The revised clinical practice guidelines for allergic bronchopulmonary aspergillosis/mycosis: A detailed and comprehensive update

Allergic bronchopulmonary aspergillosis (ABPA) was first systematically described in 1952. It was defined as a complex allergic disease caused by the immune system's response to Aspergillus fumigatus.[1] Subsequently, the concept of allergic bronchopulmonary mycosis (ABPM) caused by other fungi has been proposed. The diagnostic standards for ABPA/ABPM have gone through the Rosenberg Pattern criteria in 1977, the International Society for Human and Animal Mycology (ISHAM) criteria in 2013, and the Japanese new diagnostic criteria in 2021.[2–4] However, with an advanced comprehension of the disease, as well as the performance of up-to-date randomized controlled trials, the existing criteria were found to have discrepancies. Consequently, a new set of guidelines is urgently needed. In light of this, the ISHAM working group has recently revised the clinical practice guidelines for the diagnosis, classification, and the treatment of ABPA (M), which were published in the European Respiratory Journal.[5] We aim to emphasize major changes in the 2024 Revised ISHAM guideline and to combine our research to present a further perspective. New Changes in the 2024 Revised ISHAM Separating criteria to diagnose ABPA and ABPM ABPA is caused by A. fumigatus, and ABPM is caused by fungi other than A. fumigatus. In 2021, Japanese researchers proposed the diagnostic criteria for ABPM, showing that patients who fulfill 6 or more out of 10 criteria would be diagnosed with ABPM.[4] However, this diagnostic criterion was complex. Furthermore, unlike the ABPA criteria, it did not clearly differentiate basic from necessary conditions. Therefore, in the 2024 Revised ISHAM, the working group recommended distinct criteria for diagnosing ABPA and ABPM for the first time, which have a similar basic framework with a few differences. In patients suspected with ABPA who have an A. fumigatus-specific immunoglobulin E (IgE) level of <0.35 kUA/L, ABPM diagnosis should be considered. In addition, the detection of fungi in sputum or bronchoalveolar lavage fluid was suggested as an option for the diagnosis of ABPM. This means that ABPM diagnosis emphasizes the detection of fungi in sputum or bronchoalveolar lavage fluid. Therefore, ABPM may focus more on bronchoscopy and sputum examination than ABPA, as well as on the treatment of pulmonary fungi. These revised criteria will better support clinical doctors in differentiating and diagnosing these two diseases. Diagnostic criteria for ABPA ABPA commonly complicates the course of asthma or cystic fibrosis. In recent years, epidemiological data have shown that the global prevalence of ABPA is high, reaching 11.3% in adults with asthma[6] and 9.9% in children with asthma.[7] In addition, chronic obstructive pulmonary disease (COPD) and bronchiectasis can also be complicated by ABPA, indicating a higher prevalence of ABPA. Consequently, the 2024 guidelines have added COPD, bronchiectasis, or compatible clinico-radiological presentation as predisposing conditions. Serum total IgE, when elevated, is a non-specific indicator that can help distinguish various diseases, particularly at high levels in ABPA. We are studying the generation of high IgE in ABPA patients to better understand ABPA pathogenesis. A reduction in the critical threshold of serum total IgE levels from 1000 IU/mL to 500 IU/mL has improved the sensitivity of ABPA diagnosis from 91% to 98%,[4] thereby mitigating the likelihood of missed diagnoses. As a result of the aforementioned revisions, the latest diagnostic criteria of ABPA include the following: (1) predisposing conditions, including asthma, cystic fibrosis, COPD, bronchiectasis, or a compatible clinico-radiological presentation; (2) essential components, including A. fumigatus-IgE ≥0.35 kUA/L or a positive type 1 skin test and total IgE ≥500 IU/mL; and (3) two out of three components, which consists of peripheral blood eosinophil count ≥500 cells/μL, positive immunoglobulin G (IgG) against A. fumigatus, and transient pulmonary infiltrates on chest radiograph. Clinical classification of ABPA The clinical classification of ABPA is essential due to various disease states. In a previous study, the clinical stages were labeled from 0 to 6. However, not all patients experience the whole disease process.[3] Furthermore, the prior classification did not successfully reflect progressive severity of this disease since stage 4 (remission) is a more stable clinical state than stage 3 (exacerbation), which is counterintuitive. To address these limitations, the numbered stages have been removed and the following five categories have been retained in the new guideline: acute ABPA, response, remission, treatment-dependent ABPA, and advanced ABPA. Asymptomatic stage and glucocorticoid-dependent asthma have been removed as they did not have clear implications for ABPA treatment. In addition, the new guideline has combined newly diagnosed ABPA and exacerbation into a single category named "acute ABPA," which aims to facilitate better clinical management of this condition. Radiological classification of ABPA Chest computed tomography scan is important in diagnosing ABPA and assessing treatment response in ABPA. The imaging findings include bronchiectasis, mucus plugs, and fungal ball. Among these findings, the presence of mucus plugs is consistently associated with eosinophilic inflammation and immunologically severe ABPA. Our retrospective study also showed that patients with high-attenuation mucus presented with higher blood eosinophil cell counts, more affected lobes and segments, poorer pulmonary function, and a higher rate of relapse than those with low-attenuation mucus.[8] The 2024 Revised ISHAM guidelines have added a new classification referred to as ABPA with mucus plugging, which includes patients with non-hyperattenuating mucus plugs. This emphasizes the role of mucus plugging in ABPA and guides clinicians to focus more on the imaging features of the disease for individualized treatment. Recently, we conducted a study to explore the specific mechanism of eosinophil extracellular traps in mucus plugs, which may propose a novel therapy for this condition. ABPA treatment The final important revision on ABPA management is about treatment. The treatment principle for ABPA involves the use of anti-inflammatory agents (corticosteroids or biological agents) to control immune responses or antifungal agents (itraconazole, voriconazole, posaconazole, or nebulized amphotericin B) to reduce fungal colonization. Based on the results of randomized controlled trials over the last decade, the guidelines propose significant changes in treatment. Those with asymptomatic ABPA are not recommended for treatment. Individuals with acute ABPA (newly diagnosed or exacerbation) were recommended for treatment with a low-to-moderate dose (0.5 mg·kg−1·day−1 for 2–4 weeks, tapered and completed over 4 months) of oral prednisolone or oral itraconazole (200 mg twice a day) for 4 months as the initial therapy, while patients with recurrent ABPA exacerbations (≥2 in the last 1–2 years) are suggested to receive a combination of prednisolone and itraconazole. Patients with ABPA, who are treatment-dependent, are advised to receive long-term therapy with itraconazole, nebulized amphotericin B, or biologics that target the type-2 immune response. Despite the excellence of this guideline, we have some minor concerns about the use of monotherapy for acute ABPA treatment. Some studies have highlighted a propensity for high recurrence rates with such treatment regimens. A retrospective cohort study revealed that patients with ABPA who are receiving glucocorticoids plus antifungal therapy had a longer time to experience the first exacerbation than those who are receiving glucocorticoid therapy alone.[9] Similarly, a randomized controlled trial comparing monotherapy to combination therapy revealed a reduced rate of exacerbation within one year in patients with extensive bronchiectasis and elevated blood eosinophil counts (>1000 cells/μL) who were treated with combination therapy.[10] Furthermore, the study revealed that 78.7% and 73.2% of participants in two groups presented with adverse events. In light of these considerations, a three-arm trial with a multicentric design should be performed to compare itraconazole and prednisolone monotherapies and their combination to determine the optimal treatment strategy for acute ABPA. Notably, we may need to define in a more detail way to figure out which populations should be treated with monotherapy based on the recommendations provided in this guideline. Concern of the 2024 Revised ISHAM Individualized therapy for ABPA is necessary as the disease can occur in patients with various lung diseases. Pathogenetically, ABPA is characterized by the persistence of A. fumigatus in the airways and an exaggerated type-2 immune response, which involves eosinophilic inflammation, elevated serum IgE levels, and airway mucoid impaction. Omalizumab, an anti-IgE monoclonal antibody, is suggested for patients with ABPA.[11] Are there other types of inflammation, other than type 2, observed in ABPA, particularly in individuals with ABPA complicating COPD?[12] Meanwhile, genetic factors, such as caspase-recruitment domain family member 9 (CARD9) gene polymorphisms, have been identified in the pathogenesis of ABPA. The CARD9S12N mutation is highly prevalent among ABPA patients and associated with its clinical indicators and prognosis.[13] Mechanically,[14]CARD9S12N mediated C-type lectin receptor-induced activation of the non-canonical transcription factor nuclear factor-kappa B (NF-κB) subunit RelB, which initiated the production of the cytokine interleukin 5 (IL-5) in alveolar macrophages for the recruitment of eosinophils to drive type-2 allergic responses. Moreover, a distinct elevation in the number of circulating Th2-skewed peripheral T-helper (Tph) cells was identified, which induces the production of IgE among patients with ABPA.[15] Hence, it can be a biomarker and a potential therapeutic target in ABPA. Screening for susceptible genes and exploring the therapeutic approaches targeting this subset of T cells could be the potential directions for ABPA research in the future. The total serum IgE level is the only main quantitative indicator used to assess the treatment response of patients with ABPA. Moreover, a systematic review and meta-analysis showed that 12 out of 21 patients with ABPA exhibited a >5% reduction in total IgE levels during omalizumab treatment for 1.8–36 months. Meanwhile, the remaining nine patients did not present with changes or exhibited an increase in IgE levels.[16] Therefore, other immune indicators should be used to monitor disease status particularly in patients using biologics. Several studies have revealed that the levels of type-2 inflammatory factors, such as IL-4, IL-5, and IL-13, significantly decreased after treatment.[17] The suitability of using type-2 inflammatory factors as indicators for monitoring the efficacy of ABPA treatment is still uncertain. Moreover, our research also showed that fractional exhaled nitric oxide (FENO), with a cutoff value of 57 ppb and an area under the curve (AUC) of 0.759, could be a potential biomarker for assessing the efficacy of glucocorticoid treatment and the prognosis of patients with ABPA. FENO exhibited a higher diagnostic accuracy as compared to serum total IgE (AUC = 0.620).[18] Nevertheless, further prospective studies should be performed to evaluate whether the combined use of multiple indicators such as type-2 inflammatory factors, FENO, and serum total IgE is better for assessing response to ABPA treatment. In conclusion, the ISHAM-ABPA working group presented an updated revised clinical practice guideline on the diagnosis, classification, and treatment of ABPA/ABPM. This detailed and comprehensive guideline will contribute to a better ABPA management and emphasizes the need for further research on exploring novel biomarkers and conducting cost-effective analyses of treatment options, which will facilitate the development of individualized treatment for this disease. Conflicts of interest None. Funding This work was supported by the National Natural Science Foundation of China (Nos. 81925001 and 82330070), the Innovation Program of Shanghai Municipal Education Commission (No. 202101070007-E00097), the Program of Shanghai Municipal Science and Technology Commission (No. 21DZ2201800), and the Program of Shanghai Shenkang Development Center (No. SHDC12023110).