Jeffrey Modell Canadian Immunodeficiency Jeffrey Modell Canadian - - PowerPoint PPT Presentation

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

To review the differential diagnosis of

recurrent infections and infantile colitis T i h h i i

To review the pathogenesis, presentation,

diagnosis, treatment of a specific cause of infantile colitis infantile colitis.

Initial Case Presentation Initial work up Case Progression Let’s Focus – Infantile Colitis Discussion of a specific cause of infantile

colitis colitis

Management

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

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 (~50th) Home on day 3 of life Home 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 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

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

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 hypothyroidism

yp y

• No siblings

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

Th t CXR

Thymus present on CXR

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

• – 7.0

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 Mild restriction in 2 families, TCR Vbeta Mild restriction in 2 families,

• verall nearly normal

representation Genetics 46, XX IRAK4 – Normal 22q11 microdeletion not detected RMRP – Normal AIRE – 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 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

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

Infantile colitis with clinical evidence of

immune dysregulation

• Recurrent fevers
• Elevated inflammatory markers – ESR CRP
• Elevated inflammatory markers – ESR, CRP
• No pathogens isolated

CGD IPEX IL2 Rα (CD25) mutation WAS/?WIP

Cannioto et al, Eur J Ped, 2009

?CGD – NOBI = 203, CYB A/B genes Normal IPEX – Normal FOXP3 sequencing IL2 Rα (CD25) – Normal WAS/?WIP

Key cytokine in Immune Regulation

• Limits secretion of proinflammatory cytokines
• TNFα, IL12

Interacts with heterotetrameric IL-10 receptor

phosphorylates STAT3 SOCS3 phosphorylates 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 children

Enterocolitis < 1 yr folliculitis 1 with recurrent Enterocolitis < 1 yr, folliculitis, 1 with recurrent infections Normal immune work up

• Homozygous IL10Rα mutation 2 affected child
• Enterocolitis < 1 yr, folliculitis

normal immune w/up

Glover et al. NEJM 2009 IL10R 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 IL10 the IL10 receptor can lead to abrogated IL10 mediated signalling

IL10 Function

INFLAMMATION

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 cells p p

Sequenced IL-10, IL-10Rα and IL-10Rβ

• IL-10 and IL-10Rβ Normal
• IL-10Rα

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)

2 yr old girl

• Intractable colitis, multiple fistulae, diverting

ileostomy, polyarthritis, steroid dependent

No biologics used yet No 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 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

• IL10Rα deficient patients not reported

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

Infantile colitis is uncommon Often 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 y role & when abrogated hyperinflammatory state

Early experience with HSCT has been

encouraging.