www.jped.com.br
ORIGINAL
ARTICLE
Parameters
indicative
of
persistence
of
valvular
pathology
at
initial
diagnosis
in
acute
rheumatic
carditis:
the
role
of
albumin
and
CD19
expression
夽
Taliha
Oner
a,
Rahmi
Ozdemir
a,∗,
Dildar
Bahar
Genc
b,
Mehmet
Kucuk
a,
Cem
Karadeniz
a,
Savas
Demirpence
a,
Murat
Muhtar
Yilmazer
a,
Timur
Mese
a,
Vedide
Tavli
a,
Ferah
Genel
caIzmirDr.BehcetUzChildren’sHospital,PediatricCardiology,Izmir,Turkey bSisliEtfalTrainingandResearchHospital,PediatricOncology,Istanbul,Turkey cIzmirDr.Behc¸etUzChildren’sHospital,PediatricImmunology,Izmir,Turkey
Received23September2015;accepted15January2016 Availableonline21August2016
KEYWORDS
Acuterheumatic carditis; Albumin; CD8; CD19;
Lymphocytesubtypes
Abstract
Objective: Theaimofthisstudyistodefinethepredictorsofchroniccarditisinpatientswith acuterheumaticcarditis(ARC).
Methods: PatientsdiagnosedwithARCbetweenMay2010andMay2011wereincludedinthe study.Echocardiography,electrocardiography,lymphocytesubsetanalysis,acutephase reac-tants, plasma albuminlevels, and antistreptolysin-O (ASO) tests were performed at initial presentation.Theechocardiographicassessmentswererepeatedatthesixthmonthof follow-up.Thepatientsweredividedintotwogroupsaccordingtopersistenceofvalvularpathology at6thmonthasGroup1andGroup2,andallclinicalandlaboratoryparametersatadmission werecomparedbetweentwogroupsofvalvularinvolvement.
Results: Duringtheone-yearstudyperiod,22patientshadvalvulardisease.Seventeen(77.2%) patientsshowedregressioninvalvularpathology.Aninitialmildregurgitationdisappearedin eight patients (36.3%). Among seven (31.8%)patients withmoderate regurgitation initially, theregurgitationdisappearedinthree,andfourpatientsimprovedtomildregurgitation.Two patientswithasevereregurgitationinitiallyimprovedtomoderateregurgitation(9.1%).Infive (22.8%)patients,thegradeofregurgitation[moderateregurgitationinone(4.6%),andsevere regurgitationin4(18.2%)]remainedunchanged.Thealbuminlevelwassignificantlylowerat
夽
Pleasecitethisarticleas:OnerT,OzdemirR,GencDB,KucukM,KaradenizC,DemirpenceS,etal.Parametersindicativeofpersistenceof valvularpathologyatinitialdiagnosisinacuterheumaticcarditis:theroleofalbuminandCD19expression.JPediatr(RioJ).2016;92:581---7.
∗Correspondingauthor.
E-mail:[email protected](R.Ozdemir).
http://dx.doi.org/10.1016/j.jped.2016.01.013
diagnosisinGroup2(2.6±0.48g/dL).Lymphocytesubsetanalysisshowedasignificantdecrease intheCD8percentageandasignificantincrease inCD19percentageatdiagnosisinGroup2 comparedtoGroup1.
Conclusion: ThebloodalbuminlevelandthepercentageofCD8andCD19(+)lymphocytesat diagnosismay helptopredictchronicvalvular diseaseriskinpatientswithacuterheumatic carditis.
©2016PublishedbyElsevierEditoraLtda.onbehalfofSociedadeBrasileiradePediatria.Thisis anopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/ by-nc-nd/4.0/).
PALAVRAS-CHAVE
Carditereumática aguda;
Albumina; CD8; CD19;
Subtiposdelinfócitos
Parâmetrosindicativosdepersistênciadepatologiavalvularnodiagnósticoinicial decarditereumáticaaguda:opapeldaalbuminaedaexpressãodeCD19
Resumo
Objetivo: Oobjetivodesteestudoédefinirospreditoresdacarditecrônicaempacientescom carditereumáticaaguda(CRA).
Métodos: OspacientesdiagnosticadoscomCRAentremaiode2010emaiode2011foram incluí-dosnoestudo.Foramrealizadosostestesdeecocardiografia,eletrocardiograma,umaanálisedo subgrupodelinfócitos,provasdefaseaguda,níveisdealbuminaplasmática, antiestreptolisina-O(ASO)namanifestac¸ãoinicial.Asavaliac¸õesecocardiográficasforamrepetidasno6◦mêsde
acompanhamento.Ospacientesforamdivididosem doisgrupos deacordocoma persistên-ciadapatologiavalvularno6◦ mêscomoGrupo1eGrupo2etodososparâmetrosclínicose
laboratoriaisnainternac¸ãoforamcomparadosentredoisgruposdecomprometimentovalvular. Resultados: Duranteoperíododoestudodeumano,22pacientesapresentaramdoenc¸a valvu-lar.17(77,2%)pacientesapresentaramregressãodapatologiavalvular.Houvedesaparecimento de regurgitac¸ão moderada inicial em 8 pacientes (36,3%). Entre 7 (31,8%) pacientes com regurgitac¸ãomoderada inicialmente,aregurgitac¸ãodesapareceuem 3 e4 pacientes apre-sentarammelhorapara regurgitac¸ãoleve. 2pacientescomregurgitac¸ão graveinicialmente apresentaram melhora para regurgitac¸ão moderada(9,1%). Em 5(22,8%) pacientes, ograu deregurgitac¸ão[regurgitac¸ãomoderadaem1(4,6%)eregurgitac¸ãograveem4(18,2)] con-tinuouinalterado.OníveldealbuminafoisignificativamentemenornodiagnósticonoGrupo 2(2,6±0,48gr/dL).Aanálisedosubgrupodelinfócitosmostrouumareduc¸ãosignificativano percentualdeCD8eumaumentosignificativonopercentualdeCD19noGrupo2emcomparac¸ão aoGrupo1.
Conclusão: Onível de albumina nosangue e opercentual de linfócitos CD8e CD19 (+)no diagnósticopodemajudarapreverriscodedoenc¸avalvularcrônicaempacientescomcardite reumáticaaguda.
©2016PublicadoporElsevierEditoraLtda.emnomedeSociedadeBrasileiradePediatria.Este ´
eumartigoOpenAccesssobumalicenc¸aCCBY-NC-ND(http://creativecommons.org/licenses/ by-nc-nd/4.0/).
Introduction
The latent period of ARF (acute rheumatic fever) fol-lowing streptococcalinfections, infiltration of T-cells and macrophages in heart valves, and B-cell infiltration in Aschoffnodulesindicatethattheimmunesystemisinvolved in disease pathogenesis.1 Studies investigating the
alter-ationsincellularimmuneresponseduringARFhaveshown decreasedCD3-CD8(+)lymphocytesandincreasedCD4/CD8 lymphocyteratio.2CD8levelswerereportedtodecreasein
patientswithrheumaticheartdiseasecomparedtopatients withARForhealthysubjects,indicatinganimmuneprocess in the course of this disease, and CD8 T-cells have been shownto playan important immunoregulatoryrole inthe pathogenesis.3
B-cells perform roles such as antigen presentation, cytokine production, and the regulation of lymphoid
organogenesis,effectorT-celldifferentiation,anddendritic cell function.4 Accordingly, critical roles of B-cells have
been demonstratedin severalimmune-mediateddiseases. BecausethefateandfunctionofB-cellsaretightlyregulated bysignaltransductionthroughB-cellreceptorsand function-allyinterrelatedcellsurfacereceptors,suchasCD19,CD21, CD22,CD40canbeapotentialstrategyforregulatingthese disorders.5,6Amongthem,CD19isgenerallyconsideredasa
positiveBcellresponseregulator.7
Theplasmaalbuminlevelmaydecreaseininflammatory conditions.Hypoalbuminemia lowers plasmaoncotic pres-sure;itmaycontributetopulmonaryedemainthepresence of elevatedleftatrial pressureandcontributetothe pro-gressionofheartfailure,anditiscommonlyseeninpatients with heart failure.8 Several studies have demonstrated a
hasemphasizedthatserumalbumin <2.5g/dLasthemost independentpredictorofin-hospital mortality.10 However,
the albumin-ARFrelationship hasnever been investigated forchronicvalvulardiseaseinchildren.
Thepresentstudyaimedtodefinepredictorsofchronic carditisthroughevaluationofelectrocardiography, echocar-diography, lymphocyte subset analysis, and laboratory parametersincludingalbumin,ESR,CBC,andASOinpatients diagnosedwithacuterheumaticcarditispriortoreceiving treatmentwithsteroids.
Materials
and
methods
Twenty-two patients admitted to the pediatric cardiol-ogy unit with a diagnosis of acute rheumatic carditis betweenMay2010andMay2011wereincludedinthis ret-rospective study. Complete blood count, plasma albumin level,C-reactiveprotein(CRP),erythrocytesedimentation rate (ESR), antistreptolysin O (ASO), lymphocyte subset analysis, echocardiography, and electrocardiography were performedbeforetreatmentineligiblepatients.Thestudy wasapprovedbytheinstitutionalreviewboard.
AllpatientswithpresumeddiagnosisofARFwere evalu-atedbyechocardiographyregardlessofcardiacauscultation findings. The diagnosis of ARF was based on the mod-ified Jones criteria (2 major or 1 major+2 minor and previous Group A beta hemolytic streptococcus (GABHS) predictors).11 Valvular regurgitation wasconsidered to be
pathologic when a color jet length of at least 1cm was found, seen in at least two separate planes with a peak velocitygreaterthan 2.5m/sin echocardiographic exami-nation.PatientswhowerediagnosedwithARCforthefirst timewereincludedintostudy.Patientswithprevious diag-nosis of ARF and/or ARC were not included. Accordingly, 2mg/kg/d (max. 60mg) prednisone was initiated for all patients.Aftertwotofourweeksofprednisone,thedosage wastapered over a two-week period. Acetylsalicylic acid wasaddedtothetreatmentduringsteroidtaperatadose of90---100mg/kg/d(max.3.5g)andwasdiscontinuedafter taper,withanoveralldurationoffourweeks.
An injection of 1,200,000U benzathinepenicillinG for patientswhoweighmorethan27kgand600,000U intramus-cularforpatientswhoweigh27kgorlesseverythreeweeks istherecommendedregimenforsecondaryprevention.
Atthetimeofdiagnosis,eightpatientshadmild regurgi-tation.Amoderateandsevereregurgitationwaspresentin eightandsixpatients,respectively.Nopatientsexperienced a recurrent episode of carditis during follow-up period. Aftersteroidtherapy,acutephasereactantsremained neg-ativethroughoutthestudy.Thepatientsweredividedinto twogroups,asthosewith(Group1)andwithout(Group2) regressioninvalvularregurgitationaccordingtothe echo-cardiographicassessmentatpost-treatmentmonthsix,and thedataofthesegroupsattheinitialdiagnosiswere com-pared.Accesstothehospitaldatabasewasgrantedbythe hospitaladministration.
Echocardiography
Transthoracic two-dimensional and Doppler echocardiog-raphic evaluations of the subjects were performed with
the GE Vivid 3 device (GE Healthcare---Milwaukee, WI, UnitedStates) using3MHz and7MHz transducersfor car-diacassessment. M-modeechocardiographymeasurements wereobtainedfromtheleveloftheposteriormitralvalve accordingtotherecommendationsoftheAmericanSociety ofEchocardiography.Theseverityofvalvularregurgitation wasassessed bycolor-Dopplerechocardiographyusingthe width and extent of the jet flow. The criteria for valvu-larregurgitation usingorthogonalplaneswere a color jet observedinatleasttwoseparateplanes,acolorjetlength ofatleast1cm,andacolorjetmosaicwithapeakvelocity greaterthan 2.5m/s.The severityof mitral regurgitation andaortic regurgitation weregraded qualitatively from1 to4dependingontheobservedregurgitantjetflowinthe leftatriumor theleftventriclebycolor-Doppler echocar-diography.Themitralregurgitationandaorticregurgitation detected by color-Doppler was considered grade 1 if the jet length was 1.5cm; grade 2 if 1.5---2.9cm; grade 3 if 3---4.4cm;andgrade4if4.5cm.12 Grade1wasconsidered
asmild,grade2asmoderate,andgrades3and4assevere regurgitation.13,14
Electrocardiography
12-lead surface ECG recordings were obtained from all patients.TheQTintervalwasmeasuredfromthebeginning oftheQwavetotheendoftheTwave,definedasthepoint atwhichtheTwaveconvertedtotheisoelectricline.When aUwavewaspresent, theendof theTwavewasdefined asthe lowest point between the T and Uwaves. QT dis-persionwasdefinedasthedifferencebetweenthemaximal andminimalQTintervalson12-channelstandardECG.The QTintervalsonECGswerecorrectedusingBazett’sformula (QTc=QT/√R−R)andwereexpressedasQTc.15
Flowcytometry
Lymphocyte subgroups were measured with the indirect immunofluorescencemethod,usingmonoclonalantibodies. Themethodinvolvesthestepsofstainingwithmonoclonal antibodies,incubation,removaloferythrocytes,and mate-rialfixationwithparaformaldehyde.Monoclonalantibodies arepreparedasa panel andcontain fluorochrome.There aremanyfluorochromes withdifferentspectral character-istics;thesuspendedcellsorparticlesarepassedthrougha chamberilluminatedbyalaserlight,andthesignalsgiven by the cells as they pass by the light are collected and analyzed.Thesignalsourcemaybethephysical character-isticsofthecell,suchasthemagnitudeandgranularity,as wellasvariousfluorochromes bound tothecell. Thereby, datacan becollected regarding several propertiesof the cellor particle, such asimmunophenotype,DNA content, enzyme activities, cellular membrane potential, and via-bility. The presenceof an entity (antigen)in the cellcan beimmunologicallydemonstratedbyimmunohistochemistry methods through a stain, an enzyme attached to a pro-teinproduced in responsetosuch entity(antibody) or by immunofluorescent microscopythrough a fluorescent sub-stance.Thecellularsurfaceantigensaredefinedusingthe clusterofdifferentiation(CD)terminology.16Bloodsamples
analysiswas performed withblood collected in ethylene-diaminetetraaceticacid (2mg/mL) tubes using a Beckman CoulterFC500device.CD3,CD4,CD8,andCD19percentages werecalculated.
Laboratorytests
Knownasinflammationmarkersandidentifiedas indepen-dent risk factors for heart failure in rheumatic diseases, the following were studied: C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR);17 plasma albumin,
anegativeinflammation indicator associatedwithcardiac mortality;10 antistreptolysin (ASO) level, as an indicator
of GABHS infection. The calorimetric bromocresol green methodwasusedtoassessalbuminlevels.C-reactive pro-tein (CRP) concentrations and ASO levels were studied nephelometrically usinga Behring kit. Sedimentation was measuredusingtheWestergrenmethod.
Statisticalassessment
Statistical analyses were performed using the software SPSS for Windows v. 17.0 (SPSS; Chicago, IL, USA). Nor-mal distribution of the variables was assessed with the Kolmogorov---Smirnovtest. The t-test wasusedto investi-gatethesignificanceofdifferencesbetweenthecontroland thepatientgroups fortheserieswithregulardistribution, andtheMann---WhitneyUtestwasusedfortheserieswith irregulardistribution.p-valuesbelow0.05wereconsidered statisticallysignificant.
Results
Twenty-two patients (12 male, 10 female, mean age of 12.23±2.1years)withdiagnosisofacuterheumatic cardi-tis were included into the study. None of the patients withcarditishadSydenhamchorea,erythemamarginatum, or subcutaneous nodules. Detailed clinical and labora-torydataarepresentedinTable1.Echocardiographicand electrocardiographicassessment revealed mean fractional shortening, mean heart rate, QTc dispersion, and PR dis-tance as42.9%±4.5%, 91.10±20.27/min, 42.7±17.5ms, and 0.15±0.04s, respectively (Table 1). Electrocardio-graphiccharacteristicsdemonstratednodifferenceinterms of PR interval, mean heart rate, and QTc dispersions betweenGroup1andGroup2(p>0.05;Table2).
Routine blood tests demonstrated no association in hemoglobin, sedimentation, and ASO antibody levels betweenGroup1andGroup2,whereasthebloodalbumin levelatdiagnosis wasfound significantlylowerinGroup2 (2.6±0.48;Table2).
The echocardiographic assessment revealed combined valveinvolvementin68.2%ofthepatients,isolatedmitral regurgitation in 22.7%, and isolated aortic regurgitation in 9.1%. Seventeen (77.2%) patients showed regression in valvular pathology, whereas in five (22.8%) patients, the gradeofregurgitation(moderateregurgitationin1(4.6%), andsevereregurgitationin 4(18.2%)remainedunchanged (Table2).Atthetimeofdiagnosis,eightpatientshadmild regurgitation. A moderate and severe regurgitation was
Table1 Demographic,clinicalcharacteristics,and labora-toryparametersofthepatientsatthetimeofdiagnosis.
Characteristics
Age(years),mean±SD(range) 12.23±2.1
Malegender 22(54.5%male)
Bodyweight(kg),mean±SD 42.4±17.9
Presenceofmajorcriteria
Arthritis 18/22(81.8%)
Chorea 0/22(0%)
Presenceofminorcriteria
Fever 10/22(45.4%)
Arthralgia 3/22(13.6%)
ProlongedPRinterval 4/22(18.1%) Elevatedacutephasereactants 22/22(100%)
Laboratoryfindings
Hemoglobin(g/dL) 10.49±1.35
WBC(/mm3) 10.79
±3.91 Platelet(1000/mm3) 409
±115
ESR(h) 106±26
ASO(IU/mL) 1175±425
Albumin(g/dL) 3.21±0.55
Echocardiography
FS% 42.9±4.5
Electrocardiography
Heartrate(pulse/min) 91.10±20.27 QTcdispersion(ms) 42.7±17.5
PRdistance(sec) 0.15±0.04
Lymphocytesubsetanalysis
CD8(%) 25.65±6.14
CD19(%) 21.11±8.72
ASO,anti-streptolysineO;ESR,erythrocytesedimentationrate; FS,fractionalshortening;WS,whitebloodcellcount.
presentineightandsixpatients,respectively.Atthesixth monthoffollow-up,aninitialmildregurgitationdisappeared ineightpatients(36.3%).Amongseven(31.8%)patientswith moderate regurgitation initially, the regurgitation disap-pearedinthreepatientsandfourpatientsimprovedtomild regurgitation.Twopatientswithsevereinitialregurgitation improvedtomoderateregurgitation(9.1%).Infive(22.8%) patients, the grade of regurgitation [moderate regurgita-tion in 1 (4.6%), and severe regurgitation in four (18.2%) remained unchanged.The fateof valvular involvement in allstudypatientsisdepictedonTable3.
Lymphocytesubsetanalysisshowedlymphopeniain31.8% (seven) of thepatients. BothCD3 and CD4 T-lymphocytes were decreased in 40.9% (nine) of the patients. Further-more,CD8T-lymphocyteswerealsodecreasedin13.6% of the patients with decreased levels of both CD3 and CD4. TheCD8 percentageatdiagnosis significantlydecreased in Group 2, whereas there wasa significant increase in the CD19percentage(Table4).
Discussion
Table2 Comparisonofelectrocardiography---echocardiography,andlaboratoryfindingsofthegroupswithandwithout regres-sionincarditis.
Variable Group1 Group2 p
Number 17(77.2%) 5(22.8%)
Agerange(mean/years) 12±1.8 13±3.2 NS
Sedimentation(h) 104.1±25.7 113.6±29.4 NS
ASO(IU/mL) 1192±438 1118±418 NS
Whitebloodcell(/mm3) 10.27
±3.9 12.56±3.58 NS
Hemoglobin(g/dL) 10.75±1.36 9.6±0.91 NS
Platelet(1000/mm3) 397
±92 451±182.3 NS
Albumin(g/dL) 3.3±0.45 2.6±0.48 0.003
Fractionalshortening(%) 43.6±4.6 40.0±2.9 NS
LVEDd(cm) 4.66±0.61 4.55±0.20 NS
ECG---Heartrate 86.2±15.2 111.5±28.5 NS
ECG---QTcdispersion(sec) 0.042±0.019 0.044±0.011 NS
ECG---PRdistance(sec) 0.149±0.040 0.152±0.046 NS
ASO,anti-streptolysineO;ECG,electrocardiography;LVEDd,leftventricularenddiastolicdiameter;NS,non-significant.
Table3 Severityofvalvularinvolvementinallpatientsatthebeginningofthestudyandatthesixthmonthoffollow-up.
Initial Aftersix-months Recovery
Mitralregurgitation Aorticregurgitation Mitralregurgitation Aorticregurgitation
Case1 Mild Absent Absent Absent +
Case2 Mild Mild Absent Absent +
Case3 Mild Mild Absent Absent +
Case4 Mild Absent Absent Absent +
Case5 Moderate Mild Absent Mild +
Case6 Mild Moderate Mild Moderate −
Case7 Moderate Mild Mild Mild +
Case8 Severe Moderate Severe Moderate −
Case9 Absent Mild Absent Absent +
Case10 Mild Absent Absent Absent +
Case11 Moderate Mild Mild Absent +
Case12 Severe Absent Severe Absent −
Case13 Mild Moderate Absent Absent +
Case14 Moderate Mild Absent Absent +
Case15 Severe Mild Moderate Mild +
Case16 Absent Mild Absent Absent +
Case17 Moderate Moderate Mild Mild +
Case18 Moderate Mild Absent Absent +
Case19 Severe Mild Moderate Absent +
Case20 Severe Absent Severe Absent −
Case21 Mild Mild Absent Mild +
Case22 Severe Mild Severe Mild −
susceptible subjects: cardiac myosin epitopes, vimentin, laminin, and other intracellular proteins. This similarity causescross-reactivityleadingtoautoimmunereactionsand mayresultinmyocardialdamage.Therefore,severalstudies have attemptedtodefinethese reactionsby investigating lymphocytesubgroups.18 Miceimmunizedwith
streptococ-calM5proteindevelopedheartvalvelesions;CD4(+)T-cells andCD68(+)macrophages19weredetectedininfiltrations,
and predominant infiltration of CD4 T-lymphocytes was foundinhearttissuebiopsiesofpatientsundergoing valvu-lar surgerydue torheumatic carditis.20 The patients with
acute rheumatic fever and acute rheumatic carditis had
significantly increased CD4 T-lymphocytes, CD22 B-lymphocytes,andCD4:CD8ratioandsignificantlydecreased CD8andCD3T-lymphocytescomparedtothepatientswith chronic rheumatic carditis,streptococcalpharyngitis, and healthy subjects.2 The decreased CD8 was found to be
Table4 Comparisonoflymphocytesubsetanalysisofthe groupswith (group1) andwithout(group 2)regression in carditis.
Variable Group1(n=17) Group2(n=5) p
Lymphocyte count
2178±1024 1819±946 NS
CD3(%) 67.35±9.3 58.08±13.7 NS CD4(%) 35.82±7.5 32.8±6.47 NS CD8(%) 27.63±5.88 20.56±1.9 0.017 CD4/CD8 1.35±0.39 1.62±0.34 NS CD19(%) 19.35±7.5 29.6±6.5 0.013
NS,non-significant.
Group A beta hemolytic streptococcal superantigens and may therefore play an important immunoregulatory role inthepathogenesisofthe disease.21 Inthepresent study,
theCD4:CD8ratioincreasedinthegroupwithoutrecovery invalvular findingscomparedtothe groupwithrecovery; however, the difference was not statistically significant. The percentage of CD19-positive B cells was significantly elevatedinARFpatients,suggestingaroleofBlymphocytes ininflammation and/or autoimmunityin thepathogenesis ofthesedisorder.22Thepresentstudydemonstratedalower
CD8levelingroup2thangroup1andahigherCD19level ingroup2thangroup1atdiagnosis.
AstudybySaitoetal.demonstratedthathumansystemic sclerosispatients overexpress CD19, an important regula-tory molecule expressed by B-lymphocytes. B-cells from CD19-deficientmicearehyporesponsivetotransmembrane signals,whileB-cellsoverexpressingCD19are hyperrespon-siveandgenerateautoantibodies.Thus,aCD19-dependent signalingpathwayinBcellscontributestothedevelopment ofsystemicautoimmunity.23AstudybyIwataetal.wasthe
firsttodemonstrate thatB-cellsplayacriticalroleinthe wound-healingprocess.TheCD19expressionpositively reg-ulates thewound-healing process.Delayed wound healing inCD19-/-micewasassociatedwithdecreasedinfiltration ofneutrophilsandmacrophages.24Inthepresentstudy,the
CD8percentageatdiagnosissignificantlydecreasedinARC patientswithoutrecoveryinvalvularinvolvement,whereas therewas a significant increase in the CD19 percentage. GiventheroleofCD8andCD19(+)lymphocytesin autoim-munityandinflammation,itisbelievedthatthealteration ofthese twosubsetsof lymphocytesmight have a rolein pathogenesisandpredictionofchronicvalvularinvolvement inpatientswithARF.
The blood albumin level may decrease in inflamma-tory conditionsandheart failure. The potentialcauses of decreased plasma albumin levels in heart failure include decreased synthesis due to hepatic congestion, hemod-ilution, increased metabolic activity, inflammation, and proteinuria. For hypoalbuminemia, levels <3.5g/dL have been demonstratedtopose arisk, and albumin <2.5g/dL hasbeenshowntobeanindependentriskfactorincardiac diseases.10Inthepresentstudy,thebloodalbuminlevelat
diagnosis was2.6±0.48 in the group without recovery in valvularlesionsafterthesix-monthfollow-upfollowingthe diagnosisofactivecarditis,andthiswassignificantlylower comparedto the group with recovery in valvular lesions.
Sincethephysicalexaminationofthepatientsrevealedno edemaandnormalheight-weightpercentilesaswellas nor-mal liverfunction tests,this resultwasmostlyassociated withthe higher level of inflammation andthe severity of valveregurgitation.
An increased QT dispersion may reflect the cardiac involvementinrheumaticfeverandbeanimportant param-eterinthediagnosisandtherapeuticdecisionforrheumatic carditis. Researchers revealed the QT dispersion to be greater, with more severe valvular pathology in patients withARC. QTdispersionwasfound to bedecreased after theinitialphaseofARC,reflectinganelectrophysiological improvement inthis subgroup ofpatients. These observa-tionssuggestedthatQTdispersionincreasesinassociation withcardiacinvolvementinchildrenwithacuterheumatic fever.25However,inthepresentstudy,whencomparingthe
QTcdispersioninARCpatientswithoutrecoveryinvalvular findingstothegroupwithrecovery,theQTcdispersionwas notstatisticallydifferent.
Machado et al. revealed that ASO levels were signif-icantly higher in patients with ARF compared to those withSydenhamchorea, idiopathicarthritis,and recurrent tonsillopharyngitis.26 However,in the present study,when
comparingtheASOlevelsinARCpatientswithoutrecoveryin valvularfindingstothegroupwithrecovery,ASOlevelscould notpredictthepersistenceinvalvularpathologyinpatients withARC.Also,CRPandsedimentationlevelsfailedto pre-dict thepersistenceinvalvularpathologyinthissubgroup ofpatients.
Some studies have attempted to establish risk factors forchroniccarditisandtheinitialLVEDd,27thepresenceof
TNF-␣308G>Apolymorphism,28 deficiencyinIL4-producing CD4 cells in heart valve tissue,29 and the presence ofDQ
molecule-associatedHLA-DR7DR53werereportedas poten-tialpredictorsofchronicity.Inthepresentstudy,theblood albuminlevelandCD8-CD19levelsatdiagnosiswerefound asriskdeterminants.
Inconclusion,thebloodalbuminlevelandespeciallythe CD8-CD19expressionatdiagnosisarehelpfulindefiningthe groupatriskfordevelopingchroniccarditisinpatientswith acuterheumaticcarditis.Moreprospectiveandlarge-scale studiesareneededtofurtherevaluateimpactoflymphocyte subsetsforpredictingchronicvalvulardiseaseinARF.
Retrospective design and relatively small sample size werethemainlimitationsofthisstudy.Easyaccessto medi-calcareandantibioticsandincreasedsocioeconomicstatus in Turkey might lead to decreased incidence of ARF and mightresultinasmallerpatientcohortwithARC,compared toearlierdecades.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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