Opportunistic Infections in Aids Patients...Opportunistic Infections in Aids Patients Abstract Individuals infected with human immunodeficiency virus (HIV) often develop multiple complications

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ARCHIVES OF MEDICINE2015

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Nayara de Arruda Caceres, Mateus Mazorra Coelho Vieira,Igor Fiorese Vieira, Vanessa Figueiredo Monteleone, Luiz Jorge Moreira Neto, Simone Bonafe

DepartmentofInfectiousDiseases,MedicalSchool,CentroUniversitárioCesumar–UniCesumar,Maringa-PR,Brasil

Corresponding Author: SimoneMartinsBonafe

Department of Infectious Diseases, Medi-cal School, Centro Universitário Cesumar – UniCesumar, Maringa, Parana, Brazil

[email protected]

Tel:44-32244065

Opportunistic Infections in Aids Patients

Abstract Individuals infected with human immunodeficiency virus (HIV) often developmultiplecomplicationsandcomorbidities,amongthem,opportunisticinfections.The highest incidence of opportunistic infections was reported in the groupof patients with CD4 lymphocyte levels below 200 cells / mm. Candidiasis,toxoplasmosisandpneumocystispneumonia(PCP)werethemainrepresentatives.Candidiasis and pneumocystosis are fungal infections caused by Candida sppagents and Pneumocystis jirovesi respectively, while toxoplasmosis is causedbyToxoplasmagondii. Candida spp. is present in theoralmucosaof human ina commensal way and when the individual becomes immunosuppressed, itbecomespathogenic.ThemainmanifestationoforopharyngealcandidiasisinHIV-infectedindividualsispseudomembranouscandidiasischaracterizedbyyellowish-white plates easily removable; esophageal candidiasis presentswith dysphagiaand chest pain. The diagnosis is predominantly clinical, and oral fluconazoleremainsthetreatmentofchoice.ItisbelievedthatPCPoccursbyareactivationofalatentinfection,persontopersontransmissionandeventhroughenvironmentalsources.Itischaracterizedbyaninsidiousonsetwithprogressivedyspnea,fever,nonproductive cough and chest discomfort that getsworse over theweeks. Abronchoscopywith bronchoalveolar lavage is the gold standard diagnosis. Thetreatment with trimethoprim-sulfamethoxazole is the recommended first linechoice,prophylaxis shouldalsobeperformedwith the samedrugwhenCD4+lymphocytes<200cells/mm³.TransmissionofT. gondiioccursbydirectingestionofoocysts,byingestionofraworundercookedmeat,throughbloodtransfusion,organ transplant or via the placenta. It is believed that the toxoplasmosis inimmunocompromised individuals, usually results from reactivation bradyzoitescysts.Thesymptomsincludeheadache,confusionoralteredmentalstatus,fever,lethargy, seizures, among others. Diagnosis ismade from clinical, imaging andserology tests. The treatment of choice, a combination of pyrimethamine andsulfadiazineandprophylaxiswithtrimethoprimandsulfamethoxazoleshouldalsobeperformedwhentheCD4+Tlymphocytes<200cells/mm³.Currentknowledgeabout the epidemiology, clinical features and treatment of these diseases isimportantinthemanagementofpatientswithHIVandisthefocusofthisreview.

Keywords: Opportunistics Infections, Pneumocystosis, Oral-esophagealCandidiasis,NeurotoxoplasmosisandAIDS

IntroductionThe pandemic of human immunodeficiency virus (HIV) is oneof the biggest health crises ever faced by mankind. Overall,34.0 million people were living with HIV at the end of 2011.Sub-Saharan Africa remains the most severely affected, withalmost1in20adults(4.9%)livingwithHIV[1].InBrazilbetween1980 and 2012672 697 cases of AIDSwere recorded [2]. AIDS

(acquired immunodeficiency syndrome) appeared epidemicallyinthe1980’s.Itisanadvancedclinicalmanifestationofinfectionwithhumanimmunodeficiencyvirus(HIV),characterizedbylowlymphocytecountCD4+below200/mm³[3].

Patientswithhumanimmunodeficiencyvirus(HIV)infectionoftendevelopcomplicationsandmultiplecomorbidities,amongthemopportunistic infection(OI).Theymustalwaysbeconsideredinsymptomatic patients with HIV / AIDS [4]. Before widespread


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useofpotentcombinationoftheantiretroviraltherapy(HAART),opportunisticdiseases,whichweredefinedasinfectionsthataremore frequentormore severebecauseof immunosuppressionin HIV-infected people, were the leading cause of morbidityandmortalityinthepopulationduringthenaturalcourseofthedisease [5]. The relationship betweenHIV andOIs is basedonimmunosuppression[6].

Fromthemid-90s,thewidespreaduseofHAARTdeeplyinfluencedthe reduction of mortality associated with OI in HIV-infectedpatients, incountrieswherethesetherapiesareaffordableandcheap [5,7].Despite theHAARTera, theOIs continue to causeconsiderable morbidity and mortality in HIV-infected patients.This is due to three primary reasons: asymptomatic patientsseekmedicalassistanceonlywhenanOIbecomesanindicatorofAIDS;otherpatientsdonotmakeuseofHAARTforpsychosocialandeconomicfactors;andtherearestillthosewhodonothaveagoodresponsetoantiretroviralagentsduetopooradherence,drugtoxicity,druginteractionsorunexplainedbiologicalfactors[8,9]. The highest incidence of opportunistic infections wasreported in the group of patients with CD4 lymphocyte levelsbelow 200 cells / mm³ [10]. Studies show that the major co-morbidities associated with AIDS are candidiasis, followed bytuberculosis, pneumocystosis, toxoplasmosis, herpes, Kaposi'ssarcoma,cryptococcosis,andinfectionsbyprotozoa[11].

Therefore, early recognition and propermanagement of thesemajor OIs by health professionals are strictly necessary toreduce themorbidity andmortalityofpatientswithHIV. Thus,thepresentliteraturereviewaimstoaddressthemajordiseasesin the gastrointestinal tract, respiratory and central nervoussystem thatmanifest in patients with AIDSwhen the CD4 + Tlymphocytesarebelow200cells/mm³,whichare:candidiasis,pneumocystosisandneurotoxoplasmosis[12,10].

PneumocystosisIntroductionThe PCP is an opportunistic infection caused by PneumocystisJirovesi. Often affects the immunosuppressed, particularlyindividuals with Acquired Immune Deficiency Syndrome(AIDS) [13]. The etiologic agent rarely produces disease inimmunocompetentindividuals,butcausesseverepneumoniainindividualswithavarietyofdebilitatingmedicalconditions[14].ItisbelievedthattheinitialinfectionwithP.jiroveciiusuallyoccursinearlychildhood;two-thirdsofhealthychildrenhaveantibodiestoP.jiroveciibetween2and4yearsofage[15].

EpidemiologyPneumocystiswasoriginallyreportedbyCarlosChagas(Brazil)atthebeginningofthetwentiethcentury,morepreciselyin1909,when he observed the never before identified morphologicalforminthelungtissueofaguineapigbeingusedforthestudyofhumanamericantrypanosomiasis,mistaking itasoneoftheformspresentinastageofTrypanosomacruzi’slifecycle.Soonafter, Antonio Carini described similar structures in the lungtissueofmice infectedwithTrypanosoma lewisiandsuspectedthat the morphological form could be a new microorganism.In1912,atthePasteur Institute inParis,amoredetailedstudy

of the content from the Carini investigationwas conducted bythe coupleDelanoë. Thus, itwas confirmed that itwas a newbiological entity, by observing the samples sent by Carini andalsobyidentifyingthesestructuresinthelungsofmicewithoutinfectionwithTrypanosoma.Thisdistinctspecieswasdesignateda Pneumocystis, because it was isolated in the lung, with thespecific restrictive carinii, honoring Antonio Carini, who hadallowedsuchaninvestigation[16-18].

Themicroorganismwas classified then as protozoa until 1980.This opinion was based on the following criteria: 1) strongsimilarityofthemicroorganismmorphologyandpathologyinthehost;2)absenceofsomephenotypiccharacteristicsoffungi;3)presence ofmorphological characteristics typical of protozoan;4) ineffectiveness of antifungal drugs against the agent; 5)effectiveness of drugs commonly used to treat protozoa [19].Thus, in 1988 by DNA analysis, it was demonstrated that thePneumocystisisafungus.Afterappropriateclassification,geneticstudiesrevealeddifferentsequencesindifferentmammals,andwasfoundthatPneumocystisinhumansisdifferentfromthatinotherspecies.Therefore,in1999,FrenkelproposedchangingthenameoftheorganismthatcauseshumaninfectionPneumocystisjiroveci,namedaftertheCzechparasitologistOttoJirovec,whodescribedthemicroorganisminhumans[20,21].

P. jirovecii is an opportunistic pathogen, ubiquitous unicellulareukaryote, hard to be cultivated andwith specificity restrictedto humans. According to their biological characteristics andbecause of its tropism for the lung, P. jirovecii usually causessevere interstitial pneumonia, known as PCP or Pneumocystispneumonia (PCP) in the immunocompromised and, as a rule,asymptomaticinfectionintheimmunocompetent[22,23].

This fungus was recognized as a potential infectious agent tohumans only in the 30s and 40s of the last century, when hewasdeemedresponsibleforseveralcasesofdiseaseandsomeinterstitial pneumonia outbreaks in premature infants andmalnourished children, a result of extreme social difficultiesdue toWorldWar II [24]. It was themost common causativeagent of interstitial pneumonia in immunocompromisedchildrenbyprimarycausesandalso in individuals treatedwithimmunosuppressivedrugsafterorgantransplantationorforthetreatmentofmalignancies,particularlylymphoreticularandthecollagenases[25].

Although there was awareness that PCP caused pneumoniain immunocompromised patients, this problem assumedalarming proportions in the 1980s with the emergence ofAcquired Immune Deficiency Syndrome. During this period,70%to85%ofthoseinfectedwithhumanimmunodeficiencyvirus (HIV) developed pneumocystosis, being it the primaryopportunisticinfectionfoundintheseindividuals[26,27].Thefirst report related to a potential human immunodeficiencysyndrome occurred in 1981, when the Centers for DiseasePrevention and Control (CDC) confirmed the first cases ofpneumocystisinfiveyounggaymeninthecityofLosAngeles,raising thepossibility of an immune cell dysfunction (still ofunknownetiology),which later came tobe calledAIDS [28].Since then, considering the epidemiological context thatfollowed,pneumocystosisgainedhugeimportance,becoming


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oneoftheprioritiesintheepidemiologicalandclinicalperspectiverelatedtoHIV-infectedpatients’monitorization[29].

In industrialized countries, due to the widespread use ofpneumocytosisprophylaxis,established in theearly90sand tothe establishment of Antiretroviral Therapy (HAART) in 1996,patients had an improvement in immunity and a decrease inmortality from this infection [17]. This evolution has resultedin reduced incidence of PCP and increased life expectancy inpatientswith pneumonia. However, PCP remains an importantclinical problem, remaining as a major opportunistic infectionthat affects individuals infectedbyHIV [29].Highprevalenceofthe disease is still found in individualswho do not respond totreatment(HAART),inthosewhodonotadheretothetreatmentand/orprophylaxisandHIVpositive individualswhohavenotbeen diagnosed. The incidence is also high in countrieswherethe HIV carriers do not have access to effective antiretroviraltreatment[30,31].

TheEuropeanSurveillanceReportonHIVin2012,oftheEuropeanCentre for Disease Prevention and Control (ECDC) and theWorldHealthOrganization(WHO)showedthatintheEuropeaneconomicspace,in2012,themostcommonAIDS-definingdiseasewaspneumocystosis,with25%ofcases,followedbyesophagealcandidiasis with 13% and pulmonary tuberculosis with 10%,thusdemonstratingthat thePCPremainsacauseofsignificantmorbidityandmortalityinHIVpatients,evenafterHAART19.

PathogenesisThe transmission of pneumocystis pneumonia (PCP) is notcompletely understood, nor has its environmental niche beenfullyidentified.Fordecades,thetheoryofreactivationoflatentinfection - in which the Pneumocystis remained latent in thebody and cause diseasewhen the immune systemhas failed -waspopular.Currentlythereisevidencethattransmissionfrompersontopersonisthemostlikelywayofgettingnewinfections,although acquisition by environmental sources can also occur[32].The infectiondoesnotpromoteprotective immunity,andrecurrenceoccurs inupto50%ofcasestreated,mostlyafterayearofprimary infection[33].Riskfactorsassociatedwithhighrisk forPCP includepercentageofCD4+T lymphocytes<14%,previous episodes of PCP, oral candidiasis, recurrent bacterialpneumonia, intentional weight loss and high plasma HIV load[34].

Pneumocystis jirovesi can colonize the respiratory tract of anindividualwithout causing any signs or symptomsof infection;although the clinical significanceof colonization isnot yetwellunderstood,patientswhoarecolonizedwiththefunguscanserveasapathogenreservoir.Theymayalsobeatriskfordevelopingpneumoniaortransmitingthefungustoothers.Individualswhoare undergoing anti-Pneumocystis prophylaxis may developcolonization due to the selection of mutations that may beassociatedwithanti-microbialresistance[35].

Pneumocystishasanincubationperiodof3to12weeks[36].Itfeaturesauniquetropismforthelung,whereexistsmainlyasacellularpathogenwithout invading thehost [37].Regardlessofits sourceof transmission, infection is initiatedby the invasionof fungic propagules on type I pneumocytes in alveoli [38],

causinganintra-alveolarpneumonitisbyoccupyingtheairspacewith exudate rich in protein and trophozoites. The result is anarteriovenous intrapulmonary shunt, thickening and disruptionof the cellularmembrane and parenchymal inflammationwithsubsequentmononuclear infiltrate,alveolaredemaandfibrosis[39].

Theinflammatoryresponseinthelowerrespiratorytractismuchdiminished in AIDS patients when compared to the responsein immunosuppressed individuals without AIDS, which isconsistentwith the fact that the fungal load in the lungtissueismuchhigher in individualswithAIDSwhencompared to theimmunosuppressedwithoutAIDS[40].

ThePCPischaracterizedbysevereneutrophiliclunginflammationwhich may result in diffuse alveolar damage, impaired gasexchangeandrespiratoryfailure. Infact,respiratoryfailureanddeatharemorerelatedtothedegreeofinflammationofthelungthantheloadofthemicroorganisminpneumonia[41].

Clinical Apresentation and DiagnosisPneumoniabypneumocystisjirovesiis,inmostcases,theAIDS-definingillnessinHIV-infectedpatients,anditoccursmoreoftenwhentheThelpercellcount(CD4+)islessthan200cells/mm³[42].

In HIV infected patients, PCP generally has a more subacutecourse and a bigger duration of symptoms than in otherimmunocompromisedpatients[43].Theclinicalmanifestations,mostoftenhaveaninsidiousonsetwithsymptomsthatcanlastfor weeks to months before requiring hospitalization. It startswith progressive dyspnea, fever, non-productive cough andchestdiscomfortthatgetsworseovertheweeks[26,44].Typicalphysical examination finds are tachypnea, tachycardia and nochanges in lung auscultation. In up to a third of cases, breathsoundsmayappear,and30%to40%presentswithauscultationcrackles,alatefindingthatsuggestsgreaterseverity[35,33].OthermanifestationsassociatedwithpatientswithHIVareextremitycyanosis,weightloss,nightsweats,chillsandretrosternalchesttightness[39,21].

Oral candidiasis is themost common co-infection, constitutinganalmostuniversalfinding. Fever ispresent in themajorityofcasesanditmaybethepredominantsymptominsomepatients[26,21]. Facial seborrheic dermatitis is also common. Someinfrequentsymptomsmayoccur,suchasfeverofunknownoriginwith few respiratory symptoms or even its absence and extra-pulmonary infectionbyPneumocystis jiroveci. Extra-pulmonarydisease is rare, but can occur in any organ, especially the ear,eyes,thyroid,spleen,gastrointestinaltract,peritoneum,liverandpancreas,andhasbeenassociatedwiththeuseofpentamidineaerosolforprophylaxis[21,26].

Intheearlystages,often,allexamsareunaltered,includingchestX-rays,whichareusuallynormalin5%to10%ofcases.Thisdoesnotexcludethediagnosis,whichshouldstillbeconsideredespeciallywhenCD4+Tcellcount is lessthan200cells/mm3[45].Themostcommonradiological imageforPCPisastandardbilateralinterstitial infiltration pattern that becomes homogeneous anddiffusewiththeprogressionofthedisease,however,itmayvary


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dependingonthedegreeofimmunosuppression,thepresenceofotherconcomitantinfectionsoruseofpentamidineprophylaxisregarding pneumocystis [46]. Less common findings includemiliary pattern, heterogeneous infiltration, solitary or multiplenodules, consolidation of focal or diffuse airspace (usuallyoccur inmoreadvancedstagesofthedisease),andupper lobeinfiltratesinpatientsreceivingaerosolizedpentamidine[39,46].

Evenlessoften,thePCPmaypresentwithunilateralorasymmetricopacities.Thinwallscystsorpneumatocelesareseenin10-20%ofcases.Pneumothoraxmayoccur;infact,HIV-infectedpatientswith pneumothorax should be suspected for PCP. Cavitation,intrathoracic lymphadenopathy and pleural effusion are rare;their presence can indicate an alternative diagnosis [47-49].In the presence of an unaltered chest radiograph, computedtomography(CT)ofhighresolutioncanbeuseful[46].Thehigh-resolutionCThashighsensitivity(100%)andspecificity(89%)toPCP[48].AnegativeresultcanallowtheexclusionofPCP.

A CT scan can diagnose the disease previously undetected byconventional radiographs, suggest the coexistence of othernosologicalentities,showcharacteristicorsuggestivesignsofaspecificdiseaseandguidethebiopsysite.ThemostcharacteristicCTfindinginthesepatientsisthepresenceofareaswithground-glassattenuation,iehomogenousincreasedattenuationwithoutobscuringvascularimages.Ageographicalpatternormosaic,withnormalsecondary lobesadjacenttodiseasedones,canalsobeseen. Thefindingof this pattern in a patientwithAIDS is verysuggestiveofPCP.Thepresenceofcystsisalsoacommonfinding.The distribution can be diffuse or predominate in the upperlobes.Furthermoreatypicalmanifestationsofthediseasecanbefound, including isolated lobar disease, parenchymal opacitieswith focal nodules, nodules or excavated masses, miliarypattern,endobronchiallesions,pleuraleffusionsandhilarand/ormediastinal lymphadenopathy.Pleuraleffusion is rare,beingnoticed, in general, on patients under chemoprophylaxis [50].Thepresenceofsignificantpleuraleffusionand/orintrathoraciclymphadenopathy suggest the association of other infectiousdiseasesornon-infectious,likeKaposi'ssarcoma,tuberculosisorlymphoma[39].

The most prominent histopathological finding is the presenceof foamy intra-alveolar exudate. It refers to a proteinaceousfluid containing parasites, fibrin and cellular debris. It is thisaccumulation of fluid that is responsible for the frosted glasspattern formation in the tomography. Thickening of theinterlobular areas within the frosted glass may also occur,leading to edema and interstitial infiltration by mononuclearcells. The frosted glass pattern in association with thickenedinterlobular septa originates the pattern of paving tile. Withdisease progression, airspace consolidation areas can be seen.Thepresenceofcysticspaces iscommon.Cystscanberoughlydividedintotwotypes:Subpleuralandintraparenchymal.Cysticlesions have a predilection for the upper lobes and subpleuralregions,andtheremaybespontaneouspneumothorax[50].

The blood count reveals lymphopenia as the most commonfinding.Otherhematological abnormalities suchas leukopenia,anemia and thrombocytopenia can also occur [39]. The mostcommon laboratory abnormality associated with PCP in HIV-

infected patients, present in 90% of cases, is the high levelof lactate dehydrogenase (LDH), it being significant for theprognosis [51]. However, a high level of LDH can occur withother pulmonary diseases, especially mycobacteria and fungalinfections.Recently, lowlevelsofS-adenosylmethionineplasmawereshownassensitiveandspecificindicatorsofPCP.Moreover,the levels increasedwith thesuccessful treatmentofPCP [52].ProbablytheincreaseinLDHitismoreareflectionofunderlyinglunginflammationandattackratethanaspecificmarkerforthedisease [39,46]. However, LDH levels above 500 IU / l, due toinitialmanifestationsareassociatedwithanincreasedriskoffatalevolution[47].

Regarding exercise oximetry, we can observe a decrease inarterialO2saturationduringcontrolledphysicaleffort;however,thistestisseldomusedinourmidst.Arterialbloodgasanalysisis mandatory and provides important information, being thefinding of PaO 2 <60 mmHg very suggestive, showing severehypoxemiathatsometimesdoesnotreflecttheclinicalstatusofpatient [47].Otherfindings includehypocapniaandrespiratoryalkalosis. Hypoxemia and hypocapnia may occur even beforethe appearance of lesions on chest radiography. It also servesto assess severity andmonitor the progression of the disease[39].Theepisodesareconsideredmildwhen thePaO2 (partialpressure of arterial oxygen) is above 70mmHg or A-ADO2 (ofalveolar-arterialoxygendifference)isbelow35,whileinmoderatetosevereepisodesPaO2isbelow70mmHgorA-ADO2isabove35[21].

Becausethemicroorganismcannotbecultured,PCPisdiagnosedby directmicroscopic examination of sputum, bronchoalveolarfluid or pulmonar tissue [46]. A sputum analysis induced byhypertonicsalineinhalationistheleastinvasiveandfastermethodavailable. However, as most of these patients do not producesputumspontaneously, thisnoninvasive initialapproachcanbedifficult.Whilethespecificityofthismethodapproaches100%,thesensitivityrangesfrom55%to92%[31,53].Abronchoscopywith bronchoalveolar lavage (BAL) is the gold standard fordiagnosing PCP, with a reported sensitivity of 90-98% [31].However, bronchoscopy requires specialized personnel, roomsand equipment, is expensive and carries a risk of associatedcomplications.Thus,bronchoscopyislimitedlyavailableinmanyareasoftheworldwhoareburdenedwithHIV/AIDS;thereforeanon-invasiveprocedurefordiagnosingPCPwouldbeasignificantclinicaladvance[54].

Theuseofpolymerasechainreaction(PCR)hasbeenshowntohavegoodsensitivityandspecificityforthediagnosisofPCPininducedsputum samples and washed broncoalveolar fluid [46]. UntilthepresenttimePCRhasnotreplacedtheclinicalmicrobiologymethods for thedetectionof fungus inbronchoalveolar lavageor induced sputum. The clinical significance remains underinvestigation,mainlyduetothefalse-positives[34].

The open lung biopsy is rarely necessary [39]. Its indicationshouldbelimitedtoinfrequentandwelldefinedsituations,suchas:a)patientwithdiffuselungdiseasethatdoesnotmanagetoinduce sputum and with negative bronchoalveolar lavage andtransbronchialbiopsy;b)patientwithableedingdisorder,whereinthe washing was negative; c) patients requiring mechanical


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ventilation and inwhom both, thewashed and transbronchialbiopsy, were negative. Even in these situations, it is advisabletoholdasecondbronchoscopywithbiopsyandwashingbeforeproceedingtotheopenbiopsy[46].

Cases of immunosuppressed patientswith insidious fever lungdisease demands further investigation of possible differentialdiagnoses, such as lung diseases caused by mycobacterialinfections, pulmonary toxoplasmosis, fungal infections, CMVdisease and cancer, that often have indistinguishable clinicalpresentationandradiologicalcharacteristics[39,55].

Patients with clinical manifestations of PCP associated to anincreasedriskoffataloutcomeconsistsofelevatedserumLDH>500IU/l,PaO2<70mmHgorA-ADO2>35,lowconcentrationsof triiodothyronine (T3) and T3 reverse more than 5% ofneutrophilsinbronchoalveolarlavage,leukocytosis>12,000cells/mm3,albumin<2.8g/dL.PreviousepisodesofPCPand/orrecurrent pulmonary infections are also associatedwithworseprognosis[39,21].

TreatmentTreatment of PCP is guided by the patient’s clinical severity 50.Thus,fortherapeuticpurposes,werankthePCPasmild,moderateandsevere.Sulfamethoxazolewithtrimethoprim(SMX+TMP)isthe recommendedfirst-line treatment forHIV-infectedpatientswithmild,moderateorseverePCP,beingtheintravenoustherapygenerallyrecommendedforpatientshospitalizedwithmoderateto severediseaseand theoral therapy recommended fornon-hospitalizedpatientswithmildcases[26].

In cases of mild to moderate pneumonia (PaO2 ≥ 70 mmHg),it is used SMX+ TMP,with 15-20mg trimethoprim / kg / day,orally,everysixtoeighthoursfor21days.Thealternativeregimein caseof intolerance to sulfa is 300mgof clindamycin,orally,everysixhoursplus15-30mgofprimaquine,orally,oncedailyfor 21 days. In themoderate to severe pneumonia (PaO2 <70mmHg) the choice routeof administration is intravenous. Thechangeofintravenoustooraladministrationmustbeperformedwhenthereisclinicalimprovement.Theregimeofchoiceistheassociation of sulfamethoxazole + trimethoprim (5 mg / kg oftrimethoprim), intravenously,every six toeighthours.The full-treatingtime is21days.600mgofClindamycin, intravenously,everysixtoeighthoursplus15-30mgofprimaquine,orally,oncedailyorpentamidine4mg/kg/day,intravenously,for21daysarethemainalternativeschemesincaseofintolerancetosulfa[56].

Adjuvant corticosteroids are associated with the treatment ofPCPwhenPaO2<70mmHginairoralveolar-capillarygradient>35mmHg.ThemostcommonassociationisofPrednisone40mgorally twicedaily forfivedays,halvingeveryfivedaysuntil thecompletionofthetreatmentat21days.Alternatively,onemayuse intravenous methylprednisolone equivalent to 75% of thedoseprednisone.Theinitiationoftreatmentwithcorticosteroidsshould be performed at the same time as the PCP therapy[56,25].ThedrugofchoiceforthetreatmentofPCPforchildren isalsoSMX+TMP.Adjuvanttherapywithcorticosteroidsisalsoindicatedinthispopulation[57].

ProphylaxisSMX+TMParethedrugsofchoice forprimaryandsecondaryprophylaxisagainstPCP.AdolescentsandadultsinfectedwithHIV,includingpregnantwomen,shouldreceivePCPprophylaxisiftheirCD4+cellcountisbelow200cells/mm3oriftheyhaveahistoryoforalcandidiasis(primaryprevention)andafteranepisodeofPCP(secondaryprophylaxis)[50].HIV-infectedchildrenwithCD4+ lymphocyte count of less than 200 cells /mm3 or less than15%,children1-5yearsonCD4+lessthan500cells/mm³orlessthan15%andallHIV-infectedchildrenyoungerthan12monthsregardlessofCD4+countshouldreceivechemoprophylaxis[58].Childrenbornfrominfectedmothersshouldreceiveprophylaxisbetween4and6monthsofage[57].

Thepreferentialtreatmentisonetabletof400-800mgtwicedaily.Alternativeregimensincludedapsonewithorwithoutleucovorinand pyrimethamine, atovaquone suspension and aerosolpentamidine.Oncestarted,thePCPprophylaxisisrecommendedforlife,butitcanbestoppedinadolescentsandadultswithHIVinfectionwho responded to HAARTwith an increase in CD4 +lymphocyte count tomore than 200 cells /mm³ for at least 3months[26].

Oral-Esophageal CandidiasisIntroductionOral- esophageal Candidiasis is a fungal infection, caused byCandida sp,withC.albicansbeing thespeciesmostcommonlyisolated.Thisfungusnormally livesinmucosasandonlycausesdisease when there are pre-existing conditions that favors itsgrowth, the so called predisposing factors. It’s estimated that30to50%ofpeoplepossessthemicroorganismintheirmouthswithout evidence of clinical infection. The incidence increaseswithage,beingnear60% inpatientsover60yearsofage thathaveteeth[59].

Oropharyngealcandidiasis(OPC)andoral-esophagealcandidiasis(OEC)arebyfarthemostcommonfungal infectionsinpatientsinfectedbythehumanimmunodeficiencyvirus(HIV)oracquiredimmune deficiency syndrome (AIDS). They are indicators ofprofound immunodeficiencyandaremore frequentlyobservedinpatientswithTCD4+ lymphocytecountof<200cells,beingOECfoundinamoreadvancedstageofAIDSthanOPC[60,61].The prolonged course of infection by the HIV predisposes thepatientstorecurringepisodesofcandidiasisthatcanincreaseinfrequencyandseverityduringtheHIVdisease[62].

EpidemiologyCandidaspp.colonizestheskinandthemucosalmembranesofthe genital and gastrointestinal tract aswell as the oral cavityin a healthy individual under normal conditions [63]. The oralcavity is colonized in about 40-60%of healthy people. InHIV+individuals, theasymptomaticcolonization rate ishigher,beingapproximately 76% [64]. The colonization by Candida and theinvasive oral cavity infectionoccursmore often inHIV positivepatients [65]. The genus Candida is currently classified in theSaccharomycetes class and Saccharomycetaceae family basedinitsgenesequence[66].ThegenusCandidaiscomprisedofa


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dichotomous unicellular yeast speciemeasuring approximately2 to 6 μm that reproduces by budding, being able to groweitherasyeastorasapseudohypha;mostofthespeciesformspseudohyphas and hyphas in the tissues. The colonies vary incolor fromwhite to tanand they canhaveeither a smoothorroughsurface[67-69].

In fact,oropharyngeal candidiasis is theopportunistic infectionmostfrequentlyfoundinindividualsthathaveAIDS.Thediseaseoccursinupto90%ofpatientsduringtheprogressionoftheHIVinfection.TheoccurrenceofOPC,besidesbeingassociatedwithTCD4+lymphocyteslevelunder200cells/mm3,isalsocorrelatedtoahighviral load (>10.000copies/ml)andtotheHIVdiseaseprogression [70,71]. Although the C.albicans species seems tobeprevalentinOPC,theepidemiologyofthisinfectionisrapidlyevolvingandnon-albicansCandidaspecies,aswellasrareyeastforms, are appearing as themain opportunistic pathogen. Themost commonnon-albicansCandida speciesareC. glabrata,C.parapsilosis,C.tropicalisandC.krusei.,oftenisolatedinoralandsystemiccandidiasis[72,73].

In a Brazilian study done with 80 HIV+ individuals , in whichwerecollectedsalivasamplesandcandidiasis lesionsamples(7patientswithOPC), theC.albicanswas thespeciesmostoftenisolated in both, the saliva of patientswithout clinical lesions(49%)andpatientswithoropharyngealcandidiasis.Amongthenon-albicans,C.glabratawasthespeciesmostfrequentlyisolated[74].AccordingtoREDDINGetal.,theC.glabrataemergedasanotablepathogen in theoralmucosa,being itasaco-infectingagentwithC.albicansoras theonlydetectablespecies inorallesions. Furthermore, the C. glabrata associatedwith candidaoropharyngeal infections in HIV positive patients tend to bemoresevereanddifficult totreatthan infectionsexclusivelybyC. albicans [75]. Other studies also show predominance of C.albicansintheirsamples[76,77].

Esophageal candidiasis is themainAIDS- defining disease, anditsprevalencevariesfrom10%to16%.Inacontrolgroupstudywithpatients infectedby theHIV, theprevalenceof caseswasof25,3%intheHIVinfectedpatientsandof0.9%inthecontrolgroup(patientsnotinfectedbytheHIVsubmittedtoanupperGItractendoscopy)[78].Inthisstudy,C.albicanswastheonemostfrequentlyisolated(93,5%).IntheesophagusC.albincanswasthemicroorganismmostoftenisolated,followedbyC.dubliniensis,C.glabrata,C.kruseiandC.tropicalis[79].

With access to antiretroviral therapy, the incidence oforopharyngeal and esophageal candidiasis has declined inHIV infected patients. However, such diseases continue to bea significant problem in places with limited resources or forthosewithapoor immuneresponse,despite the realizationoftreatment[80,81].

PathogenyCandida lives as a commensal yeast in the human organism.However,underimmunocompromisingconditionstheincidenceasacarriercan increaseandrapidconversionstosymptomaticinfectionscanoccur[82].Theprotectionsagainsttheconversionfrom colonizing yeast to opportunistic/ invasive pathogen areprovidedbyboth,thesystemicandlocalimmunity.TheTh-1type

immunityprovidedbyTCD4lymphocytesisacriticalprotectioncomponent, and the secondary defense is provided by TCD8lymphocytesandoralepithelialcellsbyavarietyofmechanisms[83].

TheTCD4+anti-candidaprotectionmechanism,inamucosalevel,is not yet entirely comprehended. Recently, researchers haveshown that cytokines, especially interferon gamma, can inhibitthetransformationofcandidablastoconideatothemoreinvasivehyphaephase[84].Moreover,variousresearchersshowedthatthedecrease in levels of E- cadherin and a loss of TCD4+ cellsin themucosaareassociatedwithacuteepisodesofOPC [85].Themost commonlydescribedcauseofahigh rateof yeast intheGItractandoforalcandidiasisisantibioticsuse[84,86].Theeradicationofbacterialcompetitionis,almostcertainly,themostimportantmechanismbywhichtheantibioticsaffectthecandidaquantityinvivo.

It is believed that various secondary lines of defense areimportantfortheprotectionagainstcandidawhentheprimarydefensedonebytheTCD4+cells is insufficient.Thissecondaryline of defense includes T CD8+ cells and oral epithelial cells.In individualssusceptibletoOPC,theTCD8+cellsmigrationtooutsidetheepithelialtissueisinhibitedbecauseofthereductionofE-cadherinwithsubsequentdecreaseinepithelialcellsactivitylevel against candida, resulting in the disease. E-cadherin innormallevelspromotesthemigrationofTCD8+tooutsidetheepithelialtissue tofightagainst candida. It isbelieved that theincrease incandida levelsensues inan increasedegradationofE-cadherin, what creates a more suitable environment to theinfectionanddevelopmentofOP[87,88].

A variety of virulence factors contribute to the pathogenicityof Candida spp. including the capacity to modify cellularmorphology,abilitytoadheretoepithelialcellsandthecapacityto secrete extracellular enzymes, like phospholipases andaspartyl proteinases [89,90]. The phospholipases participatein the degradation of the phospholipids in the host’s cellularmembrane while the aspartyl proteinase degrades variousphysiologicallyimportantsubstrateslikethealbuminproteinsandskin’simmunoglobulins,contributingtothetissuepenetrationbyCandidasppandsubsequenthostinvasionduringtheprocessofinfection[91,92].

In contrast to the oropharyngeal candidiasis, little is knownaboutthehostfactorsandoperationalyeastinthepathogenyofesophagealcandidiasisandexperimentalmodelshavenotbeenestablished. However it is probable that the yeast’s virulencefactors and defects in the host’s defense mechanisms areresponsible.Esophagealcandidiasis inHIVpositivepatientscanbethefirstAIDSmanifestation.ThehighprevalenceofesophagitisinconnectionwithAIDSindicatesthecriticalroleofcellmediatedimmunitytoprotecttheesophagusagainstCandidainvasion[93].

Regarding predisposing factors for oropharyngeal candidiasisin theHIV+patient, thereductionofCD4+ lymphocytesto lessthan200cells/mm3continuestobethemost important factorfor colonization by candida and the development ofOPC [82].However, other factors can influence the defensemechanismsthatlimittheCandidaproliferation.Thefollowingcanbefound


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amongthem:antifungaltherapy,gender,useofdentalprosthesis,tobaccouse,intravenousdrugsuse,salivafluxrate,antimicrobialsalivaconstituents,lysozymereleaseandoralmucosa’simmunesystem[94,95],alcoholuse,femininegender,andahighviralload[96].

Candidaalbicansoxidizesethanolinthesaliva,whatleadstoanunexpectedhighlevelproductionofacetaldehyde.Thisproductaffects the oral mucosa, increasing its permeability, causingatrophicareasintheepithelialsurfacethathasbecomepoorinextracellularlipidsduetothealcoholuse.Glucoseconcentrationsof 18 g/dL, easily obtained from beverages, increases biofilmformation and C. albicans adhesion, what facilitates theoccurrenceofOPC [97]. The correlationbetween the femininegenderandOPCremainsuncertain. It isbelievedthatestrogenlevel deregulations can predispose an oral mucosa colonizingphase by C. albicans. This hormonewould act as a protectionfactor for vaginal candidiasis and possibly, in lower estrogenlevels, both the oral and vaginal tissue continues to be moresusceptibletofungalinfections[98].

Inastudywith2.499menwithHIVandabaselineofTCD4+cellcount higher than 200 cells/microliter, smoking increased thepseudomembranous candidiasis level risk by 40% (p less thanorequalto0.01)[99].However,anotherstudy(139peoplewithHIV)suggestedthattobaccousewasnotariskfactorforthoseindividualswithaTCD4+cellsbaseline countof less than200cells/microliter[100].TheexactmechanismofactionbywhichtobaccopredisposesCandidiasisitisnotknownbutitisbelievedthatitcompromiseslocalimmunity,inducingchangesincytokinesandreducinganti-candidaepithelialcellmediatedactivity [99].Smoking has short and long term effects in many importantaspectsofinflammatoryandimmuneresponsesintheoralcavity[101]. Cigarette smoke stops the neutrophils transmigrationthrough theoral andperiodontalmicrovasculature, suppressesthe neutrophil cell diffusion, chemokinesis, chemotaxis andphagocytosis,andresultsinthereleaseofneutrophilproteases,which can be an important mechanism in the destruction odtissue[102].

Regarding esophageal candidiasis, a low T CD4+cell countand a higher HIV-RNA viral load were identified as clinicalfactors associatedwithOEC,while themost severe endoscopyresults were associated with lower T CD4+ cell counts [103].Pharmacological suppression of the production of gastric acid,previous vagotomy, antibiotics use, functional or mechanicalesophageal alterations and endocrine diseases like diabetesmellitus,hypothyroidismandhypoparathyroidismareamongtheriskfactorsforOEC.Malnutrition,alcoholuse,advancedageandcorticosteroidstherapyhavealsobeenimplied.

The IP, protease inhibitor, an important antiretroviral therapycomponent,hasbeenassociated,byavarietyofauthors,tothedecrease in frequency of oral candidiasis by the drugs directactionagainsttheyeasts[104,105].InvitrostudieshaveshownthattheIPcaninhibitasparticproteasessecretedbyC.albicansand considerably attenuate their adhesion to epithelial cells,breaktheyeastcellmembraneintegrityanddiminishcandida’sviability.Theseresultssupporttheideathatoralcandidacolonyreduction in HIV infected patients that receive antiretroviral

therapymightnotbeonlyduetotheimmunesystem’srecovery,butalsocanresultfromadirectinhibitioneffectontheasparticproteasesbyIP[106-108].

Clinical Presentation Therearedifferenttypesoforopharyngealcandidiasisandtheyareclassified inthreegroups:acutecandidiasis,chroniccandidiasisand angular cheilitis (stomatitis). Acute candidiasis is dividedin pseudomembranous candidiasis, acute atrophic candidiasis(induced by dentures) and median rhomboid glossitis [109].AmongHIV+individuals,theerythematous,pseudomembranousandangularcheilitistypesaremoreevident.Theerythematousandpseudomembranoustypeshaveahigherincidence,followedby angular cheilitis [110]. Pseudomembranous candidiasis isconsideredthemostprevalentfungalinfectioninpatientsinfectby HIV and has been associated with the progression of thedisease;alsoitisutilizedasaclinicalmarkertodefinetheseverityoftheHIVinfection[111].

Pseudomembranous candidiasis is clinically characterized aswhite-yellowishplaques,withagelatinconsistencythatpresentsgrowth in the centrifuge and confluence [112]. The plaquesare composed by entwined hyphamass, yeasts, desquamatedepithelial cells and necrotic tissue fragments. These plaquescanberemovedbyregularscratchingwitharigidinstrumentorbyfrictionwithadrygauzecompressoracottonswab,leavingas a result an erythematous, hyperemic, eroded or ulceratedsurfacewithhemorrhagepoints,usuallysensitive[112,60].Thisallows the differential diagnosis between pseudomembranouscandidiasis and hyperplastic candidiasis, being that in thehyperplastic candidiasis the plaques cannot be removed byscratching[113].Inmostcases,theselesionsareasymptomatic,withtheexceptionofmoreseverecaseswherepatientscomplainofsensibility,burninganddysphagia[69].

Acuteerythematouscandidiasisisasymptomaticlesion,generallyassociatedwithaburningsensationinthemouthortongue.Thetongue can be a brilliant red similar to the observedwith lowvitaminB12serumlevels,lowfolateandlowferritin[109].Thereis intense sensibility due to the numerous erosions dispersedin the mucosa and due to the associated inflammation, mostcommonly located along the dorsum of the tongue, occurringalsointhesoftandhardpalate.Theselesionscancauseaburningsensationwhenthereisingestionofhotoracidicaliments.Itcanoccurindependentlyorsimultaneoustothepseudomembranousform[69].Thepersistenceofthepseudomembranouscandidiasiscanresultinlossofthepseudomembranewiththedevelopmentofalesionknownasacuteerythematouscandidiasis.Contrarytothepseudomembranous from, theoral symptomsof theacuteerythematouscandidiasisaremuchmoreaccentuatedduetothenumerouserosionsandtheintenseinflammation[112].

Angular cheilitis is a chronic inflammatory lesion characterizedclinicallybyerythema,maceration,crustsandfissures.Itaffectsthe labial commissure and many times it is symptomatic andbilateral [114]causingdiscomfort. It canoccurwithorwithouterythematous or pseudomembranous candidiasis, and it canpersist for a long time period if left without treatment [115].Thedifferentiationbetweeneachclinicalsubtypeofcandidiasis


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is doneby theappearanceof the lesionandby the symptomsdescribed by the patient. This way, the candidiasis should bedifferentiatedfromlichenplanus,leucoplasia,Fordycegranules,escharassociatedwithchemicalburns,traumaticaulcers,syphiliticplaques,keratoticlesionsanddiscoidlupuserythematosus[112].

In regards to esophageal candidiasis, it mostly presents withodynophagia,dysphagiaandretrosternalpain.EventhoughOECcanbeanextensionoftheOPC, inapproximately10%ofcasestheesophagusistheonlyregioninvolved,withOPCinvadingthedistaltwo-thirdsinsteadofthemostoftenaffectedproximalone-third.OneoccasionalcharacteristicofOECisthecompletelackofclinicalsymptomseventhoughthereisanextendedinvolvementof the esophagus [91]. In 20% to 50% of cases patients withOEC can be asymptomatic [116]. The differential diagnosis ofOEC should include gastroesophageal reflux disease (GERD),idiopathiculcersassociatedwithHIVandviralesophagitisduetocytomegalovirusorherpessimplexvirus[86].

DiagnosisThediagnosisofOPCisgenerallyclinicalandfollowedimmediatelybyempiric antifungal therapy. Initially, the clinical story shouldbe collected, followed by a detailed mouth analysis includingobservationofthesoftandhardpalateandexaminationoftheoral mucosa, after removing any prosthetics that the patientmighthave.Predisposingfactorsmustbeidentified,asmentionedabove, and resolved if possible and an evaluation of the type,severity and chronicityof the infectionmustbedone [109]. Incase of recurring candidiasis, candidiasis resistant to previoustreatmentand/orpatientsrepeatedlyexposedtofluconazol(and/or imidazole derivatives), the identification of yeasts throughfungaldirectexam,culturesandsusceptibilityteststoantifungalagentsare recommendeddue to thepossibilityof infectionbyCandidasppresistanttooneoravaritetyoftriazoledrugs[117-119].

In cases of esophageal candidiasis in HIV+ patients, thepresumptivediagnosiscanbegenerallydoneafterthebeginningof typical symptoms or by the presence of oral candidiasisassociated with esophageal symptoms and the antifungaltreatmentcanbeempiricallyinitiated.AnendoscopybeforethebeginningofantifungaltherapycanbedoneinthoseindividualswithoutconcurrentOPCorthosewithatypicalsymptoms.Ifthepatients does not improve with adequate systemic antifungaltherapy an endoscopy is recommended so that other causesof esophagitis mentioned earlier can be excluded [82]. Theendoscopy can reveal white plaques that may or may not beaccompaniedbyulceratedlesions.Itisalsorecommendedthatasamplebeobtainedformicroscopicexam,cultureandamucosabiopsy[117].

TreatmentWhenchoosinganantifungalagentfortheappropriatetreatmentof OPC and OEC a number of factors should be considered,including previous exposure to antifungal agents and correctspecies identification [120]. The treatment’s objectives are toeliminate the signs and symptoms of the disease, reduce oreliminatecolonizationandavoidrecurrences[121].Fluconazolecontinuestobetheantifungaldrugofchoice forOPCandOEC

treatment.FluconazoleisafungistaticagainstCandidaspp.withanoralbioavailabilitysuperiorto80%,whichisnotinfluencedbyconcomitantfoodingestionorgastricpH.Itspenetrationinthesalivaisexcellent.Becauseofitshepaticmetabolizationthroughthe CYP450 enzyme, many drug interactions with fluconazolewere described [120]. However, the appearance of Candidaspeciesresistanttofluconazoleinvivoandinvitrohasbeenwelldocumented[122,123].C.glabrataandC.kruseiarefrequentlyresistanttofluconazole[124].

Fluconazole,inthedosageof100mg/dayduring7to14daysisrecommendedasthefirstchoicedrugforOPCtreatment[125].Alternatives to fluconazole include mucoadhesive miconazoletablets, 10 or 50mg/ day during 7 to 14 days. Itraconazolesolutionsduring7to14days(100or200mg/day) isequivalentto fluconazole during 14 days. Itraconazole has a higher oralbioavailability and a higher incident of drug interactionswhencompared tofluconazole.Posaconazole (200mg in thefirstdayand 100mg/ day for the remaining days) is also an alternativeto fluconazole; it is considered a therapy option in caseswithfluconazoleresistantCandidasp.TopicalagentesshouldnotbeusedfortreatmentofOPCduetoitslowtolerability(sourflavor,gastrointestinaleffects,frequentdosage)andlessefficiency[125-127].

Oraladministrationoffluconazole(200mg/dayduring14to21days)isthetherapyofchoiceforOEC.Intravenousformulationscan be used in severe esophagitis cases. Topical agents arenot sufficiently efficient and should be avoided [126,128].Itraconazole (oral solution) is and alternative agent, that hasbeendescribedtobeasclinicallyandmycologicallyefficientasfluconazole[82].Voriconazole,200mgtwotimesperdayfor14to21days,isasefficientasfluconazole,butitisassociatedwithahigherincidenceofadverseeffectsandahigherpotentialfordruginteractions, visual alterations and phototoxicity in ambulatorypatients[128].EchinocandinswereevaluatedforthetreatmentofOECassociatedwithAIDS,especiallycomparingittofluconazole.Intravenous caspofungin,micafungin and anidulafangin can beused,however,theseagenteshaveahigherrecurrenceratethenfluconazole,aremoreexpansiveandarenotavailableinanoralformulation[82].

RefractoryOPCorOEC isdefinedas symptoms thatpersist formore than 14 days of treatment with 200mg/day or more offluconazole.Thissyndromeisdescribedinapproximately5%ofHIVinfectedpatients,generallyinthosewithaTCD4+cellcountlower than 50cells/IL that received antifungal/ triazole agentsmultiple times or for a prolonged time due to a high numberofOPCepisodes[129].Anyuseof topicalantifungalagent, likeamphotericinB,shouldbeavoidedbecauseofitslowefficiencyrates.TheuseofFluconazoleinamoreelevateddailydosecanbebeneficial,atleasttemporarily,particularlytheoralsuspension,duetoits increasedsalivaconcentrations.Itroconazolesolution(upto600mg/day)itisanalternativeandit’sassociatedwitharesponserateof55-75%,howeverrecurrencesoccurposteriorly.Posaconazoleoralsuspension(400mg,twiceadayfor29to90days)canalsobeutilizedandit’sefficientinupto86%ofpatientswithoropharyngealcandidiasisand/orfluconazole/itroconazole-refractory esophageal candidiasis. Caspofungin can be used in


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HIVinfectpatientswithfluconazole-refractoryOEC.AmphotericinB,amphotericinB lipidcomplex,and liposomalamphotericinBcanalsobeefficient in theprevious scenario,but considerableattentionshouldbegiventotheirtoxicityprofiles[120,130-132].

ProphylaxisDespite the proved fluconazole efficiency, antifungal primaryand/orsecondaryprophylaxisforthepreventionofOPCandOECisnotrecommended.Thedisadvantagesofprimaryprophylaxisincludethepotentialfordrug-interactionsbetweenthetriazolesand the highly active antiretroviral therapy (HAART), thedevelopmentoffluconazoleresistanceand/orcrossresistancetoazoles,thetoxicityandthecostofantifungaltherapy.Therefore,thebestprophylaxisforbothOPCandOECistheadequateuseofHAART[126,133].

NeurotoxoplasmosisIntroductionThe neurotoxoplasmosis, or cerebral toxoplasmosis, is theinfectionofthebrainbytheprotozoanToxoplasmagondii[134].TheT.gondiiwasfirstdescribedin1908inTunisia,byNicolleandManceaux[135]andwasreportedinSaoPaulo,Brazilinthesameyear[136].Only15yearslater,in1923,theparasitewasfoundinhumansandonlyin1942,incats.In1967itwasdiscoveredthattheT. gondii couldbe contracted through the fecesof Felidae,whichweredefinedasthedefinitivehostsin1970[135].

EpidemiologyAboutathirdoftheworldpopulationischronicallyinfectedwiththeparasiteT.gondii,andthemajorityofcasesareasymptomatic.However, toxoplasmosis can cause serious consequences inimmunocompromised individuals or in cases of congenitalinfection [137]. The prevalence of seropositivity for T. gondiivariesaccordingtotheindividual'shomeregion,it isestimatedthattheprevalenceintheUSisbetween15%and29.2%,whileintropicalcountriesinEuropethisratecanreachupto90%[138].

As for neurotoxoplasmosis, despite the drop in the number ofcasesduetotheimplementationofantiretroviraltherapy(highlyactive antiretroviral therapy or HAART), it continues to be themain opportunistic infection in the central nervous system inpeoplewithAIDSandtheonewhocausesmorefocallesionsinbrain[139-141].

Before the HAART implementation, prior to the mid-90s,the annual incidence of neurotoxoplasmosis in HIV-positiveindividuals with advanced immunosuppression was about 4casesper100people.With the implementationof therapytheannual incidence of neurotoxoplasmosis reduced 75%, rankingonly1caseper100patients[142].However, insomecountrieswheretheseroprevalenceoftoxoplasmosisishigh,theincidenceoftoxoplasmosisisestimatedatupto40%amongpatientswithAIDSwhonotreceivethecorrectprophylaxis[140].

PathogenesisThe lifecycle of T. gondii is characterized by being heteroxen,requiringtwoormorehostsforitsoccurrence.MembersofFelidea

familyarethedefinitivehosts,orcomplete,astheypresenttheenteroepitelialcycle,orsexual,andtheextraintestinalorasexualcycle. All the other warm-blooded animals showing only theasexualcyclearereferredtoasintermediateorincompletehosts[143].

Infelines,asaresultofthesexualphase,occurstheformationof oocysts146 which are released in a non sporulating way totheoutsideenvironmentviathefaeces.Afteraperiodof1to5daysoocystsbecomesporulatedandvirulent[145].Thefelineseliminateoocystsinfecesforonlyashortperiodinitslife.After2weeksfrominitialcontactwiththeparasitethefelids initiatethe development of immunity [146], decreasing the rate ofmultiplication and disposal of the T. gondii [147]. However,despite the short period of elimination of oocysts, a largeamountofthemarereleasedtotheexternalenvironmentand,inaddition,theoocystsareveryresistanttochemicalandphysicalagentsintheenvironment,whichmakesthemviableformonthsoryears[148].

Aftertheoocystsarereleasedintheexternalenvironment,theintermediatehostscanbecomeinfectedbyingestingsoil,waterorcontaminatedplantmaterial[145].Uponbeingingested,oocystsbecometachyzoites,whichmultiplyrapidlycharacterizingacuteoractiveinfection[149].Theseorganismshaveapredilectionforneural andmuscle tissues,which iswhere the tachyzoiteswillresultinbradyzoitesthatmultiplyslowlyandformcysts,featuringchronicinfection[150].

Withthis,inadditiontoinfectionbydirectingestionofoocysts,the felines and humans can become infected by ingesting thecystsofT.gondiibradyzoites fromotheranimals,whichoccursbyingestionofraworundercookedmeat.Addingtothesewaysof infection, humans can acquire the parasite through bloodtransfusion,byorgantransplantationorviatheplacenta[145].

Itissuggestedthatneurotoxoplasmosisinimmunocompromisedindividuals, usually (95% of cases) results from reactivation oflatentbradyzoitescysts[151].

Cystsreactivationoccurswhenthepersonisalreadyinaseverestage of immunosuppression. The neurotoxoplasmosis mayappearinindividualswhohaveaT-lymphocytesCD4+countlowerthan200permicroliter.Theriskofreactivationofcystsincreaseswith lower CD4+ levels. The increased risk of developing thediseaseoccurswhentheCD4+T-cellcountdropstolevelsbelow50cellspermicroliter[152].

With the immunosuppression, occurs a breakdown of tissuecystsformedbyprotozoaandthereleaseofbradyzoites,whichmultiply in place and latermigrate to other organs. The injurybyinfectionofToxoplasmagondiiiscausedbycellinvasionthatstarts a lysis process and consequently leads to cell andtissuedestruction[153].

The reactivationof the cyst causesa conversionofbradyzoitesintachyzoites[154].InapersonwithnormalimmunityandwithtachyzoitespresentinthebloodT-lymphocytesCD4+areactivatedandenablethereleaseoftheCD154molecule(alsocalledCD40ligand), that stimulates dendritic cells and macrophages tosecreteInterleukin12(IL-12),whichpromptsT-cellstoproduce


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interferongamma(IFN-y),stimulatatingmacrophagesandothernonphagocyticcellstocarryoutaanti-toxoplasmicresponse.Thetumornecrosisfactor(TNF-a)alsohaveprovedtobeimportantincontrolling infectionbydevelopinganintenseresponsefromTcells.Withthisadequateimmuneresponse,tachyzoiteswouldbecome bradyzoites. In HIV-positive patients, however, theexpressionofCD154inresponsetoT.gondiiisimpaired,sotheentirecascaderesponseagainsttheparasitewillfail[155].

A study conducted in São Paulo, Brazil, compared IFN-y, TNF-aandinterleukin-10(IL-10)levelsinfourpatientgroups:(1)thosewith AIDS and neurotoxoplasmosis, (2) patients with oculartoxoplasmosis, and other two control groups; (3) chronicallyinfected patients and (4) healthy patients. The resultwas thatpatients with AIDS and neurotoxoplasmosis and those withocular toxoplasmosis have higher TNF-a levels than controlsubjectsand lower IL-10and IFN-y levels.The IFN-y isrequiredfor the prevention of the reactivation of dormant cysts duringchronicinfection.TNF-aisdirectlyinvolvedinregulatinggrowthof tachyzoites,however,asexplainedabove, itdependsontheactionofTcells.Thus,IFN-yandTNF-alevelsreflecttheefficiencyoftheprotectivefunctionsagainstinfectionbyT.gondii.However,knowledgeaboutthepathophysiologyofcerebraltoxoplasmosisremainsincomplete[156].

Clinical PresentationThe symptoms of neurotoxoplasmosis consist of headache,confusionoralteredmentalstatus, fever, lethargy,convulsions,changes in coordination, focal muscle weakness, nausea orvomiting, visual disturbances, incontinence and neck stiffness.Signsofneurotoxoplasmosisconsistoffocalsigns(hemiparesis,ataxia, paralysis of cranial nerves, sensory deficits, aphasia,hemianopia), axillary temperature greater than 38.4 degreesCelsius, abnormal level of consciousness, psychomotorretardation,meningismandbehavioraldisorders.However, themainclinicalfindingsoftoxoplasmosisareheadache,confusionoralteredmentalstatus,feverorconvulsions[157].

Untreated neurotoxoplasmosis cases can progress to comawithin days or weeks. Rarely, toxoplasmosis may present as arapidlyprogressiveandfatalformofdiffuseorglobalencephalitiswithseverementalstatuschanges,nauseaorvomitingthatoftenindicateelevationofintracranialpressure[158].

DiagnosisAccordingtotheCentersforDiseaseControl(CDC),thediagnosisof neurotoxoplasmosis in AIDS patients should be assumedaccordingtothesumofthreesituations:(1)recentonsetoffocalneurologicabnormalitythatisconsistentwithintracranialdiseaseor level of reduced consciousness, (2) evidence in diagnosticbrain imaging (CTorMRI)ofa lesionwithmassaspectand (3)antibodiestoT.gondiipresentinplasmaorsatisfactoryresponseto treatment for toxoplasmosis [159]. The therapeutic successcanbetranslatedbyimprovementintheclinicalandradiologicalfindingswithreducedneurologicalsignsandsymptomsaftertheimplementationofdrugtreatment[160].

InfectionwithT.gondiiisinitiallydetectedbythedemonstrationof specific antibodies against theparasite.A rangeof different

serological tests, known as Toxoplasma Serologic profile (TSP),evaluate different antibodies to T. gondii and serum levels ofthese antibodies can increase or decrease according to theevolutionofinfection[161].

Thepresenceofanti-ToxoplasmIgGbecomespositiveinthefirst2weeksafterinfection,hasitspeakbetween1and2monthsafterprimaryinfectionandremainspositivethroughoutthepatient'slife,therefore,itisnotconsideredanaccuratemarkerofinfection,evenifitindicatestheimprobabilityofinfectionwhentheIgGisnegative.Furthermore, thepresenceof IgGcannotdistinguishlatent from active infection [161,162]. The anti-Toxoplasm IgMantibodyappearsbeforeanddecaysfasterthantheIgGantibody.InpatientsinfectedwithrecentlyacquiredT.gondii,thepresenceofIgMisdetectedinitiallyandusuallyitdecreaseswithinafewmonths.SerologicaltestsforthedetectionofIgMarenotspecificandresult inmany falsepositives.Aside from IgM, IgAand IgEantibodiescanbeappliedinthedetectionofacuteinfectionandcongenitalT.gondii.

In immunocompromised patients chronically infected withT. gondii (IgG positive), the results may indicate an apparentreactivationofthediseasewithanincreaseinlevelsofIgGandpresence of IgM [161]. However, IgM antibodies are usuallyabsent in patientswith reactivation of the disease and inHIV-positivepatientswithneurotoxoplasmosis[142].Thereforewhenthere is suspicion of toxoplasmosis in an HIV-positive patientchronicallyinfectedwithT.gondii,additionalserologicaltestswillnot add relevant information for diagnostic developments andotherdiagnosticmethodsshouldbebandied[161].

Imaging tests such as magnetic resonance and computedtomography, are indicated when the neurotoxoplasmosis issuspected in HIV-positive patients. These studies generallyshowmultiplelesionslocatedinthecerebralcortex,thecortico-medullaryjunctionorinthebasalganglia[163].

Typicalfindingsoncomputedtomography(CT)withoutcontrastare:multiplehypodenselesionscommonlywithedemaandmasseffecton itsperiphery;completely resolved injuriesor residualcalcifications,posteriortotreatment[164].Theselesionscanbeconfusedwithother typesof focalbrain lesionsandanewTC,thistimewithcontrast,candemonstrate the typical sign"ring-enhancing".

Typical MRI findings are: T1 has a hypodense image, while inthe T2 lesions present hyperdense (hypo-isodense standardsormixascanstillbefound)andthediffusion-weightedimaging(DWI)areHyperintense.Yet,T1imagewithgadoliniumcontrastshows the characteristic lesions in "ring-enhancing" (or ringsrealse),commonlycircularandwithhypointensesignals(edema)[164].Thedifferentiationofneurotoxoplasmosis fromacentralnervoussystem(CNS)lymphomacanbedifficult,asinlymphomathereisalsothepresenceofedemaandmassappearanceintheperiphery of the lesion, so to differentiate them it is indicatedtheacquisitionofapositronemissiontomography(SPECT)[165].

The evaluation of cerebrospinal fluid (CSF) is rarely used forthe diagnosis of neurotoxoplasmosis due to risk of leadingto intracranial hypertension; however, this procedure can beperformed if there isdoubtaboutthediagnosis [166].TheCSF


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evaluationfindingsmay include: highprotein, varying levels ofglucoseandmildelevationsinwhitebloodcellcountinthebloodwithapredominanceofmononuclearcells [167].Furthermore,neurotoxoplasmosiscanbediagnosedbymicroscopicevaluationbytheCSFtechnique"orWrightGiemsastain",whichcanyieldpositiveresultsinavarietyofprotozoaandhelminthes[168].ThedetectionofT.gondii’sDNAinbodyfluids,especiallyCSFobtainedby lumbar puncture, by polymerase chain reaction (PCR) mayalsobeperformedtoaidinthediagnosisofneurotoxoplasmosis,however,itisnotusuallyperformed[169].

Finally,pathologicalevaluationofbraintissuebiopsyelucidatesthedefinitivediagnosisofneurotoxoplasmosisandthefindingsof this method consist of tachyzoites or cysts surrounded byareas of inflammation. The T. gondii cystsmay appear as solidor granular cysts, the latter being secondary to mesenchymalreactionoftheglialcellsthatresults innecrotizingencephalitisandfocalvasculitis.ThereactivationofT.gondiicystscanleadtobrainabscesseswithavascularcentralareasandthecerebralareasurroundingtheinjurywilldemonstrateedemaandinflammatoryinfiltrateswith lymphocytes andplasmaaccumulationofothercellsaroundthesitevessel[170].

However,despiteconfirmingthediagnosisofneurotoxoplasmosis,biopsyofbraintissueisnotusedroutinelybecauseoftherisksinvolvedintheprocessofobtainingthetissueandbecausetheotherdiagnosticmethodscanpromoteapresumptivediagnosiswithgoodconfidencerate[170].Abiopsy is reservedforcaseswherethereisdiagnosticuncertaintyorwhenthepatientdoesnotrespondorworsenswithempiricaltreatment[171,172].

TreatmentThetreatmentofchoiceforneurotoxoplasmosisisacombinationofpyrimethaminewithsulfadiazine(SDZ-Pyr).Itisrecommendedtheadditionofleucovorintotothistherapy,toreducehematologiccomplicationsduetothemechanismoftheothertwodrugsthatimpairfolicacidsynthesis.However,mostpatientsdemonstrateintolerancetothiscombinationtherapy.Insuchcasesandafterfailureofthefirst-linetreatment(Pyr-SDZ)thetherapyofchoiceis often the combination of pyrimethamine with clindamycin,alsowithrecommendationtoaddleucovorin[142].

Classic regimen of SDZ-Pyrwith leucovorin varies according tothe patient's weight. If less than 60 kilos, a single initial doseof 200mg of pyrimethaminewill be administered orally (PO),followed by 50mg of pyrimethamine PO daily, sulfadiazine1000mgorallyevery6hoursand10 to25mgof leucovorinPO(can increase the dose to 50mg). For patientswithmore than60 kilos, themaintenancedoseof pyrimethamine is 75mgperday, of sulfadiazine is 1500mg every 6 hours and the dose ofleucovorinremainsthesame[169].Inpatientsunabletotakeoralmedication,theadministrationof10mg/kgoftrimethoprimplus50 mg/kg intravenous sulfamethoxazole should be considered[170].

The acute treatment described above should be maintainedfor 6 weeks if the patient showed clinical and radiologicalimprovement, however, if the lesions are extensive, or theresponseat6weeks isnotenough, thetimeofadministrationofthetherapymustbeprotracted.About90%showclinicaland

radiological improvement from the second week of treatmentwithPyr-SDZ.

Ingeneral,arapidclinicalimprovementmustbeobservedaftertreatment. On the third day, about 51% of patients showedneurologicalimprovement(upto91%attheendoftwoweeks)and beginning on the third week radiological improvementoccurs.Thosewhodonotgetadequateresponseattheendofthe first twoweeks orworsen clinically by the third daymustperformbiopsytoruleoutlymphoma[177].Antibodytitersarenottrustedinthetherapeuticresponse,sothepatientshouldbeevaluatedclinicallyandradiologicallyfrequently[142].

Anticonvulsants may be given to those who present seizures[142,171]. Antihistamines can be used for patients who showpruritus as an adverse reaction to sulfadiazine. Treatment inpregnantwomenisidenticaltothatofotherpatients;however,the pregnant woman should be warned that sulfadiazine cancausehyperbilirubinemiaandkernicterusinthebaby[142].

Oralcorticosteroid,suchasdexamethasone(4mgevery6hours),canbeconsideredasadjuvanttherapytopatientsintwocases:caseswheretheclinicalconditionworsenedduring thefirst48hoursoftreatment;orforthosewhohaveradiographicevidenceof deviation of the middle cerebral line or signs of increasedintracranial pressure [142]. Treatment with corticosteroidsshould be as short as possible because of the possibility ofimmunosuppressionandpatientsshouldbemonitoredconstantlyto check for the emergence of other opportunistic infections[142,170].

Regardingantiretroviraltherapy,itisnotclearwhenmedicationshouldbeinitiatedorre-initiatedinanHIVpositivepatientwithacuteT.gondii infectionand, ingeneral,themedicationcanbeadministered again after the treatment of acute toxoplasmosis[178].

ProphylaxisAll HIV-positive patients, as soon as they are diagnosed withHIV infection, should have their IgG antibody for Toxoplasmaevaluated,soitcanserveasscreeningfortheriskoftoxoplasmosisdevelopment.TominimizetheriskofbeinginfectedbyT.gondii,HIV-positive patients should: avoid eating raw or undercookedmeat,washhandsafterhandlingrawmeatandaftercontactwithsoilandwashfruitsandvegetablesbeforeeatingthem.Asforthedomesticcat,theHIV-positivepatientsshouldrequiresomeoneelsewho isnot infectedwithHIVorwhoarenotpregnant, towash thecat's litterbox. If this isnotpossible,patientsshouldwashtheirhandsaftercleaningthebox.Catsshouldnotbefedrawmeat, giving preference tomanufactured cat food. Finally,patientswithHIVshouldnotbeencouragedtogiveawaytheircatsortotesttheiranimalfortoxoplasmosis[142].

The primary pharmacological prophylaxis is recommended forpatients who are seropositive for Toxoplasma gondii and haveCD4 counts of less than 100 cells permicrolitre. PatientswithCD4 counts of less than 200 cells per microliter and with anopportunistic infection or adjacent malignancy should receiveprimaryprophylaxisaswell.Thedrugsofchoicearetrimethoprimand sulfamethoxazoleandmustbeadministereddaily.Primary


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prophylaxis can be stopped as soon as the CD4 levels riseabove 200 cells per microliter for three months [142,169].Primary prophylaxis against T. gondii with trimethoprim andsulfamethoxazoleinpatientswithCD4countslessthan100cellspermicrolitrereducedriskfortoxoplasmosisin73%[170].

Secondary pharmacological prophylaxis should be done forpatientswho have completed therapy for acute toxoplasmosisfor6weekssuccessfully,theuseofmedicationshouldbechronic,unless immune reconstitution occurs due to antiretroviraltherapy.Ifthepatientreturnstolevelslowerthan200CD4cellsper microliter, secondary prophylaxis should be reconstituted.Some studies propose the discontinuation of secondaryprophylaxis based on themaintenance of good immune levelsand the absence of clinical signs and symptoms, but none ofthempromotesagoodlevelofclinicalevidence.

Secondary prophylaxis is made with the combination ofsulfadiazine, pyrimethamine and leucovorin. In this case, thedosesofmedicationsmaybesmallerthanintheacutetreatmentofneurotoxoplasmosis. For sulfadiazine it is recommended theadministrationof500to1000mgorally4timesaday(totalof

2000 to4000mg), forpyrimethamine it is recommended25 to50mgperdayandthe leucovorindose is10to25mgperday[142,171]. For patients that do not tolerate prophylaxis withsulfadiazine,itcanbedonewithclindamycininstead.Atovaquoneas monotherapy may be considered for patients intolerant topyrimethamine[172],however,thefailurerateis26%inthefirstyear180.

ConclusionOpportunistic infections, even in the era of antiretroviraltherapy,remainamajorprobleminHIV-infectedindividuals.Theoccurrenceof pneumocystosis, and thrush neurotoxoplasmosisrepresent, in most cases, markers of AIDS progression,representinganimportantpublichealthproblemnowadays.

Early detection of this disease, as well as knowledge on theepidemiology,clinicalmanifestations,diagnosisandappropriatetherapy, allows for proper management in HIV + individuals,decreasingthechancesofpossiblecomplicationsandevolutionof the immunosuppression, improving the quality of life andreducingmorbidityandmortalityofthesepatients.


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Opportunistic Infections in Aids Patients...Opportunistic Infections in Aids Patients Abstract Individuals infected with human immunodeficiency virus (HIV) often develop multiple complications

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