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

IF 1.9 4区 医学 Q3 RESPIRATORY SYSTEM
Wanjun Wang, Mo Xian, Yongxia Lei, Juhua Yang, Lulu Wu
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Therefore, we aimed to identify <i>Aspergillus fumigatus</i> colonization in ABPA patients and compare their profile without colonization.</p><p>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 [<span>3</span>]. 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 &gt; 50%, and the appearance of new shallow infiltrates on radiology. All patients underwent a trans-bronchoscopy and bronchial mucosa biopsy. 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Higher bronchiectasis CT values (59.5 ± 7.1 vs. 34 ± 8, <i>p</i> &lt; 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 <i>p</i> &lt; 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). 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引用次数: 0

Abstract

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.

通过对组织样本进行元基因组下一代测序,检测出带有烟曲霉菌定植的过敏性支气管肺曲霉病(ABPA):具有较高恶化风险的过敏性支气管肺曲霉菌病(ABPA)的一个独特亚群。
致编辑:过敏性支气管肺曲霉菌病(ABPA)是一种由曲霉菌过敏引起的免疫性肺部疾病,曲霉菌在哮喘患者的气道中定植[1]。先前的研究表明,曲霉菌过敏性疾病中的真菌定植可导致更快的气道阻塞[2],但这些研究缺乏与临床相关性和结果的直接联系。我们回顾性分析了广州医科大学附属第一医院过敏与临床免疫科自2014年1月至2020年10月116例患者的临床资料,其中96例根据之前描述的标准被诊断为ABPA[3]。20名根据全球哮喘研究所(GINA)诊断为难治性哮喘的患者作为对照组。ABPA 恶化的定义是临床状况恶化、肺功能阻塞性恶化、总 IgE 水平上升 50%、放射学检查出现新的浅层浸润。所有患者都接受了经支气管镜检查和支气管粘膜活检。我们利用元基因组新一代测序技术检测样本中的烟曲霉菌基因组。我们的研究表明,除排出粘液栓外,有无组织定植的受试者的基本人口学特征相似。ABPA患者的嗜酸性粒细胞计数、血液烟曲霉-SIgE、IgG和总IgE水平以及铜绿假单胞菌定植率均高于重症哮喘患者。在有定植的受试者中,平均检测到 690 ± 530 bp 的烟曲霉菌核苷酸读数,但只有 3.9% 的受试者痰培养呈阳性。定植患者的 FEV1、FVC 和 FEV1/FVC 值明显较低。定植受试者的支气管扩张 CT 值更高(59.5 ± 7.1 vs. 34 ± 8,p < 0.05),受累肺叶和肺段的数量更多(4.8 ± 0.6 vs. 3.3 ± 1.2 和 16.2 ± 4.6 vs. 9.6 ± 4.9,p < 0.05)。76.4%的定植受试者存在 HAM。三组患者的随访时间几乎相同。ABPA 受试者接受的 ICS 剂量更大,口服皮质类固醇的时间更长。超过一半的定植受试者(54.9%)接受了伊曲康唑治疗。24/51(47.1% 对 24.4%)名有定植的受试者出现了 ABPA 病情加重,这一比例明显更高(表 1)。这 24 名受试者中有 22 人在初次诊断 12 个月后首次出现病情加重(附录 S2)。有定植的受试者的病情恶化发生率也明显高于无定植的受试者(分别为每 1000 人年 216 例与 132 例;p <0.01)。与严重哮喘患者相比,ABPA 患者有更多的皮质类固醇副作用(88.2% vs. 86.7% vs. 60%,p <0.05)(表 1)。这似乎与之前的研究不一致[4]。造成这种差异的部分原因可能是元基因组测序在确定微生物群定植方面比传统方法(如痰培养或实时 PCR)具有更高的特异性[5, 6]。此外,在中国,并非所有患者都能负担伊曲康唑的费用,因此大多数患者都接受了泼尼松作为初始治疗。长期的皮质类固醇治疗会促进烟曲霉菌在下呼吸道的定植[7]。因此,在元基因组测序确认后尽快对抗原进行有针对性的干预,并进行长期抗真菌治疗,可能有利于降低未来病情恶化的风险。然而,多达 76% 的患者接受过一个疗程的抗真菌治疗,但效果不佳。开始使用奥马珠单抗(omalizumab)或甲波珠单抗(mepolizumab)治疗可能是抗真菌药物的补充治疗方案[8]。如果有效,这些生物制剂可能会对 ABPA 病情加重的住院率产生积极影响,并减少医疗支出。总之,我们的研究结果提醒临床医生根据定植状态考虑多样化的个性化治疗。
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来源期刊
Clinical Respiratory Journal
Clinical Respiratory Journal 医学-呼吸系统
CiteScore
3.70
自引率
0.00%
发文量
104
审稿时长
>12 weeks
期刊介绍: Overview Effective with the 2016 volume, this journal will be published in an online-only format. Aims and Scope The Clinical Respiratory Journal (CRJ) provides a forum for clinical research in all areas of respiratory medicine from clinical lung disease to basic research relevant to the clinic. We publish original research, review articles, case studies, editorials and book reviews in all areas of clinical lung disease including: Asthma Allergy COPD Non-invasive ventilation Sleep related breathing disorders Interstitial lung diseases Lung cancer Clinical genetics Rhinitis Airway and lung infection Epidemiology Pediatrics CRJ provides a fast-track service for selected Phase II and Phase III trial studies. Keywords Clinical Respiratory Journal, respiratory, pulmonary, medicine, clinical, lung disease, Abstracting and Indexing Information Academic Search (EBSCO Publishing) Academic Search Alumni Edition (EBSCO Publishing) Embase (Elsevier) Health & Medical Collection (ProQuest) Health Research Premium Collection (ProQuest) HEED: Health Economic Evaluations Database (Wiley-Blackwell) Hospital Premium Collection (ProQuest) Journal Citation Reports/Science Edition (Clarivate Analytics) MEDLINE/PubMed (NLM) ProQuest Central (ProQuest) Science Citation Index Expanded (Clarivate Analytics) SCOPUS (Elsevier)
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