慢性阻塞性肺疾病伴肺曲霉病诊治和管理专家共识

Expert consensus on the diagnosis and treatment of pulmonary aspergillosis in patients with chronic obstructive pulmonary disease

在慢性阻塞性肺疾病(简称慢阻肺)人群中, 肺曲霉病的发病率不断上升, 可表现为侵袭性感染、慢性肺曲霉病、变应性支气管肺曲霉病等多种形式;随着免疫功能等个体状态的变化, 各种形式之间可互相转换甚至并存。同时, 慢阻肺伴侵袭性肺曲霉病多缺乏典型表现, 且部分患者有创检查受限, 给诊断和治疗带来了挑战。为此, 本共识基于循证证据和我国临床实践情况, 对慢阻肺伴肺曲霉病诊治中的重要问题提出推荐意见, 构建临床诊疗路径, 期待为改善疾病管理提供参考和指引。

The prevalence of pulmonary aspergillosis is increasing in patients with chronic obstructive pulmonary disease(COPD)and can manifest in different forms such as invasive pulmonary aspergillosis(IPA),chronic pulmonary aspergillosis(CPA)and allergic bronchopulmonary aspergillosis(ABPA).With the variations of individual conditions such as immune status,these forms of the disease may transform into each other or even overlap.Moreover,the atypical clinical manifestations and the limited use of invasive sampling techniques have posed a challenge to the diagnosis and treatment of invasive pulmonary aspergillosis in patients with COPD.To provide recommendations for the management of pulmonary aspergillosis in patients with COPD and to construct a clinical workflow,the consensus panel reviewed the evidence and critically appraised the existing studies.As the majority of the recommendations were supported by low levels of evidence,the evidence levels were not listed in the consensus and the strong and weak recommendations were expressed as“recommend”and“suggest”,respectively.Recommendations for COPD with IPA:The Panel recommends that high-resolution chest computed tomography(HRCT)be performed in patients suspected with IPA.If IPA cannot be excluded by CT scanning,mycological examination of sputum and bronchoalveolar lavage fluid(BALF)is recommended.Bronchoscopy and BALF Aspergillus-related examination are recommended in COPD patients with respiratory symptoms such as dyspnea despite the use of broad-spectrum antibiotics and systemic glucocorticoids and pulmonary infiltrates observed on chest CT.If the diagnosis is in doubt in patients with probable IPA,histopathological examination is recommended.In COPD patients with an acute infection of more than 10 days′duration,the Panel recommended the detection of Aspergillus-specific IgG antibodies in peripheral blood to aid in the diagnosis of IPA,especially in those who cannot obtain BALF.It is not recommended to initiate antifungal therapy based on clinical symptoms such as cough,fever,and dyspnea empirically in COPD patients.In critically ill patients(such as those admitted to ICU and those with respiratory failure)who are unresponsive to broad-spectrum antibiotic treatment and have imaging findings consistent with IPA,patients with HRCT or bronchoscopy findings consistent with airway invasive aspergillosis,patients with a history of oral or intravenous glucocorticoid use in the past 3 months,or patients with a history of airway Aspergillus infection or colonization,empirical antifungal therapy may be initiated after a comprehensive evaluation of Aspergillus infection risk,and at the same time,pathogen examination should be started as early as possible.Voriconazole,isavuconazole,and posaconazole are recommended as the first-line treatments for COPD with IPA.Echinocandins and amphotericin B may be used as alternative options.Antifungal treatment for COPD with IPA should be continued for at least 6-12 weeks.The duration of antifungal therapy should be determined based on clinical symptoms,pulmonary imaging,and microbiological test results.Significant lesion absorption and stabilization,as well as the elimination of related risk factors,are important references for discontinuation of treatment.Recommendations on COPD with CPA:Chest CT scan and dynamic observation are recommended for COPD with suspected CPA.Peripheral blood Aspergillus-specific IgG antibody testing is recommended in COPD patients with suspected CPA.For those who are difficult to diagnose by routine methods or need further differential diagnosis,pulmonary tissue histopathological examination is recommended.Oral itraconazole solution or voriconazole tablets are recommended as the first-line treatment options for COPD with CPA.Oral isavuconazole capsules or enteric-coated posaconazole tablets can be used as an alternative.Intravenous administration of echinocandins or amphotericin B(deoxycholate or lipid formulations)are suggested as a second-line treatment options in cases of triazole treatment failure,resistance,or intolerance.Antifungal treatment for COPD with CPA should be continued for at least 6 months,and for patients with CCPA for at least 9 months.In those with cavities communicating with the bronchial lumen,if systemic antifungal therapy is ineffective or cannot be tolerated due to adverse reactions,and surgery is also not feasible,the Panel suggests considering nebulized inhalation of amphotericin B and intracavitary injection of amphotericin B or azoles(voriconazole,itraconazole)to control recurrent hemoptysis.Recommendations on COPD with Aspergillus sensitization:When COPD patients present with refractory wheezing and/or rapid decline in lung function,it is recommended that an assessment for Aspergillus sensitization be performed,including Aspergillus-specific IgE,skin Aspergillus antigen test,Aspergillus-specific IgG,total IgE,blood eosinophil count,and sputum examination.The Panel recommends that antifungal therapy should not be routinely initiated in COPD patients with Aspergillus sensitization.For those who meet the diagnostic criteria for ABPA,antifungal therapy is suggested.The most commonly used medication is oral itraconazole solution,but other azoles such as voriconazole,isavuconazole and posaconazole enteric-coated tablets can also be chosen.The general course of antifungal therapy is 3-6 months.Recommendations on the use of glucocorticoids in COPD with pulmonary aspergillosis:In exacerbating COPD patients with secondary IPA or subacute invasive aspergillosis,the Panel suggests that the use of glucocorticoids should be controlled.For COPD patients with concomitant CPA who experience exacerbations with predominantly wheezing,it is suggested that short-term,low-dose glucocorticoids be considered on the basis of antifungal treatment to control symptoms.Glucocorticoid use for COPD exacerbations is suggested to be guided by peripheral blood eosinophil count.It is recommended to avoid systemic glucocorticoids and long-term or high-dose inhaled glucocorticoids(ICS)in stable COPD patients with concomitant CPA.In patients with concomitant Aspergillus sensitization and persistent wheezing despite standardized COPD treatment or patients with ABPA,the Panel recommends systemic glucocorticoids in combination with antifungal therapy and consideration of the use of ICS to reduce the dose of systemic glucocorticoids.Close monitoring for progression to IPA or subacute invasive aspergillosis is essential during treatment.