曲霉菌病

对于高风险患者，当怀疑其有患侵袭性曲霉菌病的可能时，应给予患者以经验性治疗：例如：无明显局部感染病灶且有对广谱抗生素治疗无反应的中性粒细胞减少的发热患者。发热症状可由非真菌性病因导致。然而，由于确定诊断具有一定的困难，因此常采用抗真菌药物进行治疗。在此情况下，可使用两性霉素 B 脂质体或棘白霉素进行治疗。[85]Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med. 2002;346:225-234.http://www.ncbi.nlm.nih.gov/pubmed/11807146?tool=bestpractice.com证据 null经验性治疗：有高质量证据证明，两性霉素 B 脂质制剂或棘白霉素在对高风险患者的治疗中显示较好的疗效：例如：无局部感染且具有对广谱抗生素无反应的发热症状的中性粒细胞减少的患者。[85]Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med. 2002;346:225-234.http://www.ncbi.nlm.nih.gov/pubmed/11807146?tool=bestpractice.com

不应使用伏立康唑进行经验性治疗（临床表现提示有感染但无进一步影像学、血清学检查确认）。

对于确诊/拟诊侵袭性曲霉菌病患者，选择伏立康唑或艾沙康唑作为治疗药物。

艾沙康唑是一种有抗曲霉菌属和毛霉菌活性的广谱抗真菌药物，适用于治疗成人侵袭性曲霉菌病。[94]Maertens JA, Raad II, Marr KA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet. 2016;387:760-769.http://www.ncbi.nlm.nih.gov/pubmed/26684607?tool=bestpractice.com

CT 扫描提示疾病和/或阳性生物标志物（例如：血清半乳甘露聚糖）的高风险患者也可进行先发治疗。侵入性检查不一定会有阳性结果或可能有操作困难，因此根据推定的诊断可能采用这些治疗方法。[99]Maertens J, Theunissen K, Verhoef G, et al. Galactomannan and computed tomography-based preemptive antifungal therapy in neutropenic patients at high risk for invasive fungal infection: a prospective feasibility study. Clin Infect Dis. 2005;41:1242-1250.http://cid.oxfordjournals.org/content/41/9/1242.longhttp://www.ncbi.nlm.nih.gov/pubmed/16206097?tool=bestpractice.com证据 null先发治疗：有中等质量的证据证明，对于 CT 扫描提示有疾病和/或阳性生物标志物（例如：血清半乳甘露聚糖 [GM]）且患侵袭性真菌感染高风险的患者，采用抗真菌药物进行预防治疗较为有效。[99]Maertens J, Theunissen K, Verhoef G, et al. Galactomannan and computed tomography-based preemptive antifungal therapy in neutropenic patients at high risk for invasive fungal infection: a prospective feasibility study. Clin Infect Dis. 2005;41:1242-1250.http://cid.oxfordjournals.org/content/41/9/1242.longhttp://www.ncbi.nlm.nih.gov/pubmed/16206097?tool=bestpractice.com

可在几日内将给药方法由静脉使用转换为口服途径。

在进行治疗后 5 至 7 天可出现临床改善；影像学表现在出现改善之前可出现恶化。

这些药物的替代性药物为两性霉素 B 脂质制剂，使用两性霉素 B 脂质体复合物或者脂质体两性霉素 B。[90]Chandrasekar PH, Ito JI. Amphotericin B lipid complex in the management of invasive aspergillosis in immunocompromised patients. Clin Infect Dis. 2005;40:S392-S400.http://cid.oxfordjournals.org/content/40/Supplement_6/S392.longhttp://www.ncbi.nlm.nih.gov/pubmed/15809925?tool=bestpractice.com[91]Walsh TJ, Hiemenz JW, Seibel NL, et al. Amphotericin B lipid complex for invasive fungal infections: analysis of safety and efficacy in 556 cases. Clin Infect Dis. 1998;26:1383-1396.http://www.ncbi.nlm.nih.gov/pubmed/9636868?tool=bestpractice.com[92]Cornely OA, Maertens J, Bresnik M, et al.; AmBiLoad Trial Study Group. Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-load regimen with standard dosing (AmBiLoad trial). Clin Infect Dis. 2007;44:1289-1297.http://cid.oxfordjournals.org/content/44/10/1289.longhttp://www.ncbi.nlm.nih.gov/pubmed/17443465?tool=bestpractice.com证据 null临床改善：有中等质量证据证明，两性霉素 B 脂质体复合物或脂质体两性霉素 B，可作为伏立康唑不耐受或治疗失败的替代性药物。[90]Chandrasekar PH, Ito JI. Amphotericin B lipid complex in the management of invasive aspergillosis in immunocompromised patients. Clin Infect Dis. 2005;40:S392-S400.http://cid.oxfordjournals.org/content/40/Supplement_6/S392.longhttp://www.ncbi.nlm.nih.gov/pubmed/15809925?tool=bestpractice.com[92]Cornely OA, Maertens J, Bresnik M, et al.; AmBiLoad Trial Study Group. Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-load regimen with standard dosing (AmBiLoad trial). Clin Infect Dis. 2007;44:1289-1297.http://cid.oxfordjournals.org/content/44/10/1289.longhttp://www.ncbi.nlm.nih.gov/pubmed/17443465?tool=bestpractice.com

棘白霉素（例如：卡泊芬净和米卡芬净）可作为单药治疗使用，也可联合两性霉素 B 脂质制剂或伏立康唑共同使用。[104]Marr KA, Schlamm HT, Herbrecht R, et al. Combination antifungal therapy for invasive aspergillosis: a randomized trial. Ann Intern Med. 2015;162:81-89.http://www.ncbi.nlm.nih.gov/pubmed/25599346?tool=bestpractice.com 可尝试对危重症患者使用联合治疗。

治疗的持续时间应取决于临床/影像学的改善和免疫状态的恢复。目前尚不明确适宜的疗程；通常治疗应持续 6 至 12 周。[2]Patterson TF, Thompson GR 3rd, Denning DW, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63:e1-e60.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967602/http://www.ncbi.nlm.nih.gov/pubmed/27365388?tool=bestpractice.com

使用集落刺激因子可减少中性粒细胞减少的持续时间。停止或减少皮质类固醇的使用有助于患者免疫功能的恢复。然而，在许多情况下，潜在的免疫缺陷可能无法被纠正（例如：有重度移植物抗宿主病的患者）。对于此类患者，其预后通常较差。对疾病进行早期诊断并早期使用抗真菌药物可改善疾病的治疗效果。[87]von Eiff M, Roos N, Schulten R, et al. Pulmonary aspergillosis: early diagnosis improves survival. Respiration. 1995;62:341-347.http://www.ncbi.nlm.nih.gov/pubmed/8552866?tool=bestpractice.com

应对有紧邻大血管或心包的侵袭性曲霉菌病病灶或来自单腔的或胸壁侵犯的严重咯血患者进行手术干预治疗。高强度化疗或干细胞移植前的单一肺曲霉病变也可选择外科手术。[100]Caillot D, Mannone L, Cuisenier B, et al. Role of early diagnosis and aggressive surgery in the management of invasive pulmonary aspergillosis in neutropenic patients. Clin Microbiol Infect. 2001;7:54-61.http://www.ncbi.nlm.nih.gov/pubmed/11525219?tool=bestpractice.com[2]Patterson TF, Thompson GR 3rd, Denning DW, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63:e1-e60.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967602/http://www.ncbi.nlm.nih.gov/pubmed/27365388?tool=bestpractice.com证据 null外科手术切除：有中等质量证据证明，外科手术切除用于以下情况时有效：在治疗邻近大血管或心包的侵袭性曲霉菌病时；来自于单一空洞的严重的大咯血或胸壁侵蚀；加强化疗之前存在单个肺病变；或干细胞移植。[100]Caillot D, Mannone L, Cuisenier B, et al. Role of early diagnosis and aggressive surgery in the management of invasive pulmonary aspergillosis in neutropenic patients. Clin Microbiol Infect. 2001;7:54-61.http://www.ncbi.nlm.nih.gov/pubmed/11525219?tool=bestpractice.com[2]Patterson TF, Thompson GR 3rd, Denning DW, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63:e1-e60.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967602/http://www.ncbi.nlm.nih.gov/pubmed/27365388?tool=bestpractice.com

对于有重度咯血症状的患者，需对其进行静脉补液和输血进行稳定。

目前尚无充足的证据来证明曲霉球对抗真菌药物治疗有效。

对于有重度咯血症状的患者，可行支气管动脉栓塞术作为临时治疗措施改善患者病情。然而，大量侧支循环的出现使得该技术具有次优性。[101]Uflacker R, Kaemmerer A, Picon PD, et al. Bronchial artery embolization in the management of hemoptysis: technical aspects and long-term results. Radiology. 1985;157:637-644.http://www.ncbi.nlm.nih.gov/pubmed/4059552?tool=bestpractice.com

对于威胁生命的咯血患者应进行外科手术治疗；但是术后发病率/死亡率仍是关键问题。重大并发症包括出血、支气管胸膜瘘、脓胸和呼吸衰竭。[102]Chen JC, Chang YL, Luh SP, et al. Surgical treatment for pulmonary aspergilloma: a 28 year experience. Thorax. 1997;52:810-813.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1758650/pdf/v052p00810.pdfhttp://www.ncbi.nlm.nih.gov/pubmed/9371213?tool=bestpractice.com[103]Regnard JF, Icard P, Nicolosi M, et al. Aspergilloma: a series of 89 surgical cases. Ann Thorac Surg. 2000;69:898-903.http://www.annalsthoracicsurgery.org/article/S0003-4975(99)01334-X/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/10750780?tool=bestpractice.com

在初级预防中，可对有移植物抗宿主病 (GVHD) 的干细胞受者和接受诱导化疗来治疗急性髓性白血病 (AML) 伴中性粒细胞减少或骨髓增生异常综合征 (MDS) 的患者使用泊沙康唑或伏立康唑进行治疗。[2]Patterson TF, Thompson GR 3rd, Denning DW, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63:e1-e60.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967602/http://www.ncbi.nlm.nih.gov/pubmed/27365388?tool=bestpractice.com

在二级预防 [即：既往患侵袭性曲霉菌病 (IA) 的患者] 中，对于需要免疫抑制的患者，再次使用抗真菌药物化疗可预防疾病的复发。[2]Patterson TF, Thompson GR 3rd, Denning DW, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63:e1-e60.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967602/http://www.ncbi.nlm.nih.gov/pubmed/27365388?tool=bestpractice.com