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  • Severe ulcerative colitis:

    The pediatric perspective

    Dan Turner MD, PhDShaare Zedek Medical Center

    The Hebrew University of JerusalemISRAEL

  • AcuteseverepediatricUC

    Pediatricdefinition

    Epidemiology

    Useofcorticosteroids

    Outcome

    Secondlinetherapy

    PediatricradiographyandTMC

  • CaseJM

    11 year old boy (39 kg), diagnosed with UC 4 months earlier, presented to ER due to a flare

    10 days of 8 bloody diarrhea/d (1 nocturnal) with moderate abdominal cramping, but no fever, and no vomiting

    No benefit to 1 week of prednisone

    Mild abdominal tenderness, but no peritoneal signs

  • TrueloveandWittsclassificationDisease activity CriteriaRemission 1 2 stools/day without blood

    No feverNo tachycardiaHaemoglobin normal or returning to normalESR normal or returning to normalGaining weight

    Mild 4 stools/day with no more than small amounts ofmacroscopic blood

    No feverNo tachycardiaAnaemia not severeESR 30

    Moderate Intermediate between severe and mild

    Severe 6 stools/day with macroscopic bloodFever > 37.5oC or 37.8oC 2/4 daysHR > 90/minuteHb 75%ESR > 30

  • SevereUC definitions

    Mild-moderate colitis Severe colitis

  • ITEM POINTS

    1. Abdominal pain No pain Pain can be ignored Pain cannot be ignored

    0 5 10

    2. Rectal bleeding None Small amount only in < 50% of stools Small amount with most stools Large amount (>50% of the stool content)

    0 10 20 30

    3. Stool consistency of most stools Formed Partially formed Completely unformed

    0 5 10

    4. Number of stools per 24 hours 0-2 3-5 6-8 >8

    0 5 10 15

    5. Nocturnal bowel movement (any diarrhea episode causing wakening)

    No Yes

    0 10

    6. Activity level No limitation of activity Occasional limitation of activity Severe restricted activity

    0 5 10

    SUM OF PUCAI (0-85)

    ThePUCAI

    Turner et al; Gastroenterology 2007;133:423-432

  • PUCAIcutoffs(n=205)

    0

    20

    40

    60

    80

    00

    170

    1385320142

    None ModerateMild severe

    PUCA

    I sc

    ore

    None: 65

    0.99 (0.99-1)

    0.98 (0.97-0.99)

    0.97 (0.95-0.99)

    0.97 (0.95-0.99)

    DefinitionDefinition AUC of ROCAUC of ROC Sens/SpecSens/Spec

    95%/99%

    89%/94%

    96%/91%

    96%/91%

    n=81

    n=42

    n=57

    n=25

    r=0.91

    P

  • HowcommonaresevereattacksinpediatricUC?

  • *

    GTA Population under 15 yearGTA Population under 15 year--olds olds (1991(1991--1996):1996): 819,533

    Admission rate: Admission rate: 28% (55/196)28% (55/196)

    Total admission burden: Total admission burden: 1.6/100,000/yr1.6/100,000/yr

    Turner D et al. Gut 2008; 57:331-338

    Population-based analysis of severe pediatric UC

  • PediatricUCdiffersfromadults

    Extensive 33%

    Proctitis 33%Left sided

    34%

    Proctitis13%

    Left-sided26%

    Extensive 62%

    HSC TorontoHSC Toronto19901990--99; n=197 99; n=197 (AM Griffiths & TD Walters20042004--2006; n=205 2006; n=205 Turner; Gastroenterology 2007

    Pediatric onset Adult onset

    Moum et al, Am J Gastro 1999; n=399Moum et al, Am J Gastro 1999; n=399

  • CaseJM

    11 year old boy (39 kg), diagnosed with UC 4 months earlier, presented to ER due to a flare

    10 days of 8 bloody diarrhea/d (1 nocturnal) with moderate abdominal cramping, but no fever, and no vomiting

    No benefit to 1 week of prednisone

    Mild abdominal tenderness, but no peritoneal signs

  • Heterogeneity controlledmetaregressionofmethylprednisoloneequivalentversuscolectomyrate

    30 40 50 60 70 80 90 1000

    1020304050607080

    r2

  • Glucocorticoidbioassay

    50childrenwithsevereUC

    SerumforGBAon3rd steroiddays

    Turner D & Kolho KL et al; In preparation

  • NorthAmericansurveyofIVsteroiddosinginseverepediatricUC

    MaxDailydoseSteroidSite

    4060mg/d1mg/kg%2MPCanada

    4060mg/d12mg/kgMPorHCequivalentUSA

    4060mg/d1mg/kg%4HCUSA

    40mg/d40mg%2MPUSA

    60mg/d2mg/kgMPUSA

    4060mg/d12mg/kg%12MPCanada

    Personal communications

  • So....whatdose?

    11.5mg/kg/dayupto4060mgdaily

    Rapidtaperingto1mgupto40mg

  • Whatistheoutcomeofstandardtherapy?

  • ShorttermoutcomeincohortstudiesofseverepediatricUC(n=293)

    Infliximab (the OSCI study)

    34% (95%CI 27-41%)

    N=128 N=99 N=20 N=11 N=13

  • JM:3dayspassedonIVCS....

    8 5 bloodystools,onenocturnal Stillabdominalpain,lesstender Feverupto37.8,novomiting

    CRP44.2mg/L Albumin43 40g/L Hb144 130g/L

    WHATSNEXT?

  • Canwepredictsteroidfailureinchildren?

    AKA,whentointroduce2nd linetherapy?

  • Lind

    gren

    (6)

    Gul

    ati (

    45)

    Lenn

    ard-

    Jone

    s (35

    )

    Trav

    is (7

    )

    Osh

    itani

    (42)

    Cha

    krav

    arty

    (43)

    Seo

    (10)

    Car

    bonn

    el (4

    6)

    True

    love

    (34)

    Ho

    (8)

    Cho

    quet

    (52)

    Osh

    itani

    (47)

    Ben

    azza

    to (5

    3)

    Kum

    ar (1

    1)

    Ello

    umi (

    55)

    Dap

    erno

    (54)

    Spic

    er (5

    9)

    Spic

    er (6

    0)

    Mey

    ers (

    61)

    Day of evaluation

    3 1 1 3 1 1 1 1 1 1-3

    1 ? 1 1-2 3 1 1 1 1

    Disease characteristics Disease extent + + + + + Disease duration Duration of present attack + + n of previous attacks + + + Previous oral steroids +

    Patient characteristics Sex + Temperature + + + + + + + Pulse rate + + + + + + + Stool frequency

    + + + + + + + + + + + +

    Blood in stool + Stool frequency change +

    Pedal edema + Laboratory results

    CRP + + + + + + + ESR + + + Albumin + + + + + + + + + Hemoglobin + + + WBC + Prothrombin + Fibrinogen + Total protein + Cholinesterase +

    Imaging Radiological

    assessment + + + + + +

    Endoscopy + + +

    Turner D et al; Clin Gastroenterol Hepatol 2007

  • Adultclinicalpredictionrulesallatthe3rd dayofIVCS

    Travis(i.e.theOxfordindex) Stoolfrequency>8/dOR38/daywithCRP>45mg/dL PPVof85%

    Thefulminantcolitisindex(i.e.Lindgren) CRP(mg/L)X0.14+Noofstools/day PPVof70%

    Hosscore

    Seoindex

    Travis et al, Gut 1996Lindgren et al, Eur J Gastroenterol Hepatol 1998; Jarnerot et al, Gastroenterology 2005Ho et al, Aliment Pharmacol Ther 2004

  • PREDICTION

    getset....go!

    Turner D et al. Gut 2008; 57:331-338Turner D et al NASPGHAN annual meeting, 2008

  • 0.0 0.2 0.4 0.6 0.8 1.0

    1 - Specificity

    0.0

    0.2

    0.4

    0.6

    0.8

    1.0Se

    nsiti

    vity

    Day 3

    0.0 0.2 0.4 0.6 0.8 1.0

    1 - Specificity

    0.0

    0.2

    0.4

    0.6

    0.8

    1.0

    Sens

    itivi

    ty

    Day 5

    Area under the curve

    Lindgren: 0.78 (0.69-0.86)

    PUCAI: 0.82 (0.75-0.90)

    Seo: 0.70 (0.60-0.80)Lindgren: 0.80 (0.69-0.90)

    PUCAI: 0.82 (0.72-0.91)

    Seo: 0.71 (0.60-0.83)

    N=92 of which 33 failed (35%) others discharged or failed

  • Prediction

    PUCAI>45onday3 startplanning

    Sens=92(95%CI7998) Spec=50(4452) NPV=94(8498) PPV=43(3745) LR=0.16

    OR=11.1 (3-49); P

  • PUCAI>70onday5 EXECUTE!

    Sens=33(2336) Spec=100(94100) NPV=87(6897) PPV=100(65100) NPV=75(7176) +LR=42.7

    OR=64 (5->1000); P70+ -

    Failure+ 10 20- 0 62

    getset....go! criteria:DAY5

    Turner D et al. Gut 2008; 57:331-338Turner D et al NASPGHAN annual meeting, 2008

  • DaystosalvageRxduringthefirstyearpostdischarge

    Days from discharge

    # at risk: PUCAI45 48 19 16 16 11

    PUCAI>45 80 26 24 20 12

    P

  • HowtointerpretabdominalXrayinchildren?

  • Age

    0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0

    Transverse colon width

    2.0

    4.0

    6.0

    8.0

    10.0

    12.0

    14.0

    16.0

    18.0RespondersNon-responders

    Transversecolonicwidthatadmission

    Turner et al. Gut 2008; 57:331-338

  • PediatricTMC1:2matchedcasecontrolstudy

    Benchimol et al. Am J Gastroenterol 2008;103:1524-1531

  • Dowehavegoodalternativestocolectomy?

  • OutcomeofcyclosporineinseverepediatricUC(n=84)

    79% (95%CI 74-84%)

  • Tacrolimusinchildren

    Openlabeluncontrolledstudy

    7daysIVCSfailure N=14(onedropout)

    Bousvaros A et al. J Pediatr 2000

    69% response at discharge)

    38% response at 1yr)

  • Short term colectomy rate:11 (9%)

    3 colectomy

    7 infliximab 7 colectomy

    2 colectomy5 response

    1 year colectomy rate:23 (18%)

    0 colectomy

    TheOSCIstudy

    Turner D et al NASPGHAN annual meeting, 2008

  • OutcomeofinfliximabinseverepediatricUC(n=101)

    77% (95%CI 68-84%)

  • Colectomy:pediatricconsiderations

    Pros

    Manyfuturetreatmentyearswithtoxicmedicaltherapy

    Qualityoflife

    Cons Crohns common

    phenotype

  • LongTermEvolutio

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