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TheburdenofseriousfungalinfectionsinLatinAmericaMostlife-threateningfungalinfectionsarenotdiagnosedbyconventionalculture,microscopyandhistopathology.Therehaveabeenmajordevelopmentsinrapidandsensitivediagnosticsforfungaldiseasesinthelastfewyearsandsoitshouldbepossibletodiagnosethevastmajorityoftheselife-threateningfungaldiseases.Withoutappropriatetreatment,deathistheusualoutcome;orforchronicinfections,continuedchronicillhealthandtheriskofdeath.Inmostcountries,the‘diagnosticgap’islarge.Surveillanceprogramsarerare.Forthesereasons,theincidenceandprevalence(combined=burden)ofthemostseriousfungaldiseasesarepoorlydocumentedinmostcountriesformostdiseases.ThissummarydocumentprovidescountryestimatesforthemostimportantseriousfungaldiseasesinLatinAmerica,usingconsistentbaselinedataonunderlyingdisordersandmethodology,andallaccessiblelocalpublications.Thepurposeofthisdocumentistoprovideabasisforplanningfordiagnostictests(andantifungaltherapy)implementation,ineachcountry.Theseestimatesarejustthat,estimates,andassuchwillnotbeprecise,aresubjecttochangebasedonunderlyingdiseasefrequencyandmanagement,outbreaksandmedicalpractice.HIV-relatedfungalinfectionsCryptococcalmeningitisCryptococcalinfectionisacquiredthroughinhalationandoccasionalcasesofcryptococcalpneumoniaorlungnodulearediagnosed.Muchmorecommonlyitleadstomeningitis,primarilyinAIDS,butalsoinotherimmunocompromisedpeopleandrarelyinthosewithoutaknownimmunedeficit.InthetablebelowwehaveestimatedthenumberofcasesofcryptococcalmeningitisineachLatinAmericancountry.Wehaveassumedthefollowing:1.Patientsnotonantiretroviraltherapy(ARVs)areatriskwithaCD4count<200/uL,andwehaveassumeda7yeardeclineofCD4cellsto<200/uLforthosenotonARVs.Wehaveaddedanadditional15%toaccountforthosewhojuststartedARVsanddefaulters.The%ofVenezuelansonARVsisfrom2016.2.UNAIDSHIVfiguresfor2017wereused.3.TheproportionofthoseCrAgpositivewithCD4cells<200/uLaretakenfromRajasingham(2017),Riera(2018)forArgentina,Borges(2019)forBrazilandunpublisheddatafromGuatemala(Samayoa)whichhasbeenappliedtocentralAmericaandVenezuela(butnotMexico).4.That76%ofcasesoccurinHIVpatients,basedondatafromColombia(Noguera,2019).5.Thatthemortalityis40%basedonarecentmulti-countrysurveyfromArgentina,Brazil,Chile,HondurasandMexico(CrabtreeRamirez,2017).

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Table1.CryptococcalmeningitiscasesinLatinAmerica

Pneumocystispneumonia(PCP)Pneumocystisjiroveciiisahuman-onlypulmonarypathogentransmittedearlyinlifeandthenrepeatedly.Immunityislimitedandimmunosuppressedpatientsaresusceptibletoinfectionfromnewgenotypes.ItisnotculturableandsoisdiagnosedbymicroscopyorPCRonrespiratoryspecimens,orcirculatingB-D-1.3glucanlevels.PatientsoftendistinctivefindingsonchestCTscan.Prophylaxiswithcotrimiseffective,butnotprotectionisnotcomplete.ThesurvivalrateinHIVpatientswithgoodtreatmentis70-90%,butonly50%innon-HIVpatients.CorticosteroidadjunctivetherapyreducesmortalityinHIVpatientsbutnotinHIVnegativepeople.AIDS-relatedPCPinadultsfromLatinAmericancountrieshasavariableincidence-from5.9to55%(Calderon,2013).SomestudiesaredoneinnewlypresentingHIVpatients,othersinthosepresentingwithrespiratorysymptomsandothersareautopsyseries.Thosereportingratesforallinpatientsaremostusefulforourestimatingpurpose,namelyVillais-Keever(2001)(Mexico-24.8%),Perez(2005)(Argentina–9.4%),NeresNorberg(2009)(Brazil–26.3%),Soares(2008)(Brazil–22.2%),Diaz(2018)(Brazil–10.8%).ThelaststudywasprospectiveinalreadydiagnosedHIVpatientsfollowedupinSWGoais,Brazil,andthereforethe10.8%incidencerepresentsARVexperiencedpatients,ratherthannewlypresentingpatients.

InthetablebelowareshowntheestimatedcasesofPCPbycountryinHIVandnon-HIVpatients.Theassumptionsare:

1.UNAIDSHIVfiguresfor2017wereused.2.Patientsnotonantiretroviraltherapy(ARVs)areatriskwithaCD4count<200/uL,andwehaveassumeda7yeardeclineinCD4countinthosenoton

Country TotalHIV%onARVs HIVnot

HIVpopulation CrAg% CMcases

CMtotal

Deaths(40%)

onARVs atrisk+15% <100CD4 HIV

Argentina 140,000 61 55,000 9,036 8 732 981 392Bolivia 22,000 44 12,100 1,988 5 97 131 52Brazil 900,000 66 310,000 50,929 8 4,023 5,391 2,157Chile 71,000 63 26,000 4,271 5 209 280 112Colombia 160,000 73 50,000 8,214 7 581 778 311CostaRica 15,000 49 7,800 1,281 11 145 194 78Cuba 31,000 75 9,000 1,479 5 72 97 39DominicanRepublic 70,000 56 31,000 5,093 5 250 334 134Ecuador 44,000 57 19,000 3,121 5 153 205 82ElSalvador 25,000 47 13,000 2,136 11 241 323 129Guatemala 47,000 43 27,000 4,436 11 501 672 269Honduras 23,000 50 11,000 1,807 11 204 274 109Mexico 230,000 70 70,000 11,500 5 564 755 302Nicaragua 9,400 53 4,409 724 5 35 48 19Panama 26,000 54 12,000 1,971 11 223 299 119Paraguay 21,000 40 12,500 2,054 5 101 135 54Peru 79,000 73 21,000 3,450 4 124 166 67Uruguay 14,000 58 5,900 969 5 47 64 25Venezuela 120,000 61 46,800 7,689 11 869 1,164 466Totals

9,172 12,291 4,916

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ARVs.Wehaveaddedanadditional15%toaccountforthosewhojuststartedARVsanddefaulters.3.That22%ofnewlypresentingpatientswithHIVandlowCD4countsdevelopPCP,basedonaroughmeanoftheabovestudies.4.ThatbasedonexperiencefromVenezuelaof30patientsdiagnosedwithPCPattheInstitutoNacionaldeHigieneRafaelRangel,60%ofpatientshaddisordersotherthanHIV(Panizo,2008).5.Mortalityis30%inHIVand50%innon-HIVpatients.Table2.PCPinLatinAmerica

DisseminatedhistoplasmosisinAIDSProgressivedisseminatedhistoplasmosisisanincreasinglycommonlyrecognizedcauseofinfectioninpatientswithadvancedHIVdiseasefromareasendemicforhistoplasmosis.TheGuianaShieldandGuatemalaarehyper-endemicareas(Medina,2017).OnlyChile,UruguayandParaguayarelowendemicityareas.DisseminatedhistoplasmosisoftenresemblesandcanbemisdiagnosedastuberculosisinAIDSandisamajorcauseofdeathamongHIVpatients.Thepresenceofskinlesions,whichcanbebiopsied,ishelpfulifpresent.Gastrointestinalsymptomsareoftenprominentindisseminatedhistoplasmosis,unlikeintuberculosis.PancytopeniaismoreprofoundthaninotherpatientswithadvancedHIVdisease.Histoplasmaantigencanbedetectedintheurineof95-100%andintheserumof80%ofpatientswithdisseminatedhistoplasmosis(Nacher,2018)–alternativemeansofestablishingthediagnosisincludebonemarroworskinbiopsy,bloodfilm(40%sensitivity)andPCR–cultureisinsensitiveandtooslow.

Country TotalHIV %onARVs HIVnotonARVs HIVpopulation PCPrisk Non-HIV Total Deathsatrisk15% 22%

Argentina 140,000 61 55,000 9,036 1,988 2,982 4,970 2,087Bolivia 22,000 44 12,320 2,024 445 668 1,113 468Brazil 900,000 66 306,000 50,271 11,060 16,590 27,649 11,613Chile 71,000 63 26,270 4,316 949 1,424 2,374 997Colombia 160,000 73 43,200 7,097 1,561 2,342 3,903 1,639CostaRica 15,000 49 7,650 1,257 276 415 691 290Cuba 31,000 75 7,750 1,273 280 420 700 294DominicanRepublic 70,000 56 30,800 5,060 1,113 1,670 2,783 1,169Ecuador 44,000 57 18,920 3,108 684 1,026 1,710 718ElSalvador 25,000 47 13,250 2,177 479 718 1,197 503Guatemala 47,000 43 26,790 4,401 968 1,452 2,421 1,017Honduras 23,000 50 11,500 1,889 416 623 1,039 436Mexico 230,000 70 69,000 11,336 2,494 3,741 6,235 2,619Nicaragua 9,400 53 4,418 726 160 240 399 168Panama 26,000 54 11,960 1,965 432 648 1,081 454Paraguay 21,000 40 12,600 2,070 455 683 1,139 478Peru 79,000 73 21,330 3,504 771 1,156 1,927 809Uruguay 14,000 58 5,880 966 213 319 531 223Venezuela 120,000 61 46,800 7,689 1,691 2,537 4,229 1,776Total 26,436 39,654 66,091 27,758

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TheburdenandlikelymortalityofdisseminatedhistoplasmosisinAIDShasrecentlybeenassessedforLatinAmerica(Adenis,2018).Wehaveusedtheseestimatesandaugmentedthemwitha3%and5%riskforCubaandDominicanRepublicbelow.ThekeyassumptionsmadeingeneratingtheseestimatesweredirectlytakenfromAdenisetal,2018):1.Histoplasmaexposureprevalenceinthegeneralpopulationwasassessedbasedonexistingliterature-24articlesrepresenting129histoplasminskinteststudiesinthegeneralpopulationofLatinAmericancountries2.HistoplasmaskintestpositiveprevalencewasassumedtobesimilarinthegeneralpopulationandthosewithHIVinfection.3.AnnualincidenceofdisseminatedhistoplasmosisinHIVpatientswascalculatedforeachcountryandadjustedforthosewith<200/uLCD4cells.3.UNAIDSHIVfiguresfor2012wereused.4.Adenisetaldescribedarangeofincidencefrom30-70%andmortalityof20-60%.Hereweshowthe50%incidenceestimateand60%mortalityestimate,assumingthatmanydiagnosesarenevermadeandthemortalityis100%inthesepatients.Table3.EstimatesofthenumberofcasesofdisseminatedhistoplasmosisinAIDSbyLatinAmericancountryinHIV,anddeaths.

Country TotalHIV %onARVs HIVnot HIVpopulation50%estimate DeathsonARVs atrisk15% Adenis 60%

Argentina 140,000 61 55,000 9,036 932 559Bolivia 22,000 44 12,100 1,988 70 42Brazil 900,000 66 310,000 50,929 2,357 1,414Chile 71,000 63 26,000 4,271 1 -Colombia 160,000 73 50,000 8,214 782 469CostaRica 15,000 49 7,800 1,281 89 53Cuba 31,000 75 9,000 1,479 44 27DominicanRepublic 70,000 56 31,000 5,093 255 153Ecuador 44,000 57 19,000 3,121 254 153ElSalvador 25,000 47 13,000 2,136 330 198Guatemala 47,000 43 27,000 4,436 1,338 803Honduras 23,000 50 11,000 1,807 259 155Mexico 230,000 70 70,000 11,500 794 477Nicaragua 9,400 53 4,409 724 89 54Panama 26,000 54 12,000 1,971 142 85Paraguay 21,000 40 12,500 2,054 45 27Peru 79,000 73 21,000 3,450 346 208Uruguay 14,000 58 5,900 969 24 14Venezuela 120,000 61 46,800 7,689 1,622 973Totals 9,773 5,863

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InvasiveaspergillosisinAIDSInvasiveaspergillosis(IA)inHIVpatientsismorecommonlyfoundinthoseoncorticosteroidsorwithneutropeniabutoccursatanylevelofCD4count.Itisusuallyasubacuteillnessoccurringover3-12weeks.Thediagnosiscanbedifficultastheradiologicalandclinicalfeaturesaresimilartootherinfections.Itisoftenmistakenfortuberculosis,ascavitationiscommononchestimaging.Aspergillusantigen,possiblyAspergillusantibody,andlungbiopsyaretheusualmeansofestablishingthediagnosis.Manyautopsyserieshavefoundabout~4%ofdeathsareattributabletoIA(range0-12%).InLatinAmerica,theprevalenceatautopsywas2.7%among74paediatricautopsies(Drut,1997),3.5%in211autopsiesinCuba(ArteagaHernandez,1998),12.5%of16autopsiesinPeru(Eza,2006)and0.4%ina250-autopsyseriesinBrazil(Soeiro,2008).BasedontheseautopsyseriesfromLatinAmericawehaveassumedthat4%areaffected.Therefore,wehavecalculatedthatIAistheprimarycauseofdeathinHIVin1,364people(Table5).IncountrieswheretheUNAIDSfiguresareincompleteweassumedthat5%ofthosenotonARVsdieannually(range3-8%).OtherfungalinfectionsOesophagealcandidiasisiscommoninlatestageHIV,affectingabout20%ofthosewithaCD4count<200/uLandabout5%ofthoseonARVs(Smith,1990;Buchacz,2010).Patientspresentwithdysphagia,nausea,vomitingandlossofappetiteandchestpain.Ithasamajorimpactonpatientsnutritionalstatus.Itmayberecurrent.InLatinAmerica,thistranslatesto~90,000cases,24,500inthosenotonARVsand65,200inthosereceivingARVs.Fluconazoleresistanceoccursin3-7%ofCandidaalbicansfromHIVpatientsandbecomesincreasinglycommonwithrecurrenttherapy,so~4,500patientswithlikelyhavefluconazoleresistanttherapy,requiringitraconazolesolutionorintravenoustherapy.CoccidioidomycosisisanoccasionalHIV-relatedinfection,butitsfrequencyinLatinAmericaisnotclear.Individualcasesreportsaredescribed.InMexico,anestimated8552cases ofcoccidioidomycosisoccurannually(probablyanunder-estimate)(Corzo-Leon,2015),buttheproportioninHIVpatientsisnotclear.AgrowingoutbreakofsporotrichosistransmittedbycatshasspreadfromBraziltoneighbouringcountries.Thisinfectionalsocancomplicate

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AIDS(Moreira,2015).ThenumberofcasesinHIVinfectedpatientsisnotknown.Paracoccidioidomycosis(PCM)alsooccursinsomepatientswithHIVandAIDS.PCMisanendemicairbornefungalinfectionislimitedtocentralandSouthAmerica.ItisnotmorefrequentinHIV-infectedindividualsbuttheclinicalcourseinco-infectedpatientstendstobemoresevere.Ina2009retrospectivecasecontrolstudy,themortalityinHIVpositivePCMpatientswas12.2%(directlyattributabletoPCM,24.4%all-causemortality)comparedto6%inHIVnegativePCMpatients(Morejon,2009).PCMhasbeenadoptedbytheWHOasaNeglectedTropicalDisease.Life-threateninginfectionsinhospitalisedpatientsandcriticalcareCandidaemiaandinvasivecandidiasisBloodstreaminfectionscausedbyCandidaarerelativelycommonandamongstthemostlethalofcausesofsepsis.Patientsatriskincludeprematureneonates,adultandpaediatricICUpatients,thosewithdiabetes,renaldysfunction,ontotalparenteralnutrition,aftermajorsurgeryorpancreatitisandfollowingmultipleclassesofantibiotics.Outbreaksaredescribed,includingoneinCostaRicacausedbyCandidaparapsilosis,witha50%mortality(Villalobos,2016).ManydifferentspeciesofCandidaareimplicated,someofwhicharefluconazoleresistantandlesscommonlyechinocandinresistant.ThenewpathogenCandidaaurishasthepropensityforoutbreaks(asinVenezuela)(Calvo,2016)andcanbemultidrugresistant.Thebenefitsofantifungaltherapywasdemonstratedinapaediatricmulti-countrysurveyinwhichmortalityfellfrom72%to24%withantifungalsinneonates(Santolaya,2014).Asmallnumberofepidemiologystudieshavedefinedtheannualincidenceinsomecountriesandareas.TheseincludeBrazilat14.9/100,000(Giacomazzi,2016),Colombiaat12.8/100,000(Alvarez-Moreno,2018),Ecuador0.9/1,000admissions(Zurita,2017),Uruguay0.75–1.64/1000(Macedo-Viñas,2018)andVenezuela16/100,000(Dolande,2017).Usingtheseestimatesandannualincidencefiguresof5/100,000(low),10/100,000(mid)and15/100,000(higher),wehaveestimatedcasesofcandidaemiaperyearbycountry(Table4).Thelow/midestimateforMexicoisinaccordwitharecentepidemiologicalstudyfrom4hospitals(Corzo-Leon,2018).

Bloodculturesareabout40%sensitivefordetectinginvasivecandidiasis(Berenguer,1993;Avni,2011;Nguyen,2012).Inalargeseriesofsurgicalintra-

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abdominalcandidiasis(Candidaperitonitis),only6%ofcaseshadapositivebloodcultureforCandida(Vergidis,2016).Fluconazoletherapyreducestheyieldfrombloodcultures(Kami,2002).Sowehaveassumedthattheactualincidenceofinvasivecandidiasis(IC)(includingintra-abdominalcandidiasis)is2.5xthatofdocumentedcandidaemia(Table4).

Table4.EstimatesannualincidencebycountryofCandidabloodstreaminfectionandinvasivecandidiasis,withlow,midandhigherestimates.

Invasiveaspergillosis

Invasiveaspergillosisisfrequentlymissedasadiagnosis,eveninthebestclinicalunits.Awidevarietyofpatientsareaffected,usuallyatalowfrequency,soclinicianshavetobeveryalerttoconsiderit.Thechestradiographisoftennegativeuntillateintheillnessandradiologicalfeaturesareoftennotdistinctive.Bloodculturesarealwaysnegativeandrespiratoryculturesinsensitive.Thebesttestfordiagnosisistheantigentest,buteventhisisoftenfalselynegative,especiallyinseruminnon-neutropenicpatients.Undiagnosedalmostallpatientsdie,anditisthecommonestmissedinfectioninintensivecareunitpatientsatautopsy.Treatmentwithvoriconazoleiseffectiveinabout70%ofcases.Asmultipleclinicalspecialtiesseethisillnessoccasionallyanddiagnosisrequiresmorethanonetest,surveillanceisnotstraightforwardandexpensivetoundertake.Therefore,estimatesofincidencearescanty.Inthehighestriskneutropenichematologypatients,antifungalprophylaxisisroutinelygiven,reducingcases,ifeffective.GAFFIhasmodeledthelikelyburdenofthemostwell-defineriskgroupswiththefollowingassumptions:1.TheriskofIAinacutemyeloidleukaemia(AML)patientsis10%,probablyaconservativeestimate(Chen,2018).

Country Population Rates Candidaemia IC Rates Candidaemia IC Rates Candidaemia IC2017 /100,000 total /100,000 total /100,000 total

Argentina 44.27 5 2,214 5,534 10 4,427 10,625 15 6,641 16,601Bolivia 11.05 5 553 1,381 10 1,105 2,652 15 1,658 4,144Brazil 209.3 14.9 31,186 77,964 14.9 31,186 74,846 14.9 31,186 77,964Chile 18.05 5 903 2,256 10 1,805 4,332 15 2,708 6,769Colombia 49.07 12.8 6,281 15,702 12.8 6,281 15,074 12.8 6,281 15,702CostaRica 4.906 5 245 613 10 491 1,177 15 736 1,840Cuba 11.48 5 574 1,435 10 1,148 2,755 15 1,722 4,305DominicanRepublic 10.77 5 539 1,346 10 1,077 2,585 15 1,616 4,039Ecuador 16.62 6.2 1,030 2,576 6.2 1,030 2,473 6.2 1,030 2,576ElSalvador 6.378 5 319 797 10 638 1,531 15 957 2,392Guatemala 16.91 5 846 2,114 10 1,691 4,058 15 2,537 6,341Honduras 9.265 5 463 1,158 10 927 2,224 15 1,390 3,474Mexico 129.2 5 6,460 16,150 10 12,920 31,008 15 19,380 48,450Nicaragua 6.218 5 311 777 10 622 1,492 15 933 2,332Panama 4.099 5 205 512 10 410 984 15 615 1,537Paraguay 6.811 5 341 851 10 681 1,635 15 1,022 2,554Peru 32.17 5 1,609 4,021 10 3,217 7,721 15 4,826 12,064Uruguay 3.457 16.4 567 1,417 16.4 567 1,361 16.4 567 1,417Venezuela 31.98 16 5,117 12,792 16 5,117 12,280 16 5,117 12,792Totals 622.004 59,760 149,399 75,339 180,813 90,917 227,293

Lowestimate Midestimate Higherestimate

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2.TheannualincidenceofAMLis4.7/100,000inhighincomecountries,3.8inthosewith‘mediumhumandevelopment’,and2.5inthosewith‘lowhumandevelopment’(UICC,2014).3.ThenumberofcasesofIAinallotherhematologicalmalignancy,bonemarrowfailureandlymphomacasesisthesameasforAML(Perkhofer,2010;Lortholary,2011;Chen,2018).4.IAinHIVisnotdiagnosedbeforedeathandcontributesto4%ofHIVdeaths.5.IAcomplicatesthecourseof2.6%ofpatientswithlungcancer(Yan,2009).6.IAoccursin1.3-3.9%ofadmissiontohospitalofCOPDpatients(Guinea,2010;Xu,2012).7.TheprevalenceofCOPDGOLDstage2-4andannualadmissionproportionsaredrawnfromseveralsources(Menezes,2005;Buist,2007;Crawford,2012;Caballero,2008;Jaganath,2015;Echazarret,2018).Table5.Modellingforinvasiveaspergillosisin4riskgroups:leukaemiaandlymphoma,lungcancer,HIVandCOPD.

Manyothergroupsofpatientsareaffectednotablyrheumatologicalconditions(4%riskinsystemiclupuserythematosus),othercancerpatientswhobecomeneutropenicorneedhighdosecorticosteroids,medicalintensivecareunitpatients(risk2-5%),thosewithliverfailure(4%)andthosewithsevereinfluenza(19%),aswellastransplantrecipients,especiallylungtransplantpatients.Overallthenumbersaffectedaresmall,apartfromICUunitswheresubstantialnumbersareaffected.Overallthereforetherearelikelytobeminimumof68,250patients(11/100,000)inLatinAmerica,andiftheIArateinCOPDhospitalizationisactually3.9%,thenaminimumof188,000or30/100,000.Anoutbreakofsevereinfluenzawouldgreatlyincreasenumbers.ThelowestimateforMexicoisconsistentwitharecentepidemiologicalstudyfrom4hospitals,scalednationally(7,851cases)(Corzo-Leon,2018).

Country Population AML IA HIV Lung IA COPD COPD% COPD IACOPD IACOPD IAtotal IArate2017 leukaemia IAdeaths cancer lungcancer GoldII-IV admissions admissions 1.3% 3.9% Low /100,000

Argentina 44.27 2,081 416 68 11,595 301 3,981,760 7.0 278,723 3,623 10,870 4,409 9.96Bolivia 11.05 276 55 24 862 22 765,066 10.0 76,507 995 2,984 1,096 9.92Brazil 209.3 7,953 1,591 600 34,511 897 12,645,044 20.0 2,529,009 32,877 98,631 35,965 17.18Chile 18.05 848 170 52 3,873 101 1,275,274 10.0 127,527 1,658 4,974 1,980 10.97Colombia 49.07 1,865 373 100 5,856 152 1,351,787 14.0 189,250 2,460 7,381 3,085 6.29CostaRica 4.906 186 37 16 452 12 151,342 10.0 15,134 197 590 261 5.33Cuba 11.48 436 87 18 6,914 180 1,659,993 10.0 165,999 2,158 6,474 2,443 21.28DominicanRepublic 10.77 269 54 48 1,379 36 1,502,778 10.0 150,278 1,954 5,861 2,091 19.42Ecuador 16.62 632 126 38 1,135 30 1,152,252 20.0 230,450 2,996 8,988 3,190 19.19ElSalvador 6.378 159 32 26 430 11 198,834 10.0 19,883 258 775 328 5.14Guatemala 16.91 643 129 9 392 10 426,000 10.0 42,600 554 1,661 701 4.15Honduras 9.265 232 46 22 387 10 279,992 10.0 27,999 364 1,092 442 4.77Mexico 129.2 4,910 982 140 7,811 203 3,946,982 10.0 394,698 5,131 15,393 6,456 5.00Nicaragua 6.218 155 31 9 322 8 190,340 10.0 19,034 247 742 296 4.76Panama 4.099 193 39 24 442 11 214,713 10.0 21,471 279 837 353 8.62Paraguay 6.811 259 52 25 766 20 406,136 10.0 40,614 528 1,584 625 9.17Peru 32.17 1,222 244 40 3,210 83 565,612 13.0 73,530 956 2,868 1,324 4.12Uruguay 3.457 162 32 12 1,574 41 250,346 10.0 25,035 325 976 411 11.88Venezuela 31.98 1,215 243 94 4,948 129 1,795,329 10.0 179,533 2,334 7,002 2,799 8.75

622.004 23,697 4,739 1,364 86,859 2,258 32,759,580 4,607,275 59,895 179,684 68,256 10.97

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ChronicpulmonaryaspergillosisChronicpulmonaryaspergillosis(previouslyknownasaspergilloma)(CPA)isasubtle,progressivelunginfection,usuallyfollowingTBorcomplicatingemphysema.ManyotherunderlyingpulmonaryconditionsareassociatedwithCPAincludingasthma,priorpneumothorax,sarcoidosis,rheumatoidarthritis,previouslungsurgeryorpneumoniaandnon-tuberculousmycobacterialinfections.Itleadstoserioushaemoptysis,progressivelungfibrosiswithdyspneaandgeneralsymptomsoffatigueandweightloss.ThekeydiagnostictestsareCXR(orCTscan)andAspergillusantibodyinserum(Denning,2018).CPAisfrequentlymis-diagnosedasTB,althoughmanyoftheradiologicalfeaturesaredistinctive.InLatinAmerica,chronicpulmonaryhistoplasmosis,coccidioidomycosisandparacoccidioidomycosisarealsopresent,eachalsodiagnosedpartlywithspecificantibodytests.InoneunpublishedstudyfromTBcentresinManaus,7%ofcasesofpossibleTBwerepulmonarymycoses,67%ofthesewereCPA.Asmallnumberofpatientscanundergosurgicalresection,althoughrecurrenceoccursin~25%(Farid,2013).About60%ofCPAcasesrespondstooralitraconazoletherapy,withreducedsymptoms,weightgain,reducedhaemoptysisandnofurtherfibrosis.Alternativetherapywithvoriconazoleandintravenousamphotericinorechinocandinarealsopartiallyeffective.Theannualmortalityisabout15%,with~75%ofpatientsdyingover5years,unlessactivelytreated(Lowes,2017).TheburdenofCPAisdifficulttoestimatebecauseofhistoricaldifficultiesindiagnosis,andmultipleriskgroups.AUKstudyfromthe1960’sfound~22%ofpatientswithacavityafterpulmonaryTBtohaveCPA,andthistranslated,using2005WHOTBdata,intoaglobalannualincidenceof372,000andprevalenceof1.17million(Denning,2011).Thesedataarebasedonpre-HIVTB,andnow2studiesfromAfricashowthattheprevalenceofCPAinHIVpatientsmirrorsthatinnon-HIVpatients(Oladele,2017;Page,2019).InUganda,theannualrateofCPAdevelopment2-7yearsaftersuccessfultreatmentforTBwas6.5%inthosewithcavitationand0,02%inthosewithout(Page,2019).Asco-infectedTB/HIVpatientssurvivelonger,therateofCPAwillrise.COPDisacommonunderlyingdisease(ie~30%)inpatientswithCPA,butCPAprevalenceinCOPDhasnotbeenascertained.TheestimatesofCPAinLatinAmericaarebasedonthefollowingassumptions:1.PulmonaryTBsurvivorsaretakenfromWHO2017countrystatisticsandassumea10%mortalityforTB.2.AfterpulmonaryTB,30%areleftwithcavitation,andthereisanannual6.5%CPArateinthesepatientsanda0.2%rateinthe70%withoutcavitation.3.TheannualincidenceofCPAisconvertedtoa5yearperiodprevalenceassuminganannualmortalityof15%.4.TBisassumedtobetheunderlyingpulmonarydiseasein20-50%ofCPApatients,dependingontheannualincidenceofTBinthepopulationand

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prevalenceofCOPD.Anindividualcountrymultiplierisappliedtoaccountforthis.Table6.EstimatedprevalenceofchronicpulmonaryaspergillosisbasedonTBannualincidenceandCOPDprevalence

Basedontheseestimates,theprevalenceofofCPApatientsfollowingTBinLatinAmericaisabout12,400,andtheoverallCPAprevalenceisabout33,600(5.4/100,000).ThisoverallfigureobscuresremarkablecountryvariationmostrelatedtoTBandCOPDrates.ThereareprobablyhighratesinPeru(Bustamante,2018)andBolivia(TBrelated),DominicanRepublic(TBandCOPDrelated)andlowratesinCostaRica,MexicoandCuba.Fungalasthma(ABPAandSAFS)Asthmaisaheterogenousdisorderwithmanydifferenttriggers,muchvariabilityinseverityandremarkablevariationofthecourseoflife.TheGlobalBurdenofDiseaseestimatesthatabout450,000peopledieofasthmaeachyear,andmostlyinadulthood(GAFFIRoadmap,2015).Themostproblematic10%ofasthmaticsconsumeabout70%ofhealthcarecostsinmedication,medicalandnursingvisits,attendanceatemergencyroomsandadmissionstohospital.Bothenvironmentalexposuretofungi(ieindampbuildings)andlong-termfungalcolonizationoftheairwayprecipitateasthmaforthefirsttimeandexacerbateasthmawithbothattacksandpersistentorpoorlycontrolledasthma(Denning,2014).Aproportionofthesepatientshaveallergicbronchopulmonaryaspergillosis(ABPA)andsomehavesevereasthmawithfungalsensitisation(SAFS).Bothentitiesrespondtooralantifungalmedication(itraconazoleandvoriconazole,andafewtoterbinafine),withresponserates~60%(Denning,2014;Li,2018).Betterasthmacontrol,withreducedcorticosteroiduseandimprovedqualityoflifearetheprincipalbenefits.Globallyabout4.8millionadultshaveABPA(Denning,2013).Thisassumesthat~2.5%(0.7-3.5%)ofadultsreferredtoaspecialistover1-4yearshaveABPA(6

Country Population TBincidence Pulmonary PulmonaryTB Cavitation TBCPA TBCPA COPD CPA CPA CPA2017 2,017 % survivors rate Incidence prevalence /100,000 multiplier Total /100,000

Argentina 44.27 12,000 84 9,072 0.30 190 598 899 4 2,391 5.40Bolivia 11.05 12,000 77 8,316 0.30 174 548 692 3 1,643 14.87Brazil 209.3 91,000 87 71,253 0.30 1,489 4,694 604 3 14,082 6.73Chile 18.05 3,200 81 2,333 0.30 49 154 707 3 461 2.55Colombia 49.07 16,000 83 11,952 0.30 250 787 275 2 1,575 3.21CostaRica 4.906 470 84 355 0.30 7 23 308 2 47 0.95Cuba 11.48 820 88 649 0.30 14 43 1,446 6 257 2.24DominicanRepublic 10.77 4,800 88 3,802 0.30 79 250 1,395 5 1,252 11.63Ecuador 16.62 7,200 82 5,314 0.30 111 350 693 3 1,050 6.32ElSalvador 6.378 4,600 90 3,726 0.30 78 245 312 2 491 7.70Guatemala 16.91 4,300 94 3,638 0.30 76 240 252 2 479 2.83Honduras 9.265 3,500 89 2,804 0.30 59 185 302 2 369 3.99Mexico 129.2 28,000 79 19,908 0.30 416 1,311 305 2 2,623 2.03Nicaragua 6.218 2,800 88 2,218 0.30 46 146 306 2 292 4.70Panama 4.099 2,200 87 1,723 0.30 36 113 524 3 340 8.31Paraguay 6.811 3,000 91 2,457 0.30 51 162 596 3 486 7.13Peru 32.17 37,000 81 26,973 0.30 564 1,777 176 2 3,554 11.05Uruguay 3.457 1,100 90 891 0.30 19 59 724 3 176 5.09Venezuela 31.98 13,000 89 10,413 0.30 218 686 561 3 2,058 6.44

622.004 249,007 187,795 3,925 12,371 33,626 5.41

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studiesfromIreland,NewZealand,China,SaudiArabiaandSouthAfrica)andthisrepresentsthewholecommunityofasthmatics.Itcouldbothunder-andover-estimateprevalence.Itislikelyanunder-estimateforIndiawherethisdiseaseismorecommon.ABPAalsooccursinchildrenbutisprobablyuncommon.SAFSisestimatedtoaffect~6.5millionadults(range3.25-13million)worldwidedependingonthefrequencyofsevereasthma(5-20%ofallasthmatics).Again,thisentityprobablyoccursinchildrentoo,butispoorlydocumented.ForLatinAmerica,estimatesforABPAandSAFShavebeenmade,intheabsenceofanyepidemiologystudiesfromthewholecontinent.Theassumptionsmadeareasfollows:1.AdultasthmaprevalenceistakenfromtheWHOWorldHealthSurveyin2002-2003byToetal(2012),Carrasco(1987)forVenezuela,andindividualcountryburdenpaperspublishedforArgentina(Riera,2018)Chile(AlvarezDuarte,2017),DominicanRepublic(Gugnani,2016)andUruguay(Macedo-Vinas,2018).2.ABPAprevalenceisassumedtobe2.5%(Denning,2013).3.Fungalsensitisationprevalenceinsevereasthmaisassumedtobe33%.4.Severeasthmaaffects10%oftheadultasthmapopulation,soSAFSprevalenceisestimatedat3.3%ofadultasthma.5.Thereisa25%overlapbetweenABPAandSAFS,sotheoverallnumberoffungalasthmacasesisreducedby25%.Table7.EstimatesoftheprevalenceofABPAandSAFSandallfungalasthmainadultsinLatinAmerica.

Theestimatesaboverelyonoldestimatesofasthmaprevalenceformanycountries.Asthmaseverityoftenincreaseswithageuptoabout70yearsandoftenco-existswithCOPDinolderadults.SkintestsurveysoffungalallergyareuncommoninLatinAmerica(Twaroch,2015)(Figure4).Figure4.Countrieswhereallergyskintestinghadbeendoneandpublishedupto2014(Twaroch,2015).

Country Population Child Adult Adultasthma Adultasthma ABPA SAFS Fungalasthma Fungalasthma2017 population population % n n n adjusted /100,000

Argentina 44.27 0.25 33.2025 13.94 4,628,429 115,711 152,738 201,337 455Bolivia 11.05 0.36 7.072 2.13 150,634 3,766 4,971 6,553 59Brazil 209.3 0.25 156.975 12.94 20,312,565 507,814 670,315 883,597 422Chile 18.05 0.23 13.8985 5 694,925 17,373 22,933 30,229 167Colombia 49.07 0.33 32.8769 6.33 2,081,108 52,028 68,677 90,528 184CostaRica 4.906 0.24 3.72856 2.39 89,113 2,228 2,941 3,876 79Cuba 11.48 0.172 9.50544 9.97 947,692 23,692 31,274 41,225 359DominicanRepublic 10.77 0.31 7.4313 9.97 740,901 18,523 24,450 32,229 299Ecuador 16.62 0.285 11.8833 2.13 253,114 6,328 8,353 11,010 66ElSalvador 6.378 0.321 4.330662 2.42 104,802 2,620 3,458 4,559 71Guatemala 16.91 0.4 10.146 2.42 245,533 6,138 8,103 10,681 63Honduras 9.265 0.324 6.26314 2.42 151,568 3,789 5,002 6,593 71Mexico 129.2 0.29 91.732 2.39 2,192,395 54,810 72,349 95,369 74Nicaragua 6.218 0.345 4.07279 2.42 98,562 2,464 3,253 4,287 69Panama 4.099 0.261 3.029161 2.42 73,306 1,833 2,419 3,189 78Paraguay 6.811 0.3 4.7677 6.4 305,133 7,628 10,069 13,273 195Peru 32.17 0.28 23.1624 6.4 1,482,394 37,060 48,919 64,484 200Uruguay 3.457 0.22 2.69646 10 269,646 6,741 8,898 11,730 339Venezuela 31.98 0.29 22.7058 6.4 1,453,171 36,329 47,955 63,213 198Totals 622.004 622.004 36,274,989 906,875 1,197,075 1,577,962

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