inflammatory bowel disease · inflammatory bowel disease 3 cd and uc. tabel 1: percentage of...

Early Diagnosis of Pediatric Crohn’s Disease - Pointing Problems and Suggestions

Maraci Rodrigues

Pediatric Gastroenterologist, Department of Gastroenterology, School of Medicine University of

Sao Paulo, Brazil

Email: [email protected]

Chapter 3

Inflammatory Bowel Disease

1. Introduction

Inflammatoryboweldisease(IBD)includesCrohn'sdisease(CD)andulcerativecolitis(UC)andcanbediagnosedinchildhoodandadolescencein25%ofcases[1].ChildrenthatcontractIBDbefore10yearsofagealmostalwayspresentwithextensivecolitisthatcannotbeclassifiedaseitherUCorCD,andremaincolitisnotdetermined(IBD-U)untilseveralyearslater[2].

Data from the literatureon the timeofdiagnosisvaryconsiderably.Apediatric IBDstudyinGermanyfoundthattheaveragetimeforCDdiagnosiswas5months(2-10months),fortheUCwas3months(1-6months)andIBD-Uwas4months(2-11months)andthegrowthdeficitwasthemostcommonsignincaseswithlatediagnosis[3].Comparedtothisstudy,thetimeintervalbetweentheonsetofsymptomsandthediagnosiswas4and2monthsinarecentFrenchstudy(EPIMAD)[4,5]and4monthsinNoroega[5],10and6monthsinItaly[6]re-spectivelyforCDandUC.

TheEuropeanstudygrouprecentlypublishedtherecordofnewdiagnosesofpediatricIBD,EuroKidsaged0-18yearsbetweentheyears2004-2009.Thisstudygatheredin2087patients,ofwhich59%werediagnosedwithCD,32%withUCand9%asIBD-U.Themeanageatdiagnosiswas12.1years(0.6-17,9years),and56%boys[7].

Pediatriciansshouldbecomefamiliarnotonlywiththetypicalbutalsoatypicalpresen-tationsofIBDbecause22%ofchildrenpresentwithgrowthfailure,anemia,perianaldisease,orotherextra-intestinalmanifestationsofthepredominantonlyinitialfeature.Adetailedfam-

InflammatoryBowelDisease

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www.openaccessebooks.comRodriguesM

ilyhistoryshouldbeobtainedbecause20%ofchildrenwithIBDhaveanaffectedrelative[2].

ThissectionwillbediscussedthediagnosisofpediatricCD.

2. Gastrointestinal Manifestations in Children and Adolescents With CD

TheclinicalmanifestationsofCDdependonthesiteofaffectedbowel,ifitisintheuppergastrointestinaltract,thesmallintestineorcolon,inthelattercasesimulatingUC.Thehighlightof theclinicalmanifestationsofCDis thepresenceofabdominalpainassociatedwithwarningsignssuchasfever,growthretardation,pubertaldelay,weightloss,pallorandperianalinvolvement(fistulas,fissuresandabscesses).Sometimes,thepicturebeginsacutelywithsymptomsofinflammatoryacuteabdomen,mimickingacuteappendicitis.Pediatricpa-tientswithCDexhibitmoreilealdiseaseattheonsetofdiseasethanadult.Throughoutevolu-tion,complicationsmayoccurasstricturebowelloopsmanifestedwithsymptomsofocclu-sionorentero-enteric,enterocutaneous,perianalfistulasorfistulasbetweenbowelloopsandadjacentorganssuchasthebladderandgenital[1,2,8].

Thegrowthdeficit thatprecedesthediagnosis is thebiggestdifferencein thechild’spresentationofCDwhencomparedtoadults.ThedelayofpubertyanddecreasedfinaladultstaturecanoccurwhenthediseaseoccursinadolescenceandthereisdelayinthediagnosisofCD.Furthermore,persistenceofthegrowthdeficiencymaybetheonlysignaltothediagnosisanddiseaseactivity,notonlyinperformancebutduringthecourseofdisease[1.2].

ToevaluatetheseaspectsofpediatricCD,weprospectivelyselected22patientswithmildly tomoderatelyactiveCD,29patientswith inactiveCDand35controls,undergoingregulartreatmentattheClinicalGastroenterologyOutpatientClinicaloftheUniversityofSaoPauloSchoolofMedicineHospitaldasClinicas,SaoPaulo,Brazil.Themeanvaluesforleanbodymass,Tannerstage,height-for-ageZscoreandBMI-for-ageZscorewerelowerintheactiveCDgroupthanintheinactiveandcontrolgroups(p<0.05forboth).Whencomparedindividually,2(9.1%)ofthepatientswithactiveCDand1(3.4%)ofthosewithinactiveCDhadshortstature(height-for-ageZscore<-2).Inaddition,7(31.8%)ofthepatientswithactiveCDand3(10.3%)ofthosewithinactiveCDweremalnourished(BMI-for-ageZscore<-2).Itisofnotethatsome(4.2%)ofourCDpatientshadaBMI-for-ageZ-score>2standarddesvia-tion[9].

ItisimportanttonotethattheveryearlyonsetofIBD(youngerthan2yearsoflife),ischaracterizedbysevereprogressivecolitis thatcanstartbeforethreemonthsoflifewithfailure to thrive,extensivecolonic inflammation,perianal involvement,arthritis, folliculitisusuallynotcompromisingthesmallbowel,imposingdifferentialdiagnosiswithmonogeneticsdisease[10,11,12,13].Table 1summarizesthemaindifferencesoftheclinicalpicturebetween


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CDandUC.Tabel 1:PercentageofClinicalPresentationInflammatoryBowelDiseaseinChildrenandAdolescents.

Presenting SymptomCrohn disease (% of patients)

Ulcerative Colitis

(% of patients)

General

Weightloss 55-80 31-38

Fever 38 NA

Anorexia 2-25 6

Growthretardation 3-4 0

Lethargy 13-27 2-12

Gastrointestinal tract

Abdominalpain 67-86 43-62

Diarrhea 30-78 74-98

Rectalbleeding 22-49 83-84

Nausea/vomiting 6 <1

Constipation 1 0

Perianaldisease 6-15 0

Mouthulcers 5-28 13

Abbreviations: NA:notapplicable.RangearederivedfromdatareportedbyKugathasanetal[14],Grif-fiths[15]andSawczenkoandSandhu[16].3. Extra-Intestinal Manifestations in Children and Adolescents with CD Despiteitsname,IBDisnotlimitedtotheintestineandabout30%ofpatientsdevelopapreviousextra-gastrointestinalmanifestationorduringevolutionoftheirdisease[17].Theextra-intestinalmanifestationsofIBDcanbedividedintoafewcategories:

•Relatedcolitis(skin,eyes,jointsandmouth)thatoccurinparallelwithdiseaseactivity

•Hepatobiliary

•Decelerationofgrowth

•Secondarycomplicationsofthedisease(nephrolithiasis,obstructiveuropathy,andgallstonepancreatitis)

•Otherevents,whichdonotmeetanypreviouscriteria(amyloidosis,cancer,vascular,hema-tologic,pulmonary,cardiacandneurological)

Table 2 summarizes the main extra-intestinal manifestations in IBD in children andadolescents


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4. Differential Diagnosis

Theclinicalpresentationofmucousandbloodydischargediarrheamaycoverseveraletiologies[1,2,8]:

•InfectiousColitis(Salmonella,Shigella,Yersinia,Campylobacter,Aeromonas,Mycobacte-riumtuberculosisandEntamoebahystolitic)

•Pseudomembranouscolitis(Clostridiumdifficile)

•Hemolyticuremicsyndrome(Escherichiacoli0157:H7)

•Parasitic(amebiasis,strongyloidiasis)

•Viral(cytomegalovirusandherpessimplex)

•Vasculitis(Henoch-SchönleinandBehcet'sdisease)

•FamilialMediterraneanFever(autosomalrecessivedisease)

•AcquiredImmunodeficiencySyndrome(AIDS)

•PrimaryImmunodeficiency

Table 3summarizesthemainsymptomsandalarmsignalstotheprimaryimmunodeficiency

Extra-intestinal manifestationPrevalence in

CD(% of patients)

Prevalence in UC

(% of patients)

Pyodermagangrenosum CR*

Joints/arthritis ----- 3.8

Osteoporosisandosteopenia 8-41 24-25

Growthdelay 81 28

Nephrolithiasis CR 3.2

Autoimunehepatitis ----- 1.3

Uveitis ----- 0.63

Amyloydosis CR

Vasculardamage 4.2 0.63

Pancreatitis 3.9 2.5

Anemia 69 40.5

Table 2:PrevalenceofintestinalmanifestationsinchildrenandadolescentswithIBD

*ExceptwherenotedbyCR(casereport)CDtotalNinchildrenrangesfrom21to26andUCtotalNrangesfrom21to158.Datafrom:JoseFAandHeymanMB[17].


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Thechildrenwithrectalbleedingcanpresentulcerativeproctitis,whichmustbedif-ferentiatedfromothercauses,suchasanalfissure,hemorrhoids,polyps,anddependingontheintensityoftheintestinalbleeding,Meckel'sdiverticulum[1,2,8].

Inchildrenwithpaininthelowerrightquadrantshouldbeexcludedacuteappendicitispossibilities,tuberculosisandlymphoma.Inpatientswithabdominalabscess,thedifferentialdiagnosis includesappendixorperforatedvasculitisand trauma. Inadolescents, should re-memberthegynecologiccauses.

Moreover, it isnecessary todifferentiate theCD fromUC,not alwayspossible taskwhenonedoesnothavedefinitivepathologicfindingsofeachdisease,stayingforsometimeColitisdenominationnotdetermined(IBD-U)in15%ofcases[18].

Whenrecurrentabdominalpainisthemainsymptominchildren,itshouldbeconsid-ered thepossibilityofdealingwithfunctionalgastrointestinaldisease(FGID),especially ifthereisintestinalandextra-intestinalsymptomsunspecific.Thus,theidentificationofcriticalfeaturesor"redflags"canhelppediatriciansrecognizethepatientwithFGIDabdominalpainorCD,avoidingtestsunnecessarydiagnosesinpatientswithFGIDandontheotherhand,topreventthedelaydiagnosisofCD[19].

InthestudybyEl-ChammasetalcharacteristicsofabdominalpainpatientFGIDweredistinctfromabdominalpaininpatientswithCD:(1)greaterstressreportsandheadache(p<0.001),(2)higherprevalenceofFGIDinfamily(irritablebowelsyndromeorconstipation,p<0.05) and (3) lower reporting hematochezia,weight loss, difficulty gainingweight andgreaterpresenceofvomiting(p<0.05).However,wakingupatnightandjointpaindidnotdifferbetweenthetwogroups.Incontrast,thepresenceofanemia,hematochezia,andweightlosswasmorepredictiveofCD(sensitivity94%)[19].

Positivefamilyhistoryofprimaryimmunodeficiency

Consanguineousparentsor>2familymemberswithearly-onsetIBDInfantile(<2years)IBD

Severe,therapy-refractaryIBD,particularlywithperianal/rectovaginaldisease/abscesses

Recurrentinfectionsintheabsenceofimmunosuppressantdrugs(particularlypulmonarydiseaseandskinabscesses)

Neutropenia,thrombocytopenia,orabnormalimmunestatus(Iglevels)intheabcenseofimmunosuppressantdrugs

Naildystrophyandhairabnormalities(trichorrhexisnodosa)

Skinabnormalities(congenitaleczema,albino)

Table 3:Alarmsignsandsymptomsforprimaryimmunodeficiency

Abbreviations: IBD:inflammatoryboweldisease;Ig:immunoglobulin.Datafrom:Levineetal[1]


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5. Diagnostic approach of CD in children and adolescents

5.1. Clinical symptoms

ThediagnosisofIBDconsistsofafewsteps,startingfromtheinitialclinicalsuspicionpediatrician,basedonclinicalsymptomsandphysicalexaminationwiththereferralofsus-pectedcasestothePediatricGastroenterologist[1,2].

5.2. Physical exam

Theprevioushistorydataofheightandweightareessentialfordetectingdecelerationofthegrowthrateandweightloss.Furthermore,itshouldbeobservedifthereisthepresenceofdelayedpubertaldevelopmentbyTannerscale[20].

Examinesthecolorofmucousmembranestodetectpallor(anemia),clubbingoffingernailsandwatchglass(presentinchronicdisease).Theoralexaminationmayshowaphthousulcers,angularcheilitisandtonguewithareductionofthepapillae(irondeficits,vitaminB12,folicacid,zinc,etc.).Skinchangesshouldberecorded(vitiligo,erythemanodosumandpyo-dermagangrenosum).

Examinationoftheabdomenmayshowthetensewall,painful,andthepresenceofmass(suggestiveofileocecalabscessorinfiltration).Theevaluationofthejointscanfindsignsoflowbackpain,arthritisorsacroiliitis.Theanalareashouldbeinspectedtodetectfissure,fis-tulasandperianalabscessesaremorecommoninCD[1,2].

6. Laboratory tests

Initially,theymustberejectedmajordiseasesthatmimicIBDthroughexams:

•Feces:stoolcultureandtestingfortoxinAandBofClostridium difficile,totheexclusionofothercausesofcolitis

•Testofthepurifiedproteinderivativeoftuberculin(PPD,purifiedproteinderivativeoftuber-culin)towardofftuberculosis

•GeneralImmunologicalevaluationtoruleoutthepresenceofprimaryimmunodeficiencies

•SerologyforAIDS

Afterthisinitialstep,asktolaboratorytestsrelatedtoinflammation,suchaserythrocytesedimentation,C-reactiveprotein(CRP),platelet,acidalpha-1-glycoprotein;iftheresultsarehigh,reinforcingthediagnosisofIBD.Oneshouldalsoaskcellbloodcount(CBC),withat-tentiontothepresenceofhypochromicanemiaandleukocytosis;andirondosingandproteinelectrophoresisfordetectionofirondeficiencyandsecondarylossorhypoalbuminemiadid


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notabsorbedbyinflamedintestinalmucosa.Amongtheserumelectrolytes,themostcommonisthehypokalemiaagainstattributedtochronicdiarrhea[1,2].

ThepatientwillbereferredtothepediatricgastroenterologistfordefinitivediagnosisofIBD.

Somenon-invasivelaboratorytestscanincreasetheCDdetectionprobability,suchaslactoferrinandcalprotectininthefaeces[21].

According to the study-levelmeta-analysis, inhigh-prevalencecircumstances, faecalcalprotectincanbeusedasanoninvasivebiomarkerofpediatricIBDonlywithasmallriskofmissingcases,anditcanhelpinselectingpatientsforendoscopicevaluationandhasthehighoverall sensitivityand thespecificity fordiagnosingIBD[22].Anotherapplicationof thismethodwasthedifferentiationbetweenfunctionaldiseaseandIBD[23].

TheuseofserologicalmarkersinchildrenwithsuspectedIBDisanoninvasivetestap-plicationattemptstoshortenthediagnosis,differentiatetheCDfromUCandcorrelatesthemtoprognosisofthedisease.ManyantibodiesagainstmicrobialcomponentsarefoundinCD,includingtheantibodyagainstoutermembraneporin-CEscherichia coli(antiOmpC),againstthesequenceI2associatedPseudomonas(anti-I2)andagainstbacterialCBir1flagina(anti-CBir1).Itwasfoundtheprevalenceof11%and56%ofanti-anti-OmpCandI2respectivelyinchildrenwithCD,withdifferencesaccordingtoageatdiagnosis.Othermarkersareanti-glicanantibodies,resultsfromtheinteractionbetweenimmunecellsandglycosylatedcellwallcomponentsoffungi,yeast,andbacteriaarefoundinCD:mannobiosideanti-carbohydrateantibodies (AMCA), anti-laminaribiose carbohydrate antibodies (FTAA), anti-carbohydrateantibodies chitobioside (ACCA), antilaminarim carbohydrate antibodies (anti-L), and anti-chitin(anti-C)carbohydratesantibodies.Only16.9%-30.5%ofpatientswerepositiveforeachoftheninpediatricCD[24].

Anti-glicoprotein2(GP2)IgGandIgA,constitutingnovelCDspecificautoantibodies,appearstobeassociatedwithdistinctdiseasephenotypesIdentifyingpatientsatayoungerage,withileocoloniclocation,andstructuringbehaviorwithperianaldisease[25].

Dosagesofliverenzymes,bilirubinandamylaseareintendedtodetectliverandpan-creaticinvolvementinIBD,thediseaseitselforsecondarytotheuseofdrugstotreatthedis-ease.

Recentmeta-analysisdeterminedtheaccuracyofdiagnosissymptoms,signs,noninva-sivetests,andtestcombinationsthatcanassisttheclinicianwithdiagnosisofIBDinsymp-tomaticchildren.Theconclusionswerechildreninthesymptomsarenotaccurateenoughtoidentifylow-riskpatients inwhomanendoscopycanbeavoided.AssessmentoffecalCal-


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protectin(FCAL),C-reactiveprotein(CRP),andalbuminfindingsarepotentiallyofclinicalvalue,giventheirabilitytoselectchildrenatlowrisk(negativeFCALtestresult)orhighrisk(positiveCRPoralbumintestresult)isIBD[26].

One such promising test, the polymorphonuclearCD64 index capitalizes on inflam-mation-inducedexpressionofFcyreceptorI(CD64markers)onneutrophilsandhasahighsensitivityandspecificityforCDinchildren[27].

NormallaboratoryevaluationresultdoesnotexcludethediagnosisofIBDbecauseap-proximately10%to20%ofchildrenwithIBDwillhavestandardlaboratoryresults[28].IfitpersiststhesuspecteddiagnosisofIBD,evenwithregularscreeningtests,shouldcontinuetheinvestigation,requestingtoupperandlowerendoscopywithserialbiopsies.

6.1. Endoscopy

UpperendoscopyandileocolonoscopywithserialbiopsiesofthedifferentsegmentsofthedigestivetractarethetestsconsideredthegoldstandardforthediagnosisofCD,anddefi-nitelyexcludesotherviral,bacterialandfungaletiologies.MacroscopiccharacteristicsoftheluminalpediatricuntreatedDCaresummarizedinTable 4.

6.2. Histology

EarlymanifestationsofpediatricIBDcanberelativelynonspecific.Initialmucosalbi-opsiesmaynotbeconclusive,delayingthediagnosisuntilsubsequentbiopsiestypicalhisto-logicfeaturesofIBD.

IncontrasttothefindingsofIBD,acuteself-limitedcolitis(CALA)doesnotshowthearchitecturaldistortionofthecrypt,basallinfoplasmocitoseandPanethcellmetaplasia.Thecombinationofthreeparameters-increaseofplasmacellsinthelaminapropria,cryptdis-tortionandatrophy-represents94%sensitivityand96%specificitytodistinguishIBDfromothernon-specificcolitis[18].

InarecentstudyinvestigatingpotentialofearlyhistologicmarkersofpediatricIBD,theauthorsconcludedthatthedistortionofcoloniccrypts,gastritisandtheaveragedensityofeosinophilsintherectosigmoidwereincreasedsignificantlyintheIBDgroupcomparedtothegroupwithfunctionalabdominalpain.Immunohistochemistrystainingfortumornecrosisfactor-αandmatrixmetalloproteinase-9wasperformedonthestomachandrectosigmoidareasdidnotrevealanysignificantdifferencesbetweenthegroupsoftheinitialendoscopicevalua-tion[29].

Microscopic characteristics of the luminal pediatric untreatedCDare summarized inTable 4.


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6.3. Radiology

Theimagingmethodfortheevaluationofthesmallintestineisveryimportanttoevalu-atetheextentofdisease,assesstheseverity,differentiatebetweenCDandUC,andidentifycomplicationssuchasfistulae,abscessesandintestinalstrictures.Thecurrenttrendistore-placetheintestinaltransitbyComputedTomographyEnterography(CTE)orMagneticRes-sonanceEnterography(MRE).Bothtechniquesprovideaperfectimageenterographyofthelumenandwallstructuresadjacenttotheintestine.MREadvantagesarethesuperiorcontrastresolutionandthelackofionizingradiation,althoughitispossibletomaintainthequalityoftheimagebyCTEthroughinteractiveimagereconstruction[30].SomepediatricMREproto-colsareavailableradiologicalstudiesshouldincludeMagneticResonancePelvictoevaluatecasesaccompaniedbyperianalabscessesandfistulas[31].

7. Further investigation

TherealizationofEndoscopyCapsuleisauthorizedbytheFoodandDrugAdministra-tion(FDA)intheUSforchildrenabove10years,buttherearereportsofchildrenyoungerthanheldthisdiagnosticmethodbyintroducingthecapsuleendoscopically.Thistestallowsevaluationoftheentiresmallbowelmucosa,andisusefulinchildrenwithpersistenthighdi-

Table 4:MacroscopicandmicroscopicfeaturesofDCpediatricluminaluntreated.

Typical macroscopic findings of CD Typical microscopic findings of CD

MucosalaphthousulcersNoncaseatinggranuloma(s)-mustberemotefrom

rupturedcrypt

LinearorserpentineulcerationFocalchronicinflammation,transmural

inflammatoryinfiltrate,submucosalfibrosis

Cobblestoning

Stenosis/structuringofbowelwithprestenoticdilatation

Nonspecific microscopic findings of CD

Imagingousurgical-bowelwallthickeningwithluminalnarrowing

Granulomaadjacenttorupturedcrypt

Perianallesions-fistula(s),abscesses,analstenosis,andcanalulcers,largeandinflamed

skintags

Mildnonspecificinflammatoryinfiltrateinlaminapropria

Skiplesions Mucosalulceration/erosion

JejunalorilealulcersSignsofchronicity(eg.cryptarchitecturalchanges,colonicPanethcellmetaplasiaandgobletcell

depletion)

NonspecificmacroscopicfindingsofCD:oedema,erythema,friability,granularity

Exudate:lossofvascularpattern,isolatedaphthousulcers,perianallesions-midlineanal

fissures,smallskitags

Abbreviations:CD:Crohndisease.ModificationofLevineAetal[1].


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Table 5:ParisClassificationforCrohn'sdisease

Age Diagnosis •A1a:0-aged<10years•A1b:10-<17years

Location •L1:1/3distalileum±limitedtothececum•L2:Colonic•L3:ileocolônica•L4A:TGIproximaltothehighangleofTreitz•L4B:TGIhighdistaltoTreitzangleandproximaltothedistalthirdoftheileum

Behavior •B1:notstenoticandnon-penetrating•B2:stenotic•B3:Penetrating•B2B3:bothpenetratingandstenosing•p:perinealdisease

Growth•G0:noevidenceofstunting•G1:withevidenceofgrowthdeficit

gestivesymptomsandradiologicalassessmentofseeminglynormalsmallintestine.TheEndo-scopeCapsulemaynotbeperformedinthepresenceofintestinalstenosis,asinthesecasesthecapsulecanberetainedinplace.Toruleoutthispossibility,onecanusepriortotheexamina-tion,acompositeofbiodegradablematerialcapsule,thesamesizeasusedfortheexamination.Ifitisexcretedintact,thepatencyoftheintestinallumenwillbeconfirmed,enablingthefinalcompletionofthecapsuleendoscope,ontheotherhand,ifthereisimpactionofthecapsuleinastenosedintestinalsegment,itwilldisintegratein40hoursduetotheactionofintestinalfluid[1].

Theexploratorylaparoscopymaybeusefulinselectedcasespatients,forexample,whenthereispossibilityofintestinaltuberculosis[1,2].

8. The classification of Paris

TheclassificationofParis[32],recentlyupdated,tocharacterizethepatientwithCDaccordingtoageatdiagnosis,locationofthedisease,inflammationbehavior.Itshouldbeap-pliedintheinitialstagingandprogressionofthedisease,andthisdetailedinTable 5.Asanadaptationtopediatricpractice,wasaddedtothediscriminatoryphenotypecharacteristicitwassubdividedaccordingtowhetherthediseasewasdiagnosedbeforeorafterthepatientwas10yearsold,thepresenceorabsenceofgrowthfailure,alsointroducedsubdivisionofuppergastrointestinaldiseaseintojejunalversusoesophago-gastro-duodenaldisease.Thedemarca-tionofthediseaseterritoryshouldbeguidedbyinflammationobservedatendoscopyorimag-ingandnotbymicroscopicInvolvement.

ThephenotypepediatricCDCharacterizedbymorewidespread intestinal inflamma-tion,oftenInvolvingthelargeandsmallbowelaswellastheuppergastrointestinaltract(pa-


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n-entericdisease)[8].

9. Conclusion

TheCDhasbecomeanincreasinglydiagnosedinchildrenofallages.Thisconditionisofparticularclinicalpictureinchildrencomparedwithadults.Performearlydiagnosisiscru-cialtoavoidanadditionalimpactonthenutritionalstatus,growingandpubertaldevelopment.ItalsorequiresattentiontotheconsequencesofCDonthepsychosocialaspectofchildrenandadolescents,asiscommoninCDschoolbreakandsocialactivities,especiallyinthosepatientswithunstableorseveredisease,requiringpsychologicalintervention.

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inflammatory bowel disease · inflammatory bowel disease 3 cd and uc. tabel 1: percentage of...

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