UNIVERSIDADE ESTADUAL DE CAMPINAS
SISTEMA DE BIBLIOTECAS DA UNICAMP
REPOSITÓRIO DA PRODUÇÃO CIENTIFICA E INTELECTUAL DA UNICAMP
Versão do arquivo anexado / Version of attached file:
Versão do Editor / Published Version
Mais informações no site da editora / Further information on publisher's website:
https://www.sciencedirect.com/science/article/pii/S0167494314001174
DOI: 10.1016/j.archger.2014.07.014
Direitos autorais / Publisher's copyright statement:
©2014
by Elsevier. All rights reserved.
DIRETORIA DE TRATAMENTO DA INFORMAÇÃO
Cidade Universitária Zeferino Vaz Barão Geraldo
CEP 13083-970 – Campinas SP
Fone: (19) 3521-6493
http://www.repositorio.unicamp.br
Understanding
red
blood
cell
parameters
in
the
context
of
the
frailty
phenotype:
interpretations
of
the
FIBRA
(Frailty
in
Brazilian
Seniors)
study
Joa˜o
Carlos
Silva
a,
Ze´lia
Vieira
de
Moraes
a,
Conceic¸a˜o
Aparecida
da
Silva
a,
Silvia
de
Barros
Mazon
b,
Maria
Elena
Guariento
a,
Anita
Liberalesso
Neri
a,
Andre´ Fattori
a,*
a
DepartmentofInternalMedicine,FacultyofMedicalSciences,CampinasStateUniversity-Unicamp,Brazil
b
DepartmentofClinicalPathology,FacultyofMedicalSciences,CampinasStateUniversity-Unicamp,Brazil
1. Introduction
Becauseofthesignificantincreaseintheelderlypopulationand
consequentnewdemandsforcare,manystudieshavesoughtto
establisheffective,easily applicablecriteria for identifyingfrail seniors(Morley,Kim,Haren,Kevorkian,& Banks,2005;Morley
et al., 2013; Walston et al., 2006). The operationalized frailty
criteria based on strictly biological characteristics proposed by Friedetal.(2001)havebeenextensivelyusedandcorroboratethe
relationshipbetweenfrailtyandphysicalvulnerability,aswellas decreasedphysiologicalreserves(Friedetal.,2001).
Inparallel,studieshaveshowntheimportanceofanemiainthe
context of the elderly both because of its relationship with
functional loss and reduced survival and because it has been
identifiedasanadditionalfactorinthedevelopmentofthefrailty
phenotype (Artz, 2008; Bross, Soch, & Smith-Knuppel, 2010;
Denny,Kuchibhatla,&Cohen,2006;Landiet al.,2007;Penninx etal.,2004).Infact,frailtyandanemiaamongolderpeopleappear
to share a common pathophysiology associated with chronic
inflammatory processes (Chang, Weiss, Xue, & Fried, 2012;
Ferrucci & Balducci, 2008; Leng, Chaves, Koenig, & Walston, 2002;Maccio&Madeddu,2012).Diseasesassociatedwithaging, suchasatherosclerosis,diabetes,kidneydisease, age-associated cardiovascularchangesandosteo-degenerativediseases,progress
with chronic inflammation and their clinical impact may be
ARTICLE INFO
Articlehistory:
Received14September2013 Receivedinrevisedform23July2014 Accepted25July2014
Availableonline14August2014
Keywords: Frailty Elderly Anemia
(redbloodcelldistributionwidth)RDW Reticulocytes
ABSTRACT
Frailtyandanemiaintheelderlyappeartoshareacommonpathophysiologyassociatedwithchronic inflammatoryprocesses.Thisstudyusesananalytical,cross-sectional,population-basedmethodology toinvestigatetheprobablerelationshipsbetweenfrailty,redbloodcellparametersandinflammatory markersin255community-dwellingeldersaged65yearsorolder.Thefrailtyphenotypewasassessed bynon-intentionalweightloss,fatigue,lowgripstrength,lowenergyexpenditureandreducedgait speed. Blood sample analyses were performed to determine hemoglobin level, hematocrit and reticulocytecount,aswellastheinflammatoryvariablesIL-6,IL-1raandhsCRP.Inthefirstmultivariate analysis (modelI), consideringonly theerythroid parameters, Hbconcentrationwas a significant variableforbothgeneralfrailtystatusandweightloss:a1.0g/dLdropinserumHbconcentration representeda2.02-foldincrease(CI1.12–3.63)inanindividual’schanceofbeingfrail.Inthesecond analysis(modelII),whichalsoincludedinflammatorycytokinelevels,hsCRPwasindependentlyselected asasignificantvariable.Eachadditionalyearofagerepresenteda1.21-foldincreaseinthechanceof beingfrail,andeach1-unitincreaseinserumhsCRPrepresenteda3.64-foldincreaseinthechanceof havingthefrailtyphenotype.InmodelIIreticulocytecountswereassociated withweightlossand reducedmetabolicexpenditurecriteria.OurfindingssuggestthatreducedHbconcentration,reduced RetAbscountandelevatedserumhsCRPlevelsshouldbeconsideredcomponentsoffrailty,whichinturn iscorrelatedwithsarcopenia,asevidencedbyweightloss.
ß2014ElsevierIrelandLtd.Allrightsreserved.
* Corresponding author at: Rua Tessa´lia Vieira de Camargo, 126, Cidade Universita´riaZeferino Vaz,Campinas, Sa˜o Paulo Zip Code:13083-887, Brazil. Tel.:+551935217878;fax:+551935217878.
E-mailaddresses:[email protected],[email protected](A.Fattori).
ContentslistsavailableatScienceDirect
Archives
of
Gerontology
and
Geriatrics
j ou rna l h om e pa ge : w w w. e l s e v i e r. co m/ l oc a t e / a rch ge r
http://dx.doi.org/10.1016/j.archger.2014.07.014
aggravatediftheyoccurconcomitantlywithanemia(Ferrucci& Balducci,2008).
In light of this, it is difficult toestablish a cause-and-effect
relationshipbetweenfrailtyparametersand anemia,the
down-ward-spiralmodelproposedbyFriedbeingthemostplausiblefor
anunderstanding of theseprocesses. Thepresent studycan be
expectedtohelp in the identificationof probablerelationships
between frailty, red blood cell parameters and inflammatory
markers, which, in the context of frailty, are equivalent to
sarcopenia.
2. Methods
2.1. Participantsandmethodology
Thestudydatawerecollectedfromasampleof residentsin
urbanCampinasaspartoftheFIBRAmulticenterpopulation-based study.Beforethedatawerecollected,participantswereinformed oftheobjectivesofthestudyandthetypeofdatathatwouldbe
collected. They signed a voluntary informed-consent form
approvedbytheCommitteeforEthicsinResearchattheSchool
ofMedicalSciences,StateUniversityofCampinas(Unicamp).
The sample consisted of 255 community-dwelling elders
recruited in their homes in various census areas for the
municipality of Campinas, Brazil. The inclusion criteria were:
being 65 years of age or older; being able to understand the
instructions; agreeing to participate; and being a permanent
residentattheaddressgiveninthelastcensus.Therecruiterswere instructedtousethefollowingexclusioncriteria:havingaclinical pictureofdementia,asevidencedbyproblemsrelatedtomemory, attention,spatialorientation,temporalorientationand
communi-cation; being bedridden or a wheelchair user; having severe
sequelaeofstroke,withlocalizedlossofstrengthand/oraphasia;
having advanced or unstable Parkinson’s disease with severe
motororspeechimpairmentsornegativeaffectivity;havingsevere auditoryorvisualdeficitsthatmadecommunicationverydifficult;
andbeinganend-stagepatient.
Sociodemographic,anthropometric,frailty-criteria, blood-pres-sureandcognitive-screeningmeasureswerecollectedforallthe
study population. Poor cognitive performance, measured by
MMSE,wasusedasanexclusioncriterion forparticipationina
secondstageinvolvingthecollectionofthefollowingmeasures: physicalandmentalhealth,functionalcapacity,careexpectations andperceivedsocialsupport(Folstein,Folstein,&McHugh,1975). Thefrailtyphenotypewasdeterminedusingthecriteriainthe
CardiovascularHealthStudyandtheWomen’sHealthandAging
Study(WHAS),whichweredescribedand validatedinprevious
publications;thecut-offpointsforfrailtyvariablesadjustedforthe
Brazilian population were published previously by our group
(Fattori,Santimaria, Alves,Guariento, &Neri,2013; Friedetal., 2001).
Bloodsamples were collected by venipuncture using sterile
materialandstoredawayfromlightindrycollectiontubesand
EDTAtubes.ThesamplesweresenttotheHematologyLaboratory
at UnicampUniversity Hospitalfor complete blood counts and
reticulocytecountsusingflowcytometryandtheSLS-hemoglobin
methodwithanXE-2100hematologyanalyzer(Sysmex
Corpora-tion,Kobe,Japan).Theserumwascentrifugedandfrozenat-808C.
Theparametersusedtodefineanemiawerethoseproposedbythe
WHO(WorldHealthOrganization),i.e.,thepresenceofanemiais
indicatedbyahemoglobin (Hb)levelbelow13g/dLinmenand
12g/dLinwomen.Inflammatorycytokineassayswereperformed
atthePhysiologyandImmunologyLaboratoryintheDepartment
ofClinicalPathology,Hospitaldas Clı´nicas,Unicamp, andatthe
Metabolism Laboratory in the School of Medical Sciences,
Unicamp. Serum erythropoietin was quantified with the EPO
AssayKitforautomatedanalysisinanImmulite1000
Immunoas-saySystem(Erlanger,Germany)bychemiluminescent
immuno-metricassay.hsCRPassayswerecarriedoutbynephelometrywith
theCardioPhase hsCRP commercial kitin a BNProSpec system
(Erlanger, Germany). IL-6 and IL-1RA werequantified withthe
Human IL-6 and IL-1RA/IL-1F3 Quantikine ELISA kits (R&D
Systems,Minneapolis,USA).
ThisworkwassupportedbyFundac¸a˜odeAmparoa` Pesquisado EstadodeSa˜oPaulo[2009/53113-1].
2.2. Statisticalanalysis
To describe theprofile of the sample in terms ofthe study
variables,frequencytablesshowingtheabsolutefrequency(n)and percentage (%)foreach categorical variable(gender,agegroup,
anemia, frailty and education) were drawn up, together with
descriptivestatistics(mean,standarddeviationandminimumand maximumvalues)ofthenumericvariables(age,individualincome
andhematologicdata).
Thecategoricalvariableswerecomparedusingthechi-square
testorFisher’sexacttest(forexpectedvalueslessthan5).Asthe
numericvariablesdidnothaveanormaldistribution,theMann–
Whitneytestwasusedtocomparethesebetweentwogroups,and
the Kruskal–Wallis test was used for three or more groups. A
significancelevelof5%(p<0.05)wasusedforallthestatistical tests.
ExploratoryanalyseswereperformedusingPCAwith
orthogo-nalvarimaxrotation;thevariablesHb,MCV,RDW,WBC,RetAbs,
EPO,hsCRP,IL-6,IL-1raandallfrailtycriteriawereincludedinthe
model. ThePCAcomponentswereselectedwheneach of them
explainedatleast10%ofthetotalvariance.
Univariateandmultivariatestepwiselogisticregression analy-sisofthedatawasalsoperformed.Gender,ageandBMI(bodymass
index) weredefinedasantecedentvariables, andtwoanalytical
modelswere thendeveloped: (I) a modelusing thenumber of
comorbidities and red cell indices individually as independent
variablesand(II)amodelthatalsoincludedinflammatorycytokine
and erythropoietin levels. In both models we used the frailty
classificationandeachofthedefiningcriteriaasoutcome,anda significancelevelof5%(p<0.05)wasusedwitha95%confidence interval.
3. Results
Ourfindingsshowagreaterprevalenceoffrailtyamongwomen
(9.2%)thanamongmen(2.4%)andagreaterproportionofrobust
individuals in themale population (51.8%) than in the female
population(39.6%).Anemiawasmoreprevalentinwomenthanin
men, although the difference was not statistically significant
(10.3%and8.6%,respectively)(datanotshown).
Asthemain objectiveofthis studywastocompareredcell
indices in frail and non-frail individuals and as physiological
differences were expected between the genders, association
analyses for each red cell parameter were carried out for the
threefrailtystatusesandeachcriterionseparatelyformalesand
females. Table1 shows that there was a statistical association
betweenweightlossinmalesandlowerserumHblevelsaswellas lowerabsolutereticulocytecount.Thisresultwasalsoobserved
amongelderlyfemales;however,unlikeinmen,lowHblevelsin
womenwerealsoassociatedwithreducedgripstrengthandgait
time,aswellaswiththegeneralfrailtyclassification(Table2). AnalysisofRDW,whichmeasuresthevariationinredbloodcell
size, revealed an association between higher values of this
parameterand elderly womenwho werefrail accordingtothe
criteriafatigueandgaittimeaswellasthefrailtystatusperse.
ThePCAmodelaccountedfor57.17%ofthevarianceandwas
composedofacomponentformedbyWBC,RetAbs,EPO,hsCRP,
IL-1raandIL-6,alldirectlyrelated(inflammatorycomponent);the
second component was formed by males with a positive
correlationwithHbandEPO (predictablephysiological
compo-nent);thethirdbyage,whichinverselycorrelatedwithHband
RetAbsanddirectlycorrelatedwiththepresenceofweightloss, EPOandreducedgaitspeed(sarcopeniacomponent);thefourthby
age witha direct correlation with RetAbs,impairment of grip
strengthanddecreasedphysicalactivity;andfinally,acomponent consistingof thedirectcorrelationbetweenIL-6,IL-1raand the presenceoffatigue.
Thedataweresubjectedtounivariateandmultivariateanalysis usingstepwiseselectionofthevariablestocorrectforconfounding
factors.In theunivariate analysis, femalegenderand agewere
statisticallyassociatedwithfrailty.Univariateanalysis(Table3)of
red cell indices showed that the presence of anemia (as a
categorical variable based on the WHO classification) and
parameters related tothered blood cell population (expressed
numericallyasserumHb,absolutenumberofredbloodcellsand
RDW)werealsoassociatedwiththepresenceoffrailty.
In multivariateregressionmodelI (Table4),which included
onlyredcellindices,thegeneralfrailtyclassificationwasrelatedto ageandserumHblevel.Absolutereticulocytecount(RetAbs)was
Table1
Comparisonofredcellparametersforseniorsforeachfrailtycriterionandfrailtystatus(males,n=82).FIBRAstudy.
MeanSD RBC Hb HCT MCV RDW RetAbs
Male
Weightloss Negative 4.770.32 14.480.86 42.982.25 90.333.92 13.530.69 54.9916.91 Positive 4.790.66 13.630.77 41.552.25 87.798.82 13.480.64 44.8710.51 pa 0.553 0.003 0.064 0.757 0.782 0.055 Fatigue Negative 4.760.38 14.340.91 42.752.33 90.084.96 13.570.66 52.5616.40 Positive 4.820.45 14.510.70 42.901.85 89.415.36 13.130.74 62.2214.41 pa 0.831 0.516 0.868 0.658 0.143 0.077
Reducedgripstrength Negative 4.770.38 14.330.89 42.682.23 89.735.08 13.500.68 54.4416.58 Positive 4.720.38 14.550.89 43.612.72 92.542.99 13.750.65 46.7113.71
pa 0.843 0.461 0.168 0.060 0.405 0.217
Reducedphysicalactivity Negative 4.770.36 14.360.87 42.692.31 89.724.57 13.520.63 51.6715.72 Positive 4.750.46 14.340.97 43.042.23 91.026.21 13.560.85 60.1017.39 pa
0.617 0.959 0.613 0.103 0.699 0.070
Gaitspeed Negative 4.760.38 14.300.88 42.602.28 89.805.10 13.530.69 53.1016.68 Positive 4.810.38 14.700.93 43.812.08 91.334.01 13.500.61 56.8414.76 pa 0.530 0.131 0.064 0.335 0.548 0.402 Frailty Robust 4.730.30 14.380.88 42.552.28 90.014.03 13.550.60 51.6716.06 Pre-frail 4.830.44 14.350.91 43.112.25 89.725.89 13.510.71 55.8516.82 Frail 4.310.40 13.801.13 41.053.04 95.301.70 13.250.49 50.2019.06 pb 0.191 0.710 0.269 0.165 0.746 0.586 a
pvaluewhentheresultsforthefrailtycriteria(negativevs.positive)werecomparedusingtheMann–Whitneytest.
b
pvaluewhenthevariablesforthethreefrailtygroupswerecomparedusingtheKruskall–Wallistest.Significantdifferences(Dunnposthoctest,p<0.05).
Table2
Comparisonofredcellparametersforseniorsforeachfrailtycriterionandfrailtystatus(females,n=173).FIBRAstudy.
MeanSD RBC Hb HCT MCV RDW RetAbs
Female
Weightloss Negative 4.500.36 13.341.02 40.232.90 89.494.36 13.560.82 56.6615.14 Positive 4.330.39 12.861.17 39.073.27 90.364.28 13.761.27 46.0015.22 pa 0.032 0.103 0.197 0.272 0.783 0.025 Fatigue Negative 4.440.36 13.231.07 39.923.05 89.964.18 13.530.91 51.2715.39 Positive 4.650.41 13.550.98 40.972.58 88.265.02 13.900.82 50.9014.14 pa 0.024 0.195 0.122 0.150 0.014 0.954
Reducedgripstrength Negative 4.500.38 13.361.05 40.283.00 89.614.61 13.570.84 51.0115.26 Positive 4.340.34 12.831.08 38.993.01 89.872.71 13.731.16 5.4314.81
pa 0.025 0.019 0.041 0.908 0.680 0.382
Reducedphysicalactivity Negative 4.500.39 13.341.04 40.222.98 89.504.44 13.540.82 50.8414.83 Positive 4.370.33 12.991.13 39.483.165 90.323.81 13.781.14 53.2616.31 pa
0.082 0.062 0.182 0.401 0.409 0.344
Gaitspeed Negative 4.500.38 13.381.03 40.292.92 89.804.43 13.490.38 51.3615.12 Positive 4.400.37 12.891.13 39.323.26 89.323.95 13.951.16 51.4115.46 pa 0.122 0.012 0.126 0.830 0.010 0.934 Frailty Robust 4.500.37 13.401.00 40.382.99 89.814.06 13.430.78 52.5315.26 Pre-frail 4.480.39 13.301.07 40.112.93 89.644.70 13.620.82 50.7015.05 Frail 4.290.35 12.461.09 38.383.39 89.393.18 14.241.43 50.1115.97 pb 0.113 0.017(A) 0.139 0.754 0.024(B) 0.556 a
pvaluewhentheresultsforthefrailtycriteria(negativevs.positive)werecomparedusingtheMann–Whitneytest.
b
pvaluewhenthevariablesforthethreefrailtygroupswerecomparedusingtheKruskall-Wallistest.Significantdifferences(Dunnposthoctest,p<0.05:(A) non-frail6¼frail,pre-frail6¼frail,(B)non-frail6¼frail).
associated with the individual criterion weight loss for both gendersandwithreducedphysicalactivityonlyinmen.InmodelII
(Table5)—whichalsoincludedinflammatorycytokinelevels—age,
serumHblevelandhsCRPwereselectedassignificantvariables
associatedwiththegeneralfrailtyclassification.Eachadditional yearofagerepresenteda1.2-foldincreaseinthechanceofbeing frail,andeach1-unitincreaseinserumhsCRPrepresenteda
3.64-fold increase in the chance of having the frailty phenotype.
MultivariateanalysisusingmodelIIrevealedthatareductionof 10106mL–1inRetAbscountresultedina 40%increaseinthe
chance of having the weight loss criterion, and that each
10106mL1 increase in this parameter also led to a 30%
increase in the chance of being positive for the metabolic
expenditurecriterion. 4. Discussion
Themodels mostcommonly usedto understand the
patho-physiology of frailty are based on an interpretation of the
syndromeastheresultofanaccumulationofdeficitsduringan
individual’s life, resulting in greater biological vulnerability, or evenareductioninanindividual’smetabolism,whichinthiscase isalsoaccompaniedbyreducedhomeostaticcapacity(Friedetal., 2001;Rockwood&Mitnitski,2011).Wesuggestthatabnormalred
cellindicescontributetothephenotypeasastressorbutalsoplaya similarroletothatofsarcopeniainthemodelproposedbyFried etal.(2001),Cesarietal.(2006),Friedetal.(2001).
LowHblevelsintheelderlyareknowntohaveaninfluenceon
unfavorableoutcomessuchasadeclineinphysicalperformance,
increased physical limitations, lengthy hospitalizations and
increased risk of death (Beghe, Wilson, & Ershler, 2004; Landi et al.,2007;Patel&Guralnik,2009;Penninxetal.,2004;Zakai etal.,2005).Frailtyhaspreviouslybeenreportedtobeassociated withreducedredcellindices,particularlytotalerythroid popula-tion,Hbandhematocrit(Kamenetzetal.,1998;Lengetal.,2002; Roy,2011).Inthepresentstudy,lowerHblevelswerestatistically
associated withweightloss,reduced gripstrengthand reduced
gaitspeed.Anotherparameterthathasreceivedlittleattentionin
the literature—RetAbs count—also exhibited a correlation with
weightloss(Tables4and5).
Whenusedinthemultivariateanalysis(modelI–Table4),Hb concentration wasa significantvariablefor bothgeneral frailty statusandweightloss:a1.0g/dLdropinserumHbconcentration representeda2.39-foldincrease(CI1.15–3.95)inthechanceofthe individualbeingfrail.RetAbscountwasalsorelatedtoweightloss andmetabolicactivity.Reticulocytesareimmatureredbloodcells
releasedin thecirculatory system, and thenormal responseto
reducedHblevelsisforreticulocytestobereleasedtocompensate for this reduction (Ferrucci & Balducci, 2008). The finding of reducedproductionofreticulocytesinindividualswithweightloss
canbeunderstoodasaninadequatebonemarrowresponseand
probablysuggeststhatreducedreticulocyteproductionissimilar toweightlossinthecharacterizationofsarcopenia(Cesarietal., 2006;Ferrucci&Balducci,2008).Reducederythroidproductionin
the bone marrow and low serum Hb concentrations are
determiningfactorsinreducedtissueoxygensupplyandtherefore predispose todevelopmentof thefrailtyphenotype(Ferrucci&
Balducci, 2008). Indeed, studies that focus on the biological
characteristics of frailty show that poor tissue perfusion is an importantfactorinthedevelopmentofsarcopenia(Fattorietal., 2013;Ferrucci&Balducci,2008;Ochiet al.,2010). Whenthese frailty-associatedchangesoccurconcomitantlywithareductionin Hbconcentration,theyadverselyaffecttissueoxygenavailability andleadtoagreaterreductioninskeletalmusclemass(Ochietal., 2010).
Theresultsofthemultivariateanalysisusingboththeproposed modelsshowedthatthepresenceofthecriterionreducedphysical activitywasassociatedwithelevatedRetAbscount.Inaddition,the
Table3
Univariateanalysisofvariablesofinterestassociatedwithfrailty.FIBRAStudy (n=255).
Variable ORa (95%CIOR) pvalue*
Femalegender 4.94 1.081–22.580 0.039 Age 0.84 0.744–0.970 <0.001 RBC 0.13 0.032–0.542 0.005 Hb 0.40 0.259–0.650 <0.001 HTC 0.77 0.660–0.913 0.008 MCV 1.00 0.900–1.127 0.891 RDW 2.15 1.263–3.683 0.019 RetAbs 0.99 0.958–1.026 0.871 SerumEPO 1.01 0.998–1.034 0.178 SerumhsCRP 4.83 1.776–13.15 0.008 SerumIL-1RA 1.00 1.000–1.003 0.081 SerumIL-6 1.02 0.910–1.143 0.458 a Ref:Non-frail. * Significancelevelp<0.05. Table4
Multivariateanalysisofvariablesofinterestassociatedwithfrailtystatus(ModelI). FIBRAstudy(n=255). Variable ORa (95%CIOR) pvalue* ModelI Outcome:Frailty Age 1.16 (1.065–1.277) 0.001 Hb 0.493 (0.270–0.899) 0.021 Weightloss Hb 0.68 (0.490–0.956) 0.026 RetAbs 0.97 (0.946–0.997) 0.029 Fatigue
Nostatisticallysignificantdifference Gripstrength Age 1.11 (1.049–1.174) <0.001 Physicalactivity Age 1.07 (1.023–1.133) 0.005 RetAbs 1.02 (1.003–1.044) 0.022 Gaitspeed Age 1.09 (1.043–1.157) <0.001 a Ref:Non-frail. * Significancelevelp<0.05. Table5
Multivariateanalysisofvariablesofinterestassociatedwithfrailtystatus(Model II).FIBRAStudy(n=255).
Variable ORa (95%CIOR) pvalue*
ModelII Outcome:Frailty Age 1.21 (1.092–1.346) <0.001 Hb 0.41 (0.212–0.823) hsCRP 3.64 (1.060–12.540) 0.040 Weightloss RetAbs 0.96 (0.942–0.992) 0.011 Fatigue
Nostatisticallysignificantdifference. Gripstrength Age 1.10 (1.046–1.173) <0.001 Physicalactivity Age 1.07 (1.023–1.133) 0.005 RetAbs 1.02 (1.001–1.043) 0.037 Gaitspeed Age 1.09 (1.037–1.155) 0.001 SerumhsCRP 3.306 (1.486–7.354) 0.003 a Ref:Non-frail. * Significancelevelp<0.05.
resultsfortheRetAbscountshowedthatthecorrelationbetween thisparameterandweightlosswastheoppositeofthecorrelation
with reduced physical activity. In the context of the model
proposedhere,theincreaseinRetAbscountcanbeinterpretedasa compensatorymechanismthatispartofthesystemicresponsetoa reductioninrestingmetabolicrateaspreviousstudieshaveshown
that reduced physical activity is one of the first phenotypic
characteristics to develop in frailty (Xue, Bandeen-Roche,
Varadhan,Zhou, &Fried, 2008). Weight lossoccurs afterthese deficitsasaresultofareductioninskeletalmuscle,whichisalso
associatedwithreducedreticulocyteproduction. Thesefindings
corroborate previous studies using computed tomography that
reportedreducedgripstrength,skeletalmusclemassanddensity
in anemicelderly individualscompared withnon-anemic ones
(Cesarietal.,2006).
In the second statistical analysis (model II – Table 5), the
variablesrelatedtoinflammatoryactivitywereincludedinorder
to characterize the relative importance of each component
(i.e.,inflammationand red blood indicesin frailty) and also to definethemarkersindependentlyassociatedwithagreaterchance ofpresentingwiththephenotype.Theinclusionoftheresultsfor
inflammatory activity in model II (Table 5) showed that only
RetAbscountcontinuedtobeassociatedwiththecriteriaweight
loss and physical activity. This is the first description of the
association between low RetAbs count and specific frailty
phenotype criteria, suggesting that this could be an objective
parameter that could easily be determined in a laboratory to
identifysarcopenia.
Willemsetal.(2012)showedthatindividualswithanemiaof
unexplainedorigin havethe samerisk of death asnon-anemic
individuals(Willemsetal.,2012).Thiswouldappeartoindicate thatareductioninHbconcentrationisanintrinsiceventinthe
normalagingphenotype.Inourstudy,however,thereductionin
Hband,particularly,RetAbscount,bothofwhichwereassociated withthe Fried frailtycriteria, didnot indicatea healthy aging
process. One drawback of our study is that it did not seek to
identifyanemicseniorsaccordingtotheetiologyoftheanemia.It
would be interesting to carry out a prospective study of the
influenceofanemiaofunexplainedoriginonthefrailtyphenotype.
InflammatoryactivityasmeasuredbyhsCRPwasstatistically
associatedwiththecriteriaphysicalactivityandgaitspeedaswell
as with general frailty status. Overall, the model showed that
frailtywasmorecloselyassociatedwiththeinflammatoryprocess thanwithredcellparameters,withtheexceptionofRetAbs.The involvementofchronicinflammationinthedevelopmentoffrailty isdescribedin theliterature(Barzilayetal.,2007;Cesarietal.,
2004; Leng et al., 2002; Li, Manwani, & Leng, 2011). In the
Invecchiare in Chianti study, Cesari et al. (2004) reported that increasedIL-6,IL-1RAandCRPlevelshadastatisticallysignificant
associationwithpoorphysicalperformanceandreducedmuscle
strengthin community-livingseniors(Cesari et al., 2004). Itis interestingtonote thatfrailtyand anemia of theelderlyshare
similar pathophysiological mechanisms based on a chronic
inflammatorystate,reinforcingthehypothesisthatinthecontext offrailtyRetAbs countis a laboratoryequivalentof sarcopenia (Ershler,2003;Ferrucci&Balducci,2008;Kamenetzetal.,1998;
Maccio & Madeddu, 2012). In this study, joint analysis of
inflammatory and red cell indices allowed us to describe the
associationbetweenandrelativesignificanceofthese character-isticsinthedevelopmentofthefrailtyphenotype.
Anotherredcellparameterthatwefoundtobeassociatedwith
thefrailtyphenotypewasRDW. Somestudieshavedescribed a
correlationbetweenincreasedRDWandanincreasedriskofdeath. AccordingtoChenetal.(2010),RDWisanearlierpredictorofarisk ofdeathfromnon-cardiovasculardisease,andPateletal.(2009)
reported that the greater the RDW, the greater the all-cause
mortality(Chenetal.,2010;Patel&Guralnik,2009).Ourresults corroboratethesefindings.
5. Conclusion
The paucity of specific symptoms of the frailty syndrome
highlightstheneedforobjectivemarkersfortheidentificationof groupsatriskofunfavorableprogression.Ourfindingssuggestthat
reduced Hb concentration and reduced RetAbs count should
perhapsbeconsideredcomponentsoffrailty,whichiscorrelated
with sarcopenia, as evidenced by weight loss. In this context,
reduced red cell indices not only indicate that poor tissue
oxygenation plays a role in the pathophysiology of frailty but
canalsobeusedasanothercriteriontodefinethephenotype.This
FIBRAstudyhasshownthatfuturelongitudinalstudiesmayhelp
determineHblevelsandRetAbscountsthatcanbeusedascriteria todefinefrailty.
Financialsupport
Fapesp2009/53113-1,Sa˜oPaulo,Brazil.
Conflictofintereststatement
Theauthorsdeclarenoconflictofinterestandnorelationship
with any people or organization that could inappropriately
influencethiswork.
References
Artz,A.S.(2008).Anemiaandthefrailelderly.SeminarsinHematology,45,261–266.
Barzilay,J.I.,Blaum,C.,Moore,T.,Xue,Q.L.,Hirsch,C.H.,Walston,J.D.,etal.(2007).
Insulinresistanceandinflammationasprecursorsoffrailty:TheCardiovascular HealthStudy.ArchivesofInternalMedicine,167,635–641.
Beghe,C.,Wilson,A.,&Ershler,W.B.(2004).Prevalenceandoutcomesofanemiain geriatrics:Asystematicreviewoftheliterature.AmericanJournalofMedicine, 116(Suppl.7A),3S–10S.
Bross,M.H.,Soch,K.,&Smith-Knuppel,T.(2010).Anemiainolderpersons.American FamilyPhysician,82,480–487.
Cesari,M.,Leeuwenburgh,C.,Lauretani,F.,Onder,G.,Bandinelli,S., Maraldi,C.,etal. (2006).Frailtysyndromeandskeletalmuscle:ResultsfromtheInvecchiarein Chiantistudy.AmericanJournalofClinicalNutrition,83,1142–1148.
Cesari,M.,Penninx,B.W.,Pahor,M.,Lauretani,F.,Corsi,A.M.,RhysWilliams,G.,etal. (2004).Inflammatorymarkersandphysicalperformanceinolderpersons:The InCHIANTIstudy.JournalsofGerontology,59,242–248.
Chang,S.S., Weiss,C.O., Xue,Q. L.,&Fried, L.P.(2012).Association between inflammatory-related diseaseburden and frailty:Resultsfrom the Women’s HealthandAgingStudies(WHAS)IandII.ArchivesofGerontologyandGeriatrics, 54,9–15.
Chen,P.C.,Sung,F.C.,Chien,K.L.,Hsu,H.C.,Su,T.C.,&Lee,Y.T.(2010).Redbloodcell distributionwidthandriskofcardiovasculareventsandmortalityinacommunity cohortinTaiwan.AmericanJournalofEpidemiology,171,214–220.
Denny,S.D.,Kuchibhatla,M.N.,&Cohen,H.J.(2006).Impactofanemiaonmortality, cognition,andfunctionincommunity-dwellingelderly.AmericanJournalof Medi-cine,119,327–334.
Ershler,W.B.(2003).Biologicalinteractionsofagingandanemia:Afocusoncytokines. JournaloftheAmericanGeriatricsSociety,51,S18–S21.
Fattori,A.,Santimaria,M.R.,Alves,R.M.,Guariento,M.E.,&Neri,A.L.(2013).Influence ofbloodpressureprofileonfrailtyphenotypeincommunity-dwellingeldersin Brazil–FIBRAstudy.ArchivesofGerontologyandGeriatrics,56,343–349.
Ferrucci,L.,&Balducci,L.(2008).Anemiaofaging:Theroleofchronicinflammation andcancer.SeminarsinHematology,45,242–249.
Folstein,M.F.,Folstein,S.E.,&McHugh,P.R.(1975).‘‘Mini-mentalstate.’’Apractical methodforgradingthecognitivestateofpatientsfortheclinician.Journalof PsychiatricResearch,12,189–198.
Fried,L.P.,Tangen,C.M.,Walston,J.,Newman,A.B.,Hirsch,C., Gottdiener,J.,etal. (2001).Frailtyinolderadults:Evidenceforaphenotype.JournalsofGerontology,56, M146–M156.
Kamenetz,Y.,Beloosesky,Y.,Zeltzer,C.,Gotlieb,D.,Magazanik,A., Fishman,P.,etal. (1998).Relationshipbetweenroutinehematologicalparameters,serumIL-3,IL-6 anderythropoietinandmildanemiaanddegreeoffunctionintheelderly.Aging, 10,32–38.
Landi,F.,Russo,A.,Danese,P.,Liperoti,R.,Barillaro,C., Bernabei,R.,etal.(2007).
Anemia status, hemoglobin concentration, and mortality in nursing home olderresidents.JournaloftheAmericanMedicalDirectorsAssociation,8,322–327.
Leng,S.,Chaves,P.,Koenig,K.,&Walston,J.(2002).Seruminterleukin-6and hemo-globinasphysiologicalcorrelatesinthegeriatricsyndromeoffrailty:Apilotstudy. JournaloftheAmericanGeriatricsSociety,50,1268–1271.
Li,H.,Manwani,B.,&Leng,S.X.(2011).Frailty,inflammation,andimmunity.Agingand Disease,2,466–473.
Maccio,A.,&Madeddu,C.(2012).Managementofanemiaofinflammationinthe elderly.Anemia,2012,563251.
Morley,J.E.,Kim,M.J.,Haren,M.T.,Kevorkian,R.,&Banks,W.A.(2005).Frailtyandthe agingmale.AgingMale,8,135–140.
Morley,J.E.,Vellas,B.,AbellanvanKan,G.,Anker,S.D.,Bauer,J.M.,Bernabei,R.,etal. (2013).Frailtyconsensus:Acalltoaction.JournaloftheAmericanMedicalDirectors Association,14,392–397.
Ochi,M.,Kohara,K.,Tabara,Y.,Kido,T.,Uetani,E., Ochi,N.,etal.(2010).Arterial stiffnessisassociatedwithlowthighmusclemassinmiddle-agedtoelderlymen. Atherosclerosis,212,327–332.
Patel,K.V.,&Guralnik,J.M.(2009).Prognosticimplicationsofanemiainolderadults. Haematologica,94,1–2.
Penninx,B.W.,Pahor,M.,Cesari,M.,Corsi,A.M.,Woodman,R.C., Bandinelli,S.,etal. (2004).Anemiaisassociatedwithdisabilityanddecreasedphysicalperformanceand musclestrengthintheelderly.JournaloftheAmericanGeriatricsSociety,52,719–724.
Rockwood,K.,&Mitnitski,A.(2011).Frailtydefinedbydeficitaccumulation andgeriatricmedicinedefinedbyfrailty.ClinicsinGeriatricMedicine,27, 17–26.
Roy,C.N.(2011).Anemiainfrailty.ClinicsinGeriatricMedicine,27,67–78.
Walston,J.,Hadley,E.C.,Ferrucci,L.,Guralnik,J.M.,Newman,A.B., Studenski,S.A., etal.(2006).Researchagendaforfrailtyinolderadults:Towardabetter under-standingofphysiologyandetiology: Summaryfromthe AmericanGeriatrics Society/NationalInstituteonAgingResearchConferenceonFrailtyinOlderAdults. csSociety,54,991–1001.
Willems,J.M.,denElzen,W.P.,Vlasveld,L.T.,Westendorp,R.G.,Gussekloo,J., de Craen,A.J.,etal.(2012).Noincreasedmortality riskinolderpersonswith unexplainedanaemia.AgeandAgeing,41,501–506.
Xue, Q. L., Bandeen-Roche,K., Varadhan, R., Zhou,J., & Fried, L. P. (2008).
Initialmanifestationsoffrailtycriteriaandthedevelopmentoffrailty phe-notypeintheWomen’sHealthandAgingStudyII.JournalsofGerontology,63, 984–990.
Zakai,N.A.,Katz,R.,Hirsch,C.,Shlipak,M.G.,Chaves,P.H.,Newman,A.B.,etal.(2005).
Aprospectivestudyofanemiastatus,hemoglobinconcentration,andmortalityin anelderlycohort:TheCardiovascularHealthStudy.ArchivesofInternalMedicine, 165,2214–2220.
