1、1,重症感染患者生物标记物的临床价值,解放军总医院全军呼吸病研究所 解立新,2,什么是生物标记物(Biomarkers),生物标志物（Biomarker）这一概念首次出现于美国国家研究委员会（NRC）在1983年出版的红皮书联邦政府风险评估中 它是指可以标记系统、器官、组织、细胞及亚细胞结构或功能的改变或可能发生的改变的生化指标，具有非常广泛的用途 目前，生物标志物广泛用于疾病诊断、判断疾病分期或者用来评价新药或新疗法在目标人群中的安全性及有效性 随着高通量全基因组学、蛋白组学、代谢组学技术的迅猛发展，有望发现更多更好的新的生物标记物 目前临床常规用于感染的如：WBC，ESR，PCT，CRP，
2、IL-6等,3,理想的生物标记物,能够明确鉴别感染与非感染（Sepsis vs. SIRS） 能够动态评价疾病严重程度和预后 期望能够鉴别细菌、真菌、病毒 在鉴别肺部感染方面具有独特的优势 能够指导抗菌药物的合理应用 -有这样理想的生物标记物吗？,4,Biomarkers for pneumonia,Potential biomarkers presented the biological state of pneumonia,Clinica Chimica Acta 419 (2013) 1925,5,Biomarkers related to sepsis,C1q:complement c
3、omponent 1 q subcomponent; HMGB1:high-mobility group protein B1; NE cell: nuroendocrine cell; PAI-1: plasminogen activator inhibitor-1; PAMPs: pathogenassociated molecular patterns; PTX3:pentraxin-related protein 3; RAGE: receptor of advanced glycation end products; sRAGE:soluble receptor of advance
4、d glycation end products TLR4: Toll-like receptor 4;,Curr Opin Infect Dis 2012, 25:328336,6,Biomarkers related to sepsis,Journal of Infection(2010) 60, 409-416,7,Procalcitonin as a diagnostic marker,Diagn Microbiol Infect Dis. 2012;73(3):221-7,8,Procalcitonin as a diagnostic marker for sepsis,Lancet
5、 Infect Dis 2013;13: 42635,PCT: Sensitivity of 077 (95% CI 072081) Specificity of 079 (95% CI 074084). ROC was 085 (95% CI 081088),Procalcitonin is a helpful biomarker for early diagnosis of sepsis in critically ill patients. Nevertheless, the results of the test must be interpreted carefully in the
6、 context of medical history, physical examination, and microbiological assessment.,9,Surviving Sepsis 2012,Use of low procalcitonin levels or similar biomarkers to assist the clinician in the discontinuation of empiric antibiotics in patients who initially appeared septic, but have no subsequent evi
7、dence of infection (grade 2C). No recommendation can be given for the use of these markers to distinguish between severe infection and other acute inflammatory states,Crit Care Med 2013; 41:580637,10,Diagnosing non-infectious fever,Current Opinion in Critical Care 2007, 13:578585,11,Diagnosing non-i
8、nfectious fever,FMF: familial Mediterranean fever,Journal of Infection(2010) 60, 409-416,12,Diagnosing non-infectious fever,Overview of the Clinical Value of Sepsis Parameters,Current Medicinal Chemistry, 2008, 15, 581-587,I/T ratio:The ratio of immature: total neutrophils LBP： lipopolysaccharide bi
9、nding protein,13,Diagnosing non-infectious fever,Feng L, et al. PLoS ONE. 2012, 7:e38400 Zhang J, et al. BMC Infectious Diseases 2011, 11:53,结论：PCT、CRP和WBC在鉴别ICU患者Sepsis和SIRS方面诊断价值不大,CRP及PCT水平在severe sepsis 与sepsis或者SIRS组间差异无统计学意义,14,Diagnosing non-infectious fever,Su LX, et al. Mediators Inflamm.20
10、13:969875.,结论：PCT、CRP在鉴别ICU患者Sepsis和SIRS方面具有一定的价值,15,Diagnosing non-infectious fever,CRP：13.19 8.03 vs. 9.55 6.52 mg/dL, P 0.033,WBC：12.98 7.58 vs.11.3 5.01 109/L, P = 0.264,PCT：2.39 (8.1) vs. 2.71(25) ng/ml，P = 0.693,结论：PCT，CRP和WBC在鉴别ICU患者因菌血症导致的新的发热方面没有诊断价值,Su LX, et al. BMC Infectious Diseases 20
11、12, 12:157,16,Biomarkers for pneumonia,Biomarkers in respiratory infections for the detection of a clinically relevant bacterial infection,Expert Rev. Respir. Med. 6(2), 203214 (2012),17,Biomarkers for pneumonia,Conclusion. The evidence for the benefits of POC CRP measurement in LRTI patients in pri
12、mary care is limited, contradictory and does not support its use to guide treatment decisions yet.,Evaluating the evidence for the implementation of C-reactive protein measurement in adult patients with suspected lower respiratory tract infection in primary care: a systematic review.,Family Practice
13、 2012; 29:383393,18,Biomarkers for pneumonia,Clinical usefulness of procalcitonin (PCT) and C-reactive protein (CRP) in patients with community-acquired pneumonia,Eur J Intern Med. 2011 Oct;22(5):460-5.,19,Biomarkers for pneumonia,Clinical usefulness of procalcitonin (PCT) and C-reactive protein (CR
14、P) in patients with community-acquired pneumonia,Eur J Intern Med. 2011 Oct;22(5):460-5.,PCT however carries some additional advantages over CRP, such as the greater specificity for infections and a more narrow range of normal concentrations,20,Comparisons of clinical data of patients with VAP on da
15、y of confirmation and patients without VAP on day 7 in ICU,结论：对于VAP的诊断，WBC敏感性最高，CPIS评分特异性最强,Su LX, et al. AM J Crit Care. 2012, 21(6)：e110-e119,Biomarkers for pneumonia,21,Discriminating Pathogens,Overview of the Clinical Value of Sepsis Parameters,Current Medicinal Chemistry, 2008, 15, 581-587,I/T
16、ratio:The ratio of immature: total neutrophils LBP： lipopolysaccharide binding protein,22,Discriminating Pathogens,Combination of biomarkers for the discrimination between bacterial and viral lower respiratory tract infections,Journal of Infection (2012) 65, 490e495,23,Discriminating Pathogens,Combi
17、nation of biomarkers for the discrimination between bacterial and viral lower respiratory tract infections,Journal of Infection (2012) 65, 490e495,24,Discriminating Pathogens,Mixed viral-bacterial CAP,BMC Pulmonary Medicine 2014, 14:123,mixed (viral-bacterial),25,Discriminating Pathogens,Cut off val
18、ues for the differentiation between infectious and noninfectious causes of inflammation,Crit Care Clin 27 (2011) 253263,26,Discriminating Pathogens,Use of Serum Procalcitonin to Detect Bacterial Infection in Patients With Autoimmune Diseases,Conclusion. Procalcitonin has higher diagnostic value than
19、 CRP for the detection of bacterial sepsis in patients with autoimmune disease, and the test for procalcitonin is more specific than sensitive.,Arthritis Rheum. 2012;64(9):3034-42.,27,Predicting Severity,Overview of the Clinical Value of Sepsis Parameters,Current Medicinal Chemistry, 2008, 15, 581-5
20、87,I/T ratio:The ratio of immature: total neutrophils LBP： lipopolysaccharide binding protein,28,Predicting Severity,Chest. 2012;141(4):1063-73.,29,Predicting Severity,Chest. 2012;141(4):1063-73.,30,Predicting Severity,Feng L, et al. PLoS ONE. 2012, 7:e38400 Zhang J, et al. BMC Infectious Diseases 2
21、011, 11:53,结论：PCT和CRP在鉴别ICU Sepsis 患者严重程度方面有一定价值,31,Predicting prognosis,结论：在预测ICU Sepsis患者死亡预后方面PCT有一定价值,Wang H, et al. SHOCK. 2012; 37(3):263-267,32,Predicting Prognosis,结论：动态评价ICU Sepsis患者死亡预后方面PCT有一定价值，SOFA更佳,Feng L, et al. PLoS ONE. 2012, 7:e38400,Predicting Prognosis,Crit Care. 2014, On peer R
22、eview,The elevated PCT level was a risk factor of death,33,34,Guiding Antibiotic Therapy,Curr Opin Crit Care 2013, 19:453460,35,Guiding Antibiotic Therapy,Curr Opin Crit Care 2013, 19:453460,36,Guiding Antibiotic Therapy,Intensive Care Med (2012) 38:940949,Duration of antibiotic therapy for the firs
23、t episode of infection,p = 0.000,37,Guiding Antibiotic Therapy,Intensive Care Med (2012) 38:940949,28-days mortality,p = 0.906,38,Procalcitonin guided antibiotic therapy algorithms could help in reducing the duration of antimicrobial administration without having a negative impact on survival,An ESI
24、CM systematic review and meta-analysis of procalcitonin-guided antibiotic therapy algorithms in adult critically ill patients,Intensive Care Med (2012) 38:940949,Guiding Antibiotic Therapy,39,Surviving Sepsis 2012,Use of low procalcitonin levels or similar biomarkers to assist the clinician in the d
25、iscontinuation of empiric antibiotics in patients who initially appeared septic, but have no subsequent evidence of infection (grade 2C). No recommendation can be given for the use of these markers to distinguish between severe infection and other acute inflammatory states,Crit Care Med 2013; 41:580
26、637,40,PCT for guidance of antibiotic therapy,Curr Opin Infect Dis 2013, 26:159167,PSI：肺炎严重程度指数（Pneumonia severity index）,41,PCT for guidance of antibiotic therapy,Curr Opin Infect Dis 2013, 26:159167,PSI：肺炎严重程度指数（Pneumonia severity index）,42,PCT for guidance of antibiotic therapy,Curr Opin Infect D
27、is 2013, 26:159167,PSI：肺炎严重程度指数（Pneumonia severity index）,43,PCT for guidance of antibiotic therapy,PCT is the only biomarker that has been extensively studied so far to help decision-making in discontinuing antibiotic therapy in adults PCT be measured to help predict infection; however, available d
28、ata are insufficient to decide on initiating antibiotics based on PCT levels In adult patients suspected of community-acquired LRTI, withholding antibiotic therapy when the serum PCT level is low (0.25 ng/mL) In patients having nosocomial LRTI, data are insufficient to recommend initiating therapy b
29、ased on a single PCT level or even repeated measurements,Annals of Intensive Care 2013, 3:21,44,PCT for guidance of antibiotic therapy,For ICU patients suspected of community-acquired infection, we do not recommend using a threshold serum PCT value to help the decision to initiate antibiotic therapy
30、 Data are insufficient to recommend using PCT serum kinetics for the decision to initiate antibiotic therapy in patients suspected of ICU-acquired infection In non-immunocompromised out- or in- patients treated for RTI, antibiotics can be discontinued if the PCT level at day 3 is 80-90%, whether or
31、not microbiological documentation has been obtained,Annals of Intensive Care 2013, 3:21,45,PCT for guidance of antibiotic therapy,ICU patients who have nonbacteremic sepsis from a known site of infection, antibiotics can be stopped if the PCT level at day 3 is 80% relative to the highest level recor
32、ded, irrespective of the severity of the infectious episode In bacteremic patients, a minimal duration of therapy of 5 days is recommended,Annals of Intensive Care 2013, 3:21,46,应用全基因组学、蛋白组学、代谢组学、贯穿组学等最新生物信息学技术，筛选对重症感染患者早期诊断、严重程度和预后评价等方面具有临床价值的新的生物标记物，可能是未来寻找新的biomarker、揭示感染发生、发展机制的有效手段 我们发现血sTREM-1
33、（可溶性髓系细胞表达触发受体-1 ）、sCD163、miR-15a、miR-16、miR-574-5p、 miR-193b、 miR-483-5p、 Vitamin D-binding protein等具有临床价值的新的生物标记物,J Trauma Acute Care Surg. 2013;74(3):940-945； PLoS ONE. 2013. 8(1): e54237； Clin Chem Lab Med 2012;50(8):1423-1428； PLoS ONE. 2012 7(7): e38400； SHOCK. 2012; 37(3):263-267； BMC Infect
34、Dis. 2011;11:53,New Biomarkers,47,鉴别Sepsis和SIRS（感染与非感染）： sTREM-1具有明显的优势，诊断的准确性最好，明显优于现有的WBC、PCT、CRP、ESR、Il-6和sCD163等指标 应用多元回归分析，sTREM-1是唯一能够鉴别感染与非感染的生物标记物,PLoS ONE. 2012 7(7): e38400；Mediat Inlmamm. 2013:969875,New Biomarkers,48,鉴别Sepsis和SIRS（感染与非感染）： 我们研究发现血清miR-15a在鉴别Sepsis和SIRS方面也同样具有很好的价值,Clin C
35、hem Lab Med 2012;50(8):1423-1428,New Biomarkers,49,早期鉴别疾病严重程度 我们的研究证明sTREM-1在早期判断疾病严重程度方面明显优于目前诊断价值最高的PCT，ROC curve高达0.9,Mediat Inlmamm. 2013;969875.,BMC Infect Dis. 2011;11:53.,New Biomarkers,50,对疾病预后的评价： 我们研究发现血清miR-574-5p早期对重症患者死亡预后的评价甚至优于目前评价价值最好的SOFA（序贯脏器衰竭评分）评分，特异性高达96.15% 动态评价患者死亡预后，sCD163则更具
36、有临床价值,SHOCK. 2012; 37(3):263-267.,Mediat Inlmamm. 2013; 969875.,New Biomarkers,51,临床肺部感染评分（CPIS）在诊断呼吸机相关肺炎特异性最高 早期预警（48h）重症患者继发急性肾功能不全（AKI），尿液sTREM-1诊断价值高于现有的BUN、sCr、CCr等指标,Crit Care. 2011; 15:R250,BMC Infect Dis. 2012; 12:157,Drive M述评：That urinary soluble TREM-1 measurement is able to predict the
37、development of sepsis-associated acute kidney injury (AKI) -Crit Care 2011, 15:1013,New Biomarkers,New Biomarkers,52,miR-122,APTT,FIB,AT III,R2=0.426 P=0.008,R2=0.398 P=0.008,R2=-0.913 P0.001,miR-122,ALT,AST,R2=0.663 P0.001,R2=445 P=0.001,miR-122可以早期预警脓毒症继发凝血紊乱，可能与肝细胞损坏相关,CCLM, 2014.52(6):927-933.,N
38、ew Biomarkers,miR-122与ARDS患者预后明显相关,Crit Care. 2014; On Publication,53,New Biomarkers,四种蛋白联合预测的病死率高于SOFA评分，APACHE II评分和PCT,Clinical SCI. 2014;126(12):857-867,Solexa测序生物信息学分析差异表达miRNAS临床验证靶基因预测,New Biomarkers,6种新miRNAs联合预测脓毒症病死率价值,PLOS ONE, 2012，e38885,更多工作在进行中,55,小结,目前没有一种生物标记物能够准确鉴别感染与非感染、鉴别病原微生物、准确
39、评价病情严重程度与预后 降钙素原（PCT）是目前临床最有价值的生物标记物，对鉴别是否是细菌感染、疾病预后和抗菌药物应用可能具有一定的价值 新的生物标记物（如sTREM-1，sCD163，miR-122等）还需要临床大样本验证 要重视临床评分如CPIS、SOFA等临床价值 Biomarker是目前的临床和基础研究热点，期望大家也加入研究队伍中，在国际舞台上有更多中国人的声音,57,小结,目前没有一种生物标记物能够准确鉴别感染与非感染、鉴别病原微生物、准确评价病情严重程度与预后 降钙素原（PCT）是目前临床最有价值的生物标记物，对鉴别是否是细菌感染、疾病预后和抗菌药物应用可能具有一定的价值 新的生物标记物（如sTREM-1）还需要临床大样本验证 要重视临床评分如CPIS、SOFA等临床价值 Biomarker是目前的临床和基础研究热点，期望大家也加入研究队伍中，在国际舞台上有更多中国人的声音,58,Thank you for your attention !,
