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

1. Theerapan Songnuy M.D.
Jan 3, 2014

2. 







Case study
Definition
Epidemiology
Clinical manifestation
Pathogenesis
Diagnosis
Management
Take Home Message

3. 
CC: refer
PI: 5d PTA
3 d PTA
4
2 d PTA
10 (
1
2546)
, multiple admissions ( 12
1
56)

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. 
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. 
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. 
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. 
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. 
PH: History of AD treatment
1m
1y
- 5 m PTA
Erythromycin ( 2wk)
Prednisolone (5) 1*3 ( 6 wk)
2
- 2 m PTA

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. 
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

13. 
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

14. 
Primary Immunodeficiency diseases
- Hyper IgE syndrome
- CGD
- CVID
Active problems:
- Lung abscess
- Empyema thoracis
- Pleural effusion

15. 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

16. 















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

17. 
CXR

18. 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)

19. 
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

21. NewEngl JMed1999a; 340: 692-702

22. 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

23. 


Hyper IgE syndrome
Type?
- Sporadic,AD, AR
Gene Analysis
- STAT3-deficient
- DOCK8-deficient
- Tyk2-deficient

24. 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


25. 


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

30. 
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

31. 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)

33. 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

34. 
-
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)

37. 




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

38. 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.


39. 


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

42. 


AD-Hyper-IgE Syndrome ( STAT3 Deficient)
AR-Hyper-IgE Syndrome ( DOCK8 Deficient)
AR-Hyper-IgE Syndrome ( Tyk2 Deficient)

43. 
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

44. 
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

46. 
Somatic Features:
- Failure of primary teeth extraction
- Vascular abnormalities; aneurysm, lacunar
infarction
- Malignancy; non-Hodgkin, Hodgkin & leukemia
- Esophageal dysfunction

47. 
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

48. 




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

49. CD 27: Memory B-cell marker

57. 






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

58. 

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

61. 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.
-

63. 
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

64. 
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)

65. 
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

67. 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

69. 
STAT3 Function
- Clinical phenotypes of HIES :
-Excessive inflammation; prolonged inflammation
in lungs (pneumatocele)
- Inadequate inflammation; “cold” boils

70. 
In vitro:
- Increased pro-inflammatory cytokines eg.
TNF-alpha, IFN-gamma, IL-12 after stimulated
by specific agonist

72. 

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)

73. 
Why increased IgE in HIES
- Hypothesis: impaired IL-21 signaling since
IL-21 receptor knock out mice showed
increased IgE

74. 
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

75. 
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)

76. 




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

77. 


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

78. 
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 )

79. 
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

80. 
Criteria***
NewEngl JMed1999a; 340: 692-702

81. 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


82. 




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

83. 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–

84. 



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

85. 
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

86. 

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

87. 
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

88. 
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

89. 
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

90. Causes of Death in HIES

91. JACI 2007; 119: 1234-40

92. JACI 2007; 119: 1234-40

93. JACI 2007; 119: 1234-40

95. 

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

96. 


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

97. 

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

98. 

Managements:
- Supportive
- ABT treatment
- ABT & antifungal prophylaxis
- Skin care
- IVIG
Causes of death:
- Infection
- Pulmonary hemorrhage

99. THANK YOU VERY MUCH