hyper ige syndrome

HYPER-IGE SYNDROMETheerapan Songnuy M.D.

Jan 3, 2014

Outline Case study Definition Epidemiology Clinical manifestation Pathogenesis Diagnosis Management Take Home Message

Case Study เด็กชายไทย อายุ 10 ปี ( วนัเกิด 1 พ.ค. 2546)

ภมูลิำาเนา จ. ตราด , multiple admissions ( 12 ธ.ค. 56) CC: refer ด้วย เหนื่อยมากขึ้น 1 วนั ก่อนมา รพ. จุฬา PI: 5d PTA สบายดี ไปทัศนศึกษาท่ี จ. จนัทบุรี 3 d PTA ไขส้งู นำ้ามูกเล็กน้อย กินยาพาราเซตามอล ทกุ 4 ชม. ได้ไป พบแพทย์ วนิิจฉัย ไขห้วดั 2 d PTA ไขส้งู เจบ็หน้าอกด้านซา้ย หายใจไมส่ะดวก เป็นมากเวลา โน้มตัวไปขา้งหน้า เจบ็ลดลงเวลานอนยกหวัสงู ไปพบแพทย์ รพ. เอกชน จ. ตราด

Case Study PI : ( ต่อ) ท่ี รพ. เอกชน ตรวจรา่งกาย และ ตรวจทางหอ้ง

ปฏิบติัการ VS: BT 37.5 C,RR 80/min, PR 104/min, BP145/81 Oxygen Sat room air 94% , Lungs: Decreased breath sound LLL CXR : Massive left pleural effusion with tracheal shift to the right, single soft tissue mass at right hilar region

Case Study PI (ต่อ) CBC: Hb 11 Hct 34 WBC 4140 N 79%

L 14% BUN/Cr : 22/0.5 E’lyte : Na 134 K 4.4 Cl 94 CO2 20 Impression : Left empyema thoracis & right lung abscess Refer มา รพ. จุฬาลงกรณ์

Case Study PH : บุตรคนท่ี 3 c/s BW 2,600 gm

- P1 DFIU GA 36 wk - P2 17-y-old female , healthy - P3 15-y-old female, healthy - P4 10-y-old male, patient : แม่ แขง็แรงดี : พอ่ ผ่ืนคันบอ่ยๆ ไมไ่ด้รกัษาประจำา G&D: ปกติ ผลการเรยีนปานกลาง, ฟนันำ้านมยงัหลดุไมห่มด( 10 ซี)่ Vaccination: ครบตามเกณฑ์ ยกเวน้ pneumococcal & influenza

Case Study PH:

Drug allergy: Nystatin ( urticaria ) Fluconazole ( urticaria ) Ketoconazole ( urticaria) Food allergy: Cow’s milk, egg, seafood, soy, wheat มaีccidental exposure บอ่ยๆ เคยกินยาแก้แพ้ และฝังเขม็ : On BF, Enfa ( flare up of AD, Nutramigen ( at 9 mon ) Neocate ( 10 mon -3 y) : Current foods; rice, chicken, pork, fish etc.

Case Study PH: Past Infections

- At 2 m of age: Bacterial lymphadenitis : Common cold q 1 m : AD treated with Elidel, zyrtec - At 2 y of age : Bacterial lymphadenitis - At 4 y of age : Bacterial lymphadenitis - At 7 y of age : Bacterial lymphadenitis & multiple abscess at thigh _ At 4 y : Serum sIgE to foods ; class 3-4

Case Study PH: History of AD treatment

- ตัง้แต่อายุ 1 m มผ่ืีนคัน เป็นๆหายๆ ได้ยาทาเป็นครัง้คราว - หลัง อายุ 1 y ติดเชื้อราท่ีเล็บ บอ่ยๆ - 5 m PTA ผ่ืนเหอ่มากขึ้น มตีุ่มหนอง ได้ยา Erythromycin ( 2wk) Prednisolone (5) 1*3 ( 6 wk) เริม่มหีน้าบวม แมใ่หห้ยุดยา - 2 m PTA แมพ่าไปพบแพทย์ แผนจนี ได้ยาสมุนไพร กิน 2 ชนิด ยาจนีผสมไขข่าว พอกท่ีฝ่าเท้าวนัเวน้วนั

Case Study Physical Examination:

- GA: A Thai boy, good consciousness, dyspnea, no cyanosis - VS : BT 37 c RR 60/min PR130/min BP 130/80 O2 sat 100% ( via mask with bag 6 L/min) BW 30 kg ( P50) - HEENT: mild pale conjunctiva, mild puffy eyelid with eczema on face, broad nasal base, no frontal bossing, LN impalpaple - Lungs : suprasternal & subcostal retraction decreased breath sound left side

Case Study Physical Examination

Heart: normal s1 s2 , no murmur Abdomen: soft, not tender, no hepato-splenomegaly Extremities: no deformities, no edema, post inflammatory hyperpigmentation both legs, clubbing of fingers Skin: Dry, erythematous papule & scaly face , arms & legs. Paronhychia Neuro: intact

Case Study Problems:

1. Acute dyspnea with decreased breath sound left lung 2. Recurrent bacterial lymphadenitis 3. Recurrent eczema 4. History of multiple foods allergy 5. History of multiple drugs allergy 6. Mild anemia 7. Mild puffy eye lids 8. Broad nasal base 9. Clubbing of fingers 10. Paronychia

Differential Diagnosis Primary Immunodeficiency diseases

- Hyper IgE syndrome - CGD - CVID

Active problems: - Lung abscess - Empyema thoracis - Pleural effusion

Investigations: CBC DATE Dec

11,2013 Dec 13, 2013

Dec 16, 2013

RBC 3.53 3.15 3.98 HGB 10.7 9.6 11.5 HCT 32.5 29.1 35.4 MCV 92.1 92.2 92.4 WBC 2990 9280 14770 N ( %) 74.3 51.7

57.4

L ( %) 19.6 28.1 28.3 M (%) 3.0 10.4 12.7 E ( %) 1.1 6.4 0.6 B (%) 0.1 0.1 0.2 Abs NC 2212 4800 8480 Abs LC 586 2610 3740 Platelet 198,000 198,000 389,000

Abs Eo= 594

Flow Cytometry (Dec 20, 2013) WBC : 12,410 Abs total Lymphocyte : 3,115 Total Lymphocyte (%) : 25.1 Abs CD3 : 2,336 CD3 ( %) : 75 Abs CD4 : 1,433 CD4 (%) : 46 Abs CD8 : 748 CD8 (%) : 24 CD 19(%) : 23 CD 56(%) : 2

Hb : 11.1 Hct : 31.7 MCV : 84.3 MCH : 29.5 MCHC : 35

Investigations CXR

Investigations11 ธ.ค. 56 -BUN/Cr : 12/0.4 - TB/DB : 0.54/0.34- ALP : 79- SGOT : 34- SGPT : 25- ALB : 3.5 ( 16ธ.ค. 56 = 3.8)- GLOB : - ( 16ธ.ค. 56 = 2.8)- TP : - ( 16ธ.ค. 56 = 6.6)

- LDH : 238

Investigations Immunoglobulin level: ( 12 ธ.ค. 56)

- IgG 815 ( 889- 1359 ) mg/dl - IgM 72.6 ( 46- 112) mg/dl - IgA 79 ( 71-191) mg/dl - Total IgE 28,700 ( < 200) IU/ml

- IgG1 658 ( 270-1290) mg/dl - IgG2 81.5 ( 110-550) mg/dl - IgG3 38.9 ( 13-250) mg/dl - IgG4 60.9 ( 7-530) mg/dl

Diagnosis

NewEngl JMed 1999a; 340: 692-702

Clinical Findings

Level Points

Highest serum IgE level

> 2,000 10

Skin abscess 3-4 4

Retained primary teeth

> 3 8

Fracture ( minor trauma)

1-2 4

New born rash present 4

Eczema severe 4

URI/year 4-6 2

Candidiasis fingernails 2

Other serious infection

empyema thoracis

4

Increased nasal width 1-2 SD 1

Scoring was done on Dec 12, 2013

Total 43

Diagnosis Hyper IgE syndrome Type?

- Sporadic,AD, AR Gene Analysis

- STAT3-deficient - DOCK8-deficient - Tyk2-deficient

Managements Supportive Care:

- O2 via mask with bag - ETT with ventilator support : PC mode, Fio2 0.5, PIP 15, PEEP 5, Rate 20 Ti 1 ICD :

- For diagnosis - For relieve symptom

Managements Empirical Antibiotics :

- Meropenam IV 60 MKD ( 17 d) - Vancomycin IV 40 MKD ( 7 d) - Augmentin 90 MKD continued Fluid IV Monitoring:

- VS - O2 sat - Blood gas - ICD content & volume - Intake/output

Investigation( cont) Pleural fluid ( 12 ธ.ค. 56)

- volume = 350 ml - character : turbid, purulent - Gram’s stain: positive cocci in chain ( many) - pH : 7 - RBC : 39,983 cells/cumm - WBC : 45,530 cell/cumm ( PMN 81% M 19%) - Protein : 5.6 g/dl - Sugar : 1 mg/dl - LDH : 7947 U/L - AFB : negative - Modified AFB : negative - Wright stain : not found

Investigation( cont)Tracheal suction Gram’s stain: gram positive cocci in chain & cluster Cultures : - Pleural fluid: no growth after 48 hr ( aerobe & anaerobe) - Hemo : no growth after 48 hr - Urine : no growth - Tracheal suction: no pathogenic organism detectedICD content: To identify bacteria by base sequencing (pending)

Progress NoteDec 15, 2013 - Off ETT , on O2 mask with bag 10 LPM - Subcutaneous emphysema, revised ICD - Serum galacto-mannan sample index = 0.21 ( > 0.5)

Dec 18, 2013 - Clinical improvedDec 23, 2013 - ICD content = 0 mlDec 24, 2013 - Off ICD - Chest PT, Cliniflow

Progress Note Pleural fluid ( Dec 20, 2013)

- Content: Sero-purulent fluid - Volume : 80 ml - pH : 6.9 - RBC: 9382 cell/cumm - WBC : 12422 cell/cumm ( N 48, M 19) - Protein : 4.8 g/dl - Sugar : 1 mg/dl - LDH : 2090 U/L

- Pleural fluid C.I.E. : Strep pneumoniae 100% by NCBI Blast Search- Blood for PHA ( pending)- Pneumococcal titer Ab ( pending)

- Anti HBs Ab: Negative ( > 10)- Fungal C/S : NG ( Dec, 12 )- Tip cath C/S : NG ( Dec, 24)

Progress Note

CT Chest ( Dec 24, 2013) No evidence of lung mass Retained ICD at left pleural cavity Small left lung volume with diffuse

smooth pleural thickening along lingular segment of LUL & LLL ( could be from chronic infection or inflammation)

Near total atelectasis of lingular segment LUL, containing focal consolidation

Passive atelectasis & small amount of left pleural effusion

Definition Hyper IgE syndrome:

- A primary immunodeficiency marked by abnormalities in the coordination of cell–cell signaling with the potential to affect TH17 cell, B cell, and neutrophil responses - Clinical manifestations include recurrent skin and lung infections, serum IgE elevation, connective tissue repair and development alterations, & vascular abnormalities & tumor development etc.

Epidemiology Job’s syndrome: described in 1966 Reference to the Biblical Job who was “

smote with sore boils” Incidence in western countries - 1/ 1 million - Male: female 1:1

http:// orpha.net/consor

Clinical Manifestation AD-Hyper-IgE Syndrome ( STAT3

Deficient) AR-Hyper-IgE Syndrome ( DOCK8

Deficient) AR-Hyper-IgE Syndrome ( Tyk2 Deficient)

Clinical Manifestation of AD-HIES

Newborn rash on face & scalp ( pustular) - Worsen by S.aureus - After NB period, cutaneous abscess, mucocutaneous candidiasis, infected dermatitis of axilla & groin etc.

Recurrent pneumonia in early childhood - S. aureus is the commonest followed by Strep. pneumoniae, H. influenzae - Purulent sputum, but lack of fever & systemic signs of inflammation - Pneumatocele & bronchiectasis that accumulate aspergillosis & gram negative bacteria

- Molds invade blood vessels & resulting to hemoptysis & disseminated infection -Other opportunistic infections; Pneumocystis jiroveci, histoplasmosis, muco-cutaneous candidiasis


Somatic Features: - Face; asymmetry, broad fleshy nose, & porous skin - Neurological; Arnold-Chiari I malformation(20% of cases), cranio-synostosis no surgery needed - Bone; minimal trauma fractures, osteopenia, hyper-extensibility, scoliosis & joint degeneration


Somatic Features: - Failure of primary teeth extraction - Vascular abnormalities; aneurysm, lacunar infarction - Malignancy; non-Hodgkin, Hodgkin & leukemia - Esophageal dysfunction

Clinical Manifestation AD-HIES French cohort study :

- Necker Enfants Malades Hospital, Paris - Detailed questionnaires completed by physicians - Clinical & labs collected from birth until Feb 2011 or their death - National Institutes of Health scoring system - Score> 40 : likely to carry AD-HIES phenotype - Score 20-40 : inconclusive - Score < 20 : unlikely

Investigations CBC; eosinophilia Serum IgE ; high ( > 2,000 IU/ul) but

normal IgG, IgA, & IgM levels Decreased memory T-cell Vary in Ab response Gene analysis

CD 27: Memory B-cell marker

Clinical Manifestation of AR-HIES (DOCK8)

Higher rate of viral infections ( M. contagiosum H. simplex, V. zoster) Higher food & environmental allergy Higher otitis media & sinusitis Higher mortality rate from sepsis Higher neurological features: hemiplegia,

CNS vasculitis Higher rate of malignancy: T-cell leukemia-

lymphoma Severe eczema, skin infection, pneumonia are

common but NO pneumatocele

Clinical Manifestation of AR-HIES (DOCK8)

Rare features: typical face, bone abnormalities

Labs: - Increased serum IgE, eosinophil - Low absolute lymphocyte count, total T-cell - Low CD4, CD8 count, normal CD4/CD8 ratio - Decreased IgM, others vary

Clinical Manifestation of AR- HIES ( Tyk2)

- Only 2 cases reported (Turkish & Japanese)- No typical facial features, bone abnormalities- The Turkish patient had axillary lymphadenitis from BCG & neuro-brucellosis after ingested un-pasturized cheese, later developed brain infarction- The Japanese patient had dermatitis, skin infectios, oral candidiasis, sinusitis, pneumonia, molluscum contagiosum etc.

Pathogenesis of AD-HIES STAT 3 gene:

- Located on chromosome 17 q21 - Encodes a transcription factors - Work in the process of STAT1, STAT4 - Translocate to nucleus - Transcription >> affect to cytokines

Pathogenesis of AD-HIES STATE 3 Gene:

- IL-6 family, IL-10 family, IL-12 family,IL-21 G-CSF, leptin - Associated with G protein-coupled receptor signaling - Association with cellular homeostasis ( involve mitochondrial regulation of reactive oxygen species generation)

Pathogenesis of AD-HIES STAT3 Function

- Intracellular cytokine receptor binds to one of four JAK protein ( JAK 1,2,3 & Tyk2) - Enhance STAT recruitment & phosphorylation - Phosphorylated STAT dimerized by Src homology2 ( SH2) domain >>> nucleus , then activate STAT- regulated genes

STATE 3 Gene

STAT3 Gene Mutation Coiled-coil domain

- Interact with other protein DNA-binding domain

- Transcriptional regulation Src homology 2 ( SH2) domain

- STAT protein dimerization & receptor contact Gene splice site/trans activation site

- Gene transcription“Dominant negative mutation” contribute to AD-HIES & decreased Th17 cell

JACI

Pathogenesis of AD-HIES STAT3 Function

- Clinical phenotypes of HIES : -Excessive inflammation; prolonged inflammation in lungs (pneumatocele) - Inadequate inflammation; “cold” boils

Pathogenesis of AD-HIES In vitro:

- Increased pro-inflammatory cytokines eg. TNF-alpha, IFN-gamma, IL-12 after stimulated by specific agonist

Pathogenesis of AD-HIES In mouse & human: STAT3 integrate to Th17 cell

differentiation & IL-17 production In HIES: near total absence of Th17 cell & impaired

IL-17 resulting in - Impair host defense through recruitment of neutrophil - Impair up-regulation of antimicrobial peptide - Prone to candida & Klebsiella infection - Impaired beta-defensin production ( prone to S. aureus infection)

Pathogenesis of AD-HIES Why increased IgE in HIES

- Hypothesis: impaired IL-21 signaling since IL-21 receptor knock out mice showed increased IgE

Pathogenesis of AR-HIES DOCK 8 Signaling:

- Located on chromosome 9p24 - Loss of DOCK8 protein function is the most common form of AR-HIES - Role of DOCK8 ; activate Rho GTPase that affects to actin cytoskeletal rearrangement

Pathogenesis of AR-HIES DOCK 8 Mutation:

- DOCK homology region 1 ( DHR1) domain ( for binding phosphatidylinositol3,4,5- triphosphate membrane-rich region) - DOCK homology region 2 ( DHR 2) domain ( for binding to Rho family GTPase)

Pathogenesis of AR-HIES DOCK8 expressed in B,T cells DOCK8 HIES : impair immunity along

various stages of B,T cells development Decreased CD8 T cell stimulation Decreased CD8 T cell clonal proliferation Decreased CD8 memory T cell

Pathogenesis of AR-HIES( Tyk2-deficient)

Tyk 2 located on chromosome 19p13.2 In a family of Janus kinase molecules Roles:

- Transduces signal which transmitted from type 1 IFN receptor, cytokine receptor sharing IL-12RB1 subunit, cytokine receptor sharing a gp 130 subunit & IL-13


Tyk2 components: 1) FERM domain ( localizes protein to plasma membrane) 2) SH2 domain ( modulate regulation of intracellular signaling cascade) 3) Kinase domain ( phosphorylate target protein )


Homozygous deletion mutation: - Impaired Th1 response, risk for mycobacteria - Decreased IFN-gamma secretion by IL-12 stimulated splenocyte - Impaired Th 17 response , risk for fungal infection

Diagnosis Criteria***

NewEngl JMed 1999a; 340: 692-702

Diagnosis STAT 3 mutation analysis is commercially available By using “ high-resolution PCR-based DNA-melting

assays” to identify & screen patients Quicker & cheaper than genome sequencing The variant can be confirmed by targeted

sequencing analysis No phenotype/genotype relationship among STAT3

mutation identified For DOCK 8 & Tyk 2 mutation only available in special research institute

Management of AD-HIES Supportive management Adequate treatment in pneumonia Bronchoscope yields for isolating microbe & removing

pus

Pneumatocele & bronchiectasis need broad spectrum ABT to cover gram negative & fungi

Skin: - Eczema care & staphylococcal prevention by bathing in bleach or swimming in chlorinated swimming pools

Management of AD-HIES Prophylaxis antibiotic

- Co-trimoxazole - Penicillinase-resistant penicillin - Cephalosporin Case report: - An-8-y-old boy - Diagnosed as HIES - Prophylaxis with cloxacillin 30 MKD and Isotretinoin - Free from skin infection for 26 months - After discontinue medication, re-infection with fever, otitis externa & cellulitis

Archives of Medical Research 35 (2004) 359–360

Management of AD-HIES IVIG :

- The most common immuno-modulator using in HIES - Decreased number of infection IFN-gamma:

- Mixed results Antihistamine –H2 & ciclosporin may help BMT : AR-HIES with DOCK8 mutation cases

cured with hematopoietic cell transplantation

Management of AD-HIES IVIG: From French Study

- From 32/60 ( 54%) received 400-500 mg/kg q 3-4 wk by IV, some cases used 100 mg/kg SC q wk - NIH score 40 - The mean age when initiation 14 y( range, 1-39 y) - Comparing incidence of bacterial pneumonia: - IVIG group; 9.3/100 pt/y - Non- IVIG group ; 27.8/100 pt/y

Rationale for IVIG Treatment

Based on recurrence of pyogenic bacterial infection & memory B-cell lymphopenia

An accelerated decline of specific Ab titers after initially normal primary Ab response &

lower than normal secondary Ab response

Clin Immunol 2008; 129:448-454

Management of AD-HIES Antifungal prophylaxis:

- In case of structural airway abnormalities - Mechanism; local epithelial impairment after recurrent bacterial pneumonia similar in cystic fibrosis or post-tuberculosis cavities - Prophylactic surgery

Management of AD-HIES Omalizumab:

- A – 32 –Y-old Thai female - NIH Scoring = 30 - Serum IgE > 2,000 iu/ml ( 10 pts) - Eosinophilia > 800 cell/ul ( 6 pts) - Severe eczema ( 4 pts) - Candidiasis of nails ( 2 pts) - Recurrent skin abscess ( 8)

APJAI 2009; 27: 233-236

Management of AD-HIES Omalizumab:

- Firstly tried topical steroid & tacrolimus - Then, systemic steroid 30 mg/d, but flare up after dose tapering - Tried Omalizumab 300 mg SC q 2 wk, clinical improve after 1 month & gradually decreased systemic steroid

APJAI 2009; 27: 233-236

Causes of Death in HIES

JACI 2007; 119: 1234-40

Take Home Message A rare primary immunodeficiency marked

by abnormalities in the coordination of cell–cell signaling with the potential to affect TH17 cell, B cell, and neutrophil responses

Clinical manifestations include recurrent skin and lung infections, serum IgE elevation, connective tissue repair and development alterations

Take Home Message STAT3 –HIES: - Pneumonia, pneumatocele, facial features, bone abnormalities DOCK 8 –HIES: - Viral skin infections, sepsis, neurological, malignancy, food allergy, decreased IgM Tyk 2-HIES: - Viral skin infections, sepsis, neurological

Take Home Message Investigations: - Eosinophilia - Hyper IgE - Decreased memory B cell - Decreased Th17 cell & IL-17 - Decreased T cell development Diagnosis - NIH scoring system - High-resolution PCR-based DNA-melting

assays

Take Home Message Managements: - Supportive - ABT treatment - ABT & antifungal prophylaxis - Skin care - IVIG Causes of death: - Infection - Pulmonary hemorrhage

THANK YOU VERY MUCH

hyper ige syndrome

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