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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.