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Jeffrey Modell Canadian Immunodeficiency Jeffrey Modell Canadian Immunodeficiency Network Primary Immunodeficiency Video Conference Rounds Rounds Monday, November 22, 2010 Moderated by: Moderated by: Prof. Chaim Prof. Chaim Roifman


  1. Jeffrey Modell Canadian Immunodeficiency Jeffrey Modell Canadian Immunodeficiency Network Primary Immunodeficiency Video Conference Rounds Rounds Monday, November 22, 2010 Moderated by: Moderated by: Prof. Chaim Prof. Chaim Roifman Roifman Division of Immunology and Allergy. The Hospital for Sick Children Presenter: Dr. Taso Dr. Taso Papadopoulos Papadopoulos Recurrent Infections and Chronic Diarrhea Potential Conflicts of Interest: none

  2. � To review the differential diagnosis of recurrent infections and infantile colitis � To review the pathogenesis, presentation, T i h h i i diagnosis, treatment of a specific cause of infantile colitis infantile colitis.

  3. � Initial Case Presentation � Initial work up � Case Progression � Let’s Focus – Infantile Colitis � Discussion of a specific cause of infantile colitis colitis � Management

  4. � Presented at 5 weeks of age, January 2008 � Transferred from a peripheral hospital ◦ workup of feeding intolerance, poor weight gain and recurrent infections and recurrent infections � Rotavirus with diarrhea – improved � Periorbital swelling - ?cellulitis

  5. � Born to a G1P0 mother, GDM on insulin with PIH over last two weeks of pregnancy � 38 + 4/7 weeks, born at community hospital � Vaginal Delivery, no resuscitation, no NICU Vaginal Delivery no resuscitation no NICU � BW 3560g (~50 th ) � Home on day 3 of life � Home on day 3 of life

  6. � Over first 5 weeks had 3 hospitalizations ◦ DOL 6 – poor feeding, lethargy, dehydration, fever � Negative septic work up ◦ DOL 13 – vomiting diarrhea poor intake fever DOL 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 y late LP so treated as ?meningitis/encephalitis, transferred to HSC

  7. � Poor weight gain, intermittent diarrhea � No thrush or diaper dermatitis � No eczema, pustular rash on face since birth � Umbilical cord separation on DOL 10 � Medications: ◦ Cefuroxime + Ranitidine ◦ Cefuroxime + Ranitidine

  8. � Family History: ◦ Non consanguineous, Caucasian parents ◦ Paternal uncle � neonatal meningitis, now well Paternal uncle � neonatal meningitis now well ◦ Maternal 1 st Cousin � died in infancy, ?GI issues ◦ Paternal Aunt, Uncle � hypothyroidism yp y ◦ No siblings

  9. � Wt 3.5kg (~10), Lt 52cm (10), HC 35cm(~10) � Non-dysmorphic, unwell but stable � Lymph nodes palpable � Pustular facial rash � Chest, CVS, Abdomen, MSK � Normal � Thymus present on CXR Th t CXR

  10. Test Test Result Result CBC CBC + differential diff ti l H b 101 WBC (B Hgb 101, WBC (Bands 9.9, PMN d 9 9 PMN 10.3, Lymph 7.34), plt 254, Normal smear Immunoglobulins Immunoglobulins IgG IgG 0 8 IgG IgG 0.8 (N 0 8 (N 2 3 (N 2.3- 2 3- Alb 26 Alb 26 14.1) 14.1) Prot 41 IgM 0.2 IgA 0.2 Specific Antibodies Not done due to age Complement CH50 1:8, C3/C4 Normal Lymphocyte Immunophenotyping Lymphocyte Immunophenotyping CD19+ 1850 CD20+ 1505 CD19+ 1850, CD20+ 1505 CD3+/CD4+ - 5106 CD3+/CD8+ - 735 CD (16+56)+ - 929 CD4/CD8 CD4/CD8 CD4/CD8 CD4/CD8 rat ratio – i o – 7.0 7 0 7 0

  11. Test Test Result Result Mitogen Stimulation PHA 401.5 vs 1024 PHA 401.5 vs 1024 TREC 4995 (N > 400copies/0.5mcg DNA) Ro/Ra Mainly naïve T cells ADA/PNP N (100/1798 nmoles/min/mL) TCR Vbeta TCR Vbeta Mild restriction in 2 families, Mild restriction in 2 families, overall nearly normal representation Genetics 46, XX IRAK4 – Normal 22q11 RMRP – Normal microdeletion AIRE – Normal not detected

  12. � Recurrent fevers, no further documented infections, cellulitis at 3 months of age � @ 5mths ◦ Recurrent Hospitalizations with intractable bloody R t H it li ti ith i t t bl bl d diarrhea

  13. � Multiple fistulae � Perianal, rectovaginal, enterocolic ◦ Colonoscopy + Biopsy – Sept 2008 & June 2009 � Colitis moderate acute activity Colitis, moderate acute activity � Some response to treatment but ongoing flares � Sulfasalazine � Azathioprine + Antibiotics + steroids (steroid dependent since age 2 years) � Diverting ileostomy @ age 2 years � Diverting ileostomy @ age 2 years

  14. � 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 normal � Dermatologic ◦ Persistent facial erythroderma since birth Persistent facial erythroderma since birth ◦ Facial cellulitis @ 4 mths ◦ Eczematous rash since 3 months

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

  16. � CGD � IPEX � IL2 R α (CD25) mutation � WAS/?WIP

  17. Cannioto et al, Eur J Ped, 2009

  18. � ?CGD – NOBI = 203, CYB A/B genes Normal � IPEX – Normal FOXP3 sequencing � IL2 R α (CD25) – Normal � WAS/?WIP

  19. � Key cytokine in Immune Regulation ◦ Limits secretion of proinflammatory cytokines ◦ TNF α , IL12 � Interacts with heterotetrameric IL-10 receptor � phosphorylates STAT3 � SOCS3 � phosphorylates STAT3 � SOCS3 � IL10R2 deficient mice = severe enterocolitis

  20. Mosser et al, Imm. Rev 2008

  21. � Glocker et al, NEJM 2009, 9 patients ◦ Homozygous IL10R β mutation � 2 affected children � Enterocolitis < 1 yr folliculitis 1 with recurrent Enterocolitis < 1 yr, folliculitis, 1 with recurrent infections � Normal immune work up ◦ Homozygous IL10R α mutation � 2 affected child Enterocolitis < 1 yr, folliculitis � � normal immune w/up

  22. � Glover et al. NEJM 2009 IL10R Deficiency and Cytokine suppression

  23. � Glover et al, NEJM 2009 ◦ Mutations in either of the two polypeptide chains of the IL10 receptor can lead to abrogated IL10 the IL10 receptor can lead to abrogated IL10 mediated signalling IL10 Function INFLAMMATION TNF α , IL12

  24. � 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 ◦ IL10R α and IL10R β sequencing NORMAL ◦ Sequenced IL-10 (IL-10 def. mice � colitis) ◦ In vitro � Mutated IL-10 did not suppress TNF α with LPS stimulation of peripheral mononuclear cells p p

  25. � Sequenced IL-10, IL-10R α and IL-10R β ◦ IL-10 and IL-10R β � Normal ◦ IL-10R α � Homozygous mutation for IVS5 +2T >C Homozygous mutation for IVS5 +2T >C � (modelling software showed that this led to a loss of splicing at intron 5)

  26. � 2 yr old girl ◦ Intractable colitis, multiple fistulae, diverting ileostomy, polyarthritis, steroid dependent � No biologics used yet No biologics used yet ◦ IL10R α mutation identified ◦ No siblings � What would you do next?

  27. � Glocker et al � only published experience ◦ IL10R β gene mutation – patient 1 � Had failed corticosteroids, MTX, thalidomide and anti- TNF α monoclonal antibodies � Had a MRD and went to transplant � Conditioned: Alemtuzumab, fludarabine, treosulfan, thiotepa thiotepa � Gut decolonization – colistin � Outcome: Grade III aGVHD managed with steroids � At one year full chimerism no GVHD remission of colitis � At one year, full chimerism, no GVHD, remission of colitis ◦ IL10R α deficient patients not reported

  28. � Continued to be clinically unwell � July 2010 ◦ Conditioned: Busulfan + cyclophosphamide ◦ MUD BMT MUD BMT � No post BMT complications � Now 5 months post � Now 5 months post ◦ 100% donor chimerism � clinically well y ◦ thriving with enteral feeds ◦ no diarrhea, perianal disease is improving

  29. � Infantile colitis is uncommon � Often associated with underlying immunodeficiency ◦ CGD, IPEX & IPEX Like, IL2R α deficiency, WAS(?WIP), CGD IPEX & IPEX Lik IL2R d fi i WAS(?WIP) IL10, IL10R α & IL10R β deficiency � IL-10 has an important immunomodulatory p y role & when abrogated � hyperinflammatory state � Early experience with HSCT has been encouraging.

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