对血液系统疾病及其肿瘤患者的抗真菌经验和诊断驱动治疗策略
2014-06-27胡炯
胡炯
摘 要 侵袭性真菌病是血液系统肿瘤患者的常见感染并发症。随着现代化疗和造血干细胞移植术的开展,侵袭性真菌病的发病率呈上升趋势。由于真菌病在临床上缺乏特异性的症状和体征,确诊困难且伴较高的病死率,故国内、外学者先后都制定了侵袭性真菌病诊断和治疗指南,推荐对临床上具有发生侵袭性真菌病高危因素、但未达到临床诊断和确诊标准的患者可采用经验治疗和诊断驱动治疗策略。本文就此两种治疗策略在患者人群、适应证和疗效等方面的异同作一述评。
关键词 侵袭性真菌病 经验治疗 诊断驱动治疗
中图分类号:R519; R733 文献标识码:A 文章编号:1006-1533(2014)09-0011-04
Abstract Invasive fungal disease (IFD) is a major infectious complication in patients with hematological malignancies. The incidence of IFD increases with the development of modern chemotherapy and hematopoietic stem cell transplantation. Due to the nonspecific clinical manifestations, diagnosis of IFD remains difficult with high mortality when treatment is delayed. Various guidelines have been developed in past decades, in which empirical or diagnostic-driven therapy was recommended for those patients with high-risk features but not yet proven IFD. The similarities and differences between two treatment strategies in the patient population, indications and efficacy are reviewed in this paper.
Key words invasive fungal disease; empirical therapy; diagnostic-driven therapy
侵袭性真菌病(invasive fungal disease, IFD)是血液系统疾病及其肿瘤患者的常见感染并发症之一。国内及欧美流行病学研究显示,血液系统疾病患者IFD的发病率总体呈上升趋势。国内近期完成的一项前瞻性、多中心流行病学研究显示,在接受化疗的血液系统肿瘤患者中,IFD的总发生率为2.1%;在接受造血干细胞移植患者中,同胞相合移植和单倍体移植患者的IFD的累积发生率分别为3.8%和7.1%。IFD在临床上缺乏特异性症状和体征,确诊困难且往往伴有较高的病死率[1-3]。针对IFD的流行现状及临床特点,目前国内、外学者已达成广泛共识积极应对,如欧洲癌症研究和治疗组织/侵袭性真菌感染协作组和美国真菌病研究组共识组、美国抗感染学会以及欧洲白血病抗感染委员会都先后发表了侵袭性真菌感染相关诊断和治疗指南[1-5]。中国侵袭性真菌感染工作组也参照国际相关指南并结合国内的流行病学和临床治疗研究结果制定了我国的侵袭性真菌感染诊断标准与治疗原则,且先后进行了4次修订,提高了国内对血液系统疾病及其肿瘤患者侵袭性真菌感染的诊断和治疗水平[6-7]。
目前,对IFD的诊断普遍采用分层诊断体系但未达到临床诊断和确诊标准的患者,包括粒细胞缺乏性发热、伴或不伴有IFD相关感染症状和体征以及有或无实验室检查依据的患者。对这两种治疗策略,在患者人群、适应证和疗效等方面都存在一定的争议,本文就此作一述评。
1 经验治疗
经验治疗是一种对具有发生IFD高危因素、尤其是血液系统疾病及其肿瘤患者出现粒细胞缺乏性发热且使用广谱抗生素治疗无效时采用的抗真菌治疗策略。虽然在临床上尚缺乏IFD确诊或临床诊断的依据,但早期的研究表明,经验治疗、尤其是覆盖念珠菌和曲霉的治疗可降低IFD的发生率及其相关死亡率,改善患者的整体预后。经验治疗是目前临床上普遍采用的抗真菌治疗策略。“CAESAR”研究提示,我国血液系统疾病及其肿瘤患者接受的抗真菌治疗中超过85%为经验治疗。新近发表的一项法国前瞻性、观察性临床研究显示,在419例接受抗真菌治疗的血液系统疾病或接受造血干细胞移植患者
经验治疗存在的问题主要是发热症状并不是IFD的特征性临床表现,粒细胞缺乏性发热的病因包括真菌感染、细菌或病毒感染、免疫性因素和移植物抗宿主病等。例如,在造血干细胞移植相关研究中发现
2 诊断驱动治疗
诊断驱动治疗即既往所称的抢先治疗BG试验可检测除接合菌和新型隐球菌外所有真菌特有的细胞壁成分、GM试验可检测曲霉细胞壁成分,它们是诊断早期侵袭性真菌感染和侵袭性曲霉感染的工具。此外,高分辨力CT的广泛应用、尤其是其可早期发现高度预示侵袭性曲霉感染可能性的肺部晕轮征或新月体征,具有较好的临床参考价值。
早期一项对异体造血干细胞移植患者进行的随机、对照研究比较了使用脂质体两性霉素提示GM试验和CT检查有助于筛选出抗真菌治疗获益患者[12]。上述诸研究提示,诊断驱动治疗策略结合临床发热、实验室检查和CT检查等指标可为临床抗真菌治疗提供更多的依据,从而避免经验治疗的盲目性且尽早发现可疑IFD患者,具有自己独特的优势。
虽然与经验治疗相比,诊断驱动治疗具有一定的优势,但目前尚无大样本循证医学证据证实诊断驱动治疗可替代经验治疗。此外,诊断驱动治疗策略的开展也存在一定的问题,如实验室检查的普及性、试剂和试验方法(如PCR方法)的标准化、GM和BG试验阳性的判断标准以及CT检查的影像学判定标准的统一等,有待进一步的临床研究加以解决。
3 临床诊断标准更新与治疗策略的选择
最近,我国的血液系统疾病及其肿瘤患者IFD诊治指南进行了第4次修订,主要更新点为:①临床诊断标准更加严格,取消了IFD诊断的次要临床标准(非特异性临床或影像学表现,包括广谱抗生素治疗无效的持续粒细胞缺乏性发热、咳嗽、流涕和鼻塞等),使达到临床诊断和拟诊IFD患者的临床和影像学表现更具特征性、临床判断依据更充分;②新增“未确定(undefined)”IFD,后者是指不符合拟诊、临床诊断和确诊标准,但同时具有IFD高危因素以及IFD相关非特异性临床、实验室检查和影像学特征的患者[6]。这两点更新对临床实践的重要意义在于临床诊断标准的严格使未确定IFD患者群体较以往有所扩大,而未确定IFD患者虽未达到拟诊IFD标准、但并没有排除IFD诊断的可能性。有临床研究发现,未确定IFD和拟诊IFD患者抗真菌治疗后的感染相关死亡率相近,提示未确定IFD与拟诊IFD患者类似[3]。
根据上述临床诊断标准和不同治疗策略的定义,归纳了不同患者群体的临床、实验室检查和影像学特征以及相应的治疗策略。其中,经验治疗主要针对粒细胞缺乏性发热患者,诊断驱动治疗主要针对未确定和拟诊IFD患者。经验治疗和诊断驱动治疗策略在启动抗真菌治疗的时机、患者的临床表现和实验室检查依据方面具有显著的差别,适用的患者人群也有所不同,两种治疗策略在临床治疗理念上似乎并不兼容。但在实践中,经验治疗和诊断驱动治疗仍将是在临床上并存的两种重要抗真菌治疗策略:在缺乏必要的实验室检查和影像学诊断技术支持的单位,经验治疗是重要的基本临床抗真菌治疗策略;而在具备开展实验室诊断技术条件的单位,经验治疗和诊断驱动治疗可作为并行的临床抗真菌治疗策略,两种治疗策略能覆盖几乎所有不同诊断级别的IFD患者。在临床实践中,临床医生不应满足于单纯采用经验治疗,而应同时积极开展各项实验室检查。无论是对仅有粒细胞缺乏性发热患者、还是拟诊或伴有非特异性临床表现的未确定IFD患者,通过寻找IFD诊断依据、研究探索和优化更敏感和更具特异性的诊断方法(如PCR方法)对提高IFD的诊断水平具有重要意义[13-14]。鉴于诊断驱动治疗需要更多的临床和实验室检查依据,故在患者选择上更适合于IFD风险较低的患者群体,而经验治疗则更适合覆盖高危患者,两种治疗策略结合可兼顾保持疗效和减少抗真菌药物使用的目标[15]。此外,开展诊断驱动治疗的临床研究也能为今后进一步优化临床抗真菌治疗提供重要的循证医学证据。
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[13] Ruhnke M, Bohme A, Buchheidt D, et al. Diagnosis of invasive fungal infections in hematology and oncology-guidelines from the Infectious Diseases Working Party in Haematology and Oncology of the German Society for Haematology and Oncology (AGIHO) [J]. Ann Oncol, 2012, 23(4): 823-833.
[14] Lass-Florl C, Mutschlechner W, Aigner M, et al. Utility of PCR in diagnosis of invasive fungal infections: real-life data from a multicenter study [J]. J Clin Microbiol, 2013, 51(3): 863-868.
[15] Cordonnier C, Pautas C, Maury S, et al. Empirical versus preemptive antifungal therapy for high-risk, febrile, neutropenic patients: a randomized, controlled trial [J]. Clin Infect Dis, 2009, 48(8): 1042-1051.
(收稿日期:2013-09-05)
[8] Herbrecht R, Caillot D, Cordonnier C, et al. Indications and outcomes of antifungal therapy in French patients with haematological conditions or recipients of haematopoietic stem cell transplantation [J]. J Antimicrob Chemother, 2012, 67(11): 2731-2738.
[9] Bow EJ. Of yeasts and hyphae: a hematologists approach to antifungal therapy [J]. Hematology Am Soc Hematol Educ Program, 2006: 361-367.
[10] Hebart H, Klingspor L, Klingebiehl T, et al. PCR-based liposomal amphotericin B treatment following allogeneic stem cell transplantation is a safe treatment strategy: preliminary results of a prospective study [J]. Blood (ASH Annual Meeting Abstracts), 2004, 104: 192.
[11] 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 [J]. Clin Infect Dis, 2005, 41(9): 1242-1250.
[12] Ji Y, Xu LP, Liu DH, et al. Positive results of serum galactomannan assays and pulmonary computed tomography predict the higher response rate of empirical antifungal therapy in patients undergoing allogeneic hematopoietic stem cell transplantation [J]. Biol Blood Marrow Transplant, 2011, 17(5): 759-764.
[13] Ruhnke M, Bohme A, Buchheidt D, et al. Diagnosis of invasive fungal infections in hematology and oncology-guidelines from the Infectious Diseases Working Party in Haematology and Oncology of the German Society for Haematology and Oncology (AGIHO) [J]. Ann Oncol, 2012, 23(4): 823-833.
[14] Lass-Florl C, Mutschlechner W, Aigner M, et al. Utility of PCR in diagnosis of invasive fungal infections: real-life data from a multicenter study [J]. J Clin Microbiol, 2013, 51(3): 863-868.
[15] Cordonnier C, Pautas C, Maury S, et al. Empirical versus preemptive antifungal therapy for high-risk, febrile, neutropenic patients: a randomized, controlled trial [J]. Clin Infect Dis, 2009, 48(8): 1042-1051.
(收稿日期:2013-09-05)
[8] Herbrecht R, Caillot D, Cordonnier C, et al. Indications and outcomes of antifungal therapy in French patients with haematological conditions or recipients of haematopoietic stem cell transplantation [J]. J Antimicrob Chemother, 2012, 67(11): 2731-2738.
[9] Bow EJ. Of yeasts and hyphae: a hematologists approach to antifungal therapy [J]. Hematology Am Soc Hematol Educ Program, 2006: 361-367.
[10] Hebart H, Klingspor L, Klingebiehl T, et al. PCR-based liposomal amphotericin B treatment following allogeneic stem cell transplantation is a safe treatment strategy: preliminary results of a prospective study [J]. Blood (ASH Annual Meeting Abstracts), 2004, 104: 192.
[11] 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 [J]. Clin Infect Dis, 2005, 41(9): 1242-1250.
[12] Ji Y, Xu LP, Liu DH, et al. Positive results of serum galactomannan assays and pulmonary computed tomography predict the higher response rate of empirical antifungal therapy in patients undergoing allogeneic hematopoietic stem cell transplantation [J]. Biol Blood Marrow Transplant, 2011, 17(5): 759-764.
[13] Ruhnke M, Bohme A, Buchheidt D, et al. Diagnosis of invasive fungal infections in hematology and oncology-guidelines from the Infectious Diseases Working Party in Haematology and Oncology of the German Society for Haematology and Oncology (AGIHO) [J]. Ann Oncol, 2012, 23(4): 823-833.
[14] Lass-Florl C, Mutschlechner W, Aigner M, et al. Utility of PCR in diagnosis of invasive fungal infections: real-life data from a multicenter study [J]. J Clin Microbiol, 2013, 51(3): 863-868.
[15] Cordonnier C, Pautas C, Maury S, et al. Empirical versus preemptive antifungal therapy for high-risk, febrile, neutropenic patients: a randomized, controlled trial [J]. Clin Infect Dis, 2009, 48(8): 1042-1051.
(收稿日期:2013-09-05)