医学检验学（PPT讲稿）Tohru Takata-癌症患者体内侵袭性真菌感染的诊断（英文）

Diagnosis of Invasive fungal infections in the cancer patientTohru Takata, MD, PhDJun 21st, 2017

Diagnosis of Invasive fungal infections in the cancer patient Tohru Takata, MD, PhD Jun 21st, 2017 1

Effect of cancer drug therapy to tumor and bone marrowanticancer drugsn1012109bonemarrow cellsanticancerdrugstumor cellscureTimetumor reductiontumor regrowth14 days7-10 daysTumor14 days7-10daysbonemarrowdecreasedhematopoieticcellsrecovery

Effect of cancer drug therapy to tumor and bone marrow 骨髄 anticancer drugs Tumor bone marrow 7-10 days tumor reduction decreased hematopoietic cells 14 days tumor regrowth bone marrow cells tumor cells Time 109 1012 cure No. of cells anticancer drugs 7-10 days 14 days recovery 2

Annual frequencies of invasivefungalinfections inautopsied cases in Japan(%)5FrequencyGuideline2003TotalCandidosisAspergillosisACryptococcosisMucormycosisOthers (Unknown)3Guideline20070198919811985199319691973197719972001200520072009（年CPFG2012AntifungalsITCZi.v.2007L-AMB2006VRCZ2005F-FLCZ2004MCFG2002ITCZ1993FLCZ1989MCZ19805-FC1979AMPH-B1962JapanesedomesticguidelinesformanagementofDeep-seatedMycosis2014

Total Aspergillosis Candidosis Cryptococcosis Mucormycosis Others (Unknown) Guideline 2003 Guideline2007 Frequency Antifungals ITCZ i.v. Annual frequencies of invasive fungal infections in autopsied cases in Japan Japanese domestic guidelines for management of Deep-seated Mycosis 2014. 3

Invasive fungal infections in autopsied cases in Japan (2011)300250Aspergillosis200Candidosis150Cryptococcosis100Mucormycosis50Chromomycosis0TrichosporonosisCandidosisptococcosisronosisAspergillosisMucormycosisaromomycosisUnknownUnknownTrichosporCryptThere are growingChrnumbersofrarefungi.Leukemia (include MDS)135/720（18.8)90/624(14.4)83/608(13.7)Solidcancer165/720(22.9)133/624(21.3)124/608(20.4)Bacterialintection159/720（221)54/624(8.7)69/608(11.3)60/720(8.3)67/624（(10.7)Malignantlymphoma66/608(10.9)19/720(2.6)6/624（1.0)Mycoses3/608(0.5)9/624(1.4)Multiplemyeloma22/720(3.1)9/608(1.5)Collagen disease48/720(6.7)48/624（7.7)51/608(8.4)Tuberculosis7/720(1.0)7/624(1.1)5/608(0.8)Renal disease26/720(3.6)14/624(2.2)8/608(1.3)5/m20(0.7)4/624（0.6)4/608(0.7)Aplasticanemia15/720(2.1)2/624（0.3)6/608(1.0)Diabetes13/720(1.8)50/624(8.0)25/608(4.1)PulmonaryfibrosisOtherdiseases151/720(21.0)140/624(22.4)155/608（25.5)720624608Total4SuzukiY,etal.MedMycolJ56(3):J99-J103,2015

Invasive fungal infections in autopsied cases in Japan (2011) Suzuki Y, et al. Med Mycol J 56(3):J99-J103, 2015. There are growing numbers of rare fungi. 4

Epidedmiology of Invasive mold disease in Europe20010.0918025.0%160Rates (9%)otRates (%) dtCharacteristicOR(95%C)dOR(95%CI)probable140proven TMD20.0%provenIMD1205489.10.454.70.570.02AllogeneicHSCT5%oftotalnumberofpatients10.0%(0.951.93)(0.85~2.33)65.341811.7Countries recruiting s5%oftotalnumberofpatients405.0%62317.21.740.0016.91.120.52Need for informed corsent58210.76.2Noneed forinformed(1.242.43)(0.711.78)consent-AML_acute.myeloeleukaemis.HSCT,hsematcooieticstemceltransplant:nulsdisease:MD5,myelodysplsstic.syndromesandrevinwo (%)otpatenlRatesofinvasivemolddiseasediffered significantlybetweenpatientstreatedforacutemyeloidleukaemia/myelodysplasticsyndromeandHscTpatientsvaried between countries,thoughnot significantlysupport the contention that only local epidemiologydata canprovideproperprevalencedataforbothgroupsof patientsDonnelyJ,etal.PIMDAStudy.ESCMIDLibraryOnlineAbstractP0028a,2014

◼ Rates of invasive mold disease - differed significantly between patients treated for acute myeloid leukaemia/myelodysplastic syndrome and HSCT patients - varied between countries, though not significantly - support the contention that only local epidemiology data can provide proper prevalence data for both groups of patients Epidedmiology of Invasive mold disease in Europe Donnely J, et al. PIMDA Study. ESCMID Library Online Abstract P0028a, 2014. 5

Invasive fungal infections in patients withcancer/hematologicalmalignanciesBackgroundshigh risk of invasive fungal infections (IFl)and high mortalityearly diagnosis is usually difficult;limited valueofmicroscopyandmycological culturesnonspecificclinicalfeatures;fevermaybeabsentwithcorticosteroidtherapyinvasive diagnostic procedures (e.g. biopsy) are difficult inhighriskpatientsduetocommonthrombocytopeniavarious treatmentsforcancer/HSCT

Invasive fungal infections in patients with cancer/hematological malignancies Backgrounds ●high risk of invasive fungal infections (IFI) and high mortality ●early diagnosis is usually difficult; limited value of microscopy and mycological cultures ●nonspecific clinical features; fever may be absent with corticosteroid therapy ●invasive diagnostic procedures (e.g. biopsy) are difficult in high risk patients due to common thrombocytopenia ●various treatments for cancer/HSCT 6

Patients at risk of invasive fungal diseases

Patients at risk of invasive fungal diseases 7

Timeline of IFl in patients with neutropenia1007No prophylaxis80Aspergillus6040Candida20020401030Duration of neutropenia (days)Prophylaxiswithfluconazole1000Recoveryfromneutropenia80Aspergillus6040°G-CSF20°Candida0201030408Wingard,JR.ClinInfectDis39:S38-43,2004

Timeline of IFI in patients with neutropenia Recovery from neutropenia G-CSF Candida Aspergillus 0 10 20 30 40 20 40 60 80 100 (%) 0 10 20 30 40 20 40 60 80 100 Candida Aspergillus (%) No prophylaxis Duration of neutropenia (days) Wingard, JR. Clin Infect Dis 39 :S38-43, 2004. Prophylaxis with fluconazole 8

Risk factors for invasive aspergillosisANG-patternEnvironmentalFactors4-93HEPAfilterAntigenexposureInfaret shapedconsolidationCavityHalosignAIDSMass likeconsolidationMacrophaeCellularimmunityNeutrophil(T cell)MembranousAIR-patternbarrierOrganfunctionPeribronchialconSolidatiortree-in-bud patternFNHematopoieticstemcelltransplantationpost-GVHD,Steroids,immunosuppressantschemotherapy9

Cellular immunity （T cell） Antigen exposure Macrophage Neutrophil Membranous barrier Organ function Environmental Factors HEPA filter AIDS FN post￾chemotherapy Hematopoietic stem cell transplantation GVHD , Steroids, immuno suppressants Risk factors for invasive aspergillosis 9

MadhdF1?E16,26188S288648ExecutiveSummaryofJapaneseDomesticGuidelinesforRiskstraficationaccordingtotheprobabilityofIFlManagementofDeep-seatedMycosis2014ProphylacticantifungalsareChairman: Shigeru KohnoCommiueemembers Kazuo Tamura',YoshihitoNiki',Koichi Izumikawa'Shinichi OkaKenji Ogawa,Junichi Kadota,KatsuhikoKamel,Yoshinobu KandaTetsuya KiuchiconsideredinpatientswithKazutoshi Shibuya,Syunji TakakuraToruTakata,YoshioTakesue",Katsuji TerIssei TokimatsuTakahiroFukuda,Shigefumi Maesaki',KoichiMakimuramorethanintermediate-riskHiroshigeMikamo",KotarouMitsutakeYoshitsuguMiyazaki"Masaaki MAkira Yasuoka',Keiko Yano',Noboru Yamanaka',and Minoru Yoshid.I.Assessmentofriskfactors.Theriskof invasivefungal diseaseisassessedaccordingtounderlyingdisease,typeoftreatment,etcHigh-risk groupIntermediate-risk groupLow-risk groupAntifungal prophylaxis isAntifungalprophylaxisisAntifungalprophylaxisisnotrecommended.consideredrecommended.Chart Ill:Indications for→Chart Ill:Indicationsfor+ Expectedduration ofantifungalprophylaxisantifungalprophylaxisneutropenia(<500/μL)forlessthan7days口口ConsolidationtherapyforRemissioninductiontherapyfor Nohigh/intermediateriskacute leukemia [acute myeloidacuteleukemiafactorsAutologousHSCTleukemia(AML),acutelymphoblasticleukemia(ALL)）(particularlywith mucosaldamage)myelodysplasticsyndrome Prolonged use of(MDS)口Allogeneichematopoieticstemcorticosteroids(0.3mg/kg.Idayofprednisolonecelltransplantation(HSCT)口Grade Il-IVacuteequivalent,for3weeksorgraft-versus-hostdiseaselonger,high-dose(GVHD).chronicGVHDdexamethasonefor(+corticosteroidtherapy)myeloma,etc...)口Expecteddurationof Treatmentwithotherneutropenia(<500/μL)for10recognizedTcelldays or longer.immunosuppressants,suchas cyclosporine, TNF-ablockers,specificmonoclonalantibodiesornucleosideanaloguesduringthepast 90daysExpecteddurationof10neutropenia(<500/μL)for7-10days

Risk strafication according to the probability of IFIk Prophylactic antifungals are considered in patients with more than intermediate-risk. 10