Allergic Bronchopulmonary Aspergillosis In Cystic Fibrosis Research Articles

Antifungal therapies for allergic bronchopulmonary aspergillosis in people with cystic fibrosis.

Allergic bronchopulmonary aspergillosis (ABPA) is an allergic reaction to colonisation of the lungs with the fungus Aspergillus fumigatus, and affects around 10% of people with cystic fibrosis. ABPA is associated with an accelerated decline in lung function. High doses of corticosteroids are the main treatment for ABPA; although the long-term benefits are not clear, and their many side effects are well-documented. A group of compounds, the azoles, have activity against A fumigatus, and have been proposed as an alternative treatment for ABPA. Of this group, itraconazole is the most active. A separate antifungal compound, amphotericin B, has been used in aerosolised form to treat invasive infection with A fumigatus, and may have potential for the treatment of ABPA. Antifungal therapy for ABPA in cystic fibrosis needs to be evaluated. This is an update of a previously published review. The review aimed to test the hypotheses that antifungal interventions for the treatment of ABPA in cystic fibrosis: 1. improve clinical status compared to placebo or standard therapy (no placebo); and 2. do not have unacceptable adverse effects. If benefit was demonstrated, we planned to assess the optimal type, duration, and dose of antifungal therapy. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, which comprises references identified from comprehensive electronic database searches, handsearches of relevant journals, and abstract books of conference proceedings. Date of the most recent search of the Group's Trials Register was 28 September 2021. We searched ongoing trials registries, most recently on 11 March 2022. Earlier, we also approached pharmaceutical companies regarding possible unpublished trials. Published or unpublished randomised controlled trials, in which antifungal treatments were compared to either placebo or no treatment, or where different doses of the same treatment were used in the treatment of ABPA in people with cystic fibrosis. The searches identified six trials; none of which met the inclusion criteria for the review. We included no completed randomised controlled trials. There is currently one ongoing trial, which we may find eligible for a future update. At present, there are no randomised controlled trials that evaluate the use of antifungal therapies for the treatment of ABPA in people with cystic fibrosis, although one trial is currently ongoing. Trials with clear outcome measures are needed to properly evaluate the use of corticosteroids in people with ABPA and cystic fibrosis.

Current Approach in the Diagnosis and Management of Allergic Bronchopulmonary Aspergillosis in Children With Cystic Fibrosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a complex pulmonary disorder characterized by a hypersensitivity reaction to Aspergillus fumigatus, and almost always seen in patients with cystic fibrosis (CF) and asthma. Fungal hyphae leads to an ongoing inflammation in the airways that may result in bronchiectasis, fibrosis, and eventually loss of lung function. Despite the fact that ABPA is thought to be more prevalent in CF than in asthma, the literature on ABPA in CF is more limited. The diagnosis is challenging and may be delayed because it is made based on a combination of clinical features, and radiologic and immunologic findings. With clinical deterioration of a patient with CF, ABPA is important to be kept in mind because clinical manifestations mimic pulmonary exacerbations of CF. Early diagnosis and appropriate treatment are important in preventing complications related to ABPA. Treatment modalities involve the use of anti-inflammatory agents to suppress the immune hyperreactivity and the use of antifungal agents to reduce fungal burden. Recently, in an effort to treat refractory patients or to reduce adverse effects of steroids, other treatment options such as monoclonal antibodies have started to be used. Intensive research of these new agents in the treatment of children is being conducted to address insufficient data.

CT evaluation of hyperattenuating mucus to diagnose allergic bronchopulmonary aspergillosis in the special condition of cystic fibrosis

BackgroundMucus plugging (MP), central bronchiectasis (CB), and consolidation/atelectasia (CA) are conventional CT signs to diagnose allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis (CF). Hyperattenuating mucus (HAM) has recently been described and may improve diagnostic accuracy. The goal of our study was to compare HAM versus conventional CT signs to diagnose ABPA in CF. Secondary objectives were to determine the optimal threshold of HAM quantitatively and to assess the diagnostic value of HAM using chest radiograph (CXR). MethodsThe study was retrospective and included 137 patients with CF, aged >6-year-old. The presence of HAM, CB, MP and CA were determined by two radiologists in consensus. HAM was quantified using an absolute mean density value (AMD) and a ratio between mucus and paraspinal muscle (DRM). Sensitivity (Se), Specificity (Sp) and Youden's J-index were calculated. The Cystic Fibrosis Conference Consensus criteria were chosen as Gold Standard. Results23 out of 137 CF patients had ABPA. Using CT, the most sensitive structural alteration was MP (Se = 91%), followed by CB (Se = 87%) and CA (Se = 70%) whereas specificities were 28%, 19% and 58%, respectively. Conversely, HAM had the highest specificity (Sp = 100%) whereas Se was 69%. HAM had the highest Youden's J-index (p < 0.001) Quantitative optimal thresholds were AMD > 78 HU (Se/Sp = 71%/98%) and DRM > 1.3 (Se/Sp = 82%/97%). HAM was unseen using CXR (Se = 0%). ConclusionHAM is the most specific CT biomarker of ABPA in CF, with good sensitivity. Our study suggests that characterization of mucus density may improve the accuracy of imaging criteria to diagnose ABPA early.

Omalizumab in allergic bronchopulmonary aspergillosis in patients with cystic fibrosis

BackgroundAllergic bronchopulmonary aspergillosis (ABPA) is a condition characterized by a Th2 response, serum eosinophilia, and increased total serum IgE to Aspergillus fumigatus. ABPA occurs in cystic fibrosis (CF) and asthma. Omalizumab is a humanized recombinant monoclonal antibody against IgE. Previous studies reported borderline results when treating ABPA with omalizumab.MethodsA retrospective study to investigate the efficacy of omalizumab in the treatment of ABPA in CF patients was conducted at 3 CF centers in Israel and Belgium. Data were obtained from the digital archive. We measured 4 outcome parameters: forced expiratory volume in 1 second, body mass index, pulmonary exacerbations, and steroid sparing.ResultsThe database was composed on the records of 9 patients. None of the outcome parameters showed any improvement. A favorable outcome was observed in patients with higher levels of posttreatment total IgE than those with lower levels. CF-related diabetes and male gender showed trends for poorer outcomes.ConclusionNo benefits were detected on treating ABPA in CF with omlaizumb. Monitoring the total IgE was not helpful. A prospective randomized double-blind study is needed.

Omalizumab treatment for allergic bronchopulmonary aspergillosis in young patients with cystic fibrosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a severe lung disease complication caused by an Aspergillus fumigatus-induced hypersensitivity that affects 2-15% of patients with cystic fibrosis (CF). The mainstay treatment consists of a combination of corticosteroids and antifungals. However, repeated or long-term corticosteroid therapies can lead to serious side effects. The monoclonal anti-IgE antibody, omalizumab, has demonstrated its efficacy in allergic asthma. As ABPA results from a hypersensitivity to a specific allergen, omalizumab might benefit CF patients with ABPA. Therefore, we conducted a retrospective study to investigate the effects of omalizumab on ABPA in CF patients. We retrospectively analyzed the clinical records of young patients with CF treated with omalizumab for an ABPA in several French CF centers. The clinical data were collected 3 months before the start of omalizumab treatment, at initiation, and every 3 months up to 12 following initiation. These data comprised clinical, biological, nutritional, and functional parameters. Eighteen patients were included (mean age: 17.1±5.2yrs). Under omalizumab was observed a stabilization of the lung function decline associated with a significant decrease in the corticosteroid daily dose (p=0.0007) and an improvement in the nutritional status (p=0.01). No serious side effect of omalizumab was reported. This study suggests that omalizumab might be an interesting therapeutic strategy in ABPA, associated with less side effects compared to long-term corticosteroids. Further randomized-controlled trials are needed to ascertain the efficacy of omalizumab in CF patients with ABPA.

Antifungal therapies for allergic bronchopulmonary aspergillosis in people with cystic fibrosis.

Allergic bronchopulmonary aspergillosis (ABPA) is an allergic reaction to colonisation of the lungs with the fungus Aspergillus fumigatus and affects around 10% of people with cystic fibrosis. ABPA is associated with an accelerated decline in lung function. High doses of corticosteroids are the main treatment for ABPA; although the long-term benefits are not clear, their many side effects are well-documented. A group of compounds, the azoles, have activity against Aspergillus fumigatus and have been proposed as an alternative treatment for ABPA. Of this group, itraconazole is the most active. A separate antifungal compound, amphotericin B, has been employed in aerosolised form to treat invasive infection with Aspergillus fumigatus, and may have potential for the treatment of ABPA. Antifungal therapy for ABPA in cystic fibrosis needs to be evaluated. This is an update of a previously published review. The review aimed to test the hypotheses that antifungal interventions for the treatment of ABPA in cystic fibrosis:1. improve clinical status compared to placebo or standard therapy (no placebo);2. do not have unacceptable adverse effects.If benefit was demonstrated, we aimed to assess the optimal type, duration and dose of antifungal therapy. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings.In addition, pharmaceutical companies were approached.Date of the most recent search of the Group's Trials Register: 29 September 2016. Published or unpublished randomised controlled trials, where antifungal treatments have been compared to either placebo or no treatment, or where different doses of the same treatment have been used in the treatment of ABPA in people with cystic fibrosis. Four trials were identified by the searches; none of which was judged eligible for inclusion in the review. No completed randomised controlled trials were included. At present, there are no randomised controlled trials to evaluate the use of antifungal therapies for the treatment of ABPA in people with cystic fibrosis, although trials in people who do not have cystic fibrosis have shown clinical and serological evidence of improvement and a reduction in the use of corticosteroids with no increase in adverse effects. Trials with clear outcome measures are needed to properly evaluate this potentially useful treatment for cystic fibrosis.

Antifungal therapies for allergic bronchopulmonary aspergillosis in people with cystic fibrosis.

Allergic bronchopulmonary aspergillosis (ABPA) is an allergic reaction to colonisation of the lungs with the fungus Aspergillus fumigatus and affects around 10% of people with cystic fibrosis. ABPA is associated with an accelerated decline in lung function. High doses of corticosteroids are the main treatment for ABPA; although the long-term benefits are not clear, their many side effects are well-documented. A group of compounds, the azoles, have activity against Aspergillus fumigatus and have been proposed as an alternative treatment for ABPA. Of this group, itraconazole is the most active. A separate antifungal compound, amphotericin B, has been employed in aerosolised form to treat invasive infection with Aspergillus fumigatus, and may have potential for the treatment of ABPA. Antifungal therapy for ABPA in cystic fibrosis needs to be evaluated. The review aimed to test the hypotheses that antifungal interventions for the treatment of ABPA in cystic fibrosis:1. improve clinical status compared to placebo or standard therapy (no placebo);2. do not have unacceptable adverse effects.If benefit was demonstrated, we aimed to assess the optimal type, duration and dose of antifungal therapy. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings.In addition, pharmaceutical companies were approached.Date of the most recent search of the Group's Trials Register: 17 March 2014. Published or unpublished randomised controlled trials, where antifungal treatments have been compared to either placebo or no treatment, or where different doses of the same treatment have been used in the treatment of ABPA in people with cystic fibrosis. Four trials were identified by the searches; none of which was judged eligible for inclusion in the review. No completed randomised controlled trials were included. At present, there are no randomised controlled trials to evaluate the use of antifungal therapies for the treatment of ABPA in people with cystic fibrosis, although trials in people who do not have cystic fibrosis have shown clinical and serological evidence of improvement and a reduction in the use of corticosteroids with no increase in adverse effects. Trials with clear outcome measures are needed to properly evaluate this potentially useful treatment for cystic fibrosis.

Vitamin D and experimental invasive aspergillosis.

Immune cells express the vitamin D receptor and vitamin D metabolizing enzymes. Favorable vitamin D effects have been indicated in tuberculosis. Vitamin D deficiency increases T helper (Th) 2 responses to Aspergillus, and it suppresses Th2 responses in cystic fibrosis-allergic bronchopulmonary aspergillosis. Can vitamin D modulate the proinflammatory effects of amphotericin B (AmB) therapy in aspergillosis? Groups of mice were infected intravenously (IV) with 3-8 × 10(6) Aspergillus fumigatus conidia. In six experiments, doses of 0.08, 2, or 4 μg/kg calcitriol (active form of vitamin D) were given intraperitoneally +/- AmB-deoxycholate (AmBd) at 0.4, 0.8, 1.2, 1.8, 3.3, or 4.5 mg/kg or 0.8 or 1.2 mg/kg IV. Calcitriol doses were selected to range from doses used in humans to those just below doses shown to decalcify murine bones. In most experiments, doses of calcitriol and AmBd (or control diluents) were given five times, on alternate days, to minimize drug-drug interactions. Calcitriol treatment began on the day of challenge, and survival assessed for 10 days. In no experiments did calcitriol alone significantly worsen or enhance survival or affect residual infection in survivors. Calcitriol also did not affect the efficacy of AmBd. In a representative experiment, AmBd at 0.8 or 1.2 mg/kg IV alone +/- calcitriol at 2 μg/kg enhanced survival (P ≤ 0.01). However, the AmBd regimens with calcitriol were not different than those without, and calcitriol alone was identical to controls. In disseminated invasive aspergillosis, calcitriol did not affect outcome nor influence antifungal efficacy.

Vitamin D regulation of Th2 Immune responses to Aspergillus fumigatus in mice and humans: role of OX40L (164.19)

Abstract 4-15% of cystic fibrosis (CF) patients develop Allergic Bronchopulmonary Aspergillosis (ABPA) characterized by heightened Th2 responses to Aspergillus fumigatus (Af). Colonization rates with Af in CF can approach 40-50% suggesting immune tolerance may prevent ABPA. We have previously shown that CD11c dendritic cells (DCs), OX40 Ligand, Vitamin D play a role in sensitization versus tolerance to Af in CF patients. We have set up an animal model to further explore the roles of CD11c DCs, OX40L, and Vitamin D in response to Af. Vitamin D deficient mice (by nutritional diet) and Vitamin D normal mice where sensitized and challenged with Af. In addition, mice were given anti-OX40L or PBS control 4 hours prior to Af challenge. Lung, lymph nodes (LN), and bronchoalveolar lavage (BAL) fluid where analyzed for Th2 cytokine production. Vitamin D deficient mice have significantly increased Th2 cytokine response to Af in lung, BAL, and LN. In addition, OX40L mRNA levels are increased in Vitamin D deficient mice compared to Vitamin D normal mice. When given anti-OX40L prior to Af challenge, Th2 response in both Vitamin D deficient and Vitamin D normal mice are attenuated confirming the critical role of OX40L driven Th2 response in Af sensitization. This suggests a critical role of OX40L in Vitamin D mediated Th2 suppression. These results support therapeutic trial of Vitamin D and/or anti-OX40L to treat ABPA in CF and suggest Vitamin D plays a role in immune tolerance to Af.

Pathogenesis of allergic bronchopulmonary aspergillosis in cystic fibrosis: current understanding and future directions

Allergic bronchopulmonary aspergillosis (ABPA) is an allergic disease characterized clinically by wheezing, pulmonary infiltrates, bronchiectasis, and fibrosis that affects patients with asthma and cystic fibrosis (CF). Although this disease has been characterized by a Th2 immune response to Aspergillus, the disease has some features such as central bronchiectasis which is not seen in other Th2 driven lung diseases such as atopic asthma. Here we will review the current pathophysiology of ABPA in CF and highlight new molecules that may affect immune responses against Aspergillus and ABPA disease pathogenesis.

Mucoid impaction: An unusual form of allergic bronchopulmonary aspergillosis in a patient with cystic fibrosis

We reported a child with cystic fibrosis (CF) who developed mucoid impaction related to allergic bronchopulmonary aspergillosis (ABPA). This is the first reported case of mucoid impaction related to ABPA in CF described to date in the literature. The case was successfully treated by corticosteroids and itraconazole therapy, but relapsed 6 months later. During exacerbation therapy, cataract formation complicated the corticosteroid treatment. We want to emphasize that 6-months therapy may be inadequate for the treatment of ABPA, and it is important to monitor for possible complications of corticosteroids therapy.

Allergic bronchopulmonary aspergillosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a common complication of cystic fibrosis (CF), occurring in approximately 10% of patients and accompanying/accounting for approximately 10% of pulmonary exacerbations. ABPA pathogenesis is dependent upon impaired clearance and dense respiratory epithelial exposure to A fumigatus (Af) spores with subsequent chemotactic recruitment of CD4+ Th2 lymphocytes specific for Af to lung tissue. Susceptibility to ABPA appears to involve risk factors including atopy and defined major histocompatibility complex-restricted alleles. Distinct cytoplasmic Af molecules (Af2, 4, and 6), now available as recombinant allergen reagents, appear to be associated with ABPA. Minimal criteria for diagnosis of ABPA in CF include clinical deterioration, elevated total serum IgE, positive immediate Af skin test or serum IgE antibodies, and Af serum precipitins/IgG antibodies or radiographic changes. Annual screening of total serum IgE is recommended from age 6 yr. Systemic glucocorticosteroids remain the mainstay of treatment. Itraconazole has an established role as a steroid-sparing agent if the patient has a slow or poor response to steroids, relapses, or is at risk for or develops steroid toxicity. Monitoring of clinical, radiographic and laboratory responses (especially total serum IgE) is essential.

Antifungal therapies for allergic bronchopulmonary aspergillosis in people with cystic fibrosis.

Allergic Bronchopulmonary Aspergillosis (ABPA) is an allergic reaction to colonisation of the lungs with the fungus Aspergillus fumigatus and affects around 10% people with cystic fibrosis. ABPA is associated with an accelerated decline in lung function. Corticosteroids, in high doses, are the main treatment for ABPA although the long-term benefits are not clear and their many side effects are well documented. A group of compounds, the azoles, have activity against Aspergillus fumigatus and have been proposed as an alternative treatment for ABPA. Of this group, Itraconazole is the most active. A separate antifungal compound, Amphotericin B has been employed in aerosolised form to treat invasive infection with Aspergillus fumigatus, and may have potential for the treatment of ABPA. Antifungal therapy for ABPA in cystic fibrosis needs to be evaluated. The review tested the hypotheses that antifungal interventions for the treatment of ABPA in cystic fibrosis: 1. improve clinical status compared to placebo or standard therapy (no placebo); 2. do not have unacceptable adverse effects. If benefit was demonstrated, the optimal type, duration and dose of antifungal therapy was assessed. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group specialist trials register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings. In addition, pharmaceutical companies were approached. Randomised controlled trials, published or unpublished, where antifungal treatments have been compared to either placebo or no treatment, or where different doses of the same treatment have been used in the treatment of ABPA in patients with cystic fibrosis. No completed randomised controlled trials were identified. No completed randomised controlled trials were identified. At present, there are no randomised controlled trials to evaluate the use of antifungal therapies for the treatment of ABPA in people with cystic fibrosis. Trials with clear outcome measures are needed to properly evaluate this potentially useful treatment for cystic fibrosis.

Sensitization toAspergillusand Allergic Bronchopulmonary Aspergillosis in a Cystic Fibrosis Population

The prevalence of sensitization to Aspergillus and of allergic bronchopulmonary aspergillosis (ABPA) was studied in 222 patients with cystic fibrosis (CF) older than 6 years of age. Sensitization to Aspergillus was evaluated by both skin prick and intradermal testing. Signs of ABPA were considered: positive prick or intradermal test or both, total serum IgE (PRIST) levels above 2 SD of the mean for age, specific IgE (RAST) ≥ 0.7 PRU/ml, serum precipitating antibodies, peripheral eosinophilia (>0.35 × 109 cells/L), and asthma. ABPA was considered probable if five criteria were achieved and possible if only four were present (always including a positive Aspergillus skin test). Of 222 patients, 124 (56%) were sensitized to Aspergillus, and they showed a worse clinical score and pulmonary function than did nonsensitized subjects. Fifty-two (23%) had ABPA without any substantial clinical difference (age, Chrispin-Norman chest x-ray score, clinical score, pulmonary function) between those with probable (n = 27) and those with possible (n = 25) ABPA. Subjects with ABPA had worse clinical score, radiologic score, and pulmonary function than those who were not sensitized to Aspergillus. These data point out the high prevalence of sensitization to Aspergillus and of ABPA in CF and their relationship with a worse clinical condition.

Variability in parameters of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis

Seventy-nine patients with cystic fibrosis (CF) were evaluated and were followed in a longitudinal, prospective fashion during a 6-year period for the development of immune parameters indicating Aspergillus fumigatus (Af) sensitization and allergic bronchopulmonary aspergillosis (ABPA). Although four patients developed frank ABPA, there was considerable variability in immune parameters in non-ABPA. Twenty-four patients became skin test positive to Af with none losing skin reactivity. Twenty-five patients developed serum precipitins to Af, whereas 12 patients lost their precipitins. Of 15 patients with an elevated total serum IgE of ≥2 SD, five demonstrated a marked decline of at least 40%. Three of 16 patients with IgE- Af became negative, whereas eight of 27 patients lost their IgG- Af. None of these patients had received corticosteroid therapy that could have accounted for the findings. Thus, patients with CF frequently lose evidence of Af sensitivity spontaneously without corticosteroid intervention. The diagnosis of ABPA in CF should not be based solely on serology and skin test results, since at any point in time, patients with CF may demonstrate variable responses to Af.