Allergic Bronchopulmonary Aspergillosis (ABPA) With Colonized Aspergillus fumigatus Detected by Metagenomic Next‐Generation Sequencing on Tissue Samples: A Distinct Subset of ABPA With a Higher Risk of Exacerbation

To the Editor: Allergic bronchopulmonary aspergillosis (ABPA) is an immunological pulmonary disorder caused by hypersensitivity to Aspergillus, which colonizes the airways of patients with asthma [1]. Previous studies have shown that fungal colonization in Aspergillus-allergic diseases could lead to more rapid airway obstruction [2], but they lack a direct link to clinical relevance and outcome. Therefore, we aimed to identify Aspergillus fumigatus colonization in ABPA patients and compare their profile without colonization. We retrospectively analyzed the clinical data of 116 patients at the Department of Allergy and Clinical Immunology, the First Affiliated Hospital of Guangzhou Medical University, from January 2014 to October 2020, of which 96 cases were diagnosed with ABPA according to the criteria described previously [3]. Twenty patients with the diagnosis of refractory asthma, according to the Global Institute for Asthma (GINA), were enrolled as controls. The definition of ABPA exacerbation was worsening of clinical status, obstructive deterioration of lung function, rising total IgE levels by > 50%, and the appearance of new shallow infiltrates on radiology. All patients underwent a trans-bronchoscopy and bronchial mucosa biopsy. We utilized metagenomic next-generation sequencing for the detection of the A. fumigatus genome from the samples. Details about the methods are in Appendix S1. Our study showed that the basic demographic features were similar in subjects with or without tissue colonization, except for the expectoration of mucus plugs. Eosinophil counts; blood A. fumigatus-sIgE, IgG, and total IgE levels; and the rate of Pseudomonas aeruginosa colonization were all higher in ABPA than in severe asthma. In subjects with colonization, an average of 690 ± 530 bp A. fumigatus nucleotide reads were detected, but only 3.9% had a positive sputum culture. The FEV1, FVC, and FEV1/FVC values were significantly lower in subjects with colonization. Higher bronchiectasis CT values (59.5 ± 7.1 vs. 34 ± 8, p < 0.05) and more numbers of involved lobes and segments were observed in subjects with colonization (4.8 ± 0.6 vs. 3.3 ± 1.2 and 16.2 ± 4.6 vs. 9.6 ± 4.9, both p < 0.05). The presence of HAM was seen in 76.4% of subjects with colonization. The duration of follow-up among the three groups was nearly identical. The ABPA subjects received a higher dosage of ICS and a longer period of oral corticosteroids. More than half of the subjects with colonization (54.9%) were treated with itraconazole. A significantly larger proportion, 24/51 (47.1% vs. 24.4%), of subjects with colonization experienced ABPA exacerbations (Table 1). Twenty-two of these 24 subjects experienced their first exacerbation after 12 months of the initial diagnosis (Appendix S2). The incidence rate of exacerbation was also significantly higher in subjects with colonization than those without colonization (216 vs. 132 per 1000 person-years, respectively; p < 0.01). Subjects with ABPA had more corticosteroid side effects than severe asthmatic subjects (88.2% vs. 86.7% vs. 60%, p < 0.05) (Table 1). In the study, we observed that ABPA tissue colonization by A. fumigatus was associated with a significantly worse clinical disease status and a higher risk of exacerbations. This seemed inconsistent with the previous study [4]. The discrepancy might be partly attributed to the higher specificity of metagenomic sequencing to identify microbiota colonization than conventional approaches (e.g., sputum cultures or real-time PCR) [5, 6]. Besides, not all patients could afford the cost of itraconazole in China, so most of them received prednisone as their initial treatment. Long-term corticosteroid therapy would facilitate A. fumigatus colonization in the lower airways [7]. Therefore, targeted intervention against the antigens soon after metagenomic sequencing confirmation and long-term antifungal therapy might be beneficial to reduce future exacerbation risks. However, up to 76% of patients had received one course of antifungal treatment with a poor response. Starting treatment with omalizumab or mepolizumab may have a role as a complementary therapeutic option with antifungals [8]. If effective, these biologics may positively impact hospitalization rates for ABPA exacerbations and reduce healthcare expenditures. In conclusion, our findings reminded clinicians to consider a diversity of personalized treatments according to the status of colonization. The authors have no conflict of interest to declare. The data that support the findings of this study are available from the corresponding author upon reasonable request. Appendix S1 Diagnosis of tissue colonization by A. fumigatus by means of metagenomic sequencing in ABPA. Appendix S2 Time to first ABPA exacerbation. Symbols indicate when an individual patient’s follow-up ended without ABPA exacerbation. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.