囊性纤维化合并变应性支气管肺曲菌病的临床分析及文献整合研究

doi:10.3969/j.issn.1674-8115.2025.08.015

摘要/Abstract

摘要：

目的·探讨囊性纤维化（cystic fibrosis，CF）合并变应性支气管肺曲菌病（allergic bronchopulmonary aspergillosis，ABPA）患者的诊断及治疗方法。方法·回顾性分析上海交通大学医学院附属上海市儿童医院呼吸科于2023年7月—2024年8月收治的5例CF合并ABPA患者的临床资料。在PubMed、Web of Science、Cochrane Library，以及中国知网等数据库中检索近10年有关这2种疾病合并的研究文献，对患者的临床表现、诊疗过程及当前相关流行病学研究进行总结与分析。结果·CF合并ABPA患者常见症状有咳嗽及咳痰加重、喘息、发热、呼吸困难等。全外显子检测提示患者囊性纤维化跨膜传导调节因子（cystic fibrosis transmembrane conductance regulator，CFTR）基因突变，汗液氯离子浓度升高。血清总免疫球蛋白E（immunoglobulin E，IgE）及烟曲霉（Aspergillus fumigatus）特异性IgE水平上升，胸部电子计算机断层扫描（computed tomography，CT）显示支气管扩张及黏液栓堵塞。CF合并ABPA极易漏诊或被误诊为哮喘。在我国，患者常先被诊断为ABPA，而白种人患者多为先诊断CF。2种疾病合并时，起始治疗通常为长期口服伏立康唑（voriconazole）等抗真菌药物联合泼尼松等糖皮质激素。若患者出现反复复发或严重副作用，则需选择合适的抗真菌药物，或尝试使用奥马珠单抗治疗。患者常合并铜绿假单胞菌感染，因此常需同时静脉滴注头孢哌酮舒巴坦等抗生素。目前，该类疾病相关流行病学研究热点涵盖临床特征、治疗方案、新诊断方法等方面。结论·ABPA与CF存在部分症状重叠，CF合并ABPA的诊断需在 CF诊断方式（如基因检测、汗液氯离子浓度检测）的基础上，结合胸部CT影像及血清学检测来诊断ABPA。2种疾病合并常导致漏诊、误诊或延迟诊断，加重患者疾病负担。目前，该类疾病相关流行病学研究主要集中在临床特征等队列研究，针对此类患者的临床药物试验较为匮乏。

关键词: 囊性纤维化, 变应性支气管肺曲菌病, 烟曲霉, 儿童, 抗真菌药物

Abstract:

Objective ·To explore the diagnostic and treatment methods for patients with cystic fibrosis (CF) complicated by allergic bronchopulmonary aspergillosis (ABPA), and to enhance clinicians' understanding of these two diseases. Methods ·A retrospectively analysis was conducted on the clinical data of 5 patients with CF complicated by ABPA admitted to the Department of Respiratory Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, from July 2023 to August 2024. A literature search was performed in PubMed, Web of Science, Cochrane Library, and CNKI for studies published in the past 10 years regarding the co-existence of these diseases. Clinical manifestations, treatment courses, and current epidemiological research were summarized and analyzed. Results ·Common symptoms of patients with CF complicated by ABPA included aggravated cough and expectoration, wheezing, fever, and dyspnea. Whole-exome aequencing indicated mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and an increase in the concentration of chloride ions in sweat. The levels of total serum immunoglobulin E (IgE) and Aspergillus fumigatus-specific IgE increased, and chest computed tomography (CT) showed bronchiectasis and mucus plugging. CF complicated by ABPA is often missed or misdiagnosed for asthma. In China, ABPA is often diagnosed before CF, whereas in Caucasian populations CF is typically diagnosed first. Initial treatment usually involves long-term oral administration of antifungal drugs such as voriconazole combined with glucocorticoids such as prednisone. For patients with frequent relapses or severe side effects, alternative antifungal agents or omalizumab therapy may be considered. Co-infection with Pseudomonas aeruginosa is common, often requiring intravenous antibiotics such as cefoperazone-sulbactam. Current epidemiological research focuses mainly on clinical characteristics, treatment regimens, and novel diagnostic methods. Conclusion ·ABPA and CF have overlapping symptoms. Accurate diagnosis of CF complicated by ABPA requires genetic testing, sweat chloride measurement, chest CT, and serological tests. The coexistence of these diseases often leads to missed, delayed, or incorrect diagnosis, increasing patient burden. Present epidemiological studies mainly address clinical characteristics with a lack of targeted clinical drug trials for this patient population.

Key words: cystic fibrosis, allergic broncho-pulmonary aspergillosis, Aspergillus fumigatus, child, antifungal agents

中图分类号:

R725.6

何晨, 颜斯蕾, 周维涛, 凌勇, 于宁宁, 蒋鲲, 钱莉玲. 囊性纤维化合并变应性支气管肺曲菌病的临床分析及文献整合研究[J]. 上海交通大学学报（医学版）, 2025, 45(8): 1066-1073.

HE Chen, YAN Silei, ZHOU Weitao, LING yong, YU Ningning, JIANG Kun, QIAN Liling. Clinical analysis and literature integration study of cystic fibrosis complicated by allergic bronchopulmonary aspergillosis[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(8): 1066-1073.

图/表 2

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Patient	Gender	Age/year	Source (nationality)	Clinical presentation	Total IgE/ IU·L^-1	Specific IgE to A. fumigatus/kUA·L^-1	Bronchiectasis	Mucoid plug	CFTR variant	Pathogen	Treatment	Outcome
1^[8]	Male	7	Beijing Children's Hospital, Capital Medical University (China)	Cough, fever	>3 000	+	+	+	+	A. fumigatus	Methylprednisolone,itraconazole,ampicillin-sulbactam,azithromycin,cefamandole	Clinical improvement
2^[8]	Male	8	Beijing Children's Hospital, Capital Medical University (China)	Cough, wheezing	>5 000	+	+	+	+	A. fumigatus	Methylprednisolone,itraconazole	Clinical improvement
3^[9]	Male	9	Marmara University School of Medicine (Turkey)	cough、wheezing、dyspnea	3 554	74.5	+	+	+	A. fumigatus	Methylprednisolone,itraconazole,voriconazole,posaconazole,meropenem,amikacin	Clinical improvement
4^[10]	Male	10	Branca Hospital (Italy)	Cough,wheezing,chest pain	4 096	26.2	+	+	+	A. fumigatus,Mycoplasma pneumoniae	Prednisolone,itraconazole,vancomycin,meropenem,ciprofloxacin	Clinical improvement
5^[11]	Female	10	Beijing Children's Hospital, Capital Medical University (China)	Cough,wheezing,dyspnea	1 700	36.1	+	+	c.293A>G/c.3068T>G	A. fumigatus,P. aeruginosa	Prednisone acetate,voriconazole,itraconazole,ceftazidime,cefoperazone-sulbactam	Bilateral lung transplantation
6^[12]	Male	11	Shengjing Hospital, China Medical University (China)	Cough,wheezing,dyspnea,fever	>5 000	Positive antigen skin test	+	+	A457P/ A107D	A. fumigatus,P. aeruginosa	Methylprednisolone,voriconazole,azithromycin,ceftriaxone, linezolid, imipenem	Relapsed
7^[13]	Male	11	IRCCS Policlinico San Matteo Foundation (Italy)	Cough,wheezing	1 056	14.6	+	+	F508del/ F508del	A. fumigatus,P. aeruginosa	Prednisone,itraconazole,omalizumab	Clinical improvement
8^[14]	Female	14	MS CURIE Emergency Children's Hospital (Romania)	Cough,wheezing,dyspnea,fever, chest pain	905	16.0	+	+	F508del/ A613T	A. fumigatus,P. aeruginosa,S. aureus	Methylprednisolone,levofloxacin,ceftazidime,vancomycin	Clinical improvement
9^[15]	Male	15	Beijing Children's Hospital, Capital Medical University (China)	Cough,hemoptysis	1 720	44.8	+	+	c.2909G>A/c.3310G>T	A. fumigatus,P. aeruginosa,S. aureus	Prednisone,voriconazole	Clinical improvement
10^[13]	Male	17	IRCCS Policlinico San Matteo Foundation (Italy)	Cough,wheezing	1 124	16.7	+	+	F508del/ G542X	A. fumigatus,S. aureus	Prednisone,itraconazole,omalizumab	Clinical improvement
11^[16]	Female	17	People's Hospital of Zhengzhou University (China)	Cough,hemoptysis,fever, chest pain	4 041	69.8	+	+	p.G241R/p.F1294Yfs*7	A. fumigatus,P. aeruginosa	Methylprednisolone,voriconazole,cefoperazone-sulbactam	Clinical improvement
12^[17]	Male	23	IRCCS Giannina Gaslini Institute Cystic Fibrosis Center (Italy)	Cough,hemoptysis	3 186	>100	+	+	F508del/ A613T	A. fumigatus,S. aureus	Prednisone,voriconazole,itraconazole,amphotericin B	Recurrent relapses with steroid-related side effects; Clinical improved after switching to amphotericin B
13^[13]	Male	28	IRCCS Policlinico San Matteo Foundation (Italy)	Cough, wheezing	1 105	15.7	+	+	F508del/N1303K	A. fumigatus,P. aeruginosa,S. aureus	Prednisone,itraconazole,omalizumab	Clinical improvement

Patient	Gender	Age/year	Source (nationality)	Clinical presentation	Total IgE/ IU·L^-1	Specific IgE to A. fumigatus/kUA·L^-1	Bronchiectasis	Mucoid plug	CFTR variant	Pathogen	Treatment	Outcome
1^[8]	Male	7	Beijing Children's Hospital, Capital Medical University (China)	Cough, fever	>3 000	+	+	+	+	A. fumigatus	Methylprednisolone,itraconazole,ampicillin-sulbactam,azithromycin,cefamandole	Clinical improvement
2^[8]	Male	8	Beijing Children's Hospital, Capital Medical University (China)	Cough, wheezing	>5 000	+	+	+	+	A. fumigatus	Methylprednisolone,itraconazole	Clinical improvement
3^[9]	Male	9	Marmara University School of Medicine (Turkey)	cough、wheezing、dyspnea	3 554	74.5	+	+	+	A. fumigatus	Methylprednisolone,itraconazole,voriconazole,posaconazole,meropenem,amikacin	Clinical improvement
4^[10]	Male	10	Branca Hospital (Italy)	Cough,wheezing,chest pain	4 096	26.2	+	+	+	A. fumigatus,Mycoplasma pneumoniae	Prednisolone,itraconazole,vancomycin,meropenem,ciprofloxacin	Clinical improvement
5^[11]	Female	10	Beijing Children's Hospital, Capital Medical University (China)	Cough,wheezing,dyspnea	1 700	36.1	+	+	c.293A>G/c.3068T>G	A. fumigatus,P. aeruginosa	Prednisone acetate,voriconazole,itraconazole,ceftazidime,cefoperazone-sulbactam	Bilateral lung transplantation
6^[12]	Male	11	Shengjing Hospital, China Medical University (China)	Cough,wheezing,dyspnea,fever	>5 000	Positive antigen skin test	+	+	A457P/ A107D	A. fumigatus,P. aeruginosa	Methylprednisolone,voriconazole,azithromycin,ceftriaxone, linezolid, imipenem	Relapsed
7^[13]	Male	11	IRCCS Policlinico San Matteo Foundation (Italy)	Cough,wheezing	1 056	14.6	+	+	F508del/ F508del	A. fumigatus,P. aeruginosa	Prednisone,itraconazole,omalizumab	Clinical improvement
8^[14]	Female	14	MS CURIE Emergency Children's Hospital (Romania)	Cough,wheezing,dyspnea,fever, chest pain	905	16.0	+	+	F508del/ A613T	A. fumigatus,P. aeruginosa,S. aureus	Methylprednisolone,levofloxacin,ceftazidime,vancomycin	Clinical improvement
9^[15]	Male	15	Beijing Children's Hospital, Capital Medical University (China)	Cough,hemoptysis	1 720	44.8	+	+	c.2909G>A/c.3310G>T	A. fumigatus,P. aeruginosa,S. aureus	Prednisone,voriconazole	Clinical improvement
10^[13]	Male	17	IRCCS Policlinico San Matteo Foundation (Italy)	Cough,wheezing	1 124	16.7	+	+	F508del/ G542X	A. fumigatus,S. aureus	Prednisone,itraconazole,omalizumab	Clinical improvement
11^[16]	Female	17	People's Hospital of Zhengzhou University (China)	Cough,hemoptysis,fever, chest pain	4 041	69.8	+	+	p.G241R/p.F1294Yfs*7	A. fumigatus,P. aeruginosa	Methylprednisolone,voriconazole,cefoperazone-sulbactam	Clinical improvement
12^[17]	Male	23	IRCCS Giannina Gaslini Institute Cystic Fibrosis Center (Italy)	Cough,hemoptysis	3 186	>100	+	+	F508del/ A613T	A. fumigatus,S. aureus	Prednisone,voriconazole,itraconazole,amphotericin B	Recurrent relapses with steroid-related side effects; Clinical improved after switching to amphotericin B
13^[13]	Male	28	IRCCS Policlinico San Matteo Foundation (Italy)	Cough, wheezing	1 105	15.7	+	+	F508del/N1303K	A. fumigatus,P. aeruginosa,S. aureus	Prednisone,itraconazole,omalizumab	Clinical improvement