Hyper IgE syndrome

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Hyper IgE syndrome
Presented by Theerapan Songnuy, MD.
Jan3, 2014

Published in: Health & Medicine, Technology
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  • 2 M: fever, I&D , admit 3 d, ABT 7d2 Y : I&D, ABT IV 4 Y : I&D, ABT IV 7 Y : I&D, ABT IV
  • Eo > 700 , aabnormal
  • IgE 29600 , 5 Y
  • Total IgE 296,000 IU/ml AT 5-y-old
  • Primary teeth = 10
  • Gene analysis not shown to be tested before, lost data
  • Massive lt pleural effusion, patchy infiltration rthilar region
  • Skin infection at scalp : bactroban bidTerramycin ointment bid at eyelids
  • NB rash : scraping show Eo, other signs ; heat, erythema, tenderness not found. Improved by oral ABT & dilute bleachHigh MB & MR from aspergillosis & gram neg ; Pseudomonas
  • Arnold-Chiari I: cerebella tonsils protrudes in foramen magnum Fracture & osteopenia found 50 %
  • sIgE gradually reduced in adoles but clinical persists
  • All need signal through STAT3
  • IL-6: PROINFLAMMATORY cytokineIL-10: anti-inflammation cytokine
  • HIES: Normal B cell number & IgG, M, A level
  • Physician score : >= 15 likely, 10-14 indeterminate, < 10 unlikely
  • Bathing in bleach: 120 ml of bleach in tub of water 15 min* 3/wkAvoid parenchymal damage
  • BMT : 2 CASES IN Germany, free of infection, viral skin for 2, 4 y
  • Recommend : Oral ABT + IVIG BENEFIT in recurrent pulm infectionAlso antifungal needed in case with pneumatocele or bronchiectasis
  • Hyper IgE syndrome

    1. 1. Theerapan Songnuy M.D. Jan 3, 2014
    2. 2.         Case study Definition Epidemiology Clinical manifestation Pathogenesis Diagnosis Management Take Home Message
    3. 3.  CC: refer PI: 5d PTA 3 d PTA 4 2 d PTA 10 ( 1 2546) , multiple admissions ( 12 1 56)
    4. 4.  PI : ( ) 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
    5. 5.  PI 14% CBC: Hb 11 Hct 34 WBC 4140 N 79% L BUN/Cr : 22/0.5 E’lyte : Na 134 K 4.4 Cl 94 CO2 20 Impression : Left empyema thoracis & right lung abscess Refer
    6. 6.  PH : - P1 - P2 - P3 - P4 : : G&D: 3 c/s BW 2,600 gm DFIU GA 36 wk 17-y-old female , healthy 15-y-old female, healthy 10-y-old male, patient ( 10 ) Vaccination: pneumococcal & ,
    7. 7.  PH: Drug allergy: Nystatin ( urticaria ) Fluconazole ( urticaria ) Ketoconazole ( urticaria) Food allergy: Cow’s milk, egg, seafood, soy, wheat accidental exposure : On BF, Enfa ( flare up of AD, Nutramigen ( at 9 mon ) Neocate ( 10 mon -3 y) : Current foods; rice, chicken, pork, fish etc.
    8. 8.  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
    9. 9.  PH: History of AD treatment 1m 1y - 5 m PTA Erythromycin ( 2wk) Prednisolone (5) 1*3 ( 6 wk) 2 - 2 m PTA
    10. 10.  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
    11. 11.  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
    12. 12.  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
    13. 13.  Primary Immunodeficiency diseases - Hyper IgE syndrome - CGD - CVID Active problems: - Lung abscess - Empyema thoracis - Pleural effusion
    14. 14. 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
    15. 15.                 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 Hct MCV MCH MCHC : : : : : 11.1 31.7 84.3 29.5 35
    16. 16.  CXR
    17. 17. 11 56 -BUN/Cr : - TB/DB : - ALP : - SGOT : - SGPT : - ALB : - GLOB : - TP : - LDH : 12/0.4 0.54/0.34 79 34 25 3.5 ( 16 ( 16 ( 16 238 56 = 3.8) 56 = 2.8) 56 = 6.6)
    18. 18.  Immunoglobulin level: ( 12 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 - IgG2 - IgG3 - IgG4 658 ( 270-1290) 81.5 ( 110-550) 38.9 ( 13-250) 60.9 ( 7-530) mg/dl mg/dl mg/dl mg/dl
    19. 19. NewEngl JMed1999a; 340: 692-702
    20. 20. Clinical Findings Level 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 4-6 2 URI/year Points 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
    21. 21.    Hyper IgE syndrome Type? - Sporadic,AD, AR Gene Analysis - STAT3-deficient - DOCK8-deficient - Tyk2-deficient
    22. 22. 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 
    23. 23.    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
    24. 24.  Pleural fluid ( 12 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
    25. 25. 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 detected ICD content: To identify bacteria by base sequencing (pending)
    26. 26. Dec 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 improved Dec 23, 2013 - ICD content = 0 ml Dec 24, 2013 - Off ICD - Chest PT, Cliniflow
    27. 27.  - 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)
    28. 28.      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
    29. 29. 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. 
    30. 30.    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
    31. 31.    AD-Hyper-IgE Syndrome ( STAT3 Deficient) AR-Hyper-IgE Syndrome ( DOCK8 Deficient) AR-Hyper-IgE Syndrome ( Tyk2 Deficient)
    32. 32.  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
    33. 33.  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
    34. 34.  Somatic Features: - Failure of primary teeth extraction - Vascular abnormalities; aneurysm, lacunar infarction - Malignancy; non-Hodgkin, Hodgkin & leukemia - Esophageal dysfunction
    35. 35.  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
    36. 36.      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
    37. 37. CD 27: Memory B-cell marker
    38. 38.        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 leukemialymphoma Severe eczema, skin infection, pneumonia are common but NO pneumatocele
    39. 39.   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
    40. 40. 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. -
    41. 41.  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
    42. 42.  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)
    43. 43.  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 STATregulated genes
    44. 44. 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
    45. 45.  STAT3 Function - Clinical phenotypes of HIES : -Excessive inflammation; prolonged inflammation in lungs (pneumatocele) - Inadequate inflammation; “cold” boils
    46. 46.  In vitro: - Increased pro-inflammatory cytokines eg. TNF-alpha, IFN-gamma, IL-12 after stimulated by specific agonist
    47. 47.   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)
    48. 48.  Why increased IgE in HIES - Hypothesis: impaired IL-21 signaling since IL-21 receptor knock out mice showed increased IgE
    49. 49.  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
    50. 50.  DOCK 8 Mutation: - DOCK homology region 1 ( DHR1) domain ( for binding phosphatidylinositol3,4,5triphosphate membrane-rich region) - DOCK homology region 2 ( DHR 2) domain ( for binding to Rho family GTPase)
    51. 51.      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
    52. 52.    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
    53. 53.  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 )
    54. 54.  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
    55. 55.  Criteria*** NewEngl JMed1999a; 340: 692-702
    56. 56. 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 
    57. 57.      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
    58. 58. 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  360 Archives of Medical Research 35 (2004) 359–
    59. 59.     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
    60. 60.  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
    61. 61.   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
    62. 62.  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
    63. 63.  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
    64. 64.  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
    65. 65. Causes of Death in HIES
    66. 66. JACI 2007; 119: 1234-40
    67. 67. JACI 2007; 119: 1234-40
    68. 68. JACI 2007; 119: 1234-40
    69. 69.   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
    70. 70.    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
    71. 71.   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
    72. 72.   Managements: - Supportive - ABT treatment - ABT & antifungal prophylaxis - Skin care - IVIG Causes of death: - Infection - Pulmonary hemorrhage
    73. 73. THANK YOU VERY MUCH

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