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侵袭性曲霉菌病--ICU患者的高危因素

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侵袭性曲霉菌病(Invasive Aspergillosis , IA)是曲霉菌感染人体致病最严重的一种形式。对于ICU的危重患者,有报道的IA的发病率高达10%,1 这个数字要高于以往其他疾病人群所报道的数字0.33-6.9%。2 事实上, 在ICU患者中,IA的危险因素有很多,不仅仅限于由EORTC/MSG指南中提到的单一的宿主因素。比如,长期糖皮质激素治疗的患者,慢性阻塞性肺病(Chronic Obstructive Pulmonary Disease, COPD),肝硬化,实体器官肿瘤,HIV感染,肺移植,以及较长时间的ICU住院(大于21天)等。3

两项针对COPD患者伴发IA研究分析发现,这类患者的临床结局都非常差,死亡率均达到了100%。4,5 在2014年另一项研究中,COPD伴发IA的死亡率为66%。1 在欧洲癌症研究和治疗组织和真菌病研究组(European Organization for Research and Treatment Cancer and Mycoses Study Group, EORTC/MSG)的标准中,类固醇使用超过三周以上被认为是IA的危险因素。对于严重的和/或持续的败血性休克患者,使用低剂量的类固醇(盐皮质激素)可以改善临床结局。6 但它们也对 巨噬细胞 杀伤曲霉菌孢子和单核细胞杀伤曲霉菌菌丝的作用存在损害。7对于有肺部疾病的患者,即使使用低剂量的类固醇,其伴发IA的风险也会更高。8 对于肝硬化患者,由于其细胞吞噬作用和趋化作用受损,被认为是导致IA发病的可能因素。9

由于ICU患者伴发IA有较高的发病率和死亡率,建立可以实现早期诊断的检测方法或诊断标准就非常有意义。 血清 曲霉菌抗或半乳甘露聚糖(galactomannan, GM)是有报道的血液肿瘤患者中IA检测的可靠手段。10GM检测比较于其他方法,可以帮助临床提早8天诊断IA。11 血清GM抗原是曲霉菌细胞壁的多糖成分,在曲霉菌菌丝侵袭机体组织时释放。这个成分可通过一步夹心酶联免疫法进行检测。近年的一些研究证实,在血液肿瘤患者中,由于GM水平升高与较差的临床结局呈强相关,因此认为GM抗原检测也可作为IA临床结局的衡量工具。12,13

GM抗原检测所使用的试剂为 Bio-Rad 公司的曲霉菌抗原检测试剂盒(PlateliaTMAspergillusAg),该试剂为一步夹心酶联免疫法,利用单克隆抗体(EBA-2)对血液循环中的GM抗原。推荐首次检测时间点一般为当临床怀疑患者发生IA时,或者需要对免疫妥协患者进行常规筛查时。1另外,对于开始进行抗真菌治疗的患者,推荐进行每周两次的GM水平监测,以帮助判断临床疗效及患者预后。14

1. Suzanne Teering, AnneliesVerreth, AnneleenPeeter, et alPrognostic value of serum galactomannanin mixed ICU patients: a retrospective observational studyAnaesthesiology Intensive Therapy 2014, vol. 46, no 3, 145–154

2. Meersseman W, Vandecasteele SJ, Wilmer A et al.: Invasive aspergillosisin critically ill patients without malignancy. Am J RespirCrit CareMed 2004; 170: 621–625.

3.Dimopoulos G, Frantzeskaki F, Poulakou G et al.: Invasive aspergillosis inthe intensive care unit. Ann NY Acad sci 2012; 1272: 31–39.

4. Bulpa PA, Dive AM, Garrino MG et al.: Chronic obstructive pulmonarydisease patients with invasive pulmonary aspergillosis: bene fit s ofintensive care? Intensive Care Med 2001; 27: 59–67.

5.Rello J, Esandi ME, Mariscal D et al.: Invasive pulmonary aspergillosis inpatients with chronic obstructive pulmonary disease: report of eightcases and r evi ew. Clin Infect Dis 1998; 26: 1473–1475.

6.Annane D, Sébille V, Ch ARP entier C et al.: Effect of treatment with lowdoses of hydrocortisone and fludrocortisone on mortality in patientswith septic shock. JAMA 2002; 288: 862–871.

7.Lionakis MS, Kontoyiannis DP: Glucocorticoids and invasive fungalinfections. Lancet 2003; 362: 1828–1838.

8. Palmer LB, Greenberg HE, Schiff MJ: Corticosteroid treatment as a riskfactor for invasive aspergillosis in patients with lung disease. Thorax1991; 46: 15–20.

9. Bailey RJ, Woolf IL, Cullens H et al.: Metabolic inhibition of polymorphonuclearleucocytes in fulminant hepatic failure. Lancet 1976; 1: 1162–1163.

10 .Maertens J, Verhaegen J, Lagrou K et al.: Screening for circulating galac­tomannan as a noninvasive diagnostic tool for invasive aspergillosis in prolonged neutropenic patients and stem cell transplantation reci­pients: a prospective validation. Blood 2001; 97: 1604–1610.

11.Maertens J, Van Eldere J, Verhaegen J et al.: Use of circulating galacto-mannan screening for early diagnosis of invasive aspergillosis in allogeneic stem cell transplant recipients. J Infect Dis 2002; 186: 1297–1306.

12. Woods G, Miceli MH, Grazziutti ML et al.: Serum Aspergillusgalactoman­nan antigen values strongly correlate with outcome of invasive asper­gillosis: a study of 56 patients with haematologic cancer. Cancer 2007; 110: 830–834.

13. Koo S, Bryar JM, Baden LR et al.: Prognostic features of galactomannanantigenemia in galactomannan-positive invasive aspergillosis.J ClinMicrobiol 2010; 48: 1255–1260.

14. Lehrnbecher T, Phillips R, Alexander S, et al. Guideline for the Management of Fever andNeutropenia in Children With Cancer and/or Undergoing Hematopoietic Stem-CellTransplantation. Journal of Clinical Oncology.2012 epub ahead of print. This manuscript is thefirst pediatric fever and neutropenia guideline. It summarizes the impact of both galactomannanand beta glucan testing in children.

 

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