Efficacy of Biologics in Patients with Allergic Bronchopulmonary Aspergillosis: A Systematic Review and Meta-Analysis.

BACKGROUND: Treatment of allergic bronchopulmonary aspergillosis (ABPA) is challenging. Biological therapies have been reported as adjunctive treatments for ABPA, primarily in case series or case reports. This study aimed to analyze the efficacy of biologics for managing ABPA both qualitatively and quantitatively. METHODS: All articles on APBA published in October 2023 were searched in PubMed, Web of Science, ClinicalTrials.gov, and Embase databases. The effects of interest were the mean changes from baseline for outcomes, including exacerbation rates, oral corticosteroids usage (OCS), and total immunoglobulin E (IgE) levels. Reported outcomes were quantitatively synthesized by usual or individual patient data (IPD) meta-analyses. PROSPERO registration number: CRD42022373396. RESULTS: A total of 86 studies were included in the systematic review including 346 patients. Sixteen studies on omalizumab were pooled for the usual meta-analysis. Omalizumab therapy significantly reduced exacerbation rates (- 2.29 [95%CI - 3.32, - 1.26]), OCS dosage (- 10.91 mg [95%CI - 18.98, - 2.85]), and total IgE levels (- 273.07 IU/mL [95%CI - 379.30, - 166.84]), meanwhile improving FEV1% predicted (10.09% [95%CI 6.62, 13.55]). Thirty-one studies on dupilumab, mepolizumab, or benralizumab were pooled to perform an IPD meta-analysis, retrospectively. Both dupilumab and mepolizumab significantly reduced exacerbation rates, OCS, and total IgE levels. Benralizumab showed a similar trend, but it was not statistically significant. Tezepelumab showed weak evidence of its effects on ABPA. All five biologics led to milder clinical symptoms (e.g., cough, wheezing) with serious adverse effects that happened once in omalizumab treatment. CONCLUSION: These results indicate the clinical benefit of omalizumab, dupilumab, and mepolizumab in patients with ABPA. Further randomized, controlled studies with a larger sample size and longer follow-up are needed to confirm these findings.

Allergic bronchopulmonary aspergillosis in a lung transplant recipient treated with mepolizumab.

Allergic bronchopulmonary aspergillosis (ABPA) is a complex hypersensitivity reaction to Aspergillus spp. ABPA diagnosis may be challenging due to its non-specific presentation. Standard ABPA treatment consists of systemic corticosteroids and antifungal agents. Mepolizumab, a monoclonal antibody against interleukin-5 seems to be a promising treatment for ABPA. Data about ABPA following lung transplantation (LuTx) are scarce. LuTx recipients are at higher risk for adverse effects of ABPA treatment compared to the general population. Here we present a case of a LuTx recipient who was successfully treated with mepolizumab for ABPA following LuTx. Prolonged administration of high dose prednisone was thus avoided. To our knowledge, this is the first case describing mepolizumab administration following LuTx. Mepolizumab seems particularly attractive as a corticosteroid-sparing agent or as an alternative option to antifungal treatments, because of its excellent safety profile and low risk of drug interactions.

Fractional exhaled nitric oxide, a potential biomarker for evaluating glucocorticoids treatment and prognosis in allergic bronchopulmonary aspergillosis.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is characterized by enhanced TH2 inflammatory response. Fractional exhaled nitric oxide (FeNO) measurement has been used as a valuable tool in predicting the development and management of asthma, another typical TH2 inflammation. However, the clinical significance of FeNO in ABPA remains unclear. OBJECTIVE: To investigate the association between FeNO and the prognosis of patients with ABPA to provide a basis for the use of FeNO in evaluating the efficacy of glucocorticoids in ABPA treatment. METHODS: This study comprised 2 parts; 58 patients were enrolled in the retrospective study. Clinical indexes in patients with different prognoses were compared, and receiver operating characteristic curve analysis was used to determine the threshold value. The prospective observational study involved 61 patients who were regularly followed up at 4 to 6 weeks and 6 months since the initial treatment. Patients were grouped on the basis of baseline FeNO values; correlation analysis was performed in the clinical data. RESULTS: Different prognoses were observed between patients with high and low baseline FeNO values, with a threshold value of 57 parts per billion. The percentage of Aspergillus fumigatus-specific IgE, percentage of positive A fumigatus-specific IgG, and relapse/exacerbation rate differed significantly between the high and low FeNO groups. Patients with higher FeNO needed longer treatment duration and showed shorter interval between glucocorticoid withdrawal and the next relapse/exacerbation. CONCLUSION: Our findings indicate that the level of FeNO is associated with the prognosis of ABPA. It can serve as an independent and valuable biomarker for evaluating the effectiveness of glucocorticoid treatment.

Case Report: Allergic Bronchopulmonary Aspergillosis and Tropical Pulmonary Eosinophilia Co-Occurrence Masquerading as Refractory Allergic Bronchopulmonary Aspergillosis.

Pulmonary infiltrates with eosinophilia are a heterogeneous group of disorders that are characterized by pulmonary infiltrates on chest radiograph and elevated levels of eosinophils in the peripheral blood. Among patients with these disorders, reports of either allergic bronchopulmonary aspergillosis (ABPA) or tropical pulmonary eosinophilia (TPE) are common. However, the simultaneous occurrence of ABPA and TPE is not often reported. We present the case of a young man with a history of asthma who was diagnosed with ABPA and TPE. Initially, the patient exhibited a partial response to treatment of ABPA, but persistent symptoms and eosinophilia led to suspicion and subsequent diagnosis of TPE. With implementation of antifilarials and steroids, the patient experienced satisfactory clinical and serological improvements. This case underscores the importance of considering multiple diagnoses in patients with overlapping symptoms and highlights the need for comprehensive management strategies in complex lung diseases.

[Allergic bronchopullmonary aspergillosis (ABPA) - an Update]. / Allergische bronchopulmonale Aspergillose (ABPA) ­ ein Update.

Allergic bronchopulmonary aspergillosis (ABPA) is a regular occurrence in everyday pneumology. ABPA should be considered in patients with severe asthma, in mould allergic patients with very high serum IgE levels and in patients with cystic fibrosis. The aim should be to make the diagnosis as early as possible in the course of the disease to avoid late complications such as bronchiectasis and fibrotic lung remodelling. Symptoms are highly variable and rather non-specific, overlapping with those of the underlying primary disease. However, clearly defined diagnostic criteria exist, so that the diagnosis can be made relatively easily if one thinks of it. In therapy, systemic steroids and antifungals (mainly azoles) play the leading role. However, biologics have been gaining in importance in recent years, especially in cases of insufficient therapy response or occurrence of side effects to standard therapies, as well as an alternative in permanently steroid-dependent patients.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

BACKGROUND: One of the major challenges in managing allergic bronchopulmonary aspergillosis remains consistent and reproducible assessment of response to treatment. RESEARCH QUESTION: What are the most relevant changes in CT scan parameters over time for assessing response to treatment? STUDY DESIGN AND METHODS: In this ancillary study of a randomized clinical trial (NebuLamB), patients with asthma with available CT scan and without exacerbation during a 4-month allergic bronchopulmonary aspergillosis exacerbation treatment period (corticosteroids and itraconazole) were included. Changed CT scan parameters were assessed by systematic analyses of CT scan findings at initiation and end of treatment. CT scans were assessed by two radiologists anonymized to the clinical data. Radiologic parameters were determined by selecting those showing significant changes over time. Improvement of at least one, without worsening of the others, defined the radiologic response. Agreement between radiologic changes and clinical and immunologic responses was likewise investigated. RESULTS: Among the 139 originally randomized patients, 132 were included. We identified five CT scan parameters showing significant changes at end of treatment: mucoid impaction extent, mucoid impaction density, centrilobular micronodules, consolidation/ground-glass opacities, and bronchial wall thickening (P < .05). These changes were only weakly associated with one another, except for mucoid impaction extent and density. No agreement was observed between clinical, immunologic, and radiologic responses, assessed as an overall response, or considering each of the parameters (Cohen κ, -0.01 to 0.24). INTERPRETATION: Changes in extent and density of mucoid impaction, centrilobular micronodules, consolidation/ground-glass opacities, and thickening of the bronchial walls were found to be the most relevant CT scan parameters to assess radiologic response to treatment. A clinical, immunologic, and radiologic multidimensional approach should be adopted to assess outcomes, probably with a composite definition of response to treatment. TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT02273661; URL: www. CLINICALTRIALS: gov).

Efficacy of omalizumab in adult patients with allergic bronchopulmonary aspergillosis: a multicentre study in China.

Despite conventional glucocorticoid and antifungal therapy, acute exacerbation and hospitalization occur frequently in patients with allergic bronchopulmonary aspergillosis (ABPA). Whether omalizumab is an effective and safe treatment for adult patients with ABPA complicating asthma. Patients with ABPA complicating asthma who were treated with omalizumab from October 2019 to May 2023 were collected from five tertiary hospitals and evaluated. The frequencies of acute exacerbation and hospitalization; the number of eosinophils; the total IgE levels; and the average monthly medical dosages after 3, 6, and 12 months of omalizumab treatment were analysed, and the data before and after treatment (up to one year) were compared. The efficacy and safety of omalizumab treatment were assessed. In total, 26 patients were enrolled. The average monthly glucocorticoid dosage significantly decreased (median 0 vs. 24 mg/m) after 6 months of omalizumab treatment compared with 3 months; 73.68% of patients discontinued glucocorticoids after ≤ 12 months of treatment. Similarly, the average monthly dosage of antifungal agents was significantly decreased (median 0 vs. 3.49 g/m) after 12 months of treatment compared with 3 months. The average monthly glucocorticoid dosage (median 213.75 vs. 65.42 mg/m, P = 0.002) and the frequency of acute exacerbation (median 0.94 vs. 0.44 events, P = 0.033) were considerably reduced after omalizumab treatment. Omalizumab is effective in reducing the frequency of acute exacerbation and the necessary dosage of glucocorticoids in adult patients with ABPA complicating asthma. Patient age and BMI may affect the efficacy of treatment.

Antifungal Resistance in Pulmonary Aspergillosis.

Aspergilli may cause various pulmonary diseases in humans, including allergic bronchopulmonary aspergillosis (ABPA), chronic pulmonary aspergillosis (CPA), and acute invasive pulmonary aspergillosis (IPA). In addition, chronic colonization may occur in cystic fibrosis (CF). Aspergillus fumigatus represents the main pathogen, which may employ different morphotypes, for example, conidia, hyphal growth, and asexual sporulation, in the various Aspergillus diseases. These morphotypes determine the ease by which A. fumigatus can adapt to stress by antifungal drug exposure, usually resulting in one or more resistance mutations. Key factors that enable the emergence of resistance include genetic variation and selection. The ability to create genetic variation depends on the reproduction mode, including, sexual, parasexual, and asexual, and the population size. These reproduction cycles may take place in the host and/or in the environment, usually when specific conditions are present. Environmental resistance is commonly characterized by tandem repeat (TR)-mediated mutations, while in-host resistance selection results in single-resistance mutations. Reported cases from the literature indicate that environmental resistance mutations are almost exclusively present in patients with IA indicating that the risk for in-host resistance selection is very low. In aspergilloma, single-point mutations are the dominant resistance genotype, while in other chronic Aspergillus diseases, for example, ABPA, CPA, and CF, both TR-mediated and single-resistance mutations are reported. Insights into the pathogenesis of resistance selection in various Aspergillus diseases may help to improve diagnostic and therapeutic strategies.

Overlap of Chronic Pulmonary Aspergillosis on Allergic Bronchopulmonary Aspergillosis.

An 80-year-old woman who developed allergic bronchopulmonary aspergillosis (ABPA) was admitted to our institution in 2023 for an enlarged pulmonary mass lesion. She had developed ABPA in 2017, and corticosteroid therapy had improved the mucoid impaction of the bronchi. Because part of the lesion remained, increased doses of corticosteroid, antifungals, and biologics were administered, but the pulmonary lesion enlarged in 2022. Bronchoscopy showed necrotic tissue in the bronchial lumen, and bronchial washing fluid showed neutrophilic inflammation and fungal hyphae. We subsequently diagnosed her as having chronic pulmonary aspergillosis overlapping ABPA, and voriconazole was started that resulted in shrinkage of the nodules.

Clinical Manifestation and Treatment of Allergic Bronchopulmonary Aspergillosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a complex hypersensitivity reaction to airway colonization by Aspergillus fumigatus in patients with asthma and cystic fibrosis. The pathophysiology of ABPA involves a complex interplay between the fungus and the host immune response, which causes persistent inflammation and tissue damage. Patients present with chronic cough, wheezing, and dyspnea due to uncontrolled asthma. Characteristic symptoms include the expectoration of brownish mucus plugs. Radiographic findings often reveal fleeting pulmonary infiltrates, bronchiectasis, and mucus impaction. However, the definitive diagnosis of ABPA requires a combination of clinical, radiological, and immunological findings. The management of ABPA aims to reduce symptoms, prevent disease progression, and minimize the future risk of exacerbations. The treatment approach involves systemic glucocorticoids or antifungal agents to suppress the inflammatory response or fungal growth and prevent exacerbations. Biological agents may be used in patients with severe disease or glucocorticoid dependence. This review provides an overview of the clinical manifestations and current treatment options for ABPA.

Iatrogenic Cushing's syndrome in a case of allergic bronchopulmonary aspergillosis treated with oral itraconazole and inhaled budesonide.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to Aspergillus fumigatus that occurs in patients with asthma or cystic fibrosis. Here, we report a case of a young female with bronchial asthma who presented to our hospital with worsening breathlessness on exertion. She was diagnosed to have ABPA and was initiated on oral itraconazole while continuing inhaled long acting beta-2 adrenergic agonist and medium dose inhaled corticosteroid (ICS) for her asthma. Three months after initiation of therapy, the patient had significant improvement in breathlessness. However, she had weight gain, facial puffiness, increased facial hair and development of striae on her inner thighs, calf and lower abdomen. Her serum cortisol levels were found to be suppressed and hence a diagnosis of iatrogenic Cushing's syndrome was made. Our case describes the potentially serious interaction between ICS and oral itraconazole, a treatment very commonly prescribed in patients with ABPA.

Effectiveness and safety of omalizumab in patients with allergic bronchopulmonary aspergillosis with or without allergic rhinitis: a retrospective chart review.

BACKGROUND: Omalizumab is a valuable alternative treatment for allergic bronchopulmonary aspergillosis (ABPA). The effectiveness and safety of this medication have not been confirmed. The main purpose of this study was to evaluate the effectiveness and safety of omalizumab for ABPA. METHODS: This study involved a retrospective chart review. The main indicators used were asthma control test (ACT) scores, lung function parameters, doses of corticosteroids, acute exacerbation, hospitalization rates, total serum immunoglobulin E (IgE) levels, and blood eosinophil counts. Related adverse events were also reviewed to evaluate the safety of omalizumab. RESULTS: Fourteen patients with ABPA were included, of whom 10 (71%) concurrently had allergic rhinitis (AR). There were improvements in the mean percentages of the forced vital capacity, percentages of the forced expiratory volume in 1 s, and ACT score after omalizumab administration (p < 0.05, p < 0.01, and p < 0.01, respectively). After the initiation of omalizumab administration, the median corticosteroid dose, acute exacerbation rate, hospitalization rate, and mean blood eosinophil count decreased when compared with the baseline values (p < 0.05, p < 0.05, p < 0.01, and p < 0.05, respectively). A reduction in the total serum IgE level was observed in patients with ABPA without AR compared with that in patients with AR (p < 0.05). One patient reported a concurrent skin rash, which spontaneously resolved without medication. CONCLUSION: It is safe and effective to prescribe omalizumab to patients with ABPA, irrespective of whether they have AR. Dose adjustment of omalizumab is safe after disease control. The total serum IgE level might be a predictor of the effectiveness of omalizumab in patients without AR.

Simultaneous diagnosis of allergic bronchopulmonary aspergillosis and Mycobacterium avium complex lung disease.

Allergic bronchopulmonary aspergillosis (ABPA) and Mycobacterium avium complex lung disease (MAC-LD) often coexist because bronchiectasis, caused by ABPA or MAC, might be an important predisposing factor for both conditions. Here, we describe a man with asthma symptoms who had centrilobular small nodules and mucoid impaction on chest CT. We diagnosed the patient with simultaneous ABPA and MAC-LD on the basis of bronchoscopy findings. Itraconazole monotherapy led to substantial clinical improvement, avoiding the adverse effects of systemic corticosteroids. Sputum culture conversion of MAC was achieved after switching from itraconazole monotherapy to combination therapy comprising clarithromycin, rifampicin and ethambutol. ABPA recurred but was controlled by reinitiation of itraconazole. Overall, corticosteroid management was avoided for 38 months. Itraconazole monotherapy may be selected as initial treatment for ABPA with chronic infection, including MAC.

Relationship between Aspergillus and asthma.

Fungal sensitization is highly prevalent in severe asthma. The relationship between fungus and asthma, especially Aspergillus fumigatus, has been the subject of extensive research. The ubiquitous presence of A. fumigatus, its thermotolerant nature, the respirable size of its conidia, and its ability to produce potent allergens are pivotal in worsening asthma control. Due to the diverse clinical manifestations of fungal asthma and the lack of specific biomarkers, its diagnosis remains intricate. Diagnosing fungal asthma requires carefully assessing the patient's clinical history, immunological tests, and imaging. Depending on the severity, patients with fungal asthma require personalized treatment plans, including inhaled corticosteroids and bronchodilators, and antifungal therapy. This review provides a comprehensive overview of the association between Aspergillus and asthma by reviewing the relevant literature and highlighting key findings. We discuss the diagnosis of various entities included in fungal asthma. We also debate whether newer definitions, including allergic fungal airway disease, offer any additional advantages over the existing ones. Finally, we provide the current treatment options for the individual entities, including A. fumigatus-associated asthma, severe asthma with fungal sensitization, and allergic bronchopulmonary mycoses.

Evidence-Based Guidelines for the Management of Allergic Bronchopulmonary Aspergillosis (ABPA) in Children and Adolescents with Asthma.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) frequently complicates asthma. There is urgent need to develop evidence-based guidelines for the management of ABPA in children. The Evidence Based Guideline Development Group (EBGDG) of the Indian Academy of Pediatrics (IAP) National Respiratory Chapter (NRC) addressed this need. METHODS: The EBGDG shortlisted clinical questions relevant to the management of ABPA in asthma. For each question, the EBGDG undertook a systematic, step-wise evidence search for existing guidelines, followed by systematic reviews, followed by primary research studies. The evidence was collated, critically appraised, and synthesized. The EBGDG worked through the Evidence to Decision (EtD) framework, to formulate recommendations, using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: Seven clinical questions were prioritized, and the following recommendations formulated. (1) Children with poorly controlled asthma should be investigated for ABPA (conditional recommendation, moderate certainty of evidence). (2) Low dose steroid therapy regimen (0.5 mg/kg/d for the first 2 wk, followed by a progressive tapering) is preferable to higher dose regimens (conditional recommendation, very low certainty of evidence). (3) Oral steroid regimens longer than 16 wk (including tapering), should not be used (conditional recommendation, very low certainty of evidence). (4) Antifungals may or may not be added to steroid therapy as the evidence was neither in favour nor against (conditional recommendation, low certainty of evidence). (5) For clinicians using antifungal agents, the EBGDG recommends against using voriconazole instead of itraconazole (conditional recommendation, very low certainty of evidence). (6) No evidence-based recommendation could be framed for using pulse steroid therapy in preference to conventional steroid therapy. (7) Immunotherapy with biologicals including omalizumab or dupilumab is not recommended (conditional recommendation, very low certainty of evidence). CONCLUSIONS: This evidence-based guideline can be used by healthcare providers in diverse clinical settings.