Jeffrey Modell Canadian ImmunodeficiencyJeffrey Modell Canadian Immunodeficiency Network

Primary Immunodeficiency Video Conference RoundsRounds

Monday, November 22, 2010

Moderated by:Moderated by:Prof. Chaim RoifmanDivision of Immunology and Allergy. The Hospital for Sick Children

PPresenter:Dr. Taso PapadopoulosRecurrent Infections and Chronic DiarrheaPotential Conflicts of Interest: none

To review the differential diagnosis of recurrent infections and infantile colitis

T i h h i iTo review the pathogenesis, presentation, diagnosis, treatment of a specific cause of infantile colitisinfantile colitis.

Initial Case PresentationInitial work upCase ProgressionLet’s Focus – Infantile ColitisDiscussion of a specific cause of infantile colitiscolitisManagement

Presented at 5 weeks of age, January 2008Transferred from a peripheral hospital◦ workup of feeding intolerance, poor weight gain

and recurrent infectionsand recurrent infectionsRotavirus with diarrhea – improvedPeriorbital swelling - ?cellulitis

Born to a G1P0 mother, GDM on insulin with PIH over last two weeks of pregnancy

38 + 4/7 weeks, born at community hospitalVaginal Delivery no resuscitation no NICUVaginal Delivery, no resuscitation, no NICUBW 3560g (~50th)Home on day 3 of lifeHome on day 3 of life

Over first 5 weeks had 3 hospitalizations◦ DOL 6 – poor feeding, lethargy, dehydration, fever

Negative septic work up◦ DOL 13 – vomiting diarrhea poor intake feverDOL 13 vomiting, diarrhea, poor intake, fever

Stool positive for Rotavirus◦ DOL 26 – right eye swelling, discharge, fever

Negative septic work up, including negative eye swab◦ DOL 35 – left eye swelling, fever

Septic work up again negative but CSF pleocytosis with p p g g p ylate LP so treated as ?meningitis/encephalitis, transferred to HSC

Poor weight gain, intermittent diarrhea No thrush or diaper dermatitisNo eczema, pustular rash on face since birthUmbilical cord separation on DOL 10

Medications: ◦ Cefuroxime + Ranitidine◦ Cefuroxime + Ranitidine

Family History:◦ Non consanguineous, Caucasian parents

Paternal uncle neonatal meningitis now well◦ Paternal uncle neonatal meningitis, now well◦ Maternal 1st Cousin died in infancy, ?GI issues◦ Paternal Aunt, Uncle hypothyroidismyp y◦ No siblings

Wt 3.5kg (~10), Lt 52cm (10), HC 35cm(~10)Non-dysmorphic, unwell but stableLymph nodes palpablePustular facial rashChest, CVS, Abdomen, MSK NormalTh t CXRThymus present on CXR

Test ResultCBC diff ti l H b 101 WBC (B d 9 9 PMNCBC + differential Hgb 101, WBC (Bands 9.9, PMN

10.3, Lymph 7.34), plt 254, Normal smear

Immunoglobulins IgG 0 8 (N 2 3- Alb 26Immunoglobulins IgG 0.8 (N 2.3-14.1)IgM 0.2IgA 0.2

Alb 26Prot 41

Specific Antibodies Not done due to ageComplement CH50 1:8, C3/C4 NormalLymphocyte Immunophenotyping CD19+ 1850 CD20+ 1505Lymphocyte Immunophenotyping CD19+ 1850, CD20+ 1505

CD3+/CD4+ - 5106CD3+/CD8+ - 735CD (16+56)+ - 929CD4/CD8 i 7 0CD4/CD8 ratio – 7.0

Test ResultMitogen Stimulation PHA 401.5 vs 1024TREC 4995 (N > 400copies/0.5mcg

DNA)Ro/Ra Mainly naïve T cellsADA/PNP N (100/1798 nmoles/min/mL)TCR Vbeta Mild restriction in 2 families,TCR Vbeta Mild restriction in 2 families,

overall nearly normal representation

Genetics 46, XX IRAK4 – Normal22q11 microdeletion not detected

RMRP – NormalAIRE – Normal

Recurrent fevers, no further documented infections, cellulitis at 3 months of age@ 5mths

R t H it li ti ith i t t bl bl d◦ Recurrent Hospitalizations with intractable bloody diarrhea

Multiple fistulaePerianal, rectovaginal, enterocolic

◦ Colonoscopy + Biopsy – Sept 2008 & June 2009Colitis moderate acute activityColitis, moderate acute activity

Some response to treatment but ongoing flares

Sulfasalazine Azathioprine + Antibiotics + steroids (steroid dependent since age 2 years)

Diverting ileostomy @ age 2 yearsDiverting ileostomy @ age 2 years

Rheumatologic◦ Polyarthritis requiring multiple joint infusions

Hips, knees, ankles, elbows◦ ?Kawasaki disease? @ 9 mths?Kawasaki disease? @ 9 mths

Prolonged fever, red lips, cervical lymphadenopathy, rash, no conjunctivitis IVIg

TRAPS TNFRSFIA gene normal◦ TRAPS – TNFRSFIA gene normalDermatologic◦ Persistent facial erythroderma since birthPersistent facial erythroderma since birth◦ Facial cellulitis @ 4 mths◦ Eczematous rash since 3 months

Infantile colitis with clinical evidence of immune dysregulation◦ Recurrent fevers◦ Elevated inflammatory markers – ESR CRP◦ Elevated inflammatory markers – ESR, CRP◦ No pathogens isolated

CGDIPEXIL2 Rα (CD25) mutationWAS/?WIP

Cannioto et al, Eur J Ped, 2009

?CGD – NOBI = 203, CYB A/B genes NormalIPEX – Normal FOXP3 sequencingIL2 Rα (CD25) – NormalWAS/?WIP

Key cytokine in Immune Regulation◦ Limits secretion of proinflammatory cytokines◦ TNFα, IL12

Interacts with heterotetrameric IL-10 receptor phosphorylates STAT3 SOCS3phosphorylates STAT3 SOCS3

IL10R2 deficient mice = severe enterocolitis

Mosser et al, Imm. Rev 2008

Glocker et al, NEJM 2009, 9 patients

◦ Homozygous IL10Rβ mutation 2 affected childrenEnterocolitis < 1 yr folliculitis 1 with recurrentEnterocolitis < 1 yr, folliculitis, 1 with recurrent infectionsNormal immune work up

◦ Homozygous IL10Rα mutation 2 affected childEnterocolitis < 1 yr, folliculitisnormal immune w/up

Glover et al. NEJM 2009IL10R Deficiency and Cytokine suppression

Glover et al, NEJM 2009

◦ Mutations in either of the two polypeptide chains of the IL10 receptor can lead to abrogated IL10the IL10 receptor can lead to abrogated IL10 mediated signalling

IL10 FunctionINFLAMMATION

TNFα, IL12

Glocker et al, Lancet, 2010◦ 2 patients, <12 months, severe colitis, fistulae◦ Both refractory to immunosuppressive treatment◦ Normal immune w/up◦ Normal immune w/up◦ IL10Rα and IL10Rβ sequencing NORMAL◦ Sequenced IL-10 (IL-10 def. mice colitis)◦ In vitro

Mutated IL-10 did not suppress TNFα with LPS stimulation of peripheral mononuclear cellsp p

Sequenced IL-10, IL-10Rα and IL-10Rβ◦ IL-10 and IL-10Rβ Normal◦ IL-10Rα

Homozygous mutation for IVS5 +2T >CHomozygous mutation for IVS5 +2T >C(modelling software showed that this led to a loss of splicing at intron 5)

2 yr old girl◦ Intractable colitis, multiple fistulae, diverting

ileostomy, polyarthritis, steroid dependentNo biologics used yetNo biologics used yet

◦ IL10Rα mutation identified◦ No siblings

What would you do next?

Glocker et al only published experience◦ IL10Rβ gene mutation – patient 1

Had failed corticosteroids, MTX, thalidomide and anti-TNFα monoclonal antibodiesHad a MRD and went to transplant

Conditioned: Alemtuzumab, fludarabine, treosulfan, thiotepathiotepaGut decolonization – colistin

Outcome: Grade III aGVHD managed with steroidsAt one year full chimerism no GVHD remission of colitisAt one year, full chimerism, no GVHD, remission of colitis

◦ IL10Rα deficient patients not reported

Continued to be clinically unwell July 2010 ◦ Conditioned: Busulfan + cyclophosphamide

MUD BMT◦ MUD BMTNo post BMT complicationsNow 5 months postNow 5 months post ◦ 100% donor chimerismclinically welly◦ thriving with enteral feeds ◦ no diarrhea, perianal disease is improving

Infantile colitis is uncommonOften associated with underlying immunodeficiency

CGD IPEX & IPEX Lik IL2R d fi i WAS(?WIP)◦ CGD, IPEX & IPEX Like, IL2Rα deficiency, WAS(?WIP), IL10, IL10Rα & IL10Rβ deficiency

IL-10 has an important immunomodulatory p yrole & when abrogated hyperinflammatory stateEarly experience with HSCT has been encouraging.