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High dose intravenous y globulin treatment
for hyperimmunoglobulinemia E syndrome
Hajime Kimata MD PhD
Hirakata City , Osaka, Japan
Background: Hyperimmunoglobu linemia syndrome HIE S) is an inflammatory skin disease,
and m ana geme nt of it is not satisfactory. However, high-dose intravenous ,/-globulin IVG G)
is a safe and effective treatment for Kawasaki disease.
Methods: I initially treated two patients with Kawasaki disease, both of w hom also had
HIES , with IVGG . Subsequently, I treated patients with HIE S a lone, atopic dermatitis,
Kawa saki disease, or idiopathic thrombocytopenic purpura with IV G G a nd mea sured serum
IgE levels and in vitro spontaneous IgE productio n by peripheral blood m ononu clear cells
fro m patients. Direct effects of IgG on in vitro IgE production were also studied.
Results: IV GG treatment remarkably improved severe eczema in patients with HIE S with or
without Ka wasa ki disease an d in patients with atopic dermatitis. Moreover, serum IgE levels
and in vitro spontaneous IgE production were decreased in these patients but no t in patients
with Kaw asa ki disease or idiopathic thrombocytopenic purpura. The addition of high
concentrations of IgG to cultures of peripheral blood mon onuelea r cells fro m patients with
H IE S or atopic dermatitis decreased in vitro spontaneous IgE production. Moreover, IgG also
decreased IgE production by normal B cells stimulated with interleukin-4 plus anti-CD40
monoclonal antibody.
Conclusion: IV G G is effective in the treatment of severe eczema in patients with H IE S and
atopic dermatitis. IV GG also decreased enhanced IgE productio n both in vivo and in vitro. J
ALLERG Y CLIN IMMUNOL 1995;95:771-4.)
Key words: Hyperimmunog lobulinemia E syndrome, IgE production, intravenous ,/-globulin,
eczema, atopic dermatitis, interleukin-4, Kawasaki disease
H y p e r i m m u n o g l o b u l i n e m i a E s y n d r o m e HIES)
i s an inf lammatory skin disease charac te r ized by
(1) severe eczema, (2) r ecur rent s taphylococca l
infec t ions of the skin and s i nop ulm onar y tr ac t , (3)
cold subcutaneous abscesses , and (4) h igh se rum
I gE l e ve l s? Ma na ge m e n t o f H I ES i s no t s a t is f ac -
tory.2, 3
H i gh- dose i n t r a ve nous y - g l obu l i n ( I V G G ) i s a
sa fe and e f fec t ive t r ea tme nt fo r Kawasaki d isease .
Mor e ove r , I V G G a l so r e ve r se d l ymphoc y t e ac t iva -
t ion in vivo.4 I t r e a t e d t w o pa t i e n ts w ho ha d
K a w a sa k i d is e a se a nd H I ES w i t h h i gh - dose I V G G ,
w hi c h r e su l t e d i n i mpr ove me n t o f s e ve r e e c z e ma
assoc ia ted wi th HIES. Subsequent ly , pa t ients wi th
H I ES a l one o r w i t h a t op i c de r ma t i t i s w e r e t r e a t e d
From the Department of Pediatrics, Shin kor i Hospital,
Hirakata City, Osaka, Japan.
Received for publication May 4, 1994; revised June 23, 1994,
accepted for publication Aug. 17, 1994.
Reprint requests: Hajime Kimata, MD, PhD , Department of
Pediatrics, Ky oto University Hospital, Kawahara-cho 54,
Shogoin, Sakyo-ku, Kyoto, 606 Japan.
Copyright © 1995 by M osby-Year Book, Inc.
0091-6749/95 $3.00 + 0 1/1/611087
Abbreviations used
AU: Arb itrary units
HIES: Hyperimmunoglobulinemia E syn-
drome
IL: Interleukin
ITP: Idiopathic thrombocy topenic purpu ra
IVG G: Intrav enou s y-globulin
PBMCs: Peripheral blood mono nuclear cells
w i t h I V G G , a nd sk i n sympt oms i mpr ove d i n a l l
pa t ients . Only a s ingle course of IVGG was given;
t ha t i s, no m a i n t e na nc e t he r a py w a s r e qu i r e d .
METHODS
Patients
Patient 1 is a 3-year-old boy who has had HIES since
the age of 1 year. He had frequent scalp abscesses
caused by Staphylococcus aureus, chronic otitis media,
and severe eczema. He had been admitted to hospitals
several times for treatment of pneumonia, including
pyothorax caused by S. aureus. Topical steroids and
77
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772
Ki ma ta J ALLERGYCLIN MMUNOL
M AR C H 1995
15-
5000-
10
5
patient 1 (O • m)
patient 2 ( O / k I- 1)
0000
5000=
E
¢
LLI
¢J
o
o
>
c-
t~
I
, - -
C
E
y -globulin ~
~ t
0
0
I I I I 111
0 7 14 21 28
-30
-20
l
E
\
133
t--
e-
O
o
I . .
LM
m
¢tJ
o
e-
C
o
¢tJ
ays after treatment
FIG. 1. Serum total IgE levels serum ant i-staphylococcal IgE levels and in vit ro spontaneous
IgE product ion af ter high-dose IVGG treatment.
TABLE
I. E f fe c ts o f h i g h - d o s e I VGG t r e a t m e n t o f s e r u m I gE l e v e l s a n d i n v i t r o s p o n t a n e o u s I g E
p r o d u c t i o n i n v a r i o u s p a t i e n t s
Serum IgE (IU/ml)*
IgE production (ng/ml)t
Patient Age Day Day Day Day Day Day
No. Di ag no si s (yr) 0 14 28 0 14 28
3 H IE S 2.5 4120 2112 612 9.4 6.1 2.0
4 A D 3.2 3213 1051 314 3.4 1.2 0.5
5 A D 5.0 6238 4627 821 8.2 5.1 1.2
6 KD 1.6 56 42 58 <0.2 <0.2 <0.2
7 KD 2.0 31 25 28 <0.2 <0.2 <0.2
8 ITP 6.5 121 135 109 <0. 2 <0. 2 <0.2
9 ITP 2.4 103 112 101 <0.2 <0.2 <0.2
AD Atop ic derma titis; KD, Kawasaki disease.
*Mean serum IgE IU/L) after day 0 before treatment) and after 14 and 28 days of treatment.
tMe an spontaneous IgE production in vitro after day 0 before treatment) and after 14 and 28 days of treatment.
an t i b io t i cs had been unhel p fu l i n t r ea t ing eczema. He
al so had Kawasak i d i sease and r ece i ved IVG G Ven i l on;
Tei j in , Ltd . , Tokyo, Japan) at 400 rag/day for 5 days,
af ter which his fever subsided. Eczema and skin infec-
t i ons a l so i mproved r em arkab l y a f t e r 5 days o f t r ea t men t
and d i sappeared a l t oge t her a f t e r 28 days .
Pat ient 2 is a 2~/2-year-old girl who has h ad HI ES since
the age of 7 months. She had severe eczema, cold skin
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. I A L L E RG Y C L I N I M M U N O L K i m a t a 77
VOLUME 95 NUMBER 3
T BLE
I i .
Ef fects o f IgG on immunog lobu l in p roduct ion in v i t ro
IgE ng/m l) IgM ng/m l) igA ng/rnl )
Pat ient
N o . D ia g n os is I g G - I g G + I g G - I g G + i g G - I g G +
1 H I E S a nd K D 24 .2 3 .8 230 223 82 71
2 H I E S a nd K D 11 .5 1 .2 101 99 45 42
3 H I E S 9 .8 2 .4 82 89 23 26
4 A D 3.6 0 .5 103 112 32 29
5 A D 2.7 0 .3 298 286 68 71
6 K D < 0 .2 < 0 .2 112 109 51 48
7 K D < 0 . 2 < 0 . 2 7 8 7 6 2 3 2 6
8 I T P < 0 . 2 < 0 . 2 2 4 8 2 3 1 8 9 7 8
9 I T P < 0 . 2 < 0 . 2 6 7 7 1 2 4 2 1
1 0 N o r m a l P B M C s < 0 . 2 < 0 . 2 1 5 7 1 61 6 7 7 1
1 1 N o r m a l P B M C s < 0 . 2 < 0 . 2 6 7 6 9 3 2 3 0
12 N o r m a l PB M C s + I L- 4 6 .1 1 .2 211 201 99 92
13 N o r m a l PB M C s + I L- 4 4 .4 0 .5 121 128 56 59
14 N o r m a l B + I L- 4 / a n t i - C D 40 8 .3 2 .1 58 49 22 31
15 N o r m a l B + I L- 4 / a n t i - C D 4 0 9 .6 1 .7 36 41 25 29
AD
Atopic dermati t is; KD, Kawasaki disease. PBMC s from various pat ients w ere cultured with medium, and PBM Cs (10-13) or B
cells (14 and 15) from norma l dono rs were cultured w ith medium (10 and 11) or stimulated with IL-4 (800 U/ml) (12 and 13) or
with IL-4 plus B anti-CD40 monoclonal ant ibody (0.1 Ixg/ml) (14 and 15), and IgG (2 mg/ml) was added. After 14 days of culture,
immunoglobulin production was determined. Results were the means from triplicate cultures.
abscesses , chro nic sinusi ti s , a nd lung abscesses cause d
b y
aureus.
Top i c a l s t e r o i d s a nd a n t i b i o t i c s a nd o r a l
a n t i a l l e r g i c m e d i c a t i on w e r e w i t hou t e f f e c t i n t r e a t i ng
e c z e m a . S h e r e c e iv e d I V G G a t 4 0 0 m g / d a y f o r 5 d ay s fo r
t r e a t m e n t o f K a w a s a k i d i s e as e , a f t e r w h i c h h e r f e v e r
s ubs i de d . Ec z e m a a nd s k i n i n f e c t i on w e r e s i gn i f i c a n t l y
i m pr ove d a f t e r 5 da ys a nd d i s a ppe a r e d a f t e r 21 da ys .
S e v e r a l o t h e r p a t ie n t s w e r e a l s o t r e a t e d w i th I V G G a t
4 0 0 m g / k g / d a y f o r 5 d a y s a f t e r i n f o r m e d c o n s e n t w a s
o b t a i n e d ( T a b l e I ) . O n l y a si n gl e c o u r s e o f I V G G w a s
g i ve n . Pa t i e n t 3 i s a 21A -ye ar -o ld b oy w ho ha s ha d H I ES
s i nc e the a ge o f i ye a r . H e ha d s e v e r e e c z e m a , c o l d s k i n
a bs c e s s e s, c h r on i c b i l a t e r a l o t it i s m e d i a , a nd f r e q ue n t
e p i so d e s o f p n e u m o n i a c a u s e d b y S. aureus. Pa t i e n t s 4
a nd 5 a r e g i r l s w ho ha d a t op i c de r m a t i t i s w i t h s e ve r e
e c z e m a . Top i c a l s t e r o i d s a nd o r a l a n t i a l l e r g i c m e d i c a -
t i o n w e r e u n h e l p f u l . A f t e r 5 d a y s o f tr e a t m e n t w i t h
I V G G , s e v e r e e c z e m a i n t h e s e p a t i e n t s ( p a t i e n t s 3 , 4 ,
a n d 5 ) i m p r o v e d s i g n i f i c a n t l y a n d a l m o s t d i s a p p e a r e d
a f t e r 28 da ys . Pa t i e n t s 6 a nd 7 a r e bo ys w h o ha ve
K a w a s a k i d i s e a s e , a nd pa t i e n t s 8 a nd 9 a r e g i r l s w ho
h a v e id i o p a t h i c t h r o m b o c y t o p e n i c p u r p u r a ( I T P ) . P a -
t i e n t s 6 , 7 , 8 , a n d 9 h a d n o a l l e r g y o r e c z e m a , a n d
t h e i r s e r u m I g E l e v e ls w e r e w i th i n t h e n o r m a l r a n g e
( T a b l e I ) .
C e l l c u l t u r e
P e r i p h e r a l b l o o d m o n o n u c l e a r c e l l s ( P B M C s ) w e r e
o b t a i n e d f r o m p a t i e n t s o n d a y 0 ( b e f o r e I V G G t r e a t -
m e n t ) a n d a f t e r 7 , 1 4 , 2 1, a n d 2 8 d a y s o f I V G G
t r e a t m e n t . P B M C s w e r e a l s o o b t a i n e d f r o m n o r m a l
c o n t r o l s u b je c t s o f t h e s a m e a g e . P B M C s w e r e c u l t u r e d
( 2 × 105 /0 .2 m l / w e l l) w i t h m e d i um a l one . PB M C s ob -
t a i n e d o n d a y 0 w e r e a l so c u l t u r e d i n e i t h e r t h e a b s e n c e
o r p r e s e n c e o f h u m a n I g G ( 2 m g / m l ) . A l t e r n a t i v e l y ,
P B M C s a n d B c e l l s f r o m n o r m a l c o n t r o l s u b j e c t s w e r e
c u l t u r e d w i t h i n t e r l e uk i n ( I L) - 4 ( 800 U / m l ) a nd I L- 4
p l us a n t i - C D 40 m onoc l ona l a n t i body ( 0 .1 ~g / m l ) , r e -
s p e ct iv e ly , a s d e s c r i b e d a b o v e . I m m u n o g l o b u l i n p r o d u c -
t i o n w a s m e a s u r e d b y E L I S A a f t e r 1 4 d a y s o f t r e a t m e n t . 5
The s pe c i f i c i t y o f t he a s s a y w a s c on f i r m e d , a s r e po r t e d
previous ly.S. 6 Leve ls of Ig E as low as 0 .2 ng /ml c ould b e
d e t e c t e d i n t h e p r e s e n c e o f 2 m g /m l I g G . S e r u m I g E ,
I g M , I g A , a n d a n t i - s t a p h y l o c o c c a l I g E a n t i b o d y l e v e l s
w e r e m e a s u r e d b y E L I S A . 6, 7 S e r u m a n t i- s t a p h y lo c o c c a l
I gE l e ve l s w e r e e xp r e s s e d a s a r b i t r a r y un i t s ( A U ) pe r
m i ll il it er , w h e r e 1 A U / m l r e p r e s e n t s t h e a m o u n t p r e s e n t
i n a 1 :1 0 d i l u ti o n o f t h e H I E S p o o l e d s e r u m . I n n o r m a l
c on t r o l s ub j e c t s a nd i n pa t i e n t s w i t h a t op i c de r m a t i t i s ,
K a w a s a k i d i s e a s e , o r I TP , s e r um a n t i - s t a phy l oc oc c a l I gE
l e vel s w e r e l e s s t ha n 0 .1 A U / m l . 7
R E S U L T S
I n p a t i e n t s 1 a n d 2 , s e r u m I g E l e v e l s , a n t i -
s t a p h y l o c o c c a l I g E l e ve ls , a n d i n v i t ro I g E p r o d u c -
t i o n d e c r e a s e d g r a d u a l l y a n d r e t u r n e d t o a l m o s t
n o r m a l a f t e r 2 8 d a y s o f I V G G t r e a t m e n t ( F ig . 1) .
I n c o n t r a s t , s e r u m I g M o r I g A l e v e ls o r i n v i t ro
s p o n t a n e o u s I g G , I g M , o r I g A p r o d u c t i o n b y
P B M C s d i d n o t d e c r e a s e i n e it h e r p a t ie n t ( d a t a n o t
s h o w n ) . N o s i d e e f fe c ts w e r e o b s e r v e d . A f t e r 6
m o n t h s , b o t h p a t i e n t s w e r e f r e e o f c o r o n a r y a n e u -
r y sm s , e c z e m a , a n d s t a p h y l o c o c c a l in f e c t io n s ; a n d
n o m a i n t e n a n c e t h e r a p y w a s r e q u ir e d .
I V G G t r e a t m e n t a ls o d e c r e a s e d s e r u m I g E le v -
e ls a n d s p o n t a n e o u s I g E p r o d u c t i o n i n v i tr o i n t h e
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77 imata J ALLERGY CLIN IMMUNOL
MARCH 995
pa t i e n t w i th HI E S a lone pa t i e n t 3 ) a nd in t he
pa t i e n t s w i th a top i c de r m a t i t i s T a b l e I) . I V G G
a l so de c r e a se d s e r um a n t i -s t a phy loc oc c a l I gE l ev-
e ls f r om 5 .2 AU /m l a t ba se l i ne t o 0 .3 AU /m l a f t e r
2 8 d a y s o f t re a t m e n t . I n c o n t r a s t, I V G G t r e a t m e n t
d id no t de c r e a se se r um I gE l e vel s i n pa t ie n t s w i th
Ka wa sa k i d i se a se o r I T P T a b le I) . A f t e r I V GG
t r e a t m e n t , e c z e m a i m p r o v e d r e m a r k a b l y i n p a -
t i e n t s w i th HI E S or a top i c de r m a t i t i s ; f e ve r sub-
s ide d i n pa t i e n t s w i th Ka w a sa k i d i se ase , a nd p l a t e -
l e t c oun t i nc r e a se d f r om 10 a nd 31 x 109/L a t
base l ine to 156 and 218 x 109/L in pa t ien ts wi th
I T P pa t i e n t s 8 a nd 9 , r e spe c ti ve ly ). T h e r e f o r e t he
f a i l u re o f s e r um I gE l e vel s t o de c r e a se wa s no t due
to t h e d i f f e r enc e s i n t he e f f ec t s o f I VG G.
T he e f fe c t s o f I gG on I gE pr o duc t ion w e r e a l so
s tud i e d i n v i tr o . As shown in T a b le I I , a dd i t i on o f
I g G d e c r e a s e d s p o n t a n e o u s I g E p r o d u c t i o n i n
pa t i e n t s w i th HI E S or a top i c de r m a t i t i s w i thou t
a f f e c t i ng spon ta ne ous p r oduc t ion o f I gM or I gA .
I n c o n t r a s t , n o s p o n t a n e o u s I g E p r o d u c t i o n w a s
obse r ve d i n pa t i e n t s w i th Ka wa sa k i d i se a se o r I T P
or i n nor m a l c on t r o l sub j e c t s . I n t he se c a se s t he
a d d i t io n o f I g G h a d n o e f fe c t o n p r o d u c t i o n o f I g E ,
I g M , o r I g A . T h e n t h e e f f ec ts o f I g G o n I L - 4 -
i n d u c e d I g E p r o d u c t i o n w e r e s t u d ie d . I g G i n h ib -
i t ed I g E p r o d u c t i o n b y n o r m a l P B M C s s t im u -
l a t e d w i t h I L - 4 w i t h o u t a f f e c t in g p r o d u c t i o n o f
I g M o r I g A . M o r e o v e r , I g G a l s o s e l e c t i v e l y
i n h i b i t e d I g E p r o d u c t i o n b y n o r m a l B c e l ls s ti m -
u l a t e d w i t h I L - 4 p l u s a n t i - C D 4 0 m o n o c l o n a l
a n t i b o d y T a b l e I I ).
D I S U S S I O N
I h a v e d e m o n s t r a t e d t h a t h ig h - d o s e I V G G t r ea t -
m e n t i m p r o v e d s e v e r e e c z e m a a n d d e c r e a s e d Ig E
pr odu c t ion b o th i n vivo a nd i n v it r o i n pa t ie n t s w i th
H I E S . I V G G a ls o im p r o v e d e c z e m a a n d d e c r e a s e d
I gE pr oduc t ion i n pa t i e n t s w i th a top i c de r m a t i t i s ,
wh e r e a s i t ha d n o e f f e c t on se r um I gE l e ve ls in
pa t i e n t s w i th Ka wa sa k i d i se a se o r I T P . Subse q ue n t
s tudy r e ve a l e d t ha t I gG se l e ct i vely i nh ib i t e d I gE
pr oduc t ion i nduc e d by I L - 4 . I t i s poss ib l e t ha t
e n h a n c e d I g E p r o d u c t i o n i n p a t ie n t s w i th H I E S o r
a top i c de r m a t i t i s m a y be due t o i n v ivo a c t i va ti on
of B ce l ls by IL-4, as I and o thers h ave previou sly
r e por te d .5 , 6, s I V G G m a y a t t e nu a t e t h i s a c t i va ti on .
De ta i l e d m e c h a n i sm s o f t he se l ec t ive inh ib i t ion o f
I g E p r o d u c t i o n b y I V G G a r e c u r r e n tl y u n d e r
inve s ti ga ti on . H igh- dose I VG G m a y be a sa f e a nd
e f fe c t ive t r e a tm e nt f o r H I E S a nd a top i c de r m a t i ti s .
M or e ove r , t he f i nd ing t ha t I gG inh ib i t s I L - 4-
i n d u c e d I g E p r o d u c t i o n in T c e l l - d e p e n d e n t a n d T
c e l l - i n d e p e n d e n t c u l t u r e s m a y b e u s e f u l f o r t h e
s tudy o f I gE r e gu l a t ion .
R E F E R E N E S
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2. Souillet G, Rousset F, de Vries JE. Alpha-interferon treat-
ment of patients with byper IgE syndrome. Lancet 1989;2:
1384.
3. Thompson RA, Kumararatne DS. Hyper-IgE syndrome and
H2-receptor blockade. Lancet 1989;2:630.
4. Leung DY, Burns JC, Newburger JW, Geha RS. Reversal of
lymphocyte activation in vivo in the Kawasaki syndrome by
intravenous gammaglobulin. J Clin Invest 1987;79:468-72.
5. Kimata H, Yoshida A, Fujimoto M, Mikawa H. Effect of
vasoaetive intestinal peptide, somatostatin, and substance P
on spontaneous IgE and IgG4 production in atopic patients.
J Immunol 1993;150:4630-40.
6. Kimata H, Mikawa H. Nedocromil sodium selectively nhib-
its IgE and IgG4 production in human B cells stimulated
with IL-4. J Immunol 1993;151:6723-32.
7. Dreskin AC, Goldsmith PK, Gallin JI. Immunoglobulins in
the hyperimmunoglobulin E and recurrent infection (Job s)
syndrome. Deficiencyof
a n t i S t a p h y l o c o c c a l a u r e u s
immuno-
globulin A. J Clin Invest 1985;75:26-34.
8. Rousset F, Robert J, Anadary M, et al. Shifts in interleukin-4
and interferon-~ production by T cells of patients with
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