2018年臨床醫(yī)生如何看待真菌感染與定植

1、2024/3/12,內(nèi)容提要,,侵襲性曲霉感染誤診分析,念珠菌定植問題,腹腔念珠菌感染診治問題,1,2,3,,真菌概述,酵母菌屬,曲霉菌屬,深部真菌感染,念珠菌屬,隱球菌屬,,,,,,,,常見的侵襲性念珠菌感染部位,,,,定植不是感染 定植不是與感染沒有一點關(guān)系,定植≠感染,污染：外來物質(zhì)或能量的作用，導致生物體或環(huán)境產(chǎn)生不良效應的現(xiàn)象。定植：各種微生物經(jīng)常從不同環(huán)境落到人體，并能在一定部位定居和不斷生長、繁殖后代，這種現(xiàn)象通常稱

2、為“定植”。感染：是指細菌、病毒、真菌、寄生蟲等病原體侵入人體所引起的局部組織和全身性炎癥反應。,,,,,,侵襲性真菌病確診(proven)診斷標準,正常無菌部位并不包括所有與外界相通的器官，即呼吸道、泌尿生殖道、消化道等，因為上述器官是念珠菌屬常見的定植部位。念珠菌病診斷與治療：專家共識. 中國感染與化療雜志.2011；11（2）：81-95,,念珠菌屬于類酵母樣菌，有酵母相和菌絲相酵母相為芽生孢子，在無癥狀寄居及傳播中起作

3、用，不引起癥狀菌絲相為芽生孢子伸長呈假菌絲，大量繁殖，侵襲組織能力加強，出現(xiàn)臨床癥狀 需要注意的是，念珠菌中的光滑念珠菌不能產(chǎn)生假菌絲/菌絲，所以，臨床不能因為“鏡檢念珠菌處于酵母相”就排除感染,,酵母相,菌絲相,念珠菌多為假菌絲,,,念珠菌鏡檢假菌絲或菌絲,,Colonization with Candida has been identified as an important risk factor w

4、ith high predictive value for development of invasive disease (particularly with increasing numbers of colonized sites).,,念珠菌定植 侵襲性念珠菌感染,,,,,,,,,,定植菌爭議的焦點,Invasive candidiasis in the intensive care u

5、nit. Crit Care Med 2006. 34(3):857-863Eggimann P，Garbino J，Pittet D．Epidemiology of Candida species infections in critically ill non-immunosuppressed patients．Lancet Infect Dis，2003，3(11)：685-702．,,PK,,,多部位念珠菌定植是發(fā)生侵襲性念珠

6、菌感染的獨立危險因素。念珠菌定植后導致侵襲性感染的途徑可能有：破壞胃腸道黏膜屏障入血；從中心靜脈導管入血，從局部感染蔓延至全身。,,,定植與感染的關(guān)系,Lipsett PA．Surgical critical care=fungal infections in surgical patients．Crit Care Med，2006，34(9 Suppl)：S215-224．,約有50％～86％的重癥患者發(fā)生念珠菌定植，但臨床有

7、5％～30％發(fā)展成嚴重侵襲性念珠菌感染。,,Although colonization does not define infection, these data support the well-known role of Candida colonization as a key factor in the decision to start early antifungal treatment for ICU patients.,

8、A bedside scoring system (“Candida score”) for early antifungal treatment in nonneutropeniccritically ill patients with Candida Colonization. Crit Care Med 2006. 34(3):730-737.,,,,,定植與感染的死亡率,,S.S. Magill et al. Diagnost

9、ic Microbiology and Infectious Disease 55 (2006) 293– 301,進展為IC的百分比,The anatomic site of Candida colonization in 182 surgical intensive care unit (SICU) patients who participated in a randomized trial of fluconazole

10、 to prevent candidiasis.A total of 2851 surveillance fungal cultures collected from 5 anatomic sites were analyzed.Surveillance fungal cultures of particular anatomic sites may help differentiate patients at higher

11、 risk of developing IC from those at low risk.,,,P=0.02,P=0.04,P=0.01,13.2%,2.8%,8.0%,1.2%,8.4%,0.0%,定植可進展為侵襲性念珠菌病,,對于懷疑系統(tǒng)性念珠菌感染的患者，應同時進行痰(或其他氣道分泌物)、尿、胃液、糞(或直腸拭子)、口咽拭子5個部位的念珠菌定量培養(yǎng)。 口咽和直腸拭子念珠菌只要≥1 cfu，胃液、尿≥105 cfu

12、/L，痰≥107 cfu/L就認為念珠菌定植陽性。,,念珠菌定植指數(shù)(CI),Pittet D，Monod M，Suter PM，et a1．Candida colonization and subsequent infections in critically ill surgical patients．Ann Surg，1994，220(6)：751—758．,,口咽和直腸拭予念珠菌≥102 cfu，胃液、尿、痰≥108 cfu/L

13、才能判定念珠菌定植陽性，如CI≥0.5或CCI≥0.4就認為有侵襲性念珠菌感染的可能。,,校正念珠菌定植指數(shù)(CCI),Piarroux R，Grenouillet F，Balvay P，et a1．Assessment of pre-emptive treat—ment to prevent severe candidiasis in critically ill surgical patients．Crit CareMed，2004

14、，32(12)12443—2449．,,念珠菌指數(shù)(CS),將患者的危險系數(shù)相加，就得到該患者的CS。研究結(jié)果顯示，CS>2.5時診斷侵襲性念珠菌感染的敏感性為81％，特異性為74％。,,CS=0.908×腸外營養(yǎng)支持+0.997×手術(shù)+1.112×CCI+2.038×嚴重膿毒癥。,,,Lean C， Ruiz—Suntans S， Saavedra P，et a1．A bedsid

15、e scoring system (”Candida score”)for early antifungal treatment in nonneutropenic critically i11 patients with Candida colonization．Crit Care Med，2006，34(3)：730—737．,,In addition to multifocal Candida species colonizati

16、on, three other risk factors were found to be significant predictors of proven candidal infection in the logistic regression model:Use of total parenteral nutrition；Surgery on ICU admission；Clinical manifestations of

17、severe sepsis.,,Score,1,1,2,1,,A bedside scoring system (“Candida score”) for early antifungal treatment in nonneutropenic critically ill patients with Candida Colonization. Crit Care Med 2006. 34(3):730-737.,,We shall o

18、nly need the presence of sepsis and any one of the three other remaining risk factors or the presence of all of them together except sepsis in order to consider starting antifungal treatment for one particular patient

19、.,,,,,Logistic regression model,A bedside scoring system (“Candida score”) for early antifungal treatment in nonneutropenic critically ill patients with Candida Colonization. Crit Care Med 2006. 34(3):730-737.,,2008年亞太危重

20、病論壇也指出，重癥高危患者如同時具有高度念珠菌定植應予以抗念珠菌治療，同時亦應考慮局部區(qū)域的真菌流行病學資料。,要正確看待CI、CCI、CS,Hsueh PR，Graybill JR，Playford EG，et a1．Consensus statement on the management of invasive candidiasia in intensive care units in the Asia—Pacific reg

21、ion．Int J Antimicrob Agents，2009，34(3)：205—209．,使用定植指數(shù)推測侵襲性念珠菌感染診斷只是一種“可能性”診斷。對于可能發(fā)生侵襲性念珠菌感染的高?；颊邔嵤﹦討B(tài)監(jiān)測，一旦病情 變化應及時給予搶先治療，既要防止發(fā)生進一步的侵襲性念珠菌感 染，降低病死率，又要避免不必要的抗真菌藥物臨床應用，以降低患 者醫(yī)療費用和抗生素附加損害。,,Eggimann等更明確地為搶先治療下定義

22、，即對具有多個侵襲性念珠 菌感染高危因素且CCl≥0.4的膿毒癥患者早期給予抗念珠菌治療。,定植菌搶先治療的定義,同時他認為實施搶先治療可降低外科重癥患者侵襲性念珠菌感染確診 病例的發(fā)生和降低病死率。,Eggimann P，Garbino J，Pittet D．Epidemiology of Candida species infection in critically ill non-immunosuppressed pa

23、tients．Lancet Infect Dis，2003，3(11)：685—702．,,,,痰培養(yǎng)陽性的臨床意義？,如果患者存在明顯的高危因素，有肺部感染的臨床表現(xiàn)又不能用其他 病原菌感染解釋，血清真菌感染標志物（如G試驗）陽性，此時痰培 養(yǎng)念珠菌為唯一病原體且為反復培養(yǎng)陽性或為純培養(yǎng)，可以作為針對 念珠菌診斷性或經(jīng)驗性治療的依據(jù)，至少提醒臨床醫(yī)生應提高警惕， 特別是除肺外還有其他部位也分離到

24、念珠菌時。,懷疑念珠菌肺炎的患者在呼吸道標本檢測的同時應做血液真菌培養(yǎng)，如 血培養(yǎng)分離出念珠菌，且與呼吸道分泌物培養(yǎng)結(jié)果相一致，有助于念珠 菌血癥繼發(fā)肺念珠菌病或肺炎合并念珠菌血癥的診斷。,,2024/3/12,內(nèi)容提要,,侵襲性曲霉感染誤診分析,念珠菌定植問題,腹腔念珠菌感染診治問題,1,2,3,,1,3,,呂新生，腹部外科2004年第17卷第3期,,腹腔臟器的感染,腹膜腔感染,,病原體(主要是微生物)侵入宿主腹腔，且

25、造成明顯損害而引起的感染性疾病,腹腔感染,,腹腔感染定義,,,曹彬等. 侵襲性念珠菌院內(nèi)感染的流行病學調(diào)查. 中華醫(yī)學雜志 2008;88(28)1970-1973,白念珠菌（57.1％）熱帶念珠菌（19.5％）光滑念珠菌（14.3％）近平滑念珠菌（2.6％）,念珠菌腹腔感染位居第二位,,,常見的腹腔念珠菌感染,念珠菌腹膜炎,急性胰腺炎、膽囊炎合并念珠菌感染,腹腔膿腫（念珠菌感染）,,,腹腔念珠菌感染的高危因素,Immunode

26、ficiency.Prolonged exposure to antibiotics.Upper GI tract perforations (One should therefore always take into account the possibility of Candida involvement in patients experiencing tertiary peritonitis) .,1.Sott

27、o A, Lefrant JY, Fabbro-Peray P, et al. Evaluation of antimicrobial therapy management of 120 consecutive patients with secondary peritonitis. J Antimicrob Chemother 2002; 50:569–576.2.Charles PE. Multifocal Candida spe

28、cies colonization as a trigger for early antifungal therapy in critically ill patients: what about other risk factors for fungal infection? Crit Care Med 2006; 34:913–914.,,Philippe Montravers et al. Candida as a risk fa

29、ctor for mortality in peritonitis. Crit Care Med. 2006;34(3):646-52,一項多中心、回顧性對照研究，在教學及非教學醫(yī)院的17個ICU進行 其中確診院內(nèi)腹膜炎的患者中，腹水病原菌分離率以白念最多,腹水中病原菌分離率(%),白念珠菌n=39,腸桿菌科n=31,腸球菌n=19,厭氧菌n=11,大腸桿菌n=15,白念是腹腔感染的主要致病真菌,,胃腸道是念珠菌寄居

30、的主要場所 大量的念珠菌定植 致病 在空腔臟器穿孔或腸壁手術(shù)時，念珠菌可滲漏到腹腔多數(shù)可被腹膜迅速清除在一些病人中會進行腹膜播種，可導致腹腔念珠菌感染，也可播散 至血流和腹部之外的組織和器官,Thierry Calandra et al. Clinical Trials of Antifungal Prophylaxis among Patients Undergoing Surgery. CID. 2

31、004;39 (4):S185-192,,腹腔侵襲性念珠菌感染的發(fā)生機制,,,,,分離的念珠菌在腹腔感染中起致病作用,爭議,,目前大量的研究顯示 念珠菌腹腔感染死亡率高達：27%~77% 強烈主張抗真菌的搶先治療（經(jīng)驗治療）,Thierry Calandra et al. Clinical Trials of Antifungal Prophylaxis among Patients UndergoingSurgery. CID.

32、 2004;39 (4):S185-192,對腹腔念珠菌感染的看法,腹腔分離的念珠菌是“無辜的牽涉者”,,在271例 ICU腹膜炎患者中，83例念珠菌腹膜炎患者,Dupont H,et al. Arch Surg. 2002 Dec;137(12):1341-6.,死亡率(%),N=83,N=188,念珠菌腹膜炎,非念珠菌腹膜炎,11%,念珠菌腹膜炎死亡率高,,,比利時的Ghent 大學醫(yī)院感染疾病中心的ICU，對1995.1

33、-2002.12入住ICU的急性重癥胰腺炎胰腺壞死感染的患者46例進行分析，分析真菌感染發(fā)生率,Jan J. De Waele et al. CID 2003;37(7):208-213,胰腺真菌感染的真菌菌種分布:白念珠菌為主,SAP真菌感染幾乎全部為念珠菌,,SAP合并念珠菌感染與細菌感染的不同,Am J Gastroenterol. 2009 Aug;104(8):2065-70.,1992-2001，207 例SAP患者 52

34、例確認有細菌感染（IBI），其中30例 (15%) 合并真菌感染（IFI）， 7例原發(fā)，23例繼發(fā),,,IFI 57.7%,,,,Antibiotic 40%~100%TPN 42%~85%,,5%~68%,Am J Gastroenterol. 2011 Jul;106(7):1188-92.,SAP合并腹腔念珠菌感染：薈萃分析,,Local treatmentDebridement or necrosectomy Minim

35、ization of intraoperative hemorrhageMaximization of postoperative removal of retroperitoneal debris and exudatessystemic antifungal treatment needs to be started early in the course of the disease.,Am J Gastroenterol.

36、2011 Jul;106(7):1188-92,防治SAP合并腹腔念珠菌感染的措施,,腹腔念珠菌膿腫,腹腔膿腫,隔下膿腫原發(fā)性通過血流傳播所致繼發(fā)性為腹腔內(nèi)化膿性感染的并發(fā)癥，其中最常見的為急性闌尾炎穿孔、胃十二指腸潰瘍穿孔以及肝膽系統(tǒng)的急性炎癥，占隔下膿腫的60%~85%盆腔膿腫腸袢間膿腫,,念珠菌腹腔感染中腹腔膿腫占：36.8%,THIERRY CALANDRA et al. CLINICAL SIGNIFICANCE

37、OF CANDIDA ISOLATED FROM PERITONEUM IN SURGICAL PATIENTS. The Lancet.1989;December 16.P1437-1440,腹腔念珠菌膿腫發(fā)生率,,體會1. 診斷問題,社區(qū)獲得性腹腔感染重癥型（嚴重病理生理指標紊亂、高齡、免 疫抑制）與醫(yī)院獲得性腹腔感染的病原菌可能為真菌。繼發(fā)性腹膜炎經(jīng)常規(guī)外科處理后，腹腔感染癥狀緩解48h后復發(fā) 或腹腔感染癥狀持續(xù)存

38、在時，病原菌可能為真菌感染。高危腹腔感染此前應用過抗生素的病人，真菌感染的可能性更大。腹腔感染部位取得的標本應足以代表臨床感染。G試驗可以作為參考。,,體會2. 治療問題,如果腹腔膿液培養(yǎng)結(jié)果示念珠菌生長，對重度社區(qū)獲得性或醫(yī)院 獲得性感染病人推薦進行抗真菌治療。如果分離得到白念珠菌，推薦使用氟康唑。對氟康唑耐藥的念珠菌，推薦棘白菌素類抗菌藥（如卡泊芬凈、 米卡芬凈）。危重病人的初期治療推薦棘白菌素，不推薦

39、三唑類抗菌藥。由于兩性霉素B不良反應較大，初期不推薦應用兩性霉素B。如果抗感染治療4~7d后，病人仍有持續(xù)或復發(fā)的腹腔感染征 象，應進行CT或超聲等影像學檢查明確診斷，并行經(jīng)驗性抗真菌 治療。,,2024/3/12,內(nèi)容提要,,侵襲性曲霉感染誤診分析,念珠菌定植問題,腹腔念珠菌感染診治問題,1,2,3,,Meersseman et al. Clinical Infectious Diseases 2007; 45:20

40、5–16,COPD合并呼吸衰竭入住ICU，接 受皮質(zhì)激素治療胸片：兩肺局灶性滲出、模糊、右 側(cè)胸腔積液BAL培養(yǎng)：流感嗜血桿菌（+）、 霉菌（-）血清GM（-）BAL GM 2.6ng/ml尸檢：IPA,例1. AECOPD呼吸衰竭患者,Meersseman et al. Clinical Infectious Diseases 2007; 45:205–16,肝移植受體者胸片：右側(cè)片狀實變影，類似

41、肺部感染BAL：細菌、霉菌（-）血清GM（-）尸檢：播散性曲霉,例2.肝移植患者,Meersseman et al. Clinical Infectious Diseases 2007; 45:205–16,急性粒細胞白血病骨髓移植后接受高 劑量抗排異治療4月胸片：右側(cè)肺片狀滲出、胸腔積液CT：右側(cè)肺局部實變影伴有空洞、 有液平；第4、5肋骨破壞；左側(cè)肺鍥 型實變影胸腔積液培養(yǎng)：煙曲霉,例3.骨髓

42、移植患者,Meersseman et al. Clinical Infectious Diseases 2007; 45:205–16,晚期糖尿病腎移植2月胸片及CT：兩下肺斑片狀陰影伴空 洞、右側(cè)胸腔積液血清GM 0.1ng/ml、BAL GM 5.7ng/ml經(jīng)支氣管活檢：煙曲霉死于三尖瓣心內(nèi)膜炎（曲霉）,例4.腎移植患者,這些病人如果沒有活檢或尸檢的話，你會診斷侵襲性曲霉感染嗎,？,IPA 誤診的原因,The

43、diagnosis of IPA in non-neutropenic critically ill patients is difficultsigns and symptoms are non-specific.A positive result of a culture of a respiratory specimen or positive findings of a direct microscopic examina

44、tiononly one-half of patients with IPA. The predictive value of a positive culture result depends largely onwhether the patient is immunocompromised and ranges from 20% to 80%.,1.Trof et al. Intensive Care Med 2007;33

45、:1694–7032.Hope WW, Walsh TJ, Denning DW. Laboratory diagnosis of invasive aspergillosis. Lancet Infect Dis 2005; 5:609–22.3.Tarrand JJ, Lichterfeld M,Warraich I, et al. Diagnosis of invasive septate mold infection

46、s: a correlation of microbiological culture and histologicor cytologic examination. Am J Clin Pathol 2003; 119:854–8.,,Meersseman et al. Clinical Infectious Diseases 2007; 45:205–16,,IPA的危險因素,GM 抗原的敏感性與特異性,Correlates

47、 with fungal burden in animal and clinical studies Sensitivity and specificityLimitations in non-neutropenic patients (SOT)Detected in CSF, bronchoalveolar lavage (BAL) fluid,Serologic testing techniques of galact

48、omannan (GM) hold promise for patients with hematologic malignancy.GM Studies of neutropenic patients have revealed high rates of sensitivity (67%~100%) and specificity (86%~99%). However, in a retrospective observatio

49、nal study of a medical ICU population, serum GM was elevated in only 53% of patients with IA. Detection of serum GM is probable not a sensitive marker for IA (especially in non-neutropenic patients).,Meersseman et al.

50、Clinical Infectious Diseases 2007; 45:205–16,GM試驗在IPA的價值,GM has to be stressed that the available data from patients with (haematological) malignancies and after solid organ transplantation can not be extrapolated to the

51、 critically ill patient in general. In the meantime, due to lack of more reliable, non-invasive diagnostic tests, the GM assay could be used as an additive tool in the diagnostic work-up of IPA.,Trof et al. Intensive Ca

52、re Med 2007;33:1694–703,GM試驗可以作為IPA的輔助診斷,IPA高風險病人的診治策略,Monique A S H Mennink-Kersten, J Peter Donnelly, and Paul E VerweijTHE LANCET Infectious Diseases Vol 4 June 2004,,,,possible,probable,proven,38 patients probab

53、le (n = 28) proven (n = 10) . 37% patients ≥2 risk factors for IA. All probable IA were diagnosed by BAL. Proven IA was reached by positive histopathologic and culture results of samples autopsy (n = 4) percuta

54、neous (n = 3) transbronchial biopsy (n = 3).,A. Hidalgo et al. / European Journal of Radiology 71 (2009) 55–60,HRCT與GM的相關(guān)性,HRCT 分類,Airway invasive aspergillosis 氣道侵襲性曲霉病Aspergillus bronchiolitis （“tree-in-bud” patt

55、ern）Aspergillus bronchopneumonia（air-space consolidation） angioinvasive aspergillosis 血管侵襲性曲霉病“halo” of ground-glass “air-crescent sign”,Logan PM, Primack SL, Miller RR, Muller NL. Invasive aspergillosis of the ai

56、rways: radiographic, CT, and pathologic findings. Radiology 1994;193:383–8.2. Franquet T, Muller NL, Gim´enez A, Guembe P, de la Torre J, Bagu´e S. Spectrum of pulmonary aspergillosis: histologic, clinica

57、l, and radiologic signs. Radiographics 2001;21:825–37.,,,氣道侵襲性曲霉病,A. Hidalgo et al. / European Journal of Radiology 71 (2009) 55–60,GM: 0.7~0.9,GM: 0.6~1.0,血管侵襲性曲霉病,A. Hidalgo et al. / European Journal of Radiology 71 (2

58、009) 55–60,GM: 2.2,GM: 1.7~2.0,HRCT與 GM 在 IPA的相關(guān)性,,A. Hidalgo et al. / European Journal of Radiology 71 (2009) 55–60,1.7,3.2,研究結(jié)論（1）,Serum GM levels may be lower in patients with airway IA than in those with an angioinva

59、sive form. （氣道侵襲性曲霉病的血清GM水平比血管侵襲性曲霉病低）HRCT findings of airway IA are very similar to those of others infection such as viral infection. （氣道侵襲性曲霉病的HRCT影像學表現(xiàn)與其他感染，比如病毒感染非常近似）,A. Hidalgo et al. / European Journal of

60、 Radiology 71 (2009) 55–60,研究結(jié)論（2）,A lower or even negative GM result does not effectively exclude airway invasive fungal disease. （GM水平低或陰性不能除外氣道侵襲性曲霉?。〨iven the very high sensitivity of HRCT and the high specificit

61、y of the serum GM in these patients were both complementary tests in the diagnosis of IA. （HRCT的高敏感性和GM的高特異性對于IPA診斷具有輔助作用）,A. Hidalgo et al. / European Journal of Radiology 71 (2009) 55–60,小結(jié)（1）,重視危險因素IPA的危險因素包括：結(jié)締組織病

62、、使用激素治療、肝衰竭、CRRT治療，與傳統(tǒng)的危險因素明顯不同。越來越多的證據(jù)表明，COPD已成為IPA最主要的危險因素，其次是自身免疫性疾病、實體器官移植、肝硬化。ICU患者氣道分離出曲霉菌不論是定植或侵襲，都是不良預后的指標，和高死亡率相關(guān)，應予以重視。,小結(jié)（2）,正確認識影像學與GM目前很多IA的GM多用于腫瘤患者早期診斷，并非為ICU專門制定的，可能不適用于ICU患者。 IA患者影像學表現(xiàn)可作為輔助診斷的手段，但重度免

63、疫抑制患者有高陽性預測值的暈輪征、半月征，在重癥患者中可能不存在或被其他肺部病變所掩蓋。無血液系統(tǒng)疾病尤其是中性粒細胞缺乏的患者中，只有5%~25%能見到暈輪征、半月征。因此，重癥合并IPA的患者其影像學并無特異的表現(xiàn)。BAL中的GM比血清GM檢測敏感性要高。當采用0.5的臨界值檢測BAL中的GM，其敏感性和特異性分別為88%和87%，而血清GM僅為42%。,到位不越位！,危險（宿主）因素 臨床特征（癥狀+影像學）