真菌性脓毒症诊治进展

安徽省立医院 重症医学科周树生,真菌性脓毒症诊治进展,The Epidemiology of Sepsis in the United States from 1979 through 2000,N Engl J Med 2003; 348:1546-1554,Long-term mortality and medical care charges in patients with severe sepsis.,Crit Care Med.2003Sep;31(9):2316-23.,Cumulative mortality rate among patients with severe sepsis,Distribution of various microorganisms and sites of infection in severe sepsis patients and the outcome according to the microorganisms and sites of infection in severe sepsis patients,Crit Care Med 2007; 35: 2538-2546,Epidemiology of severe sepsis in critically ill surgical patients in ten university hospitals in China,Characteristics of critically ill patients in ICUs in mainland China,Crit Care Med.2013Jan;41(1):84-92,Patient Outcome and Risk Factors There were 1,034 survivors: 986 (76.0%) were discharged home, and 48 (3.7%) were still in the hospital on November 30, 2009. There were 263 nonsurvivors(20.3%): 211 died in the ICU, and the other 52 died in the general wards.,Bin Du, MD; Youzhong An, MD; Yan Kang, MD et al;,2004年，11个国际医学组织的感染和脓毒症诊治方面的专家，出版了第一个改进重症脓毒症和脓毒症休克预后的指南。这个工作组联合其他工作组在2006年和2007年再次举行会议，用新的循证方法论系统来评估证据的质量和推荐力度，以更新该指南文件。这些建议的目的是用来指导临床医生治疗重症脓毒症和脓毒症性休克的病人。需要指出的是，当医生面对具体病人独特的临床指标时，这些指南中的建议不能取代临床医生的决策。,2008 201211个国际组织 15个国际组织 29个国际组织44位委员 55位委员 69位委员135篇参考文献 341篇参考文献 636篇参考文献,Chest.1992 Jun;101(6):1644-55,不足之处：标准存在的敏感性高但特异性差的问题,ACCP/SCCM 1992,Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis,New diagnostic Criteria for Sepsis:2012,Crit Care Med. 2013 Feb;41(2):580-637.,New diagnostic Criteria for Sepsis:2012,Crit Care Med. 2013 Feb;41(2):580-637.,One case:女性，85岁，住院号：2260073,主诉：患者系“反复咳嗽、咳痰三年，加重一周”入院入院时间：2013年3月26日转入时间：2013年4月05日诊疗过程：入我院干部病房后出现发热现象，同时伴有胸闷、气喘加重，痰培养示细菌（嗜麦芽窄食假单胞菌及热带念珠菌）；2012年5月行肺CT检查示“间质性肺炎”,One case:女性，85岁，住院号：2260073,2013年4月5日出现呼吸困难加重，氧饱和度下降至82%，予以积极的对症处理后，症状不能改善，故转入我科加强治疗。,转入后检查,急诊生化 K5.05mmol/L,Na141.1mmol/L,CL113.0mmol/L,Ca1.46mmol/L,CREA248.4umol/LCO2 15.8 mmol/L,AG 17.30,GLU 3.01mmol/L,ALB 16.3g/L,入科诊断：重症医院获得性肺炎(吸入性)；感染性休克？；呼吸衰竭(型)；间质性肺疾病(IPF/IIP)；3级高血压，极高危；老年性痴呆；慢性肾衰竭。诊疗计划：1、一般治疗，纠正休克；2、气管插管、机械通气（轻度镇痛镇静）；3、抗感染治疗（头孢哌酮舒巴坦 2.0 静脉滴注 q12h ;灭滴灵注射液 0.5g 静脉滴注 bid;）；4、补液、营养支持及维持水电解质平衡等对症支持处理；,血气分析+乳酸: PH 7.072,PCO2 32.6mmHg,PO2 47.2mmHg,ABE -19.1mmol/LSBE -19.0mmol/L，Lac 5.5mmol/L。 CURB-65评分:4分,同时，进一步完善病原学诊断（血培养，痰培养等）,Because invasion of the lung parenchyma by Candida species with resulting Candida pneumonia is a rare event, controversy surrounds this entity. In fact, the isolation of candidal species from respiratory secretions is most often not clinically significant.,Am J Respir Crit Care Med. 2011 Jan 1;183(1):96-128.,An official American Thoracic Society statement: Treatment of fungal infections in adult pulmonary and critical care patients.,At Memorial Hospital and New York Hospital, 30 patients.The Candida pulmonary disease appeared to be significant clinical factor in only three cases.Pulmonary disease caused by Candida species.Am J Med. 1977 Dec;63(6):914-25.,To date, few data are available on the Candida species that cause PC, It is of note that in our series, the various non-albicans species of Candida did not appear to be more likely to cause PC than is Candida albicans.,Pulmonary candidiasis in patients with cancer: an autopsy study.Clin Infect Dis. 2002 Feb 1;34(3):400-3. Epub 2001 Dec 17.,ANCA：C-ANCA（-）及P-ANCA（-）,尿常规：阴性,4月07日,4月08日,4月09日,4月10日,4月11日,4月12日,4月13日,升压药物去甲肾难以撤除，尿量逐渐减少,调整抗生素（替考拉宁）,?,转入后检查,复查床边胸片无明显进展性改变。,It is a clinical syndrome in which focal infiltrates begin with some clinical association of acute pulmonary infection(i.e.fever,expectoration,malaise,or dyspnea)and despite a minimum of 10 days of antibiotic therapy patients either do not improve or worsen clinically or radiographic opacities fail to resolve within 12 weeks of the onset of the pneumonia.,Nonresolving pneumonia（无反应性肺炎）,Curr Opin Pulm Med.2005 May;11(3):247-52.,Progressive andnonresolvingpneumonia.,Nonresolving pneumonia definitions（无反应性肺炎）,Failure to respond to antimicrobial treatment was classified as nonresponding or progressive pneumonia.Nonresponding pneumonia was defined as persisting fever38and/or clinical symptoms (malaise,cough,expectoration,dyspnea)after at least72h of antimicrobial treatment.,Antimicrobial treatment failures in patients with community-acquired pneumonia: causes and prognostic implications.Am JRespirCritCareMed.2000Jul;162(1):154-60.,444 patients, 49 patients (11%) had a repeated investigation because of antimicrobial treatment failure.,Considerations when a patient with community-acquired pneumonia is not improving,1、女性，85岁；2、“反复咳嗽、咳痰三年，加重一周伴胸闷、气喘”，长期服用抗生素及激素；3、抗生素治疗效果差（无反应）；4、CD4/CD8=1.1,总结分析病史特点：,诊断：无反应性肺炎,Results: Treatment failure occurred in 215 patients (15.1%): 134 early failure (62.3%) and81 late failure (37.7%).The causes were infectious in 86 patients (40%),non-infectious in 34 (15.8%).,Thorax.2009Nov;59(11):960-5.,Risk factors of treatment failure in community acquired pneumonia.,The main causes of early failure were progressive pneumonia (n=54), pleural empyema (n=18) lack of response (n = 13), and uncontrolled sepsis (n = 9).,Arch Intern Med.2010Mar 8;164(5):502-8.,Causes and factors associated with early failure in hospitalized patients with CAP,Results ：The following showed the prevalence rates of the causes: infection 41.7%,unknown causes 50.0%,non-infectious causes 8.3%,Diagnosis and Treatment of Nonresponding Pneumonia PatientsPJCCPVD January 2012,Vol,20 No.1（顾靖华）,进一步完善相关检查,重症医学科(ICU)患者是侵袭性真菌感染(IFI)的高发人群,并日益成为导致ICU患者死亡的重要病因之一。ICU患者最突出的特点：解剖生理屏障完整性的破坏。 重症患者侵袭性真菌感染诊断和治疗指南中华医学会重症医学分会,N Engl J Med 2003; 348:1546-1554,The Epidemiology of Sepsis in the United States from 1979 through 2000,Int J Antimicrob Agents.2008;32:S87-91,Epidemiology of candidemia in intensive care units,外周静脉,CVC,血培养检查结果（微生物室电话提前报，5月9日下午）,BDG=102 pg/ml,TheUniversityofVirginia risk factors scoring system：36,Nosocomial Bloodstream Infections in US Hospitals:Analysis of 24,179 Cases from a Prospective Nationwide Surveillance Study.,Clin Infect Dis.2004 Aug 1;39(3):309-17.,107 (39.5%) patients with isolated candidemia, 77 (28.4%) with invasive candidiasis. In 37% of the cases, candidemia occurred within the first 5 days after ICU admission.,Crit Care Med.2009May;37(5):1612-8,One hundred eighty ICUs in France,Ann Surg.2001 Apr;233(4):542-8. Pelz RK,Hendrix CW,Swoboda SM,Int J Antimicrob Agents.2009Sep;34(3):205-9,Consensus statement on the management of invasive candidiasis in ICU in the Asia-Pacific Region,CHINA SCAN team,Non albicans54.7%,C. albicans41.8%,mixed infection,otherCandida species,Diagnostic confirmation was basedsolely on at least one positiveblood culture in 290 (94.8%) casesDiagnosis was confirmed by histopathology in one patient (0.3%),Invasive candidiasis in intensive care units in China: a multicentre prospective observational study.,J Antimicrob Chemother.2013 Mar 29.1-9 Fengmei Guo1,Yi Yang1, Yan Kang,et al.,Crit Care. 2008;12(1):R5,Impact of invasive fungal infection on outcomes of severe sepsis: a mul-ticenter matched cohort study in critically ill surgical patients,Outcomes of candidemic septic shock patients compared with bacteremic septic shock patients,Crit Care Med. 2002 Aug;30(8):1808-14.,International Guidelines for Management of Severe Sepsis and Septic Shock: 2012what actually changed about fungus?,Use of the 1,3 beta-D-glucan assay (grade 2B), mannan and anti-mannan antibody assays (2C).,Change 1:Diagnosis,Intern Med.2011;50(22):2783-91,Diagnosis of invasive fungal disease using serum (13)-D-glucan: a bivariate meta-analysis.,NOTE. AUC, the area under the summary receiver operating characteristic curve; CI, confidence interval; galactomannan ,GM; IA, invasive aspergillosis; IFD, invasive fungal disease; NLR, negative likelihood ratio; PLR, positive likelihood ratio; SEN, sensitivity; SPE, specificity.,Pooled Test Performance of the Included Studies in the Meta-Analysis,Internal control detection was positive for all samples that were negative by PCR. The median time from diagnostic cultures for Candida to collection of samples for PCR and BDG was 4 days (interquartile range: 1-6 days).Abbreviations: BDG, 1,3-b-D-glucan; PCR, polymerase chain reaction.a Candidemia and deep-seated candidiasis groups included 5 patients who had both conditions.b Deep-seated candidiasis included patients with intra-abdominal infections and infections of other sites (bone and devitalized surrounding tissue, n=2; lumbar spine device, n=1; cranial abscess, n=1).c PCR was positive if positive result was obtained on plasma and/or sera.d P values are for sensitivities of the respective assays, as determined by McNemar test.,Performance of Polymerase Chain Reaction and 1,3-D-Glucan Assays,Clin Infect Dis.2012 May;54(9):1240-8.,Change 2:DiagnosisUse of low procalcitonin levels or similar biomarkers to assist the clinician in the discontinuation of empiric antibiotics in patientswho initially appeared septic, but have no subsequent evidence of infection (grade 2C).,Diagn Microbiol Infect Dis. 2012 Jul;73(3):221-7,Am J Respir Crit Care Med.2001 Aug 1;164(3):396-402,Areas under the ROC were: PCT, 0.92; IL-6, 0.75; IL-8, 0.71,clinical model with PCT, 0.94, and clinical model without PCT, 0.77,Baseline Plasma Levels of PCT, IL-6, and IL-8,Clinical experiences with a new semi-quantitative solid phase immunoassay for rapid measurement ofprocalcitonin.,Clin Chem Lab Med.2000 Oct;38(10):989-95.,Crit Care Med.2006 Jul;34(7):1996-2003.,Global diagnostic accuracy odds ratios for procalcitonin,Procalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: a systematic review and meta-analysis,Review Article,A PCTcut-off value of 2ng/mL separated Candida sepsis from bacterial sepsis with a sensitivity of 92%, a specificity of 93%,and positive and negative predictive values of 94%. The best cut-off value for CRP to separate bacterial sepsis from Candida sepsis was 100mg/L,with a sensitivity of 82% and a specificity of 53%The combination of CRP(with a cut-off value of 100mg/L) and PCT(with acut-off of 2ng/mL)did not increase sensitivity or specificity for a diagnosis of Candida sepsis.,Markers ofsepsisandorgandysfunctionattimeofbloodculture.Dataareexpressedasmedian.,Procalcitoninlevelsinsurgicalpatientsatriskof candidemia,J Infect. 2010 Jun;60(6):425-30.,Serum levels of C-reactive protein (CRP) and procalcitonin (PCT) on the studied days according to the presence of invasive fungal infection (IFI) or bacterial infection (BI).,Eur J Clin Microbiol Infect Dis.2005Apr;24(4):272-5.,Value of measuring serum procalcitonin, C-reactive protein, and mannan antigens to distinguish fungal from bacterial infections,Serum levels of C-reactive protein (CRP) and procalcitonin (PCT) on the studied days according to the presence of invasive fungal infection (IFI) or bacterial infection (BI).,Eur J Clin Microbiol Infect Dis.2005Apr;24(4):272-5.,Value of measuring serum procalcitonin, C-reactive protein, and mannan antigens to distinguish fungal from bacterial infections,成也萧何，败也萧何,Eur J Clin Invest.2008 Oct;38(10):784-5,Acute influence of aerobic physical exercise on procalcitonin,马拉松也能升高PCT,Change 2:DiagnosisUse of low procalcitonin levels or similar biomarkers to assist the clinician in the discontinuation of empiric antibiotics in patientswho initially appeared septic, but have no subsequent evidence of infection (grade 2C).,Diagn Microbiol Infect Dis. 2012 Jul;73(3):221-7,Patients randomized to the PCT group had a significantly shorter median ICU length of stay than control subjects (3 d;range, 118 d, vs. 5 d; range, 130 d, respectively; P=0.03), and a tendency to stay for a shorter period in the hospital (14 d; range, 564 d, vs. 21 d; range, 589 d;P=0.16),Am J Respir Crit Care Med.2008Mar 1;177(5):498-505,Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial.,Lancet.2010Feb 6;375(9713):463-74,Change 3: Diagnosis,Time to positivity of blood culture (TTP) can predict different Candida species instead of pathogen concentration in candidemia,J Clin Microbiol.2008Jul;46(7):2222-6,Time to blood culture positivity as a marker for catheter-related candidemia,Time to blood culture positivity as a marker for catheter-related candidemia,Accuracy of a TTP cutoff of 30 h for the diagnosis of CRC in 50 patients with indwelling CVCs,J Clin Microbiol.2008Jul;46(7):2222-6,In patients with an indwelling CVC,definite CRC group exhibited significantly shorter TTP than cultures from the non-CRC group (17.32 h versus 37.75 h; P 0.009).,Time to blood culture positivity as a marker for catheter-related candidemia,The time to detection of C. glabrata was significantly longer than for other Candida species.In conclusion, our results suggest that the TTP may be a useful tool in the evaluation of patients with candidemia who have an indwelling CVC, and in selected cases, it may support a decision to retain the catheter.,DISCUSSION,Time to positivityofblood culturesofdifferent Candida species causing fungaemia,The mean TTP for all isolates causing candidaemia was25.924.9 h.The TTP for C. glabrata was significantly longer than the TTP of the other species.In contrast, the TTP of C. tropicalis was significantly shorter than that of the other three species.,J Med Microbiol.2012May;61(Pt 5):701-4,Time to positivity of different Candida species,Eur J Clin Microbiol Infect Dis.2013 Feb 1.,Department of Clinical Laboratory, Peking University First Hospital, Beijing, China,1996-2005,The appropriateness of initial antimicrobial therapy, the clinical infection site, and relevant pathogens were retrospectively determined for 5,715 patients with septic shock in three countries.Inappropriate initial antimicrobial therapy for septic shock occurs in about 20% of patients and is associated with a fivefold reduction in survival,Chest.2009Nov;136(5):1237-48.,ESCMID* guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adul