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1、Changes in the epidemiological landscape of invasive mould infectionsand diseaseCornelia Lass-Flo rl1*and Manuel Cuenca-Estrella21Division of Hygiene and Medical Microbiology,Medical University of Innsbruck,Scho pfstrae 41,6020 Innsbruck,Austria;2Department of Mycology,Centro Nacional de Microbiolog
2、?a,Instituto de Salud Carlos III,Ctra.Majadahonda-Pozuelo Km 2,Majadahonda,Madrid,Spain*Corresponding author.Tel:!43-512-9003-70700;E-mail:Cornelia.lass-floerli-med.ac.atBoth authors made an equal contribution to the article.Although a wide varietyofpathogensareassociatedwith invasivemoulddiseases,A
3、spergillusspp.have historic-allybeenoneofthemostcommoncausativeorganisms.Most invasivemouldinfectionsarecausedbymembersof the Aspergillus fumigatus species complex and an emerging issue is the occurrence of azole resistance inA.fumigatus,with resistance to amphotericin B documented in other Aspergil
4、lus spp.The epidemiology of inva-sive fungal disease has shifted in recent years as non-A.fumigatus Aspergillus spp.and other moulds have be-comeprogressivelymore important,although therearenoconsolidated data ontheprevalenceof less commonspecies of moulds.The incidence of mucormycosis may havebeen
5、underestimated,which is a potential concernsince species belonging to the order Mucorales are more resistant to antifungal agents than Aspergillus spp.Allspecies of Mucorales are unaffected by voriconazole and most show moderate resistance in vitro to echinocan-dins.Fusarium spp.maybethe secondmost
6、common nosocomialfungalpathogen afterAspergillus in some ter-tiary hospitals,and show a susceptibility profile marked by a higher level of resistance than that of Aspergillusspp.Recently,Scedosporium aurantiacum has been reported as an emerging opportunistic pathogen,againstwhich voriconazole is the
7、 most active antifungal agent.Other mould species can infect humans,although inva-sive fungal disease occurs less frequently.Since uncommon mould species exhibit individual susceptibility pro-files and require tailored clinical management,accurateclassification at species level of the aetiological a
8、gent inanyinvasivefungaldiseaseshouldberegardedasthestandardofcare.AspergillosisInvasive aspergillosis(IA)currently constitutes the most commoncause of infectious pneumonia-related mortality in patientsundergoing HSCT and is an important cause of opportunisticrespiratory and disseminated infections
9、in other immunocom-promised patients.1Overall,the genus Aspergillus contains about250 species divided into eight subgenera(Aspergillus,Fumigati,Circumdati,Candidi,Terrei,Nidulantes,WarcupiandOrnati),2whichin turn are subdivided into several sections or species complexes.Of these,40 species are known
10、 to cause diseases in humans.MostinvasiveinfectionsarecausedbymembersoftheA.fumigatus species complex,followed by A.flavus,A.terreus andA.niger species complexes.3These data contrast withepidemiolo-gical data from a decade previously,where the majority of caseswere due to A.fumigatus.4Irrespective o
11、f this,some institutionsmayfindA.flavusorA.terreustobethemostfrequentlyrecoveredspeciesofAspergillus.5Considerationshouldbegiventotheinfect-ing species of Aspergillus since some representatives may displayresistancetoabroadpanelofantifungaltherapies.Both the change in microbial epidemiology and the
12、steady risein aspergillosis have multiple causes.These include the increasingnumber of patients with weakened immune systems such as pa-tients with cancer and organ transplant recipients,and advancesand modifications to healthcare practices in response to world-wide concerns about hospital-associate
13、d aspergillosis.In addition,azole resistance seems to be an emerging problem in some geo-graphical areas,and it has been reported that cryptic species ofAspergillus with resistance to antifungal agents can be more com-monthanexpected.25Patient populationsIt is estimated that?200000 cases of IA occur
14、 worldwide peryear.6Approximately 50%affect patients with haematologicalmalignancies such as AML and ALL,and recipients of allogeneicHSCT.7,8The risk of early infections is influenced by the underlyingdisease,presence of persistent neutropenia,type of stem cell andconditioning protocols;late infecti
15、ons are associated with theonset of graft-versus-host disease and with cytomegalovirus(CMV)infection and disease.9Environmental factors such asnearby construction work or inadequate infection control can playa contributory role.Gene polymorphisms affecting the innate im-mune response,such as the tol
16、l-like receptor 4,10interleukin-1bVCThe Author 2017.Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.All rights reserved.For Permissions,please email:.i5J Antimicrob Chemother 2017;72 Suppl 1:i5i11doi:10.1093/jac/dkx028Downloaded from https:/ by gu
17、est on 19 December 2019and b-defensin 1,11long pentraxin 37,12and dectin-1,13,14areassociatedwithahigherriskofdevelopingIA.Impairedproductionof reactive oxygen species,and qualitative and quantitative im-mune cell defects,also increase risk.1517The introduction ofmould-active prophylaxis with posaco
18、nazole resulted in a reduc-tion of IA incidence in haemato-oncological patients from 15.5%to 7%,18but on the other hand led to observations of rare fungalpathogens being involved in breakthrough infections.19Mortalityrates associated with IA in haematological patients reached29%.11,20The dominant ri
19、sk factor for IA in solid organ transplant recipi-ents is not the depletion of phagocytic neutrophils21,22but theirfunctional impairment by immunosuppressant drugs.The 1yearincidence of invasive mould infections in this setting is highest forIA(0.65%),with the majorityofinfections typicallyoccurring
20、 morethan 3 months after transplantation(late-onset infection).23IA iscommonly found in lung and heartlung recipients.Airway colon-ization in lung transplant recipients with cystic fibrosis is a risk fac-tor for disease following transplantation.24,25Increasing intensityof immunosuppression,haemodia
21、lysis and CMV infection are riskfactors for liver and renal transplant recipients.26,27Donor CMVseropositivityisariskfactorforlate-onsetinfection.ICU patients represent the second largest at-risk population forIA,with incidence rates varying between 6.1 and 57/1000 ICUadmissions.28,29This applies to
22、 patients suffering from chronicobstructive pulmonary disease and receiving high-dose cortico-steroids,and those with severe alcoholic liver cirrhosis.30,31Mortality rates range from 46%to 80%.4,2123,25The degree,dur-ation and type of immunodeficiency influence pathogenesis anddisease outcome.21,22I
23、t is not uncommon for IA to be associatedwith concurrent viral respiratory infections due to H1N1 influenzaoradenovirus.32The pathogens:from A.fumigatus to non-A.fumigatusAn emerging issue is the occurrence of azole resistance inA.fumigatus.The full extent of the problem is still unknown,butthegloba
24、lprevalenceofazoleresistanceinAspergillusisestimatedtobe?3%6%.33ResistantisolateshavebeenidentifiedinEurope,the Middle East,Asia,Africa,South America and,recently,in theUSA.34Some studies suggest that resistance in A.fumigatus maybe partially driven by the use of agricultural azoles,which protectcro
25、psfromfungi.OtherspeciesofAspergillusmayalsoberesistantto amphotericin B,including A.lentulus,A.nidulans,A.ustus andA.versicolor.Hence,the identification of unknown Aspergillus clin-ical isolates to species level may be important given that differentspecies have variable susceptibilities to multiple
26、 antifungal drugs.Thus,knowledge of the species identity may influence the choiceof appropriate antifungal therapy.Table 1 provides an overview ofsusceptibility trends from infections due to a non-A.fumigatusspeciescomplex.Other mould infectionsMany mould species are able to cause opportunistic inva
27、sive fun-galdiseasessincetheyaresaprobeswithacosmopolitanpresenceand are widely distributed in the environment.These filamentousfungi are usually rare pathogens,but their prevalence appears tohave increased steadily over the last two decades.Rare species offilamentous fungi can cause colonization an
28、d superficial mycoses,as well as local infections after penetrating trauma and dissemi-nated diseases in patients withpredisposing factors.The course ofinfection can differ between mould species,and some exhibit adecreased susceptibility or are even intrinsically resistant to anti-fungal agents.41It
29、 is therefore highly relevant to obtain an accur-ate species identification to inform clinical management.Theepidemiological features of the most common species of the raremouldsimplicatedinhumaninfectionsaresummarizedinTable2.MucormycosisMucormycosisisthediseasecausedbyorganismsbelongingtotheorderM
30、ucorales.The most common species of Mucorales involvedin human infections are the Rhizopus spp.although other speciesbelonging to the genus,such as Mucor,Rhizomucor,Lichtheimia,Mycocladus,Apophysomyces,Saksenaea,Cunninghamella,Cokero-myces and Syncephalastrum,have also been isolated in cases ofmucor
31、mycosis.48,49The classical risk factors for mucormycosis arediabetes and penetrating trauma,but immunosuppression andgranulocytopenia have become the most common predisposingfactorsinmanytertiaryhospitalsoverrecentyears.8,23There are no reliable data to assess the incidence of this myco-sis in the g
32、eneral population.A number of studies have reportedan incidence of 0.51.2 cases per million inhabitants/year.50Somepopulation-based surveys have isolated Mucorales species in5%15%of clinical samples with filamentous fungi.In recent re-ports,mucormycosiswas7-foldlesscommonthanIAinhaemato-logicalpatie
33、nts,andmortalityratesrangedfrom25%to50%.42Some studieshave pointed outthat the incidence of mucormy-cosismay beunderestimateddue tothe lowperformance of diag-nostictechniquesbasedonconventionalmicrobiologicalprocedures,such as culture and microscopy.The most usefulmethodsfordetectingMucoralesarestil
34、lmicroscopicexaminationof tissues and histopathology,which offer moderate sensitivityand specificity.Recent clinical studies have reported that mucor-mycosis is the cause of.10%of all invasive fungal infectionswhen techniques based on DNA amplification by quantitativeDNA51areusedtocomplementconventi
35、onalmethods.5254Species belonging to the order Mucorales are more resistant toantifungalagentsthanAspergillusspp.AllspeciesofMucoralesareunaffected by voriconazole and most show moderate resistancein vitro to echinocandins.55,56In fact,the use of voriconazole asfirst-line treatment for aspergillosis
36、,and use of echinocandins asempiricaltreatmentforfebrileneutropeniaanddisseminatedcan-didiasis,have been blamed for the increased incidence of mucor-mycosis.57Amphotericin B and posaconazole show the mostpotent activity in vitro against the Mucorales.5860Current guide-lines recommend the polyenes as
37、 first-line treatment,with posa-conazole as alternative and salvage therapy.42Both itraconazoleand isavuconazole exhibit an intermediate activity in vitro againstthese fungal species.61In vitro activity of azoles against Mucoralesis species-dependent with Mucor spp.being less susceptible andLichthei
38、mia spp.and Rhizopus spp.exhibiting the lowest MICs.AlthoughtheMICvaluesforposaconazolearelowerthanforisavu-conazole,in the clinical setting this may be compensated for byhigherisavuconazoleexposureatstandarddosing.60Lass-Flo rl and Cuenca-Estrellai6Downloaded from https:/ by guest on 19 December 20
39、19Table 1.Features of selected non-A.fumigatus infectionsSpeciesDiseasesSpecific characteristicsReferencesEmericella nidulansIA in CGDMore virulent than A.fumigatusHigher mortalityPropensity to spread from the lung to adjacentstructures and to disseminateIntrinsic resistance to amphotericin B35Emeri
40、cella quadrilineataIA in CGD and IAResistant to caspofungin?35Aspergillus calidoustusIAPropensity to disseminateIntrinsic resistance to azolesIntrinsic resistance to caspofungin?35,36Aspergillus terreusIAPropensity to disseminate(63%)Intrinsic resistance to amphotericin B5Aspergillus tubingensisIA,a
41、irway colonizationand ear infectionsAcquired resistance to azolesLower propensity to disseminate(10%-30%)37Aspergillus lentulusIAResistant to azoles and echinocandinsResistant to amphotericin B38Aspergillus alliaceusIAGM negativeHigh MICs of amphotericin Band caspofungin35Aspergillus carneusIAGM low
42、 positive39Aspergillus novofumigatusIAResistant to azoles35Aspergillus alabamensisMainly airwaycolonizationResistant to amphotericin B40Aspergillus ustusIAResistant to amphotericin B,azolesand echinocandins36Aspergillus felisIAHigh MICs against voriconazole and caspofungin35IA,invasive aspergillosis
43、;CGD,chronic granulomatous disease;GM,galactomannan.Table 2.Epidemiological features of rare mould speciesSpeciesDiseasesSpecific characteristicsReferencesMucoralesIFD in patients with risk factorsIncreasing prevalence in haematological patientsHigher mortality than aspergillosisResistance to vorico
44、nazole42Fusarium spp.Local and disseminated mycosesin patients with risk factorsLeading cause of IFD in haematological patientsin some areas(Brazil)Mortality.75%in IFD casesUnpredictable resistance to some antifungal agents43,44ScedosporiumapiospermumcomplexColonization,local infections and IFDsMore
45、 common in temperate areasHigh mortality in IFD casesVoriconazole is the most potent antifungal agent against them43,45ScedosporiumprolificansColonization,local infections and IFDsMore common in southern Europe,Australia and CaliforniaMortality.90%in IFD casesMultiresistant organism43,46Other rare m
46、ouldspeciesColonization,local infections and IFDsUnreliable data on prevalence and mortalityIdentification at species level and AST are compulsoryfor correct management43,47IFD,invasive fungal disease;AST,antifungal susceptibility testing.Epidemiology of invasive mould infectionsJACi7Downloaded from
47、 https:/ by guest on 19 December 2019Infections by Fusarium spp.The genus Fusarium includes several fungal species complexes.These are ubiquitous soil saprophytes and pathogenic for plants.Onlya fewspeciescauseinfectionsinhumans.43Amongthesearethe species complexes F.solani,F.oxysporum,F.verticillio
48、ides andF.proliferatum.Fusariumspp.havebeeninvolvedinsuperficialanddeep mycosis and are the leading cause of fungal keratitis in theworld.43,62Clinical interest is currently growing since they havebeenidentifiedas emerging andmultiresistantpathogens causingopportunisticdisseminatedinfections.63,64Fe
49、w clinical studies have described the incidence of Fusariumspp.Several surveys haveindicated that Fusarium could be the se-cond most common nosocomial fungal pathogenafter Aspergillusin some tertiary hospitals.41In some geographical areas,clinicalstudieshavecalculatedthatFusariumspp.causebetween3%an
50、d5%of invasive fungal diseases.44A Spanish population-basedstudy found Fusarium spp.in only 1.2%of mould clinical isolatesrecovered from deephumansamples,including tissues,sterileflu-ids and respiratory secretions.50However,in Brazil,Fusarium is theleadingcauseofinvasivemouldinfections,followedbyAsp