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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

1. Davis SD, Schaller J, Wedgewood RJ. Job s syndrome.

Recurrent cold staphylococcal abscesses. Lancet 1966;1:

1013-5.

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

elevated serum IgE levels and the modulatory effects of

these lymphokines on spontaneous IgE synthesis. J ALLERGY

LIN IMMUNOL

1991;87:58 69.

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