspergillosis in people with cystic fibrosis. This is an updated version of the review. To evaluate the efficacy and adverse effects of anti-IgE therapy for allergic bronchopulmonary aspergillosis in people with cystic fibrosis. We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews. Last search: 27 July 2015.We searched the ongoing trial registry clinicaltrials.gov for any ongoing trials. Latest search for clinicaltrials.gov: 23 October 2015. Randomized and quasi-randomized controlled trials comparing anti-IgE therapy to placebo or other therapies for allergic bronchopulmonary aspergillosis in people with cystic fibrosis. Two review authors independently extracted data and assessed the risk of bias in the included study. They planned to perform data analysis using Review Manager. Only one study enrolling 14 participants was eligible for inclusion in the review. The double-blind study compared a daily dose of 600 mg omalizumab or placebo along with twice daily itraconazole and oral corticosteroids, with a maximum daily dose of 400 mg. Treatment lasted six months but the study was terminated prematurely and complete data were not available. We contacted the study investigator and were told that the study was terminated due to the inability to recruit participants into the study despite all reasonable attempts. One or more serious side effects were encountered in six out of nine(66.67%) and one out of five(20%) participants in omalizumab group and placebo group respectively. There is lack of evidence for the efficacy and safety of anti-IgE (omalizumab) therapy in people with cystic fibrosis and allergic bronchopulmonary aspergillosis. There is a need for large prospective randomized controlled studies of anti-IgE therapy in people with cystic fibrosis and allergic bronchopulmonary aspergillosis with both clinical and laboratory outcome measures such as steroid requirement, allergic bronchopulmonary aspergillosis exacerbations and lung function.